Datasets:

clinicalnlplab

/

PubMed_Summ_1shot_test

like 0

PubMed_Summ6500

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: this article traces the growth in the use of swing - bed services by medicare beneficiaries from 1984 through 1987 . in the context of the medicare program , swing beds are beds that can be used by small rural hospitals to furnish both acute and post - acute care . to be covered under medicare , the post - acute services must meet the same level of care requirements applied to the reimbursement of services by skilled nursing facilities ( snfs ) . states have the option of also covering swing - bed services at the intermediate care level under their medicaid programs . the swing - bed concept was incorporated into the medicare program by the provisions of the omnibus reconciliation act of 1980 ( public law 96 - 499 ) . the law authorized the medicare and medicaid programs to cover swing - bed services furnished by rural hospitals with fewer than 50 beds . the provisions of the law were based on the experiences gained in demonstration projects that began in rural hospitals in utah during the early 1970s and later expanded to iowa , south dakota , and texas . the program takes advantage of the declining acute care occupancy rates and the surplus bed capacity that became increasingly common among rural hospitals during the 1970s . it provided these hospitals a means of obtaining additional revenues without incurring significant additional costs . at the same time , it provided greater access to post - acute nursing care services in rural areas where such services tend to be thinly dispersed . the regulations governing medicare coverage of post - acute services furnished in swing - bed hospitals were issued by the health care financing administration in july 1982 . the method of paying for skilled nursing care services furnished by a swing - bed hospital was based on the assumption that these hospitals incur a relatively low incremental cost to provide post - acute care . they use the personnel , equipment , and facilities already in place to serve acute care patients . additional service requirements to meet the special needs of nursing care patients ( e.g. , patient activities , discharge planning ) would not require a major expansion of staff . accordingly , the per diem reimbursement rate for the routine care component of post - acute services covered under medicare in a swing bed was set at a rate equal to the average paid by the medicaid program to snfs for skilled nursing care during the prior calendar year in the state where the hospital is located . the period following the issuance of the swing - bed regulations was marked by intense federal efforts to contain the rise of hospital costs to the medicare program . the tax equity and fiscal responsibility act ( tefra ) was passed in september 1982 ; the social security amendments of 1983 instituted the prospective payment system ( pps ) for hospital reimbursement ; and the deficit reduction act ( defra ) of 1984 reinstated a new version of the medicare separate reimbursement limits for hospital - based and freestanding snf care that had been eliminated under tefra . this rapid pace of change in the bases by which medicare reimbursed hospitals for acute and post - acute care induced uncertainty among rural hospitals as to whether it was worthwhile electing the swing - bed option . this was reflected in the initial slow rate of applications by eligible hospitals for certification as a swing - bed facility . however , as the incentives provided by pps at the acute and post - acute interface became clearer , the rate of election increased . this is reflected in table 1 that shows the rate at which hospitals became certified to furnish swing - bed services . by the end of 1983 , about 18 months following the issuance of the regulations , only 149 of an estimated 2,236 hospitals eligible to elect the swing - bed option had done so . by mid-1987 , the proportion was approaching the halfway point . the increasing participation of hospitals in the provision of post - acute skilled nursing care services resulted in swing beds gaining an increasing share of the medicare snf market . as summarized in table 2 and detailed in table 3 , admissions to swing - bed hospitals for snf services increased from 3.0 percent of all medicare snf admissions in 1984 to 9.7 percent in 1987 . the swing - bed share of medicare - covered snf days increased from 1.5 to 6.0 percent during the same period . reimbursements for swing - bed care increased from 2.0 percent of snf reimbursements in 1984 to 6.2 percent in 1987 . shaughnessy , schlenker , and silverman ( 1988 ) reported findings that help to interpret the data in table 3 . they found that swing - bed patients have substantially shorter stays and greater rehabilitation potential than do nursing home patients . swing - bed patients , in greater proportion than nursing home patients , were found to need intense medical and skilled care for such problems as recovery from surgery , hip fractures within the past 6 weeks , shortness of breath , and the need for intravenous catheters . nursing homes tend to treat patients with problems more typically seen in institutional long - term care settings ; such as , incontinence , impaired cognitive functioning , and dependence in carrying out activities of daily living ( e.g. , feeding self , dressing ) . each type of facility seems particularly suited to care for patients who can be , respectively , characterized as needing intense subacute care or as the traditional long - term care patient . the evaluation concluded , at the subacute phase , the quality of services furnished by hospitals was found to be better overall than those services furnished by nursing homes . on the other hand , nursing homes provide higher - quality , traditional , long - term care services . in addition to providing a partial explanation for the differences in length of stay , case - mix explains some of the differences in covered charges . the evaluation report estimates ( based on 1985 data ) that the more intense but shorter term care required by swing - bed patients results in costs about 20-percent higher per day than the average nursing home patient . , swing - bed covered charges averaged $ 185 per day compared with $ 169 for all snf days . reimbursement of routine swing - bed services based on the state medicaid program 's average per diem reimbursement to skilled nursing facilities for routine care services during the previous year kept the difference in reimbursement per day to only $ 2 in 1987 ( $ 79 to $ 77 ) . a second report evaluated the impact of medicare 's prospective payment system ( pps ) on the swing - bed program ( shaughnessy et al . , 1988 ) . this evaluation found that , despite higher per diem costs for post - acute swing - bed services the overall costs for an episode of illness tended to be lower for patients discharged from a swing - bed hospital patients discharged from acute care in hospitals with swing - bed programs were more likely to receive swing - bed care than patients discharged from comparison hospitals . such patients also received less medicare nursing home ( snf ) and home health care . subsequent acute care use and cost also tended to be lower for patients discharged from acute care in swing - bed hospitals . the overall result was a slightly lower total cost of care ( both excluding and including the cost of the initial acute care episode ) for patients discharged from acute care in swing - bed hospitals . one factor that may explain the narrowing gap from 1984 to 1987 in the medicare reimbursement per day is the decreasing average length of covered stay in all snfs , including skilled nursing services furnished by swing - bed hospitals ( table 3 ) . as shown in table 3 , this average decreased from 26.6 days in 1984 to 21.5 days in 1987 . this would reflect the decrease in snfs , since during the period 1984 - 87 , the average length of nursing care stay increased in swing - bed hospitals . the shorter length of stay decreases the proportion of payment to snfs made by beneficiaries because of the coinsurance kicking in on the 21st day . thus , medicare payments averaged over fewer coinsurance days increases the average medicare payment per covered day . another factor narrowing the difference in the average reimbursement per day may be the method of reimbursing for post - acute routine care services by swing - bed hospitals . ancillary services which include : supplies , operating room use , drugs , laboratory and radiology services , and anesthesia , are reimbursed at cost . the per diem amount that swing - bed hospitals receive for routine care services is based on the state medicaid program 's average per diem reimbursement to skilled nursing facilities for routine care services during the previous year . for the purposes of the ensuing discussion routine care charges are usually characterized as room and board charges , but embedded in the cost base on which the charges are established are allocations for such overhead costs as general and nursing administrative services , maintenance and repairs , operation of the physical plant , laundry and linen , housekeeping , dietary services , central services and supply , medical records , and social services . the per diem average amounts charged to medicare from 1985 through 1987 by swing - bed facilities and snfs for accommodations and ancillary services to skilled nursing care patients are shown in table 4 . the average per diem routine care charges by swing - bed hospitals increased by about one - half the rate of increase of the snfs ( table 4 ) . average per diem charges for ancillary services furnished by snfs increased at more than double the rate of swing - bed hospitals although the latter was still 50-percent higher in 1987 . the latter relationship is not unexpected , given the characteristics of post - acute swing - bed patients described earlier and the greater access to ancillary services generally available in hospitals . in interpreting these figures , the reader should bear in mind that from 1985 through 1987 total covered days of care furnished by snfs decreased . based on the data available for this analysis , it is not possible to apportion reimbursements to routine care or ancillary services . assuming there is a concomitancy between costs and charges , it is clear that reimbursements per day to snfs have been rising in closer consonance to the rise in covered charges than has been the case for swing - bed hospitals ( table 3 ) . this suggests that the current method of paying for routine swing - bed services may not be keeping up with the rate of increase in the hospital 's costs of providing routine swing - bed services . however , in light of increasing participation in the swing - bed program , it may be supposed that swing - bed hospitals were still recovering the marginal cost of furnishing post - acute routine swing - bed services in 1987 . based on 1984 data , the evaluation report estimated that , on average , swing - bed hospitals incurred an incremental cost per day for routine post - acute care of about $ 33 to $ 34 . the average routine care revenues received exceeded the costs by $ 8 to $ 10 per day . the 1987 data suggest that the difference between marginal routine care costs and revenues may be narrowing . however , given full cost reimbursement for ancillary services , the marginal revenue for otherwise empty beds seems to be attractive for eligible hospitals . the geographic distribution of the use of and medicare payments for swing - bed services in 1987 in relation to all snf services is shown in table 5 . as expected , the number of swing - bed hospitals and the use of swing - bed services were concentrated in the north central and south census regions which contain large expanses of rural areas . of the 1,058 hospitals that submitted a bill for swing - bed services , almost one - half ( 504 ) were located in the north central states . only 16 hospitals in the northeast region were certified to furnish swing - bed services : 9 in new hampshire , 4 in vermont , and 3 in pennsylvania . of the 179 hospitals certified in the west to furnish swing - bed services , 131 ( 73 percent ) were in the mountain states . in the north central states , 18 percent of all admissions for snf services were to swing - bed hospitals . in the south , in the largely urbanized northeast , less than 1 percent of the admissions for snf services were made to swing - bed hospitals . however , new hampshire and vermont are notable exceptions to the patterns of the northeast . in these two states , more than one - fourth of the admissions for snf services were to swing - bed hospitals . admissions to swing - bed hospitals are based on the residence of the patient . where admissions to swing - bed hospitals are noted in states with no swing - bed facilities , admission to a facility in a neighboring state the west census region presents a dichotomy between the mountain states and pacific coast states . in the mountain states , almost 12 percent of the admissions for snf services were to swing - bed hospitals . in four of the mountain states ( montana , idaho , wyoming , and new mexico ) , more than 20 percent of the admissions for snf services were to swing - bed hospitals with wyoming having almost 60 percent going to swing - bed hospitals . the remaining mountain states show less than 10 percent of the admissions for snf services going to swing - bed hospitals . only 1 percent of the admissions for snf services in the pacific coast states went to swing - bed hospitals ; alaska , with 21 percent , was the only pacific coast state with more than 7 percent using swing - bed hospitals for snf care . the states showing more than 50 percent of the admissions for snf services going to swing - bed hospitals were : north dakota , south dakota , kansas , mississippi ( the highest at 89 percent ) , and wyoming . delaware and the district of columbia were the only jurisdictions with no admissions for swing - bed services . figure 1 displays the geographic patterns of admissions to swing - bed hospitals as a percent of all snf admissions . for the individual states , the relationship among admissions , covered days of care , charges , and reimbursement is about that indicated for 1987 in table 2 . as previously mentioned , about 89 percent of the admissions for snf services in mississippi went to swing - bed hospitals . swing - bed hospitals accounted for almost 91 percent of the covered snf days of care and received 82 percent of snf reimbursements . mississippi was the only state in which the average length of snf stay in a swing - bed hospital ( 18.2 days ) exceeded the statewide average ( 17.9 days ) . the data presented in this article and the findings of the evaluation indicate that the rural hospital swing - bed program has been working as might have been anticipated : swing - beds have assumed the provision of a significant portion of post - acute care services in many states with large rural areas . the post - acute case mix in swing - bed hospitals represent more short term , intense level of care requirements than those in snfs . swing - bed hospitals seem better suited to meeting nursing care needs of these types of patients than do rural snfs , which seem more suited to meeting the needs of the traditional long - term care nursing home patients . higher average total charges per day for swing - bed patients suggest that they tend to be more expensive to care for than are the patients in snfs ; especially in the use of ancillary services . per diem reimbursements for swing - bed services have been growing at an average annual rate of about one - third of that for snfs . the latter finding raises question as to whether the current basis for reimbursing for post - acute routine care services in swing - bed hospitals causes per diem revenues to rise at a slower rate than per diem costs . the current difference between marginal costs and revenues seem sufficient to attract increasing participation by rural hospitals with fewer than 50 beds . however , given the different behavior of the overhead as well as the direct cost components of the costs for routine care services in hospitals and snfs , the current method of paying for routine swing - bed services may require re - examination some time in the future . this may become more apparent when the experiences of the larger rural swing - bed hospitals brought into the program by the omnibus budget reconciliation act of 1987 ( public law 100 - 203 ) are analyzed . under this legislation , the swing - bed option was extended to rural hospitals with fewer than 100 beds . providing an incentive to small rural hospitals to continue rendering swing - bed services may require re - examination of the bases on which payment for these services are made . OUTPUT:

under medicare , swing beds are beds that can be used by small rural hospitals to furnish both acute and post - acute care . the swing - bed program was instituted under the provisions of the omnibus reconciliation act of 1980 ( public law 96 - 499 ) . under medicare , post - acute care in the hospital would be covered as services equivalent to skilled nursing facility level of care . data show that the program has had a rapid rate of growth . by 1987 , swing beds accounted for 9.7 percent of the admissions to skilled nursing facility services , 6.0 percent of the covered days of care , and 6.2 percent of the reimbursements . over one - half of the swing - bed services are furnished in the north central states .

PubMed_Summ6501

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: patients with univentricular heart malformations are at increased risk of suffering from thromboembolic events ( te ) . at least 20% of patients with univentricular hearts have reported to experience te , of which 25% are fatal . despite the high incidence of te , no consensus has been reached regarding the role of long - term anti - thrombotic treatment in this group of patients . here , we present a case of a 19-year - old woman with a univentricular heart who suffered a major stroke . a 19-year - old woman born with a univentricular heart was found unconscious in her bed in the morning . she was respiratory and circulatory stable with no fever at admission to the local hospital . the glasgow coma scale score was 5 ( eyes , 1 ; verbal , 1 ; motor , 3 ) . an electrocardiogram showed sinus rhythm , left axis deviation , and left - sided hypertrophy , but was otherwise normal . a test of arterial blood gasses revealed a fully compensated metabolic acidosis with ph 7.37 ( normal range 7.377.45 ) and base excess 7.7 mm ( 3.0 to 3.0 mm ) . venous blood tests showed raised plasma lactate 3.7 mm ( 0.72.1 mm ) , plasma myoglobin 280 g / l ( 1949 g / l ) , plasma glucose 8.6 mm ( 4.27.2 mm ) , plasma fibrin d - dimer 1.0 mg / l ( 0.00.5 mg / l ) , and inr 1.5 ( < 1.2 ) , whereas the remaining standard tests were all normal , including hemoglobin , leucocyte differential count , electrolytes , c reactive protein , liver and pancreas enzymes , renal parameters , plasma ethanol , plasma paracetamol , and plasma salicylate . shortly after admission , the patient developed babinski reflexes and a pronounced decorticate posture with spontaneous flexion of the arms over the chest and extended legs with feet turned inward . after a tracheal tube was inserted and assisted ventilation was initiated , the patient was transferred to the neurological intensive care unit at a tertiary hospital . a repeated computed tomography scan and magnetic resonance imaging of the head were performed , as well as a computed tomography angiography of the head and the neck . these scans unveiled a major stroke located in the left cerebral ( figure 1 ) and cerebellar hemispheres , corresponding to the areas supplied by the left middle and posterior cerebral arteries and the left superior cerebellar artery . a segmental occlusion in the top of the basilar artery was identified ( figure 3 ) . finally , a transthoracic echocardiography was performed , revealing a well - functioning univentricular heart with no detectable thrombi . warfarin was prescribed and the patient gradually regained consciousness . however , a severe right - sided hemiparesis persisted and the patient was transferred to a local neurorehabilitation unit . later , a magnetic resonance imaging scan of the thorax and upper abdomen was performed ( figure 4 ) . the patient had been referred to a cardiologist at the age of 5 months due to shortness of breath and failure to thrive . cardiac ultrasound and catheterization had revealed a double inlet left ventricle ( figure 5 ) and a hypoplastic right ventricle without transposition of the great arteries . symptoms were caused by heart failure due to high pulmonary flow , which was treated by pulmonary artery banding . at the age of 6 years , a total cavopulmonary connection ( tcpc ) , including a lateral tunnel with fenestration to the right atrium , was established . the surgical procedure markedly improved the patient s well - being , and , at the age of 13 years , the fenestration was closed . life - long prophylactic antithrombotic treatment with salicylic acid was prescribed . during the last surgical intervention , the patient suffered mild brain damage and was now described as behaving at the level of a 12-year - old . postoperative echocardiography revealed good systolic function of the left ventricle and mild right atrioventricular valve regurgitation . since no cardiac thrombi were identified , it is not known whether the described stroke was caused by a cardiac - derived embolus or spontaneous cranial thrombi . spontaneous thrombi in 19-year old patients are , however , extremely rare . hence , seen in the light of a known cardiac malformation , the probability of a cardiac - derived cerebral embolus is very high . the incidence of univentricular hearts is reported to be between 0.5 and three cases per 10,000 live births.1 today , patients with univentricular heart conditions are usually treated surgically with a three - stage tcpc / fontan procedure,2 which separates the systemic and pulmonary venous return a precondition for adequate oxygenation of the arterial blood entering systemic circulation . the technique has evolved from the classic fontan3 ( right atrium - to - pulmonary artery connection ) through an intracardiac lateral tunnel procedure , and it is currently performed in many centers as an extracardiac tunnel procedure by insertion of a tube graft between the inferior vena cava and the pulmonary artery.4 te , both systemic venous and arterial , are a major cause of early and late mortality in tcpc patients . the reported incidence of te in these patients varies from 3% to 25% , depending on study design , imaging technique , and follow - up period duration . studies with longer follow - up periods and more sensitive imaging studies suggest an incidence of at least 20% , of which the mortality rate is 25%.59 asymptomatic pulmonary emboli have been detected in 16% of tcpc patients . although the etiology for the high risk of te is not well defined , possible explanations include abnormal blood flow in the univentricle , arrhythmias , venostasis , dehydration , protein - losing enteropathy , and coagulation abnormalities . no stratification of te risk has been made between the different types of surgical intervention . such data would be very useful and should be compared against the efficacy of each treatment . procoagulant factors ( factors ii , v , vii , ix , and x ; plasminogen ; and fibrinogen ) and anticoagulant factors ( protein c and antithrombin iii ) are lower than normal controls prior to stage two or three of tcpc completion.10,11 increased platelet reactivity prior to tcpc completion has also been shown . a recent report , however , found no significant differences in thromboelastography ( a global whole - blood assay of coagulation ) in pediatric tcpc patients compared with healthy children.12 despite the high incidence of te , no consensus has been reached about the role of long - term antiplatelet or anticoagulation therapy in those patients who remain in stable sinus rhythm . some studies advise against routine anticoagulation,13 whereas others recommend routine antiplatelet14 or anticoagulation therapy.15,16 one recent study suggests that antiplatelet and anticoagulation therapy are equally effective in preventing te.17 te reduce quality of life18 and cause sudden death19 in adult patients with fontan circulation . therefore , in these patients , the benefit of long - term prophylactic antiplatelet or anticoagulation therapy must be carefully considered and weighed against the risk of detrimental hemorrhagic side effects . disagreement about antithrombotic therapy in tcpc patients warrants future study that compares the different therapeutic strategies . future studies should most likely be observational case - control studies due to the practical and ethical problems associated with randomized controlled trials . the need for such studies is emphasized by the presented case , which might suggest that more aggressive antithrombotic strategies should be routinely introduced . OUTPUT:

patients with univentricular heart malformations are at increased risk of suffering from thromboembolic events . we present a case of a 19-year - old woman born with a univentricular heart who suffered a major stroke while being treated with only salicylic acid . at least 20% of patients with univentricular hearts have been reported to experience thromboembolic events , of which 25% are fatal . despite the high incidence of thromboembolic events , no consensus has been reached regarding the role of long - term anti - thrombotic treatment in this group of patients . this lack of consensus warrants future studies that compare the different therapeutic strategies .

PubMed_Summ6502

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: patients with underlying or comorbid medical condition , psychotic depression , and those who were already on psychotropic medicines were excluded from the study . cases having contraindication for imipramine and/or lithium treatment were also excluded from the study . the aim of the study and the method adopted was explained to each patient and his / her cooperation was solicited . findings of physical examination , mental status evaluation , sociodemographic data were recorded on a specially designed pro forma . all baseline investigations including electrocardiogram and thyroid function were carried out as per standard guidelines . all patients were randomly assigned to one of the two groups : group a patients were given tablet imipramine and placebo . group b patients were administered tablet imipramine and tablet lithium carbonate as per schedule given below . the assessment of psychopathology was done by structured interview of the hamilton depression / melancholia scale designed by williams . the investigator had reviewed the records maintained at this center and found that clinical response was recorded in almost all cases at the dose range of 100150 mg . barring unforeseen developments , each patient was to be brought up to dose of 150 mg by day 14 . lithium carbonate was administered in such a way as to achieve a serum lithium concentration in the range of 0.60.8 meq / l by day 7 . lithium concentration was measured by atomic absorption spectrophotometry . the nursing staff who administered the drugs was blind to the nature of regimen given to the patients . students t - test was utilized to test the significance of the difference of means of scores at weekly intervals while categorical data were put to chi - square test , using the statistical package for social sciences - version 16.0 ( spss 16.0 . the investigator had reviewed the records maintained at this center and found that clinical response was recorded in almost all cases at the dose range of 100150 mg . barring unforeseen developments , each patient was to be brought up to dose of 150 mg by day 14 . lithium carbonate was administered in such a way as to achieve a serum lithium concentration in the range of 0.60.8 meq / l by day 7 . lithium concentration was measured by atomic absorption spectrophotometry . the nursing staff who administered the drugs was blind to the nature of regimen given to the patients . students t - test was utilized to test the significance of the difference of means of scores at weekly intervals while categorical data were put to chi - square test , using the statistical package for social sciences - version 16.0 ( spss 16.0 . demographic and clinical details of depressed patients in both groups did not show any significant differences [ table 1 ] . the two groups did not differ in duration for their current depressive episode [ table 2 ] . the patients did not differ in terms of frequency a particular symptom [ table 3 ] . depression scores of group a and group b patients at baseline and percentage reduction of scores at weekly intervals is shown in tables 4 and 5 , respectively . comparison of two groups in depression ratings at baseline and at weekly intervals [ table 6 ] . there is no difference between the two groups at baseline , but the difference is significant at the end of 1 week , 2 week , 3 week , and 4 week . demographic and clinical details of depressed patients duration of index episode at outset most common symptoms at the time of initial assessment depression scores of group a patients at baseline and at weekly intervals depression scores of group b patients at baseline and at weekly intervals comparison of two groups in depression ratings at baseline and at weekly intervals ( unpaired t - test ) mean percentage reductions in depression ratings at weekly intervals for both the groups revealed a larger reduction in depression ratings for group b as compared to group a at end of 1 , 2 , 3 , and 4 week [ figure 1 ] . difference between the baseline scores and at scores at weekly intervals for groups a and b is shown in table 7 . there are significant reductions in depression ratings for both groups at 1 week , 2 week , 3 week , and at 4 week intervals . however , the decline in scores is more for group b as compared to group a. the mean serum lithium level for the group achieved was 0.555 ( standard deviation : 0.186 ) . the plasma serum levels of lithium correlated with the clinical response positively at 1 week but had no correlation at 4 weeks [ table 8 ] . mean percentage reductions in depression ratings at weekly intervals for both the groups revealed a larger reduction in depression ratings for group b as compared to group a at the end of 1 , 2 , 3 , and 4 week difference between the baseline scores and at scores at weekly intervals for groups a and b ( student 's paired t - test ) mean serum lithium levels and percentage response at 1 week and at 4 weeks for group b patients majority ( 65% ) of patients of group b showed at least 25% improvement in depression ratings by the end of the 1 week . although the sample size in nonresponder group ( i.e. , < 25% by 1 week ) is small , but the trend shows a positive correlation of response with female gender , married status of the patient , absence of an enduring psychosocial problem , and a positive family history for a mood disorder [ table 9 ] . difference in variables associated with response at 1 week within group b between partial responders ( i.e. , having response > 25% and ) and nonresponders ( i.e. , having response < 25% ) the most common side effect for group a was dry mouth whereas it was digital tremor for the group b patients . other side effects encountered were constipation , postural hypotension , foul taste , blurred vision , urinary problems , palpitations , and impotence . manic switch for 2 patients in group a and dysarthria and arrhythmia in one patient each for group b were exclusively group specific [ table 10 ] . the last century was often termed as the century of anxiety . in contrast , 21 century can perhaps be described as the age of depression as evidenced by the fact that it is one of the most common scourges causing distress and disability . although remarkable advances in somatic and psychological interventions have brought in salutary change , but patients are still obliged to endure the anathema at least for a few weeks until the administered drugs start to take effect . ongoing research holds promise of rationalizing and optimizing drug therapies so as to provide maximum benefit to the patient . the current study was a step in this direction wherein an attempt was made to curtail the lag period of tca response by the addition of lithium from the outset and comparing it with the same tca monotherapy in a double - blinded randomized controlled study . the means are comparable to a similar study where mean age was about 39 years ( 39.5 for imipramine and 38.5 for imipramine + lithium group ) . a total of five patients in group a and 1 patient of group b [ table 1 ] shared a positive family of a mood disorder . a total of 6 patients of group a and 5 patients of group b [ table 1 ] had a history of mental or neurological illness . however , none of the patients had a concurrent medical or surgical illness and were not on any psychotropic medications ( exclusion criteria ) . the trial was extended to include unipolar , recurrent depression as well as dysthymic patients [ table 1 ] against an earlier study where they restricted the sample to only bipolar depressed with melancholic features . duration of the index depressive episode was identical for both the groups [ table 2 ] . the symptom profile for patients of both the groups at baseline [ table 3 ] is in agreement with a similar study , which suggests higher prevalence of somatic rather than cognitive symptoms in depressed subjects of this country . in the current study , patients receiving lithium and imipramine combination responded more rapidly and completely than the imipramine - placebo groups [ tables 4 , 5 and figure 1 ] . the differences in response between the two groups at the end of 1 week , 2 week , 3 week , and 4 weeks were both statistically significant and clinically meaningful . the mean percentage change in depression ratings [ figure 1 ] after 1 week ( 38.37% ) for the lithium + imipramine group was higher than the imipramine + placebo group ( 14.97% ) . although the difference between the two groups [ table 6 ] was not significant at baseline ( t = 0.5891 , p > 0.05 ) , but it was significant at week 1 ( t = 3.8747 , p < 0.01 ) , week 2 ( t = 3.6895 , p < 0.01 ) , week 3 ( t = 2.8153 , p < 0.01 ) , and at week 4 ( t = 2.2682 , p < 0.05 ) . the important clinical relevance in the finding is that the combination proves its superiority over monotherapy in that it brought a faster onset of action which persisted during the duration of the study . the mean percentage reduction at 4 weeks [ figure 1 ] of depression ratings was higher ( 96.2% ) for group b ( imipramine + lithium combination ) than that of 60.5% for group a ( imipramine + placebo combination ) implying that the combination brought a more complete remission . the findings are supported by a similar study who found better efficacy at 6 weeks rather than at 4 weeks . the principal hypothesized mechanism of action of imipramine is its ability to inhibit reuptake of both serotonin and noradrenaline . the exact mechanism of action of lithium remains a mystery though recent research points toward its salubrious effect in stabilizing ionic and molecular transmission . lithium is also known to produce striking enhancements in some aspects of serotonergic functions , which is also caused by imipramine . although the exact pharmacodynamics and pharmacokinetics were not the principal foci of this study , it appears that the superior response to the combination may have been obtained because of two separate actions concomitantly by imipramine ( in monoamine enhancement at the synaptic cleft ) and lithium ( in altering intra - neuronal signal pathways ) at molecular level . the strategy is not new to medical profession and is an accepted norm in the treatment of malignancies and chronic infections such as tuberculosis and hiv . lithium is not known to interfere with pharmacokinetics of imipramine , and the combination has been described to be a safe and effective one . at the outset , it was not known as to what degree patients would be tolerating the combination , and the emergence of side effects ( in the form of coarse digital tremor ) at the predefined serum levels of 0.60.9 meq / l was underestimated . emergence of this side effect in the combination group warranted a more cautious approach and serum lithium targets were revised from 0.60.9 the strategy helped in restricting the tremor to only a mild form , which was acceptable to the patients . the use of other antitremor agents such as clonazepam or propranol was of course considered but was not required as tremors reached acceptable levels by just lowering the mean serum lithium levels . that the therapeutic effect was obtained with this much concentration is supported by earlier studies , which suggest that lower concentrations may be as effective as higher concentration for augmentation purpose . moreover , correlation studies at 1 week and at 4 weeks [ table 8 ] suggest a mildly significant positive correlation at 1 week and an insignificant correlation at 4 weeks . lithium was administered for 4 weeks because the intent was to augment imipramine and interest was in early response . how far is the combination likely to be beneficial beyond 4 weeks is subject to further evaluation . however , existing research supports its use , and it may be an alternative in difficult cases . on further analysis , it is seen that 14 out of 20 patients in group b ( i.e. 70% ) showed a higher than 25% response in depression ratings by the end of 1 week [ table 9 ] . a search was made to study the variables associated with difference in response of more than 25% and that of < 25% . the variables of age , occupation , educational status , interpersonal relations , past history of mental or neurological illness , depression typology , or duration of index depressive episode did not significantly influence the outcome though the variables of gender ( of being females ) , married status , absence of enduring psychosocial problem , and a positive family history for a mood disorder predicted a better response . it appears fairly reasonable to presume at this stage that the response to lithium plus imipramine combination was quicker and superior than tricyclic monotherapy alone and it was seen across majority of depressed subjects . the limiting factor of the study was small sample size and a narrow spectrum of depressive disorders which were studied . concurrent administration of lithium and imipramine from the outset produced quicker antidepressant response in unipolar depression and the effect was evident in 70% of the patients by the end of the 1 week . OUTPUT:

background : treatment of depressive episode often poses a challenge . although there are numerous medicines available for its treatment but they all have a lag period of 23 weeks before they start showing their result.aim:the aim of the present study was to test the hypothesis that an initial lithium - tricyclic antidepressant ( tca ) combination has a quicker and better antidepressant effect than standard tca treatment in unipolar depression.materials and methods : twenty unipolar depressed inpatients under lithium - tca treatment were compared with twenty patients with similar diagnosis treated with tca - placebo combination . the duration of the study was 4 weeks under double - blind conditions.results:initial lithium - tca treatment reduced depressive symptoms significantly more than tca alone . the difference was evident from 1st week onward and persisted at 4 weeks.conclusion:lithium augmentation of tca at the outset offers a strategy to reduce the lag period of antidepressant action . the choice can be made for those patients who are likely to benefit from long - term prophylaxis .

PubMed_Summ6503

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the subject of ideals in topological space has been studied by kuratowski and vaidyanathaswamy . an ideal on a topological space ( x , ) is a nonempty collection of subsets of x which satisfies ( i ) a and b a implies b and ( ii ) a and b implies a b . given a topological space ( x , ) with an ideal on x and if (x ) is the set of all subsets of x , a set operator ( ) : (x ) (x ) , called a local function of a with respect to and , is defined as follows : for a x , a( , ) = { x xu } , for every { u (x ) } where (x ) = { u x u}. a kuratowski closure operator cl ( ) for a topology (x , ) , called the -topology , finer than is defined by cl(a ) = a a( , ) ; when there is no chance for confusion , we will simply write a for a( , ) and for ( , ) . if is an ideal on x , then ( x , , ) a of an ideal space ( x , , ) is said to be -open if a int(a ) . a subset a of an ideal space ( x , , ) is said to be pre--open if a int(cl(a ) ) . the family of all pre--open sets in ( x , , ) is denoted by po(x , ) or simply po(x ) . clearly po(x ) . the largest pre--open set contained in a , denoted by pint(a ) , is called the pre--interior of a. the smallest pre--closed set containing a , denoted by pcl(a ) , is called the pre--closure of a. a subset a of an ideal space ( x , , ) is said to be --open if a int(cl(int( ) ) ) . the family of all --open sets is a topology finer than . we will denote the --interior subset of a of x by int(a ) . a subset a of an ideal space ( x , , ) is -dense if cl(a ) = x. a space ( x , , ) is -submaximal if every -dense subset of x is open . let ( x , , ) be an ideal space and let a be a subset of x. then pint(a ) = aint(cl(a ) ) . let ( x , , ) be an ideal space and let a be a subset of x. then pint(a ) = aint(cl(a ) ) . a pre--open set a of a space ( x , , ) is said to be pre--regular pre--open if a = pint(pcl(a ) ) . the complement of a pre--regular pre--open set is called pre--regular pre--closed set , equivalently a = pcl(pint(a ) ) . a subset a of a space ( x , , ) with an ideal is said to be pre--regular if it is pre--open and pre--closed . a is pre--open which implies a = pint(a ) = pint(pcl(a ) ) . hence a is pre--regular pre--open . but consider the ideal space ( x , , ) where x = { a , b , c } , = { , { a } , { b } , { a , b } , x } , and = { , { a}}. here { a } is pre--regular pre--open but not pre--closed . consider the ideal space ( x , , ) where x = { a , b , c } , = { , { a } , { b } , { a , b } , x } , and = { , { a}}. here { a } is pre--regular pre--open but not pre--closed . moreover , the intersection of two pre--regular pre--open sets is not pre--regular pre--open in general as example 4 shows . consider the ideal space ( x , , ) where x = { a , b , c } , = { , { b , c } , x } , and = { , { a}}. here po(x ) = { , { b } , { c } , { a , b } , { a , c } , { b , c } , x}. thus , a = { a , b } , b = { a , c } are both pre--regular pre--open . consider the ideal space ( x , , ) where x = { a , b , c } , = { , { b , c } , x } , and = { , { a}}. here po(x ) = { , { b } , { c } , { a , b } , { a , c } , { b , c } , x}. thus , a = { a , b } , b = { a , c } are both pre--regular pre--open . consider the space ( x , ) with an ideal as in example 4 . here consider the space x = { a , b , c } and = { , { a } , { b } , { a , b } , x } , = { , { a}}. here { a } is pre--regular pre--open but not -open . observe that every pre--regular pre--open set is pre--open but the converse need not be true . here let ( x , , ) be an ideal space and let a , b be any subsets of x. then the following hold.(a)if a b , then pint(pcl(a ) ) pint(pcl(b)).(b)if a pio(x ) , then a pint(pcl(a)).(c)for every a po(x ) , pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a)).(d)if a and b are disjoint pre--open sets , then pint(pcl(a ) ) and pint(pcl(b ) ) are disjoint.(e)if a is a pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed.(f)if a is pre--regular pre--open , then pint(a ) is pre--regular pre--open . let ( x , , ) be an ideal space and let a , b be any subsets of x. then the following hold.(a)if a b , then pint(pcl(a ) ) pint(pcl(b)).(b)if a pio(x ) , then a pint(pcl(a)).(c)for every a po(x ) , pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a)).(d)if a and b are disjoint pre--open sets , then pint(pcl(a ) ) and pint(pcl(b ) ) are disjoint.(e)if a is a pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed.(f)if a is pre--regular pre--open , then pint(a ) is pre--regular pre--open . if a b , then pint(pcl(a ) ) pint(pcl(b ) ) . if a pio(x ) , then a pint(pcl(a ) ) . for every a po(x ) , pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a ) ) . if a and b are disjoint pre--open sets , then pint(pcl(a ) ) and pint(pcl(b ) ) are disjoint . if a is a pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed . proof ( a)suppose a bpcl(a ) pcl(b ) . therefore pint(pcl(a ) ) pint(pcl(b)).(b)suppose that a po(x , )a = pint(a ) pint(pcl(a)).(c)it is obvious that pint(pcl(a ) ) po(x , ) , so by ( b ) we have pint(pcl(a))pint(pcl(pint(pcl(a ) ) ) ) . on the other hand pint(pcl(a ) ) pcl(a ) which implies pcl(pint(pcl(a)))pcl(pcl(a ) ) = pcl(a ) . therefore , pint(pcl(pint(pcl(a))))pint(pcl(a ) ) . hence pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a)).(d)since a and b are disjoint pre--open sets , we have ab = which implies apcl(b ) = apint(pcl(b ) ) = . since pint(pcl(b ) ) is pre--open , pcl(a)pint(pcl(b ) ) = . hencepint(pcl(a))pint(pcl(b ) ) = .(e)given that a is pre--regular pre--open , a = pint(pcl(a ) ) implies x a = x pint(pcl(a ) ) = pcl(pint(x a ) ) . therefore , pcl(x a ) = pcl(pint(pcl(x a ) ) ) . hence pcl(x a ) is pre--regular pre--closed.(f)by ( e ) if a is pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed . hence x ( pcl(x a ) ) is pre--regular pre--open that implies pint(a ) is pre--regular pre--open . ( a)suppose a bpcl(a ) pcl(b ) . therefore pint(pcl(a ) ) pint(pcl(b)).(b)suppose that a po(x , )a = pint(a ) pint(pcl(a)).(c)it is obvious that pint(pcl(a ) ) po(x , ) , so by ( b ) we have pint(pcl(a))pint(pcl(pint(pcl(a ) ) ) ) . on the other hand pint(pcl(a ) ) pcl(a ) which implies pcl(pint(pcl(a)))pcl(pcl(a ) ) = pcl(a ) . therefore , pint(pcl(pint(pcl(a))))pint(pcl(a ) ) . hence pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a)).(d)since a and b are disjoint pre--open sets , we have ab = which implies apcl(b ) = apint(pcl(b ) ) = . since pint(pcl(b ) ) is pre--open , pcl(a)pint(pcl(b ) ) = . hencepint(pcl(a))pint(pcl(b ) ) = .(e)given that a is pre--regular pre--open , a = pint(pcl(a ) ) implies x a = x pint(pcl(a ) ) = pcl(pint(x a ) ) . therefore , pcl(x a ) = pcl(pint(pcl(x a ) ) ) . hence pcl(x a ) is pre--regular pre--closed.(f)by ( e ) if a is pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed . hence x ( pcl(x a ) ) is pre--regular pre--open that implies pint(a ) is pre--regular pre--open . suppose a bpcl(a ) pcl(b ) . therefore pint(pcl(a ) ) pint(pcl(b ) ) . it is obvious that pint(pcl(a ) ) po(x , ) , so by ( b ) we have pint(pcl(a))pint(pcl(pint(pcl(a ) ) ) ) . on the other hand pint(pcl(a ) ) pcl(a ) which implies pcl(pint(pcl(a)))pcl(pcl(a ) ) = pcl(a ) . therefore , pint(pcl(pint(pcl(a))))pint(pcl(a ) ) . hence pint(pcl(pint(pcl(a ) ) ) ) = pint(pcl(a ) ) . since a and b are disjoint pre--open sets , we have ab = which implies apcl(b ) = apint(pcl(b ) ) = . since pint(pcl(b ) ) is pre--open , pcl(a)pint(pcl(b ) ) = . hencepint(pcl(a))pint(pcl(b ) ) = . given that a is pre--regular pre--open , a = pint(pcl(a ) ) implies x a = x pint(pcl(a ) ) = pcl(pint(x a ) ) . therefore , pcl(x a ) = pcl(pint(pcl(x a ) ) ) . hence pcl(x a ) is pre--regular pre--closed . by ( e ) if a is pre--regular pre--open , then pcl(x a ) is pre--regular pre--closed . hence x ( pcl(x a ) ) lemma 6 . for an ideal topological space ( x , , ) the following are equivalent . for an ideal topological space ( x , , ) the following are equivalent . proof(a ) ( b ) : let a be a -dense set that implies cl(a ) = x which implies int(cl(a ) ) = x , so that a int(cl(a ) ) = x. by ( a ) every pre--open set is open and hence a is open.(b ) ( a ) : let b be a pre--open subset of x , so that b int(cl(b ) ) = g , say . b ) = cl(x g ) cl(b ) = ( x g ) cl(b ) = x , and thus ( x g ) b is -dense in x. thus ( x g ) b is open . now b = ( ( x g ) b)g is the intersection of two open sets , so that b is open . ( a ) ( b ) : let a be a -dense set that implies cl(a ) = x which implies int(cl(a ) ) = x , so that a int(cl(a ) ) = x. by ( a ) every pre--open set is open and hence a is open . ( b ) ( a ) : let b be a pre--open subset of x , so that b int(cl(b ) ) = g , say b ) = cl(x g ) cl(b ) = ( x g ) cl(b ) = x , and thus ( x g ) b is -dense in x. thus ( x g ) b is open . now b = ( ( x g ) b)g is the intersection of two open sets , so that b is open . if a space ( x , ) with an ideal is -submaximal , then any finite intersection of pre--open set is pre--open . if a space ( x , ) with an ideal is -submaximal , then any finite intersection of pre--open set is pre--open . prooffrom lemma 6 , every pre--open set is open and hence a finite intersection of pre--open set is pre--open . from lemma 6 , every pre--open set is open and hence a finite intersection of pre--open set is pre--open . if a space ( x , ) with an ideal is -submaximal , then any finite intersection of pre--regular p--open set is pre--regular pre--open . if a space ( x , ) with an ideal is -submaximal , then any finite intersection of pre--regular p--open set is pre--regular pre--open . n } be a finite family of pre--regular pre--open sets . since the space x is -submaximal , then by lemma 6 , {oii = 1,2 , therefore , {oii = 1,2 , , n}pint(pcl(oi ) ) . also , for each i = 1,2 , , n , oi oi which implies pint(pcl(oi))pint(pcl(oi ) ) . also , each oi is pre--regular pre--open that implies oi = pint(pcl(oi ) ) which implies pint(pcl(oi))oi and so oi = pint(pcl(oi ) ) . n } be a finite family of pre--regular pre--open sets . since the space x is -submaximal , then by lemma 6 , {oii = 1,2 , , therefore , {oii = 1,2 , , n}pint(pcl(oi ) ) . also , for each i = 1,2 , also , each oi is pre--regular pre--open that implies oi = pint(pcl(oi ) ) which implies pint(pcl(oi))oi and so oi = pint(pcl(oi ) ) . it should be noted that an arbitrary union of pre--regular pre--open set is pre--regular pre--open . but the intersection of two pre--regular pre--closed sets fails to be pre--regular pre--closed as shown by example 9 . consider the ideal space ( x , , ) as in example 3 . clearly , { a , c } , { a , b } are pre--regular pre--closed but their intersection is not pre--regular pre--closed . consider the ideal space ( x , , ) as in example 3 . clearly , { a , c } , { a , b } are pre--regular pre--closed but their intersection is not pre--regular pre--closed . the following hold for a subset a of a space ( x , , ).(a)if a is pre--closed , then pint(a ) is pre--regular pre--open.(b)if a = pint(a ) , then pcl(a ) is pre--regular pre--closed.(c)if a and b are pre--regular pre--closed sets , then a b if and only if pint(a ) pint(b).(d)if a and b are pre--regular pre--open sets , then a b if and only if pcl(a ) pcl(b ) . the following hold for a subset a of a space ( x , , ).(a)if a is pre--closed , then pint(a ) is pre--regular pre--open.(b)if a = pint(a ) , then pcl(a ) is pre--regular pre--closed.(c)if a and b are pre--regular pre--closed sets , then a b if and only if pint(a ) pint(b).(d)if a and b are pre--regular pre--open sets , then a b if and only if pcl(a ) pcl(b ) . if a is pre--closed , then pint(a ) is pre--regular pre--open . if a = pint(a ) , then pcl(a ) is pre--regular pre--closed . if a and b are pre--regular pre--closed sets , then a b if and only if pint(a ) pint(b ) . if a and b are pre--regular pre--open sets , then a b if and only if pcl(a ) pcl(b ) . proof(a ) since a is pre--closed , a = pcl(a).now , pint(pcl(pint(a ) ) ) = pint(pint(a ) ) = pint(a ) . hence pint(a ) is pre--regular pre--open.(b ) now pcl(pint(pcl(a ) ) ) = pcl(pcl(a ) ) = pcl(a ) . hence pcl(a ) is pre--regular pre--closed.(c ) given that a and b are pre--regular pre--closed sets , therefore , a = pcl(pint(a ) ) and b = pcl(pint(b ) ) . clearly , pint(a ) pint(b ) if a b.conversely , pint(a ) pint(b ) . now a = pcl(pint(a ) ) pcl(pint(b ) ) b. hence a b.(d ) given that a and b are pre--regular pre--open , therefore , a = pint(pcl(a ) ) and b = pint(pcl(b ) ) . therefore , pcl(a ) pcl(b).conversely , pcl(a ) pcl(b ) . now a = pint(pcl(a ) ) pint(pcl(b ) ) b. ( a ) since a is pre--closed , a = pcl(a ) . ( b ) now pcl(pint(pcl(a ) ) ) = pcl(pcl(a ) ) = pcl(a ) . hence pcl(a ) is pre--regular pre--closed . ( c ) given that a and b are pre--regular pre--closed sets , therefore , a = pcl(pint(a ) ) and b = pcl(pint(b ) ) . clearly , pint(a ) pint(b ) if a b. conversely , pint(a ) pint(b ) . now a = pcl(pint(a ) ) pcl(pint(b ) ) b. hence a b. ( d ) given that a and b are pre--regular pre--open , therefore , a = pint(pcl(a ) ) and b = pint(pcl(b ) ) . now a = pint(pcl(a ) ) pint(pcl(b ) ) b. a subset a of an ideal topological space ( x , , ) is said to be -rare if it has no interior points in . theorem 11 . then the following hold.(a)the empty set is the only subset which is nowhere dense and pre--regular pre--open.(b)if a is pre--regular pre--closed , then every -rare set is pre--open then the following hold.(a)the empty set is the only subset which is nowhere dense and pre--regular pre--open.(b)if a is pre--regular pre--closed , then every -rare set is pre--open . the empty set is the only subset which is nowhere dense and pre--regular pre--open . if a is pre--regular pre--closed , then every -rare set is pre--open . then a = pint(pcl(a ) ) = pcl(a)int(cl(pcl(a ) ) ) , by lemma 1 . therefore , a pcl(a)int(cl(cl(a)))pcl(a)int(cl(a ) ) = pcl(a) = .(b ) suppose a is pre--regular pre--closed . then a = pcl(pint(a ) ) = pint(a)cl(int(pint(a)))pint(a ) cl(int(a ) ) = pint(a ) = pint(a ) . then a = pint(pcl(a ) ) = pcl(a)int(cl(pcl(a ) ) ) , by lemma 1 . therefore , a pcl(a)int(cl(cl(a)))pcl(a)int(cl(a ) ) = pcl(a) = . ( b ) suppose a is pre--regular pre--closed . then a = pcl(pint(a ) ) = pint(a)cl(int(pint(a)))pint(a ) cl(int(a ) ) = pint(a ) = pint(a ) . hence a is pre--open . an ideal space ( x , , ) is called extremally pre--disconnected if the pre--closure of every pre--open set is pre--open . theorem 12 . for a topological space ( x , , ) the following are equivalent.(a)(x , , ) is extremally pre--disconnected.(b)every pre--regular pre--open subset is pre--regular . for a topological space ( x , , ) the following are equivalent.(a)(x , , ) is extremally proof(a ) ( b ) : assume ( x , , ) is extremally pre--disconnected . hence a is pre--closed which implies a is pre--regular.(b ) ( a ) : suppose a is pre--open . then pcl(a ) is pre--regular pre--closed which implies x pcl(a ) is pre--regular pre--open . ( a ) ( b ) : assume ( x , , ) is extremally pre--disconnected . then pcl(a ) is pre--regular pre--closed which implies x pcl(a ) is pre--regular pre--open . let ( x , , ) be an extremally pre--disconnected space and a x. then the following are equivalent:(a)a is pre--regular,(b)a = pcl(pint(a)),(c)x a is pre--regular pre--open,(d)a is pre--regular pre--open . let ( x , , ) be an extremally pre--disconnected space and a x. then the following are equivalent:(a)a is pre--regular,(b)a = pcl(pint(a)),(c)x a is pre--regular pre--open,(d)a is pre--regular pre--open . then a is pre--open and pre--closed and so a = pint(a ) and a = pcl(a ) . hence a = pcl(pint(a)).(b ) ( c ) : let a = pcl(pint(a ) ) . then x a = x pcl(pint(a ) ) = pint(pcl(a ) ) so x a is pre--regular pre--open.(c ) ( d ) is clear.(d ) ( a ) follows from theorem 12 . then a is pre--open and pre--closed and so a = pint(a ) and a = pcl(a ) . then x a = x pcl(pint(a ) ) = pint(pcl(a ) ) so x a is pre--regular pre--open . ( d ) ( a ) follows from theorem 12 . an ideal space ( x , , ) is called locally pre--indiscrete if every pre--open subset of x is pre--closed ( or ) if every pre--closed subset of x is pre--open . then the following are equivalent.(a)(x , , ) is locally pre--indiscrete.(b)every pre--open subset is pre--regular.(c)every pre--open subset is pre--regular pre--open.(d)pint(pcl({x } ) ) , for every x x.(e)the empty set is the only nowhere dense subset of x. let ( x , , ) be an ideal space . then the following are equivalent.(a)(x , , ) is locally pre--indiscrete.(b)every pre--open subset is pre--regular.(c)every pre--open subset is pre--regular pre--open.(d)pint(pcl({x } ) ) , for every x x.(e)the empty set is the only nowhere dense subset of x. ( x , , ) is locally pre--indiscrete . pint(pcl({x } ) ) , for every x x. the empty set is the only nowhere dense subset of x. proof(a ) ( b ) : assume that ( x , , ) is locally pre--indiscrete . hence a is pre--regular.(b ) ( c ) : if a is pre--open , then a = pint(a ) . also by hypothesis , hence a is pre--regular pre--open.(c ) ( d ) : since { x } is preopen , { x } is pre--open . by ( c ) , { x } is a pre--regular pre--open set . therefore , { x } = pint(pcl({x})).(d ) ( e ) : by theorem 11 , in any space , the empty set is the only subset which is nowhere dense and pre--regular pre--open.(e ) ( a ) : suppose that a is a pre--closed set . now int(cl(a pint(a ) ) ) = int(cl(a ( aint(cl(a ) ) ) ) ) = int(cl(a(x a)(int(cl(x a ) ) ) ) ) = int(cl(a(x a)(a int(cl(a ) ) ) ) ) = int(cl(a int(cl(a))))int(cl(a ) int(cl(a ) ) ) = int(cl(a ) cl(int(cl(a))))int(cl(a ) ( int(cl(a ) ) ) ) = . therefore a pint(a ) is nowhere dense which implies a = pint(a ) , and so a is pre--open . hence is a locally pre--indiscrete . ( a ) ( b ) : assume that ( x , , ) is locally pre--indiscrete . let a be a pre--open subset of x. by hypothesis , a is pre--closed . hence a is pre--regular . ( b ) ( c ) : if a is pre--open , then a = pint(a ) . also by hypothesis , ( c ) ( d ) : since { x } is preopen , { x } is pre--open . by ( c ) , { x } is a pre--regular pre--open set . ( d ) ( e ) : by theorem 11 , in any space , the empty set is the only subset which is nowhere dense and pre--regular pre--open . ( e ) ( a ) : suppose that a is a pre--closed set . now int(cl(a pint(a ) ) ) = int(cl(a ( aint(cl(a ) ) ) ) ) = int(cl(a(x a)(int(cl(x a ) ) ) ) ) = int(cl(a(x a)(a int(cl(a ) ) ) ) ) = int(cl(a int(cl(a))))int(cl(a ) int(cl(a ) ) ) = int(cl(a ) cl(int(cl(a))))int(cl(a ) ( int(cl(a ) ) ) ) = . therefore a pint(a ) is nowhere dense which implies a = pint(a ) , and so a is pre--open . hence is a locally pre--indiscrete . an ideal space ( x , , ) is said to be pr - door if every subset of x is either pre--regular pre--open or pre--regular pre--closed . let ( x , , ) be a pr - door space ; then every pre--open set in the space is pre--regular pre--open . let ( x , , ) be a pr - door space ; then every pre--open set in the space is pre--regular pre--open . prooflet a be a pre--open subset of x. since x is pr - door , a is pre--regular pre--closed and so a = pint(pcl(a ) ) which implies that pinta = pint(pint(pcl(a ) ) ) . let a be a pre--open subset of x. since x is pr - door , a is pre--regular pre--closed and so a = pint(pcl(a ) ) which implies that pinta = pint(pint(pcl(a ) ) ) . a subset a of x is both --open and --closed ; then a is a pre--regular pre--open set a subset a of x is both --open and --closed ; then a is a pre--regular pre--open set . prooflet a be an --open and --closed set . then a is a pre--open and pre--closed set and hence a is a pre--regular pre--open set . let a be an --open and --closed set . then a is a pre--open and pre--closed set and hence a is a pre--regular pre--open set . let ( x , , ) be an ideal space . a subset a of x is --open and pre--regular pre--open ; then a = int(cl(int(a ) ) ) . a subset a of x is --open and pre--regular pre--open ; then a = int(cl(int(a ) ) ) . then a int(cl(int(a ) ) ) . and a is pre--regular pre--open which implies a = pint(pcl(a))pint(cl(int(pcl(a))))pint(cl(int(a)))int(cl(int(a ) ) ) . then a int(cl(int(a ) ) ) . and a is pre--regular pre--open which implies a = pint(pcl(a))pint(cl(int(pcl(a))))pint(cl(int(a)))int(cl(int(a ) ) ) . OUTPUT:

we deal with the new class of pre--regular pre--open sets in which the notion of pre--open set is involved . we characterize these sets and study some of their fundamental properties . we also present other notions called extremally pre--disconnectedness , locally pre--indiscreetness , and pre--regular sets by utilizing the notion of pre--open and pre--closed sets by which we obtain some equivalence relation for pre--regular pre--open sets .

PubMed_Summ6504

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: lichen sclerosus et atrophicans ( lsa ) is a chronic inflammatory muco - cutaneous disorder , characterized by sclerotic and atrophic lesions , most commonly found in adult women . it affects the anogenital area in 8598% of the cases and less frequently the extrgenital area . the most commonly affected extragenital areas are the neck and the shoulders , but also the inner thighs , the submammary area , the wrist and occasionally the oral mucosa . the involvement of the scalp is not frequent and its outcome could be similar to scarring alopecia , which could be the result of different diseases . the etiology of lsa is still unknown . besides the genetic and local factors ( koebner phenomenon ) and the autoimmune hypothesis , supported by the association of different autoimmune disorders , especially of thyroid origin ( 30% of cases ) , an infectious hypothesis has also been proposed . a 57-year - old caucasian woman presented with a history of asymptomatic frontoparietal lesion . such lesion , which had been developing over the 3 previous years , was initially erythematous and became progressively atrophic and sclerodermic . the patient had been living in a highly endemic area for borrelia burgdorferi , but she could not recall any tick bite or erythema chronicum migrans . she also reported the simultaneous onset of migrating diffused myoarthralgias involving knees , hands , ankles , elbows , shoulders , as well as short - term memory impairment for two years , worsened previous seasonal insomnia for one year . moreover , she presented migrating paresthesias involving the left side of the body for one month . the dermatological examination revealed an atrophic - sclerodermic lesion of about 10 cm in length and 3 cm in width , from the scalp to the centre of the forehead as reported in figure 1 . the skin was thin , inelastic , mother - of - pearl in shade , with erythematous margins of the lesion with subsequent scarring alopecia as well ( figure 1 ) . figure 1lichen sclerosus et atrophicans with frontoparietal distribution , mimicking scleroderma en coup de sabre . a skin biopsy was obtained from the scalp and after histological examination three different pathologists confirmed independently the diagnosis of lsa . it consisted of epidermal atrophy , oedema with superficial layer , hyperkeratosis and collagen production with cell rarefaction . lymphoid infiltrate was observed even in the dermal - subepidermal junction indicating a possible later evolution of the lsa toward morphoea ( figure 2 ) . figure 2h&e stained section of the lesion ( a ) 2,5 magnification of the entire histological section , ( b ) 20 magnification of the lichen sclerosus et atrophicans features ( c ) 40 magnification of the lymphatic infiltrate . h&e stained section of the lesion ( a ) 2,5 magnification of the entire histological section , ( b ) 20 magnification of the lichen sclerosus et atrophicans features ( c ) 40 magnification of the lymphatic infiltrate . serological igm and igg for borrelia burgdorferi with enzyme - linked immunoassay test ( elisa ) confirmed by western blot analysis was negative . anti - nuclear antibodies ( ana ) , extractable nuclear antigen antibodies ( ena ) , anti - native dna antibodies ( n - dna ) , anti - neutrophil cytoplasmic antibodies ( anca ) and erythrocyte sedimentation rate were negative . pcr analysis for the detection of borrelia burgdorferi was performed on dna obtained from formalin - fixed paraffin - embedded skin biopsy , blood and urine as previously reported . the diagnosis of lyme borreliosis was made on the basis of clinical data , supported by the pcr positivity for borrelia genome . the patient underwent antibiotic treatment with 2 cycles ceftriaxone 2 gr / day i.v for 21 days . after about 6 months since the beginning of antibiotic therapy , the lesion had not progressed , all other clinical symptoms improved and blood pcr resulted negative . the patient received vitamin e 400 mg 2x / day per os for 3 months and applied topic vitamin e prior to uva-1 therapy . thanks to this combined therapy a remarkable regression of the atrophic - sclerodermic lesion was observed . this report describes a case of lsa , which was unusual for the involvement of the scalp . the lesion was mimicking scleroderma en coup de sabre , which is a frontal or frontoparietal linear morphoea characterized by a linear band of depressed atrophy on skin and scalp . the classical features of lsa are represented by hypopigmented papules that coalesce into white plaques with epidermal atrophy . although anogenital lsa is associated with a risk of 45% of squamous cell carcinoma , extragenital lesions do not seem to carry any risk of malignant degeneration . the isolated linear frontoparietal involvement was described in few cases and may clinically simulate scleroderma en coup de sabre , requiring careful histopathological recognition . in this case it has already been reported that overlap of histologic features between lsa and morphoea may occur , however in the reported case the clinical and the histologic features were not ambiguous of lsa . the possible later evolution toward morphoea in this case , due to the migration of the lymphatic infiltrate , is not unusual since morphoea and lsa may be closely related such that the latter could be considered the superficial expression of the same disease process which results in morphoea . regarding the possibility of an infectious etiology of lsa , since the first proposal by aberer and stanek in 1987 several european studies some atrophic skin diseases have been proposed as manifestation of lyme borreliosis with contradictory results . the detection methods , the examined specimens , such as sera , skin biopsies and urine , together with the different geographic region could explain the conflicting results on the association of borrelia with morphoea and lichen sclerosus et atrophicus . moreover in the manifestation of long standing infection of borrelia the paucity of microorganisms could lead to a low detection rate by pcr , especially when the analysis is performed on archival biopsies . no decision can be made to date as to whether bb plays a role as causative agent of different types of circumscribed scleroderma and lsa . with regard to the disparate findings in different geographic areas , it can be speculated that lsa may be caused in some cases by bb genotypes which are present in that area only . to support this infectious etiology in endemic regions , the fact that in this case borrelia dna was detected both on dna obtained from the biopsy and from blood and urine , strongly supports the hypothesis that borrelia has a causative role on the onset of this unusual lsa . moreover , the geographical location , middle europe , has been highly associated with borrelia prevalence . indeed , it is well known that there are significant geographic differences in borrelia infections with a higher prevalence in areas in middle europe . to further support this theory , lyme disease affects mostly the skin : about 80% of all lyme borreliosis cases present skin manifestations . we recognise that classical dermatological events include erythema chronicum migrans ( ecm ) , lymphadenosis benigna cutis ( labc ) or borrellial lymphocytoma ( bl ) and acrodermatitis cronica et atroficans ( aca ) , but there is growing evidence that some cases of other cutaneous manifestations could be related to borrelial late infection , mostly borrelia afzelii . common laboratory tests are not usually revealing for the diagnosis of lyme borreliosis and serologic tests support the diagnosis , but are not always essential in this regard . in this case of lsa mimicking scleroderma en coup de sabre , an associaton with lyme borreliosis is proposed . to our knowledge , this is the first case of lsa , mimicking scleroderma en coup de sabre , which was associated with lyme borreliosis . our findings indicate an association between this particular form of lsa and borrelia , suggesting that borrelia burgdorferi itself could represent a causative agent of this atypical form of lsa , however it can not be excluded that borrelia could be only one of the predisposing agent triggering it . in conclusion we propose that tissue pcr for dna of borrelia should be performed in patients with lsa in endemic area , because it could represent a rare manifestation of borreliosis , and in those cases lsa should be treated with proper antibiotic therapy in order to eradicate the microorganism . OUTPUT:

lichen sclerosus et atrophicans ( lsa ) is a chronic , inflammatory skin disease of unknown etiology , characterized by atrophy.we report a case of lsa with frontoparietal distribution , mimicking scleroderma en coup de sabre , causing scarring alopecia . the case was associated with borrelia infection . the lesion improved with 2 cycles of antibiotic therapy with ceftriaxone 2 gr / day i.v for 21 days associated with uva-1 therapy and local and systemic vitamin e supply ( 400 mg 2x / day per os for 3 months ) . this case stresses the importance of identifying clinical manifestations associated with lyme disease and the use of tissue pcr to detect borrelial dna in patients with these lesions , but characterized by negative serology for borrelia .

PubMed_Summ6505

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: with regard to the importance and notable role of human power in an organization , investigation of the elements , which increase staff 's function and reduce absenteeism and desertion and ultimately lead to an increase in efficiency , is of great importance for researchers and experts . nursing managers should design an attractive workplace which can absorb new nurses in addition to preserving the existing staffs in the system . therefore , high quality of work life has been suggested as an important issue in many organizations including the world health organization ( who ) from 1970s . quality of work life was suggested in early 70s and was investigated from different angles during several past decades . walton is one of the experts who have investigated work life in eight dimensions ( fair and adequate payment , safe working environment , provision of opportunities for continued growth and security , rule of law in organization , social ties , life work , overall living space , integrity of the organization , and development of human capabilities ) . in the 80s , american and european managers pointed to quality of work life as one of the most interesting methods to cause motivation and as a solution for designing and job enrichment , as well as a tool to solve the problems and organizational gordian knot . quality of work life was used in the nursing context by attridge and challahan from 1990 . the last version of nurses work life quality model was suggested by brooks and anderson in 2001 , in which nurses quality of work life was considered in four dimensions . work life home life work life / home life dimension reveals the nurses life experience at work and home . work world dimension describes vast social impacts as well as the effects of changes on the functioning of nursing profession . nurses as a giant group of health providers who handle human lives should have an appropriate work life in order to take care of the clients properly . results of a study on quality of work life in nurses of tehran university of medical sciences in 2006 showed that 70% of nurses were not satisfied with their work life quality , and complained of most of their work life dimensions . research conducted in hospitals in tehran in 2010 showed an inverse correlation between nurses level of anxiety and quality of work life . this is why the human resources section should try to improve its personnel 's quality of work life . improvement of personnel 's quality of work life has been mentioned as one of the important issues to guarantee health system stability , as high work life quality is essential to absorb and preserve the staffs . results of a study conducted in 2010 on the association between work life quality and organizational commitment among fire fighters in malaysia showed a significant association between the two factors . workplace is one of the factors affecting the quality of given care , retaining nurses , and cost efficacy . research on the necessity of nurses work life improvement in 2003 showed that an increase in nurses work life quality leads to an improvement in patients care and nurses communication with patients families . work life has a major share in satisfaction with other life dimensions like family , leisure , and health . results of a study conducted in 2008 on the association between occupational stress and work life quality in army nurses showed an inverse association between the two factors . one of the duties of the managers in a health services organization is to take action for improvement of work life quality and education of coping strategies , as some stressful elements like workplace violence are inevitable in these organizations and prevention of their psychological and behavioral effects is essential . workplace violence is one of the factors that lead to a decline in nurses work life quality and satisfaction and has a negative effect on the quality of patients care and satisfaction as well as nurses efficiency and competency . its real level is unknown yet , as what we see is just the tip of an iceberg . violent behaviors in workplace cause the staffs to experience anxiety , stress , fatigue , and depression , and reduce job satisfaction and organizational commitment . higher frequency of exposure to workplace violence leads to major mental hazards and negatively affects the victim 's behavior . negative atmosphere , created after workplace violence , affects patient - staff communication and results in lower responses of nurses to patients needs , and consequently , the patients are less satisfied with the quality of health care . many studies showed that nurses were dissatisfied with their job security , so they were worried about their unsafe workplace . results of a study conducted in 2011 on 384 employees of kerman bahonar copper company showed an inverse correlation between work life dimensions and employees aggression . the researchers of the present study aimed to define and conduct a study on the quality of work life and its association with workplace violence of nurses in the emergency departments , with regard to the effective role of nurses in health services efficiency and patients and families satisfaction . the obtained results can make nursing managers determined to make a more proper background for improvement of the function and work life of nurses exposed to workplace violence , as well as patients care through control and management of workplace violence and making necessary changes in the working conditions . this is a descriptive correlational study conducted in the emergency wards of selected hospitals in isfahan in 2012 . the number of nurses with at least 1 year of work experience in the emergency ward ( n = 360 ) ok was determined by referring to nursing offices of the selected hospitals . to calculate the sample size , modified cochran formula was adopted in which existence or absence of violence was considered 50 . total number of nurses with bs and at least 1 year of work experience in the research environment was 360 . total number of subjects was estimated to be 186 and the sample size of each hospital was randomly allocated by quota sampling through proportion . in the second stage , the questionnaires were completed by qualified nurses meeting the inclusion criteria ( having a bs degree in nursing , being mentally balanced , and having at least 1 year of work experience in the emergency ward and working in this ward at the time of study ) . the nurses who defectively completed the questionnaire were left out of study and sampling went on until the required number of subjects was selected . demographic information ( 10 questions ) , 2 . investigation of workplace violence exposure in a 1-year period ( 4 questions ) , and 3 . each item was scored 1 - 6 based on likert 's scale ( absolutely disagree = 1 ; disagree = 2 ; relatively disagree = 3 ; agree = 4 ; relatively agree = 5 ; and absolutely agree = 6 ) . quality of nursing work life(qnwl ) questionnaire was designed by brooks and anderson in 2001 and its validity was confirmed . all the participants were given verbal and written information about the purpose of the study . written informed consent was obtained from all nurses and they were free to withdraw from the study at any time . its reliability was calculated by cronbach 's alpha ( = 0.93 , = 0.917 ) which showed an acceptable value . questionnaire of exposure to workplace violence was a researcher - made brief form of a standard questionnaire which was designed by the who , international nursing association , and public services association in 2003 , whose questions were modified to four questions related to goals of the present study . content validity was used for assessing its validity , wherein the questionnaire was given to 10 academic members of the nursing faculty after preparation of the primary draft , and then , their indications were applied to the questionnaire . the data in the present study were quantitative and qualitative ( nominal and ordinal ) . descriptive ( mean , sd ) and inferential ( pearson correlation coefficient ) statistical tests were used to analyze the data through spss version 16 . subjects mean age was 33.76 ( 7.13 ) years ; 70.4% of nurses were married and 29.6% were single . about 26.9% were males and 73.1% were females , 32.3% had work experience of 1 - 5 years , 30.1% had 610 years , and 37.7% had > 10 years work experience in the emergency ward . the highest number of exposures to verbal violence ( 41.4% ) was more than four times , and for physical violence ( 9.1% ) , it was two times . about 76.9% of the nurses were exposed to verbal violence and 26.9% to physical violence . subjects work life quality and each of its dimensions and statistical indexes have been separately presented in table 1 . association between the number of nurses exposed to verbal and physical workplace violence and their work life quality and its dimensions have been presented in table 3 . frequency distribution and mean scores of work life quality and its dimensions in emergency nurses responses of nurses in emergency wards to work life items association between the number of nurses exposure to verbal , physical workplace violence and work life quality and its dimensions improvement of work life quality is counted as a long - term and practical way to absorb and preserve human resources , which should be considered by health care managers . nurses work life quality dimensions and their association with the number of workplace violation exposures are discussed as follows . most of the nurses were dissatisfied with this dimension and mentioned the reasons as family 's needs , working hours , and low energy after doing their daily tasks . nurses reported that they spend a long time at their workplace , so they have little energy after work and can not fulfill their families needs , which is consistent with the results reported in previous studies . disproportionate salary and reward was one of the reasons for nurses dissatisfaction with their work life quality . behavioral theories like mallow and herzberg behavioral theories showed that fulfillment of primary needs is essential as the individuals can not concentrate on higher needs if their primary needs are not met . in the present study , 93.5% of nurses believed that their salary was not balanced with the inflation rate in market , which is in line with previous studies . meanwhile , 57% of nurses in the us believed their salary was balanced with their expenses . nurses low income is one of the major reasons for their job dissatisfaction and desertion . about 81.2% of the nurses believed that they had high workload , which is consistent with previous studies . on the other hand , 67.2% of the nurses believed they were not independent in taking care of the patients , which concords with former studies in which nurses reported they had low autonomy in decision making about patients care . about 88.7% of the nurses believed there were not adequate nursing personnel in their work environment and 64.5% believed that they were given extra non - nursing tasks . shortage in human resources and increase of nurses workload act as pressure factors among nurses , which lead to professional and organizational desertion . despite the shortage in human resources , these dimensions of malutilization of nursing force can increase the shortage of nursing force in a vicious cycle and affect nurses skills and experiences . such challenges may impose a notable pressure on nurses and negatively affect nurses perception of work life . managerial methods act as one of the problems in this dimension , which include lack of managers supervision , feedback , participation in decision making , higher level of managers respect toward nurses , inefficient nursing strategies and policies concerning facilitation of work , and modification of nurses concerns so that they think their struggles are not officially noted by nursing managers . previous studies on quality of work life for nurses show that nurses recognition and function directly affect their intention to stay in nursing profession . load of work in nurses , without authorities reward , leads to an increase in nurses intention to leave their profession . about 58.5% of nurses believed they were not able to communicate with their supervisors and nurse managers . in a study on the quality of work life among nurses in the us , 72% of nurses reported to have proper communication with their nursing managers and supervisors , which is not consistent with the results of the present study . communication with supervisors and other colleagues is among the factors which are associated with job satisfaction . about 84.9% of nurses believed that the security section did not make a secure environment for the nurses , and about 87.6% believed that their workplace was not physically , mentally , and verbally safe . the findings of the present study showed that 76.9% and 26.9% of nurses were exposed to verbal and physical violence , respectively , in the year prior to study , which shows a high prevalence and is in line with a study conducted in babol university of medical science in 2009 . as the staffs in health care system are exposed to workplace violence , prevention of violence and providing education of the necessary interventions against violence should be followed at all levels of an institute . the authorities should also help promotion of staffs services , especially that of nurses , by making a secure workplace . there is a negative correlation between the number of exposures to verbal and physical violence and work life quality and its dimensions , which has not been studied so far . most of the nurses were dissatisfied with this dimension and mentioned the reasons as family 's needs , working hours , and low energy after doing their daily tasks . nurses reported that they spend a long time at their workplace , so they have little energy after work and can not fulfill their families needs , which is consistent with the results reported in previous studies . disproportionate salary and reward was one of the reasons for nurses dissatisfaction with their work life quality . behavioral theories like mallow and herzberg behavioral theories showed that fulfillment of primary needs is essential as the individuals can not concentrate on higher needs if their primary needs are not met . in the present study , 93.5% of nurses believed that their salary was not balanced with the inflation rate in market , which is in line with previous studies . meanwhile , 57% of nurses in the us believed their salary was balanced with their expenses . nurses low income is one of the major reasons for their job dissatisfaction and desertion . about 81.2% of the nurses believed that they had high workload , which is consistent with previous studies . on the other hand , 67.2% of the nurses believed they were not independent in taking care of the patients , which concords with former studies in which nurses reported they had low autonomy in decision making about patients care . about 88.7% of the nurses believed there were not adequate nursing personnel in their work environment and 64.5% believed that they were given extra non - nursing tasks . shortage in human resources and increase of nurses workload act as pressure factors among nurses , which lead to professional and organizational desertion . despite the shortage in human resources , these dimensions of malutilization of nursing force can increase the shortage of nursing force in a vicious cycle and affect nurses skills and experiences . such challenges may impose a notable pressure on nurses and negatively affect nurses perception of work life . managerial methods act as one of the problems in this dimension , which include lack of managers supervision , feedback , participation in decision making , higher level of managers respect toward nurses , inefficient nursing strategies and policies concerning facilitation of work , and modification of nurses concerns so that they think their struggles are not officially noted by nursing managers . previous studies on quality of work life for nurses show that nurses recognition and function directly affect their intention to stay in nursing profession . load of work in nurses , without authorities reward , leads to an increase in nurses intention to leave their profession . about 58.5% of nurses believed they were not able to communicate with their supervisors and nurse managers . in a study on the quality of work life among nurses in the us , 72% of nurses reported to have proper communication with their nursing managers and supervisors , which is not consistent with the results of the present study . communication with supervisors and other colleagues is among the factors which are associated with job satisfaction . about 84.9% of nurses believed that the security section did not make a secure environment for the nurses , and about 87.6% believed that their workplace was not physically , mentally , and verbally safe . the findings of the present study showed that 76.9% and 26.9% of nurses were exposed to verbal and physical violence , respectively , in the year prior to study , which shows a high prevalence and is in line with a study conducted in babol university of medical science in 2009 . as the staffs in health care system are exposed to workplace violence , prevention of violence and providing education of the necessary interventions against violence should be followed at all levels of an institute . the authorities should also help promotion of staffs services , especially that of nurses , by making a secure workplace . there is a negative correlation between the number of exposures to verbal and physical violence and work life quality and its dimensions , which has not been studied so far . with regard to the above - mentioned negative correlation , it can be noted that workplace violence is a negative element reducing nurses work life quality . as the work life quality of nurses working in selected hospitals in isfahan is less than moderate , managers and authorities in hospitals should make policies for promotion of nurses work life quality through the following interventions : hospital managers should consider improvement of working conditions and making a supportive , friendly , and intimate environment for all the staffs , involving nurses in decision making and respecting their viewpoints , and designing a payment system based on nurses real function and nursing managers and supervisors more efficient humanistic communications.nurses work life quality is influenced by social , executive , managerial , and specific cultural conditions , and the present study revealed a negative correlation between the number of nurses exposed to violence and work life quality . with respect to the outcomes of workplace violence and its effect on work life quality , managers and authorities of these hospitals should think of solutions for the same . as the work life quality of nurses working in selected hospitals in isfahan is less than moderate , managers and authorities in hospitals should make policies for promotion of nurses work life quality through the following interventions : hospital managers should consider improvement of working conditions and making a supportive , friendly , and intimate environment for all the staffs , involving nurses in decision making and respecting their viewpoints , and designing a payment system based on nurses real function and nursing managers and supervisors more efficient humanistic communications . nurses work life quality is influenced by social , executive , managerial , and specific cultural conditions , and the present study revealed a negative correlation between the number of nurses exposed to violence and work life quality . with respect to the outcomes of workplace violence and its effect on work life quality as the work life quality of nurses working in selected hospitals in isfahan is less than moderate , managers and authorities in hospitals should make policies for promotion of nurses work life quality through the following interventions : hospital managers should consider improvement of working conditions and making a supportive , friendly , and intimate environment for all the staffs , involving nurses in decision making and respecting their viewpoints , and designing a payment system based on nurses real function and nursing managers and supervisors more efficient humanistic communications.nurses work life quality is influenced by social , executive , managerial , and specific cultural conditions , and the present study revealed a negative correlation between the number of nurses exposed to violence and work life quality . with respect to the outcomes of workplace violence and its effect on work life quality , managers and authorities of these hospitals should think of solutions for the same . as the work life quality of nurses working in selected hospitals in isfahan is less than moderate , managers and authorities in hospitals should make policies for promotion of nurses work life quality through the following interventions : hospital managers should consider improvement of working conditions and making a supportive , friendly , and intimate environment for all the staffs , involving nurses in decision making and respecting their viewpoints , and designing a payment system based on nurses real function and nursing managers and supervisors more efficient humanistic communications . nurses work life quality is influenced by social , executive , managerial , and specific cultural conditions , and the present study revealed a negative correlation between the number of nurses exposed to violence and work life quality . with respect to the outcomes of workplace violence and its effect on work life quality OUTPUT:

background : nurses as the major group of health service providers need to have a satisfactory quality of work life in order to give desirable care to the patients . workplace violence is one of the most important factors that cause decline in the quality of work life . this study aimed to determine the quality of work life of nurses in selected hospitals of isfahan university of medical sciences and its relationship with workplace violence.materials and methods : this was a descriptive - correlational study . a sample of 186 registered nurses was enrolled in the study using quota sampling method . the research instrument used was a questionnaire consisting of three parts : demographic information , quality of work life , and workplace violence . collected data were analyzed using descriptive and inferential statistics by spss version 16.results:the subjects consisted of 26.9% men and 73.1% women , whose mean age was 33.76 ( 7.13 ) years . 29.6% were single and 70.4% were married . about 76.9% of the subjects were exposed to verbal violence and 26.9% were exposed to physical violence during past year . mean score of qnwl was 115.88 ( 30.98 ) . about 45.7% of the subjects had a low level of quality of work life . there was an inverse correlation between the quality of work and the frequency of exposures to workplace violence.conclusions:according to the results of this study , it is suggested that the managers and decision makers in health care should plan strategies to reduce violence in the workplace and also develop a program to improve the quality of work life of nurses exposed to workplace violence .

PubMed_Summ6506

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: it is well established that the human body generates a wide variety of volatile organic compounds ( vocs ) some that are present in exhaled breath , emitted through the skin and released by urine samples . as human - specific signatures , these vocs can be considered as non - invasive biochemical probes that can track normal and abnormal metabolic processes in the body , bacterial and inflammatory processes , and provide invaluable information on exposure to environmental pollutants and/or toxins [ 17 ] . volatile aldehydes are widespread in human tissue and fluids and play important roles in functional processes . they have been reported to be common constituents of human urine [ 810 ] , exhaled breath , and present in skin emanations [ 1317 ] . some members of this chemical class have been detected in human blood and found to be released by in vitro human cell cultures [ 1921 ] . in the medical context , volatile aldehydes have been suggested to be biomarkers of lung cancer [ 2,19,20,2225 ] , liver cancer , and breast cancer ( see table 1 ) . some aldehydes are thought to be cytotoxic intermediates with several functions , such as signal transduction , gene regulation , and cellular proliferation . recently , efforts have been made to employ volatile aldehydes in safety and security applications [ 9,15,3032 ] . thus , there is growing evidence provided by a number of studies suggesting that chemical analysis of human odor could considerably improve effectiveness of search and rescue operations ( usar ) organized after disasters resulting in building collapse ( e.g. , earthquakes , tropical storms , explosions ) . although the origin of some aldehydes in human organisms is unclear , several sources could explain their occurrence . these include ( i ) alcohols metabolism [ 3335 ] , ( ii ) reduction of hydroperoxides by cytochrome p450 , ( iii ) oxidative stress , ( iv ) diet and ( v ) environmental exposure ( e.g. tobacco smoking ) . within this framework , a precise and reliable identification , and ultimately quantification , of volatile aldehydes proton - transfer reaction mass spectrometry ( ptr - ms ) is frequently employed in biological , medical , and environmental studies for detecting and quantifying volatile organic compounds [ 4350 ] . its applicability stems from its versatility , excellent sensitivity ( low pptv concentration levels ) , and real - time response . the application of a time - of - flight ( tof ) mass analyser in ptr - ms instruments notably improves their resolving power and , thereby , the discrimination between isobaric compounds . the recent employment of additional precursor ( reagent ) ions such as no , o2 , and kr instead of the usual h3o ( creating a selective reagent ionization time of flight mass spectrometry ( sri - tof - ms ) ) has further enhanced the analytical possibilities of this technique . the primary goal of the present work was to investigate the product ion distributions for the reactions with no ions of 22 aldehydes involved in human physiology and pathophysiology using a sri - tof - ms , a variant of the well - established ptr - ms technique . the reactions of no with vocs in sri - tof - ms are relatively poorly known , inhibiting their use for trace gas analysis , but it is certain that for most such reactions multiple product ions will result , as can also happen using h3o reagent ions in ptr - ms . an interesting advantage of no as a reagent ion is that different chemical classes of vocs have their typical reactions with no ( charge / electron transfer , hydride ion ( h ) , transfer , hydroxide ion ( oh ) transfer , alkoxide ion ( or ) transfer , and no / analyte molecule association ) , as has been summarized in a detailed review paper . this ion chemical variability is of potential value because it allows in some cases the separation of functional isomers . 22 aldehydes were selected for inclusion in the present study as guided by the available literature that reports their presence in human urine , breath , blood , and skin emanation , as summarized in table 1 . single - compound standard mixtures were prepared from liquid aldehydes , the majority of which were purchased from sigma aldrich ( austria ) ; acetaldehyde ( 99% ) , n - propanal ( 97% ) , n - butanal ( 99% ) , n - pentanal ( 97% ) , n - hexanal ( 98% ) , n - heptanal ( 95% ) , n - octanal ( 99% ) , n - undecanal ( 97% ) , 2-methyl propanal ( 99.5% ) , 3-methyl butanal ( 97% ) , 2-ethyl hexanal ( 96% ) , 2-methyl 2-propenal ( 95% ) , and ( e)-2-butenal ( 99% ) . moreover , n - nonanal ( 95% ) , n - decanal ( 95% ) , 2-propenal ( 95% ) , and benzaldehyde ( 99% ) were obtained from fluka ( switzerland ) , whereas , 2-methyl butanal ( 90% ) , 3-methyl 2-butenal ( 97% ) , ( e)-2-methyl 2-butenal ( 97% ) , ( e)-2-undecenal ( 90% ) , and furfural ( 98% ) were provided by safc ( usa ) . the compound purities are also given in table 2 for assistance in the interpretation of the product ion distributions of the no / aldehyde reactions . first , single - compound primary standards were prepared in 1-l glass bulbs ( supelco , canada ) . before usage , each bulb was thoroughly cleaned with methanol and dried at 70 c under the flow of high - purity nitrogen for at least 12 h to remove potential contaminants . the bulb was then evacuated using a membrane vacuum pump and approximately ( 0.51 ) l of liquid analyte was injected through a rubber septum . next , the bulb was heated to 100 c for 30 min to ensure complete evaporation and then the pressure was balanced to ambient pressure with high - purity cylinder air . the desired standard mixtures were prepared by transferring appropriate volumes of the primary standard into 3-l volume transparent tedlar bags ( skc inc . , usa ) filled with predefined amounts of purified and humidified air , the latter being produced by a gaslab calibration mixtures generator ( breitfuss messtechnik , germany ) . effectively , for each compound the product ion distribution was investigated using 3 distinct concentration levels of each aldehyde in air ranging approximately from 25 to 150 ppbv and at two different absolute humidity levels of essentially 0 and 3.5% . the no / aldehyde reactions were studied using an ionicon analytik ( innsbruck , austria ) type 8000 sri - tof - ms instrument , a variant of the familiar ptr - ms flow - drift tube instruments . the no precursor / reagent ions were generated by the ionization mechanism extensively described elsewhere , essentially by charging the hollow cathode discharge ion source with high purity dry air . the settings of the ion source were chosen as follows : ion source current 5 ma , source voltage ( us ) 20 v , source - out voltage ( uso ) 70 v , and source valve opening 40% . with these settings the major parasitic impurity ions , as detected downstream by the analytical tof - ms , were h3o , o2 , and no2 at relative levels ( parasitic ion / no ) of 0.30.6% , 11.5% , and 12% , respectively in the air carrier / buffer gas . the no / aldehyde reactions occurred in the carrier / aldehyde sample gases in the flow / drift tube at a total pressure of 2.23 mbar and a gas temperature of 60 c . moreover , the voltage along the drift section was set to 600 v leading to an e / n ratio of approximately 130 td . the high resolution realized by the tof analyzer ranged from m / z 1 to 500 and were acquired at a time of 30 s by co - adding 750,000 single 40-s long tof - ms extractions recorded at a sampling frequency 1/t = 10 ghz . this corresponds to a theoretical upper limit m/m of 90,000 at m / z 100 ( the flight time of these ions being 18 s ) . however , the actual mass resolution obtained from the detected peaks was 4000 at m / z 100 . this high resolution allows the separation of ions at nominally the same integer mass , for example , the nominally isobaric ions c3h7 and ch3co ions that are sometimes produced simultaneously in the analysis of gaseous matrices containing hydrocarbons , aldehydes and ketones . the mass calibration was based on three impurity peaks always present in the spectra : h3o ( 19.0178 ) , no ( 30.9945 ) , and no2 ( 45.9924 ) . the standard mixtures entered the flow / drift tube of the sri - tof - ms instrument at a steady flow rate of 10 ml / min via a two - meter - long , heated ( 40 c ) teflon transfer line . the total duration of a single measurement was 5 min , which corresponds to 10 mass spectra acquired per concentration level . effectively , the average of these 10 spectra was used to determine the percentages of the product ions resulting from each no / aldehyde reaction . single - compound standard mixtures were prepared from liquid aldehydes , the majority of which were purchased from sigma aldrich ( austria ) ; acetaldehyde ( 99% ) , n - propanal ( 97% ) , n - butanal ( 99% ) , n - pentanal ( 97% ) , n - hexanal ( 98% ) , n - heptanal ( 95% ) , n - octanal ( 99% ) , n - undecanal ( 97% ) , 2-methyl propanal ( 99.5% ) , 3-methyl butanal ( 97% ) , 2-ethyl hexanal ( 96% ) , 2-methyl 2-propenal ( 95% ) , and ( e)-2-butenal ( 99% ) . moreover , n - nonanal ( 95% ) , n - decanal ( 95% ) , 2-propenal ( 95% ) , and benzaldehyde ( 99% ) were obtained from fluka ( switzerland ) , whereas , 2-methyl butanal ( 90% ) , 3-methyl 2-butenal ( 97% ) , ( e)-2-methyl 2-butenal ( 97% ) , ( e)-2-undecenal ( 90% ) , and furfural ( 98% ) were provided by safc ( usa ) . the compound purities are also given in table 2 for assistance in the interpretation of the product ion distributions of the no / aldehyde reactions . first , single - compound primary standards were prepared in 1-l glass bulbs ( supelco , canada ) . before usage , each bulb was thoroughly cleaned with methanol and dried at 70 c under the flow of high - purity nitrogen for at least 12 h to remove potential contaminants . the bulb was then evacuated using a membrane vacuum pump and approximately ( 0.51 ) l of liquid analyte was injected through a rubber septum . next , the bulb was heated to 100 c for 30 min to ensure complete evaporation and then the pressure was balanced to ambient pressure with high - purity cylinder air . the desired standard mixtures were prepared by transferring appropriate volumes of the primary standard into 3-l volume transparent tedlar bags ( skc inc . , usa ) filled with predefined amounts of purified and humidified air , the latter being produced by a gaslab calibration mixtures generator ( breitfuss messtechnik , germany ) . effectively , for each compound the product ion distribution was investigated using 3 distinct concentration levels of each aldehyde in air ranging approximately from 25 to 150 ppbv and at two different absolute humidity levels of essentially 0 and 3.5% . the no / aldehyde reactions were studied using an ionicon analytik ( innsbruck , austria ) type 8000 sri - tof - ms instrument , a variant of the familiar ptr - ms flow - drift tube instruments . the no precursor / reagent ions were generated by the ionization mechanism extensively described elsewhere , essentially by charging the hollow cathode discharge ion source with high purity dry air . the settings of the ion source were chosen as follows : ion source current 5 ma , source voltage ( us ) 20 v , source - out voltage ( uso ) 70 v , and source valve opening 40% . with these settings the major parasitic impurity ions , as detected downstream by the analytical tof - ms , were h3o , o2 , and no2 at relative levels ( parasitic ion / no ) of 0.30.6% , 11.5% , and 12% , respectively in the air carrier / buffer gas . the no / aldehyde reactions occurred in the carrier / aldehyde sample gases in the flow / drift tube at a total pressure of 2.23 mbar and a gas temperature of 60 c . moreover , the voltage along the drift section was set to 600 v leading to an e / n ratio of approximately 130 td . the high resolution realized by the tof analyzer ranged from m / z 1 to 500 and were acquired at a time of 30 s by co - adding 750,000 single 40-s long tof - ms extractions recorded at a sampling frequency 1/t = 10 ghz . this corresponds to a theoretical upper limit m/m of 90,000 at m / z 100 ( the flight time of these ions being 18 s ) . however , the actual mass resolution obtained from the detected peaks was 4000 at m / z 100 . this high resolution allows the separation of ions at nominally the same integer mass , for example , the nominally isobaric ions c3h7 and ch3co ions that are sometimes produced simultaneously in the analysis of gaseous matrices containing hydrocarbons , aldehydes and ketones . the mass calibration was based on three impurity peaks always present in the spectra : h3o ( 19.0178 ) , no ( 30.9945 ) , and no2 ( 45.9924 ) . the standard mixtures entered the flow / drift tube of the sri - tof - ms instrument at a steady flow rate of 10 ml / min via a two - meter - long , heated ( 40 c ) teflon transfer line . the total duration of a single measurement was 5 min , which corresponds to 10 mass spectra acquired per concentration level . effectively , the average of these 10 spectra was used to determine the percentages of the product ions resulting from each no / aldehyde reaction . the channel procentages were calculated using the signal intensities corrected for the mass dependent discrimination of the instrument ( transmission ) . only product ions with abundance greater than 0.5% of the total signal were included in the table unless they clearly originated from the species under study ( e.g. , the small adduct ion in the benzaldehyde reaction ) , although the stated purities of the aldehydes ( see section 2.1 ) , which range from 90 to 99% , means that product ions percentages should be considered in the light of the specific purities of each aldehyde . the abundance percentages listed for each reaction are the averages of values obtained for 3 distinct mean concentrations ( from 10 spectra ) of the aldehydes in the dry air and the humid air , as indicated in table 2 . at these low interaction energies the reactions are generally considered to occur by an intimate ion molecule interaction forming an excited intermediate complex , in the present reactions ( nom ) * , which can either spontaneously undergo unimolecular decomposition back to the reactants or forward to fragmentation product ions , or be partially or totally stabilized by a third body collision ( with the bath gas atoms and/or molecules in which the reaction occurs ) resulting in the stable nom adduct ion . looser or longer range interactions can occur , usually at higher interaction energies as in ion - neutral beams via the process of exothermic charge / electron transfer , but heavy particle exchange , such as hydride ion , h , transfer , rarely occurs at long distance . in all the reactions in the present series a significant , often dominant reaction mechanism is seen to be hydride ion transfer generating ( mh ) ions , as indicated by the percentage product ions given as bold in table 2 . this is in accordance with earlier studies carried out under the thermalized condition of the sift and sift - ms [ 6264 ] . this strongly implies that these no / aldehyde reactions in the thermalized sift - ms , and even the suprathermal sri - tof - ms reactors , do proceed via close interactions and the initial formation of the intermediate ( nom ) * excited complexes . in the sift experiments , the observed product ions for the saturated alkanals mostly result from h transfer , occasionally the partial formation of nom adduct ions in the case of the unsaturated alkenals , and rarely ions that result from chemical rearrangements within the excited complex however , it is known and expected from mechanistic considerations that the lifetimes of these ( nom ) * complexes decreases with increasing interaction energy and gas temperature and so their lifetimes are expected to be shorter in sri - tof - ms flow / drift reactors than in thermalized sift - ms flow tube reactors ( carrier gas temperature typically 25 c ) . this will diminish the probability of seeing stabilized nom adduct ions in the sri - tof - ms reactor at similar carrier / buffer gas pressures but at the higher carrier gas temperature of 60 c ( see below ) . in the present flow / drift tube experiments , significant percentages of fragment ions are also seen for both the alkanals and alkenals reactions , most often as hydrocarbon ions cnhm , and this must be due to the elevated ion molecule interaction energies in the flow / drift tube and the possible injection from the ion source of energetic ions such as n2 that will not be seen downstream by the analytical mass spectrometer because of reactive loss . thus , fragmentation occurs in addition to hydride ion transfer for all these aldehyde reactions , as can be seen by the multiple product ions in many reactions , with the exception of the 2-undecenal and furfural reactions , seen in table 2 . consider first the no / acetaldehyde reaction that results in only the ch3co product ion and an hno neutral molecule . it is straightforward to show that this reaction is exothermic by 0.7 ev ( electron volts ) , yet this reaction is known to be relatively slow even under sift - ms conditions ; it is uncertain what its rate will be under ptr - ms conditions , but this would need to be ascertained if the no / acetaldehyde reaction is to be exploited for analysis . the fraction of ( mh ) to the total product ions in the no / propanal reaction indicated in table 2 and fig . 1 is 100% for moist carrier / sample gas and < 100% in dry air when obviously additional product ions are seen:(1a)no + c2h5cho c2h5co + hno(1b) c2h5 + co + hno(1c) c2h3 + ( ch2o + hno ) hydride ion transfer ( 1a ) is exothermic by 1.1 ev and is thus more exothermic than in the analogous acetaldehyde reaction . but what are the neutral products of reactions ( 1b ) and ( 1c ) ? the fragmentation channel ( 1b ) leading to a closed shell hydrocarbon ion is calculated to be endothermic by > 2 ev to produce two radical neutrals hco , and no , and endothermic by only 1 ev to produce the closed shell molecules co and hno . reaction ( 1c ) is very endothermic by > 4 ev to produce three neutral products cho , h2 and no and this is very unlikely , but it is less endothermic at 3.2 ev to produce the two products indicated as ch2o and hno . thus , it is problematic to identify the neutral products of these apparently very endothermic reactions , especially so because of the uncertainty in the kinetic energy distribution of the ions in the flow / drift tube ( but which must depart from maxwellian and is probably skewed toward the high energy tail ) , the vibrational state of the reactant no ions , and the interaction energies of the reactant ions and aldehyde molecules . what is certain is that the interaction energies will be elevated above the thermal energies prevailing in sift studies and this could drive endothermic reactions as apparently is the case for several of the reaction channels indicated for other reactions listed in table 2 . in support of the likely elevated interaction energies in the flow / drift tube reactors is the detailed analysis of hydrated hydronium ions , h3o(h2o)n , in ptr - ms flow / drift tube reactors by de gouw et al . , which indicates that the monohydrate ion h3oh2o , which has an h3o h2o binding energy of 1.4 ev , is entirely dissociated at an e / n of 130 td as adopted in the present experiments . this implies that ions like c2h5co , such as may be formed in reaction ( 1a ) , could fully dissociate to c2h5 and co. even so , it is difficult to see how reactions that are apparently endothermic by much more than 1 ev for ground vibronic state no ions can occur . it is therefore futile to attempt to define the reactions fully or even to guess the neutral products for the minor channels of these reactions when their origins are so uncertain . in summary , for the c3c7 alkanal reactions , co elimination is observed as a common fragmentation mode of the hydride ion product ( mh ) leading to the observed closed shell hydrocarbon ions cnh2n+1 . for c6c11 n - alkanals the hydride ion transfer process may be followed by the elimination of an h2o molecule ( or formation of dihydroxyamine h3no2 as a single neutral product ) , but this could only be substantiated by detailed consideration of the energetics of the reactions ; this uncertainty is indicated by bracketing the probable neutral products of each reaction in table 2 . the energy required for fragmentation of the primary product ion ( mh ) to eliminate co or h2o molecules can be acquired in multiple collisions with the n2 and o2 molecules that excites internal vibrational modes of ( mh ) ions , since at an e / n of 130 td the effective temperature of the interaction can be 500800 k . interestingly , the possible h2o molecule elimination is apparently not occurring for the branched alkanal reactions for which the major mechanism can be interpreted as the elimination of cnh(2n1)o groups and the formation of hydrocarbon ions , c3h7 and c4h9 ( see table 2 ) . in the case of n - alkanals , the percentage ( branching ratio ) of the ( mh ) hydride ion transfer products exhibits an interesting dependence on the number of carbon atoms in the molecule ( see fig . 1 ) that varies from 100% for the acetaldehyde reaction to a minimum percentage ( 13% ) for the n - hexanal reaction . for instance , the percentage of ( mh ) ions for the n - octanal reaction is 27% , whereas for the n - undecanal reaction it is about 85% . this phenomenon may assist identification of heavier alkanals in the sri - tof - ms(no ) instrument , but it would be complicated for the analysis of real matrices that contain mixtures of aldehydes and other trace compounds . why does the plot of ( mh ) ion percentage signal levels have the form shown in fig . 1 ? the answer must lie to some extent in the nature and the energetics of individual product channels of the no / m reactions , specifically the lifetime of the intermediate ( nom ) * excited complexes and the accessibility of the other reaction channels . the production of ( mh ) ions is exothermic for all the reactions , but others of the observed channels may also be exothermic , especially so for those reactions where ( mh ) production is relatively small fraction of the total product ions . the lifetimes of the ( nom ) * excited complexes are generally assumed to be shorter for small m and to increase with molecular weight of m , as a consequence of the increasing number of vibrational modes of the complex in which the binding energy can be temporarily dispersed . a combination of these parameters could explain the increased efficiency of ( mh ) production within the longer - lived complexes of the larger alkanals . the presence of a side - chain in the aldehyde molecule promotes greater fragmentation of isomeric aldehydes , as can be seen in table 2 . however , this effect seems to occur only when the methyl ( or ethyl ) group is located at the second position of the main carbon chain . for example , the abundance of the ( mh ) product ion of n - pentanal and 3-methyl butanal reactions is very similar at 1415% , whereas the fraction of this ion in the 2-methyl butanal reaction is only 2% . a similar effect can be seen by comparing the n - butanal and the 2-methyl propanal reactions ( 18% vs 4% ) , and the n - octanal reaction with the 2-ethyl hexanal reaction ( 27% vs 2% ) . the same holds true for the alkenal reactions ( e.g. , 96% for 2-butenal vs 26% for 2-methyl 2-propenal ) . consequently , the identification of 2-methyl(ethyl ) aldehydes by sri - tof - ms(no ) could be problematic in biological matrices using only this information . a further interesting point is that in the reactions of no with the largest alkanal , n - undecanal , in some unsaturated aldehydes , the heterocyclic furfural , and the aromatic benzaldehyde , small stable nom association product ions are observed , as indicated in italics in table 2 . the percentages are only small , but greatest for the furfural and 2-undecenal reactions where they reach approximately 10% of the total product ions . this reaction product channel has been seen previously for some unsaturated aldehydes in sift studies and is attributed to the proximity of the ionization energies ( ie ) of the aldehydes with ie of no , which results in charge transfer complexing that prolongs the lifetime of the ( nom ) * intermediate complexes . this interesting phenomenon is especially efficient in the association of no ions with ketones in sift reactors . it can also be reported here that a recent spot investigation of the no / n - undecanal reaction in a ( thermalized ) sift experiment significantly revealed a 40% no / undecanal adduct ion together with a 60% hydride ion channel and no significant fragmentation channels . amongst all the aldehydes included in this study , charge transfer was only observed in the furfural reaction ( 50% of the total product ions ) , this process being marginally exothermic because the ionization energy , ie , of the furfural molecule at 9.22 ev is just lower than the ie of no ( 9.26 ev ) . this charge transfer efficiency will be assisted by the increased no / furfural molecule interaction energy in the sri - tof - ms reactor . the presence of water molecules in the sample / carrier gas has little or no effect on the product ion distributions for all these no / aldehyde reactions except for the n - propanal reaction ( see table 2 ) for which in humid air the only observed product ion is ( mh ) . this is probably due to the fact that the product c2h5 and c2h3 ions of the no / propanal reaction can rapidly react with water molecules in moist air and thus be eliminated from the reactor and not be seen by the downstream mass spectrometer . this will generally be the case for product ions of the type mh , where m has a proton affinity ( pa ) lower than the pa of water molecules ( 691 kj mol ) . this applies to protonated acetylene c2h3 ( pa = 641.4 kj mol ) and protonated ethylene c2h5 ( pa = 680.5 kj mol ) , as appear in reactions ( 1b ) and ( 1c ) . this observation is consistent with an analogous phenomenon in sift - ms reported by francis et al . . significantly , the abundance of the c3h5 product ion for other aldehyde reactions reduced somewhat in the spectra obtained for the humid sample / carrier gas ( see e.g. , this product ion for the 2-methyl propanal and the 3-methyl butanal reactions ) . although , the chemical structures of the particular c3h5 product ions are not established , three c3h4 underlying structural isomers are possible , all three having higher pa than water molecules ( allene : 775 kj mol , propyne : 748 kj mol , and cyclopropene : 818.5 kj mol ) . whilst the differences in these pa and that of water molecules is rather large and so proton transfer will be inhibited , it could be partially promoted by the elevated energies of the ion molecule interactions in the sri - tof - ms flow / drift reactor and because of the very large number density of the h2o molecules in the sample / carrier gas at an absolute humidity of 3.5% . the results of the present study of the reactions of no with some 22 aldehydes , compromising several n - alkanals , several branched chain alkanals , and several alkenals , indicates that most of the reactions result in multiple ion products , but common ( mh ) product ions are seen that result from hydride ion transfer with the fractional abundance of these ions increasing with the alkanal molecular mass . a series of hydrocarbon ions , cnhm , appear at widely differing percentages of the total ion products at m / z values that reflect the complexity ( atomicity ) of the aldehyde molecules . more specifically , alkanals exhibited a higher degree of fragmentation than the alkenals and the branched aldehydes dissociated most commonly at the position 2 . it must be emphasized that these ion product distributions will surely depend on the actual value of e / n used in the sri - tof - ms instrument . whilst increasing the humidity of the sample / carrier gas had little effect on the product ion branching ratios , such serious fragmentation limits the value of sri - tof - ms using no reagent ions for the identification of aldehydes , especially when more than one of these compounds occur together in real samples such as exhaled breath and the headspace of biological fluids . analytical sensitivity is diminished when multiple ion products of the analytical reactions occur unless such is carefully accounted for . it is also imperative that the rate constants for the analytical reactions be determined under the actual conditions of the reactor in order to obtain reliable quantification . this is especially so for these no reactions occurring in the flow / drift tube , because minor association channels are seen which is a clear warning of rate constants that can vary ( usually decrease ) with increasing interaction energy . in this regard , it is worthy of note that the rate constant for the no / acetaldehyde is much less than the collisional rate constant even under the thermal conditions of the sift system and would most probably decrease with increasing e / n in the flow / drift tube of a sri - tof - ms system . OUTPUT:

highlightsreactions of 22 aldehydes with no+ in sri - tof - ms were investigated.hydride ion transfer was the common ionization mechanism generating ( mh)+ ions.small fractions of the adduct ion no+m were also seen for some unsaturated alkenals.almost all reactions resulted in partial molecule fragmentation producing hcs ions .

PubMed_Summ6507

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: considerable research attention over the past several decades has focused on isolating the physical and psychological effects of induced abortion [ 15 ] . the majority of abortions in the united states are performed early in pregnancy and most of the research pertaining to indicators of postabortion health has logically involved the study of women who have undergone 1st trimester abortions . however , it is significant to note that 12%-13% of the annual 1.2 million u.s . abortions are performed after the first trimester [ 68 ] and this translates out to approximately 144,000 per year , with 3.7% or 36,000 taking place at 1620 weeks and 1.3% or 15,600 occurring beyond the 20th week of pregnancy . although empirical data is in short supply , a few large scale research efforts have revealed that 2nd trimester ( 1324 weeks ) and 3rd trimester ( 2536 weeks ) abortions pose more serious risks to women 's physical health compared to 1st trimester abortions [ 9 , 10 ] . the abortion complication rate is 3%6% at 12 - 13 weeks gestation and increases to 50% or higher as abortions are performed in the 2nd trimester . data spanning the years from 1988 to 1997 , bartlett and colleagues reported the following rates of abortion - related mortality : 14.7 per 100,000 at 1315 weeks of gestation , 29.5 per 100,000 at 1620 weeks , and 76.6 per 100,000 at or after 21 weeks . based on the potential for serious consequences associated with late - term abortion , a first step toward reducing the numbers of late - term abortions is to gain a comprehensive understanding of why women decide to terminate as opposed to continue a pregnancy once they have allowed the pregnancy to progress for several months . according to the guttmacher institute , the most frequently endorsed reasons for late - term abortions include the following : ( 1 ) not realizing one is pregnant ( 71% ) , ( 2 ) difficulty making arrangements for an abortion ( 48% ) , ( 3 ) fear of telling parents or a partner ( 33% ) , and ( 4 ) feeling the extended time is needed to make the decision ( 24% ) . in the guttmacher study , only 8% of the women sampled indicated pressure not to have an abortion from someone else was part of the reason for delay and fetal abnormalities were identified as factoring into only 2% of all late - term abortion decisions . for example , decision ambivalence is often characteristic of women who undergo abortions in the 2nd trimester and beyond [ 1214 ] . further , women who obtain 2nd trimester abortions have reported more deficient social supports and more energy expended toward assessing the resources available to help them keep a child compared to women who obtain 1st trimester abortions [ 14 , 15 ] . research suggests that 30% of women who delay an abortion beyond 16 weeks are afraid to tell those closest to them about the pregnancy . when compared to women obtaining earlier abortions , women who obtain late - term abortions are more likely to experience stronger attachment to the fetus , have more moral or religious objections to abortion , and concede to an abortion based on the wishes of others [ 15 , 16 ] . finally , women who seek late - term abortions ( after 16 weeks ) are significantly more likely to be under age 18 , black , unemployed , and/or poor . as indicated above there is not an extensive published literature on the physical effects of late abortions ; however there are even fewer published studies on women 's mental health outcomes after 2nd trimester abortions . nevertheless , it is logical to anticipate more serious mental health problems in response to abortions occurring later in pregnancy compared to earlier terminations for various reasons : ( 1 ) awareness that the fetus has developed more fully prior to the termination , ( 2 ) women have more opportunity to bond with the developing fetus , ( 3 ) there may be more active desire to maintain the pregnancy , and/or ( 4 ) pressure from others to abort may be more pronounced . in fact , most of the established predictors of late - term abortion described above , including decision ambivalence and dissatisfaction , lacking support to carry to term , a strong attachment to the fetus , timing during adolescence , and low income are predictors of poor postabortion psychological adjustment in the general abortion literature [ 1722 ] . in a study of british women who had prostaglandin - induced abortions between 2024 weeks gestation and felt fetal movements , further , sderberg et al . reported that 37.5% of women who underwent 2nd trimester abortions experienced extreme postabortion emotional problems . although these studies indicate that late - term abortions are more likely to initiate psychological problems , they were both very small scale and did not involve direct comparisons to women undergoing 1st trimester abortions with logical controls for variables likely to discriminate between the two populations . empirical evidence of a link between 1st trimester abortion and ptsd symptoms has accumulated in recent years [ 2630 ] . in fact 1220% of women with an abortion history meet the full diagnostic criteria for ptsd with considerably higher percentages of women experiencing some trauma symptoms , while not meeting the full criteria [ 2830 ] . even when the full criteria are not met , the more ptsd symptoms present , the greater the risk of psychological impairment and suicidal ideation . in the current study , comparisons were made between women who had an early elective abortion ( up to 12 weeks gestation ) and women who had undergone a later elective abortion ( 13 weeks gestation or later ) based on individual ptsd symptoms , ptsd symptom subscale scores ( intrusion , avoidance , and hyperarousal ) , total ptsd scores , and the degree to which ptsd symptoms met the full dsm - iv diagnostic criteria . as an anxiety disorder , ptsd is initiated by exposure to a psychosocial stressor which is perceived to be traumatic . this disorder is comprised of three stressor - related criteria not present before the trauma : ( 1 ) intrusion which involves persistent and unwanted reexperiencing of the traumatic event in the form of recurrent and distressing memories , flashbacks , and hyperreactivity to associated stimuli ; ( 2 ) avoidance which pertains to persistent and deliberate efforts to avoid recalling the traumatic event using various forms of denial , dissociation or detachment ; and ( 3 ) hyperarousal which is a general uneasiness or jumpiness that may include insomnia , the tendency to startle easily , feelings of impending danger or disaster , trouble concentrating , extreme irritability , and possibly violent behavior . although no previous studies have been published comparing the mental health of women undergoing early and late term abortions , the evidence reviewed above is sufficient to hypothesize that abortions occurring across the 2nd trimester and into the 3rd trimester would be associated with higher levels of ptsd symptomatology than 1st trimester abortions . since 2nd and 3rd trimester abortion are less common than 1st trimester abortions and women may be more reticent about acknowledging such abortions due to stronger social prohibitions against later terminations , web - based data collection was deemed a useful method in that it affords a high level of anonymity . the obvious drawback to this methodology is the risk for selection bias wherein more women who have struggled with an abortion experience may be more inclined to participate due to the increased salience of the experience and a possible quest for answers . established benefits of internet data collection include time and cost efficiency [ 32 , 33 ] , access to difficult to reach populations [ 34 , 35 ] , and enhancement of participant comfort and engagement [ 36 , 37 ] . a review by skitka and sargis , indicated that as early as the years 2003 to 2004 , 21% of apa journals had published at least one study with online data collection , suggesting this is rapidly becoming an established mode of data collection . the most frequently cited criticism of web - based surveys is that they are comprised of convenience samples , rendering generalization difficult [ 39 , 40 ] . however , even this shortcoming engenders benefits such as clarity and thorough responses that are less inclined to be contaminated by social desirability biases and underreporting [ 4143 ] . several published papers indicate that online data collection is equivalent to more traditional data collection methodologies in terms of reliability , validity , and representativeness [ 4447 ] . the primary goal of the present exploratory study was to compare the mental health status of a sample of women who experienced a 1st trimester abortion ( up to 12 weeks gestation ) to women who had a 2nd or 3rd trimester abortion ( 13 weeks and beyond ) . in the analyses , sociodemographic and personal history factors , particularly those related to significant life stressors such as exposure to abuse , that may systematically vary across the two groups ( early and late ) were controlled in order to more accurately examine the independent effects of abortion timing . a secondary goal was to provide additional descriptive data on women who delay abortion decisions until the 2nd and 3rd trimesters with a focus on variables pertaining to the abortion decision . surveys were posted on an internet website from april , 2005 through august , 2008 . although the time frame was chosen for convenience , the goal was to collect data until a minimum of 50 women who experienced a late - term abortion had responded in order to insure adequate statistical power . all respondents who had experienced an abortion and completed at least 95% of the items on the survey were included . participants were informed that submission of the survey constituted consent to participate and they were told they could withdraw at any point . informational website links offering support or counseling services recruitment occurred through email requests to us - based crisis pregnancy centers and to a few additional organizations that offered postabortion counseling . questions comprising the survey addressed five sociodemographic characteristics ( age , race , education , marital status , and number of children ) , meaningfulness of religious affiliation , abortion history , reasons for abortion , perceived adequacy of preabortion counseling , partner agreement in abortion decision - making , political opinion regarding abortion at time of procedure , relationship status with the partner , mental health history , abuse history , trauma symptoms related to abortion , abortion - related anger , relationship problems , sexual problems , and general stress attributed to abortion . the majority of items measuring demographic characteristics , personal history , and the circumstances surrounding the abortion were dichotomous ( yes / no ) . the precise nature of the items and response options are easily identified by the data in tables 1 and 2 . posttraumatic stress disorder symptoms were assessed with the ptsd checklist - civilian version ( pcl - c ) . for the purposes of the present investigation , a score of 1 was entered for each item endorsed on the scale at the level of moderately , quite a bit , or if the respondents indicated not at all or only a little bit she was not identified as having the corresponding symptom . subscale score ranges were from 0 to 5 for intrusion or reexperience ( 5 items ) , 0 to 7 for avoidance ( 7 items ) , and 0 to 5 for hyperarousal ( 5 items ) . respondents were considered to have met the symptom criteria for a diagnosis of ptsd based on dsm - iv criteria : ( 1 ) one or more endorsements of intrusion , ( 2 ) three or more endorsement(s ) of avoidance symptoms , and ( 3 ) two or more endorsements of hyperarousal symptoms not present prior to the abortion . reliability and validity evidence for the pcl is provided by weathers and colleagues . with the current sample , internal consistency reliability estimates using cronbach 's alpha for the full scale and for the intrusion , avoidance , and hyperarousal subscales were equal to .92 , .82 , .80 , and .82 , respectively . all analyses were conducted using spss software and included both basic descriptive statistics and inferential statistical tests to examine the hypotheses and conduct secondary tests of the data . specific analyses conducted included independent t - tests , analyses of variance ( anova ) , analyses of covariance ( ancova ) , multivariate analyses of variance ( manova ) , multivariate analyses of covariance ( mancova ) , and logistic regression . in the analyses wherein statistical controls were employed , the following variables were entered : race , marital status at the time of the abortion , number of years of formal education , number of abortions , number of years since the target abortion , having received mental health counseling before the abortion , having been hospitalized for emotional problems before the abortion , meaningfulness of the respondent 's religion , and a childhood or adult history of physical or sexual abuse . surveys were completed by 374 women with 81% of the respondents indicating u.s . citizenship . additional respondents identified the following countries of citizenship : england ( 4% ) , canada ( 6.4% ) , and australia ( 2.7% ) , with smaller percentages from france , ireland , norway , romania , czechoslovakia , germany , sweden , new zealand , south africa , kenya , mexico , nicaragua , brazil , nepal , and south korea . the average age of the respondents was 38 years at the time the survey was completed ( sd = 11.1 ) . also , at the time of the survey , 48.0% were married for the first time , 10.5% were married for the second time , 12.1% were divorced and single , 2.2% were separated , and 26.4% had never married . religious affiliations were indicated to be 81.6% christian , 3% jewish , 9.5% other , and 8.6% none at the time of the survey . most of the sample endorsed liberal views of abortion at the time of the procedure , with 24% believing abortion should be legal for any reason throughout pregnancy and an additional 36% contending abortion should be available for any reason during the 1st trimester . only 24% felt it should be legal under various circumstances and 16% believed it should never be legal . approximately 14% ( n = 52 ) reported having undergone an abortion between 13 and 30 weeks gestation ( m = 16.87 weeks ; sd = 4.24 ) and 86% reported abortions up to 12 weeks gestation ( m = 8.23 weeks ; sd = 2.39 ) the women reported an average of 15 years ( sd = 11.8 ) had passed since the abortion and again no significant differences were observed between the early and late groups . table 1 provides the full sample frequencies for respondents ' race , education , marital status , number of children , number of abortions , meaningfulness of religion , mental health counseling prior to the abortion , hospitalizations for emotional reasons before the abortion , and the experience of physical and sexual victimization in childhood and adulthood . use of independent t - tests and logistic regression analyses revealed no significant differences between the early and late abortion groups relative to age , ethnicity , marital status at the time of the abortion , religious orientation , meaningfulness of religion , marital status at the time the survey was completed , education , number of children , number of abortions , mental health counseling prior to the abortion , preabortion hospitalizations for emotional problems , and the experience of sexual abuse in childhood or adolescence . however , the women who obtained late abortions were more likely to report having been the victim of physical abuse in childhood ( t ( 373 ) = 2.37 , p < .001 ) , to have been the victims of physical abuse in adulthood ( t ( 273 ) = 2.05 , p = .044 ) , and to have been the victim of sexual abuse in adulthood ( t ( 373 ) = 2.94 , p = .005 ) . table 2 provides data regarding the percentage of study respondents from the early and late abortion groups who indicated agreement with various parameters surrounding the abortion decision . as indicated by the data presented , logistic regression analyses revealed that women who had experienced a late - term abortion were significantly more inclined to report the following : ( 1 ) the pregnancy was desired by their partner : ( 2 ) someone other than their partner pressured the decision : ( 3 ) the respondent left her partner before the abortion : ( 4 ) the respondent 's partner did not know about the abortion until afterwards : and ( 5 ) physical health concerns factored into the abortion decision . in contrast , women who secured earlier abortions were more likely to report abortion decision agreement with their partner and they were more likely to report that mental health , financial , and educational concerns factored into their decision to abort . in order to test the hypothesis that 2nd and 3rd trimester abortions would be more stressful than 1st trimester abortions , several analyses were conducted that enabled the researchers to determine if women experiencing late - term abortions are generally more at risk for ptsd symptoms . a manova was conducted using timing of the abortion ( early versus late in pregnancy ) as the independent variable and the three subscales of the pcl as the dependent variables . the multivariate effect was significant , f ( 3,322 ) = 2.69 , p = .046 . in addition , the univariate effect for the intrusion subscale was significant , f ( 1,324 ) = 7.49 , p = .007 , with the means for the early and late abortion groups equal to 2.42 ( sd = 1.63 ) and 3.13 ( sd = 1.64 ) , respectively . similarly , the difference between the two abortion timing groups was significant for the hyperarousal subscale , f ( 1,324 ) = 4.76 , p = .030 , with the mean for the early group lower ( m = 2.22 ; sd = 1.78 ) than the mean for the late group ( m = 2.85 ; sd = 1.95 ) . the variables in this first analysis were then entered into a mancova with controls for several demographic and personal experience variables ( race , marital status at the time of the abortion , number of years of formal education , number of abortions , number of years since the target abortion , having received mental health counseling before the abortion , having been hospitalized for emotional problems before the abortion , meaningfulness of the respondent 's religion , and a childhood or adult history of physical or sexual abuse ) . the results revealed only one significant univariate effect , for the intrusion subscale , f ( 1 , 260 ) = 4.91 . the adjusted mean for the early group was equal to 2.51 ( se = .103 ) and the adjusted mean for the late group was equal to 3.15 ( se = .26 ) . an anova was conducted with abortion timing groups again employed as the independent variable and total pcl scores as the dependent variable . the initial unadjusted effect was significant , f ( 1 , 342 ) = 5.89 , p = .016 , with the late group identifying significantly more trauma symptoms ( m = 10.52 ; sd = 5.13 ) than the early group ( m = 8.65 ; sd = 4.81 ) . however , when the covariates listed above were entered into an ancova with these same independent and dependent variables , the result was not significant , f ( 1 , 260 ) = 3.16 , p = .077 . a series of logistic regressions were computed to assess the extent to which a late - term abortion was associated with an increased risk of having met the dsm - iv criteria for the intrusion , avoidance , and hyperarousal subscale scores and for ptsd generally . although the data presented in table 3 indicates a higher percentage of late - term abortion respondents meeting the ptsd criteria for the subscales and for the full scale , the results of the logistic regression analyses were not significant . a second manova and a second mancova were conducted using timing of abortion groups as the independent variable and the 17 items on the ptsd scale as separate dependent variables in an effort to identify specific trauma symptom differences between the two groups . however , several univariate tests were significant in each analysis , and the results are provided in table 4 . after applying the control variables , the late - term group was significantly more likely to report repeated disturbing dreams , reliving the abortion , and trouble falling asleep . without the controls , the same items were significant as were feeling emotionally numb , super alert or watchful , and feeling jumpy or easily startled . exploratory analyses were performed to examine the extent to which ptsd scores varied as a function of the reasons that factored into women 's abortion decisions . in these analyses , the seven reasons for abortion ( mental health , physical health , finances , education , career , family size , and social concerns ) listed in table 2 operated as independent variables . in one test , a mancova , the scores on the three pcl subscale scores served as the dependent variables ; whereas in the second test , an ancova , total pcl scores were employed as the dependent measure . all the control variables used in the previous analyses were included in these analyses as well . due to power concerns , these exploratory analyses could only be conducted with the full sample rather than exclusively focusing on the late - term group . the results of the exploratory mancova indicated that only the multivariate effect for social reasons was significant , f ( 3,176 ) = 4.14 , p = .007 , with the univariate tests for the intrusion f ( 1,178 ) = 12.86 , p = .007 , avoidance f ( 1,178 ) = 7.70 , p = .006 , and hyperarousal subscales f ( 1,178 ) = 4.40 , p = .007 also significant . in each case , higher means were observed for women who identified social reasons compared to those who did not cite social reasons as relevant to their decisions to abort . specifically the means on the intrusion , avoidance , and hyperarousal subscales were equal to 1.74 ( se = .26 ) , 3.16 ( se = .34 ) , and 1.74 ( se = .29 ) , respectively , for the group who did not report social reasons as relevant to their decision to abort . in contrast , the means on the intrusion , avoidance , and hyperarousal subscales were equal to 2.99 ( se = .21 ) , 4.41 ( se = .27 ) , and 2.53 ( se = .23 ) , respectively , for the group who did report social reasons as relevant to their decisions . in the ancova with total pcl scores examined , again only the univariate effect for social reasons was significant , f ( 1,178 ) = 9.04 p = .003 . the mean pcl total score for the group that did not indicate social reasons were part of their decision to abort was 6.63 ( se = .74 ) ; whereas the mean for the group that noted said social reasons were relevant to their decision was considerably higher , 9.93 ( se = .59 ) . finally , a logistic regression with the same statistical controls employed indicated that women who noted social reasons were relevant to their decision to abort were 186% more likely to experience ptsd symptoms consistent with meeting the dsm - iv diagnostic criteria , or = 2.86 ( ci = 1.57 5.23 ; p = .001 ) . the purpose of this study was to test the hypothesis that women who undergo 2nd and 3rd trimester abortions would be more traumatized than their peers who experience 1st trimester abortions as evidenced by significantly higher rates of ptsd symptoms . after instituting statistical controls for race , marital status , formal education , number of abortions , number of years since the abortion , mental health counseling and hospitalizations for emotional problems before the abortion , meaningfulness of the respondent 's religion , and a childhood or adult history of physical or sexual abuse , all the group differences were in the hypothesized direction but only a few were statistically significant . specifically , the difference in intrusion subscale scores was statistically significant and when individual ptsd items were examined , the late - term group was found to report more disturbing dreams , more frequent reliving of the abortion , and more trouble falling asleep . the first two of these items are intrusion subscale symptoms and the last is a symptom from the hyperarousal subscale . differences between the groups were few due to a large percentage of women from both the early and late abortion groups reporting symptoms of ptsd . in fact , 52.5% and 67.4% in the early and late abortion groups , respectively , met the dsm - iv symptom criteria , a considerably higher percentage than in earlier published reports [ 2830 ] . first , for this particular sample of women , a great deal of time had elapsed since the abortion ( an average of 15 years ) and the symptoms could conceivably have developed later in this extended time frame . for example , developmental changes including both normative and nonnormative life events could have been quite stressful and added to the salience of the abortion ( e.g. , difficulties conceiving a wanted pregnancy , a miscarriage , or relationship problems , etc . ) . second , the fact that the current sample was characterized by high rates of exposure to potentially traumatizing physical and sexual abuse in childhood and adulthood may have yielded a sample with increased susceptibility to experiencing the abortion as a trauma . third , because the data were collected anonymously and voluntarily , women who had been more negatively affected may have been more interested in the study and were therefore more willing to participate than women who were less adversely impacted . fourth , in this study the participants were asked if they had experienced the symptoms on the pcl at any point after the abortion and as a result of the abortion , but they were not asked to indicate the symptom duration . therefore , the high numbers meeting the symptom criteria for ptsd evidenced in this investigation should be viewed cautiously and future studies should incorporate more comprehensive assessments of ptsd symptoms , ideally using clinician administered diagnostic tools . finally , more than a quarter of the current sample had experienced more than one abortion and the effects may have been cumulative . there is evidence that repeated abortion increases the risk for mental health problems [ 49 , 50 ] . specifically , freeman reported that repeated abortion patients exhibited significantly higher distress scores on measures of interpersonal sensitivity , paranoid ideation , phobic anxiety , and sleep disturbance when compared to women who had only one abortion . in that study , somatization , hostility , and psychoticism were likewise elevated in the group of women who had more than one abortion . similarly , niemela and colleagues found that finnish women seeking a second abortion rated lower on impulsivity , emotional balance , realism , self - esteem , life stability , and in the capacity for positive personal relationships compared to women with only one abortion . a secondary objective of this study was to identify possible differences in the context of abortion decision - making associated with an early versus late abortion . when compared to a 1st trimester abortion the following differences pertaining to the context of the abortion decision were observed in those who had 2nd or 3rd trimester abortions : ( 1 ) the abortion was more likely to have been desired by the partner , ( 2 ) the abortion was less likely to have been desired by both parties , ( 3 ) there was more pressure from someone other than the partner to abort , ( 4 ) male partners were less likely to have been informed of the abortion until afterwards , and ( 5 ) women were more inclined to have left the partner before undergoing the procedure . in general , these results are indicative of more ambivalence and conflict surrounding the decision and the likelihood of less stable partner relationships among women who obtain later abortions . logically , women who are unsure about how to proceed with an unplanned pregnancy are more likely to put off the decision to abort , perhaps hoping that their circumstances will improve and enable them to carry to term . other significant differences between the early and late - term groups related to reasons for the abortion . in particular , mental health , financial , and educational concerns figured into decisions to abort more often with 1st trimester abortions compared to later abortions . the only reason that was more frequently reported by the women undergoing later abortions compared to the women who had early abortions was a general category of physical health concerns with nearly 30% of the late abortion group voicing these concerns compared to approximately 15% of the early group . unfortunately no data were gathered pertaining to the specific nature of the concerns and future research should examine the extent to which these factors were based on preexisting conditions or concerns introduced by the pregnancy . interestingly , social concerns such as embarrassment were the most frequently reported concern , with endorsement by 62% of the late term group and 69.1% of the early group . this may have been an additional reason why so many women in the sample experienced stress afterwards as they likely chose the abortion to preserve their reputations despite ambivalence or actually desiring to continue the pregnancy . some of the women may have also come to feel the abortion was not sufficiently justified . the least commonly identified reason for the choice to abort was family size with approximately 13% of the women in each group indicating this concern entered into their decision . the results of the exploratory analyses employing the full sample of women , both those who had early and late abortions , indicated that social reasons for an abortion were strongly related to pcl total scores and to intrusion , avoidance , and hyperarousal subscale scores . with a large percentage of the participants reporting that social reasons entered into their decisions , this could be an additional explanation for why the ptsd rates were so high in the sample . these data suggest that women who postpone their abortion into the 2nd or 3rd trimester experience elevated risk for certain forms of unwelcome re - experience of the abortion procedure , likely requiring active professional intervention . relief from intrusive memories whether in the form of flashbacks or disturbing dreams may only occur if the individual learns to effectively integrate memories of the traumatic experience with other aspects of her past as well as with contemporary experiences and emotions . this is a process that ordinarily involves not only uncovering painful memories , but also transforming them in a personally meaningful way in order to bring relief . verbalizing traumatic experiences and sharing with others is an essential component of this complex healing process and sadly due to the guilt and related shame which frequently occur in conjunction with an abortion experience , many women may never confide in others and are unable to effectively integrate traumatic memories . over time , the triggers that initiate the intrusion may become more generalized and debilitating as well . for example , a woman may initially experience intrusive symptoms whenever she sees a nurse if most of her interaction was with a nurse during the abortion and then with time , contact with any health care professional in a uniform may initiate an episode of reliving the abortion . social reasons for both early and late abortions were related to numerous ptsd symptoms ; therefore , professionals should examine the extent to which women are selecting abortions for social reasons , such as to protect their reputation or to avoid embarrassment . in such cases the abortion may , over time , feel unwarranted or frivolous to the woman and incite deep feelings of guilt or remorse that can trigger trauma symptoms . in addition , under such circumstances there is the possibility that the woman desired the pregnancy but decided not to go through with it for social reasons . the research cited previously has shown that pregnancy wantedness is a predictor of postabortion distress . based on employment of a convenience sample , the relatively small number of respondents with late - term abortion experience , and reliance on self - report , this study is most appropriately viewed as a pilot for future analyses of the psychological impact of later - term pregnancy termination procedures . nevertheless , securing a sample of any size is not an easy prospect when the focus is on late - term abortion and there are very few published reports on this seriously understudied and potentially quite fragile population . based on societal interest in the morality and legality of late - term abortion , data related to the psychological sequelae of late - term abortion is needed in order to protect women 's mental health . ( 1 ) do women who have later abortions tend to experience intrusive trauma - related symptoms for a longer duration than women who have earlier abortions due to the nature of late - term abortion procedures ? ( 2 ) are women with abuse histories who may be primed for trauma more prone to experiencing serious trauma symptoms after an abortion and are they less likely to seek needed help and achieve inner peace due to compromised self - esteem , self - blame , or shame ? ( 3 ) are there other mental health problems , such as depression , anxiety , and substance abuse that tend to occur more frequently after later abortion compared to early abortion ? ( 4 ) assuming differences are detected and late - term abortions are identified to be more emotionally taxing on women , who are most at risk for mental health problems and what specific characteristics of 2nd and 3rd trimester abortions make them more traumagenic ? as long as 2nd and 3rd trimester abortions are medical services that are freely available to women residing in the u.s , we have an ethical obligation to more fully understand the mental health risks involved and to convey this information in a sensitive manner to women as they struggle with difficult abortion decisions . OUTPUT:

the primary aim of this study was to compare the experience of an early abortion ( 1st trimester ) to a late abortion ( 2nd and 3rd trimester ) relative to posttraumatic stress disorder ( ptsd ) symptoms after controlling for socio - demographic and personal history variables . online surveys were completed by 374 women who experienced either a 1st trimester abortion ( up to 12 weeks gestation ) or a 2nd or 3rd trimester abortion ( 13 weeks gestation or beyond ) . most respondents ( 81% ) were u.s . citizens . later abortions were associated with higher intrusion subscale scores and with a greater likelihood of reporting disturbing dreams , reliving of the abortion , and trouble falling asleep . reporting the pregnancy was desired by one 's partner , experiencing pressure to abort , having left the partner prior to the abortion , not disclosing the abortion to the partner , and physical health concerns were more common among women who received later abortions . social reasons for the abortion were linked with significantly higher ptsd total and subscale scores for the full sample . women who postpone their abortions may need more active professional intervention before securing an abortion based on the increased risks identified herein . more research with diverse samples employing additional measures of mental illness is needed .

PubMed_Summ6508

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: denosumab ( dmab ) is a fully human monoclonal antibody against the receptor activator of nuclear factor-b ligand ( rankl ) , a molecule that is crucial for the formation , function , and survival of osteoclasts.1 dmab binds rankl with high affinity and specificity , and inhibits the rankl / rank interaction , thus reversibly reducing osteoclast - mediated bone resorption . in phase 1 and phase 2 studies , dmab was demonstrated to decrease bone turnover and to increase bone mineral density ( bmd),25 and in the freedom trial ( fracture reduction evaluation of denosumab in osteoporosis every six months , nct00089791 ) , a randomized placebo - controlled phase 3 study , the subcutaneous administration of dmab 60 mg every 6 months for 36 months significantly reduced the risk of vertebral and nonvertebral fractures , and reduced the risk of hip fracture in postmenopausal women with osteoporosis.6 moreover , in the open - label extension of this study , dmab therapy beyond the third year of treatment was associated with a further reduction in nonvertebral fracture rate , and was associated with a continued low vertebral fracture rate that persisted through 8 years of continuous administration , with an overall safety profile that remained consistent over time.7 on the basis of available evidence , in 2010 , dmab was approved for the treatment of postmenopausal osteoporosis , thus becoming a further therapeutic option for the reduction of fracture risk in addition to the other available antiresorptive therapies ( ie , bisphosphonates and selective estrogen receptor modulators ) and the anabolic teriparatide.8 the available studies comparing the effect on bmd and bone turnover of dmab and bisphosphonates , which are the most frequently used agents for the management of osteoporosis , showed significantly greater gains in bmd at all measured skeletal sites913 and greater reduction in bone turnover912 with dmab compared to bisphosphonates with a similar safety profile . however , both bisphosphonates and dmab , in association with calcium and vitamin d , appear to be about equally effective in clinical trials in reducing the risk of fragility fractures,14 which represent a considerable problem of public health , considering the increasing fracture - related morbidity , mortality , and medical costs in many regions of the world.15 it must be considered , however , that any therapy , even if proved to be effective in clinical trials , requires adherence to achieve successful treatment outcomes . persistence is the duration of time from initiation to discontinuation of therapy , while compliance is the degree to which a patient takes the medication as prescribed.16 accordingly , nonpersistence and noncompliance are usually defined as a gap in therapy greater than 90 days and a medication taken less than 80% of possible treatment days , respectively.16 adherence to osteoporosis treatments is particularly challenging for health care professionals treating osteoporosis . indeed , persistence and compliance with osteoporosis therapies are generally poor , thus leading to a significant reduction in their antifracture efficacy,17 which in turn leads to increased human and economic costs.18 in order to understand the extent of the problem , it is worth explaining that previous studies showed that one - third to one - half of treated patients are not adherent to oral bisphosphonate treatment,19 and that the majority of patients discontinue oral bisphosphonate treatment within 1 year,17,19 with a mean persistence of only 184 days.17 in comparison with oral dosing regimens , persistence seems to be greater with an intravenous bisphosphonate administered less frequently , like the annual infusion of zoledronic acid , but it is anyway suboptimal . indeed , a variable proportion of patients from one - third to two - thirds across studies did not receive a second administration of the drug , often because of adverse effects ( postinfusion syndrome).2022 these findings are due to the fact that treatment adherence among patients with chronic diseases like osteoporosis depends on various factors , among which difficult dosing regimens , high dosing frequency , and the occurrence of side effects play a significant role in reducing compliance and persistence . moreover , patient perception about the necessity of the prescribed medication to treat osteoporosis and their concerns about potential adverse effects are important and potentially modifiable determinants of adherence , especially if clarified and addressed at the beginning of the treatment . finally , understanding patient preference may be a strategy to improve adherence to osteoporosis therapy , since a lower treatment satisfaction is associated with an increased risk of discontinuing or switching the ongoing osteoporosis medication , as compared with a higher treatment satisfaction.23 in this review , we will focus on the results of studies that investigated patient preference and adherence to dmab for the treatment of postmenopausal osteoporosis in comparison with alternative osteoporosis therapies , especially bisphosphonates , in order to establish who can take more advantage of dmab therapy , to understand the possible factors that influence medication - taking behavior , and to discover potential strategies for improving adherence . patient preference to and satisfaction with a specific drug are important determinants of adherence to therapies for chronic diseases , including osteoporosis.23,24 preference is a relative index of desirability , and it can be measured as a choice between alternatives or scaled as a degree of desirability,25 while treatment satisfaction measures the degree to which patient expectations with different features of the ongoing treatment ( eg , perceived efficacy , presence and severity of side effects , convenience , and bother with treatment ) are met.25 available studies typically compared patient preference to and satisfaction with dmab versus bisphosphonates , especially alendronate , which is usually the first - line medication for the treatment of postmenopausal osteoporosis.2628 since existing questionnaires assessing preference to and satisfaction with osteoporosis treatments were considered inadequate for the comparison between a weekly oral tablet and a 6-monthly subcutaneous injection , a new tool , the preference and satisfaction questionnaire ( psq ) , was developed to compare dmab and alendronate.25 the psq consists of 34 items that explore preference ( the treatment choice made by a patient ) , satisfaction ( the degree to which the features of a specific drug actually meet the patient expectations ) , and finally , bother ( the degree to which the patient is disturbed by certain features of the treatment).25 in the determining efficacy : comparison of initiating denosumab versus alendronate ( decide ) trial and the study of transitioning from alendronate to denosumab ( stand ) , two international , double - blind , double - dummy , randomized , phase 3 head - to - head trials comparing dmab with alendronate,9,10 psq was completed after 12 months of treatment or upon study discontinuation.26 among the subjects who expressed a preference , significantly more patients , who were blinded to their treatment assignment , preferred the injection over the tablet , and were more satisfied overall and with the dosing frequency of a 6-monthly injection over a weekly tablet after 12 months of treatment . moreover , more patients indicated that they would choose the 6-monthly injection , which was better fitted to their lifestyles , for long - term use or continuation of treatment . finally , among patients who expressed bother with treatments , more patients found that the weekly tablet was more bothersome than the 6-monthly injection.26 a subsequent multicenter , randomized , open - label , 2-year crossover trial , the denosumab adherence preference satisfaction ( daps ) study,28 enrolled drug - nave postmenopausal women with low bmd , who were randomized in one of two treatment sequences : dmab subcutaneously every 6 months for 1 year followed by alendronate orally once weekly for 1 year , or vice versa . at each follow - up visit , subjects completed questions about preference , satisfaction , and bother , which were taken from the psq . at baseline and at 6 months , subjects reported lower mean scores concerning preference for alendronate than for dmab , at 12 months significantly more subjects treated with dmab than with alendronate reported to be either satisfied or quite satisfied with the dosing frequency , route of administration , convenience , and expressed overall satisfaction with the ongoing dmab treatment.27 the final results from both years of the daps study further confirmed the data obtained before the crossover : at the end of the study , 92.4% of subjects preferred subcutaneous dmab injections over alendronate tablets , and 91.2% of subjects said that they would choose dmab injections for long - term treatment . in addition , at 24 months , regardless of the treatment sequence , a greater proportion of subjects reported that they were quite / very satisfied with the attributes of dmab compared with those of alendronate.28 a recent study evaluated the change in treatment satisfaction in women with postmenopausal osteoporosis who were suboptimally adherent with prior daily or weekly bisphosphonate therapy and who were shifted to subcutaneous 6-monthly dmab or monthly oral bisphosphonate ( ibandronate or risedronate).29 in such study , a post hoc analysis of the results of two international , multicenter , randomized , open - label studies that had bmd and bone turnover variations as primary endpoints,12,13 was performed . the change in treatment satisfaction was assessed using the treatment satisfaction questionnaire for medication ( tsqm ) , a tool validated for the measure of patient satisfaction with treatments of different chronic diseases and which consists of 14 items to assess an individual s perception of four domains of treatment satisfaction : 1 ) effectiveness , 2 ) side effects , 3 ) convenience , and 4 ) global satisfaction.30 the results of the study showed that osteoporotic postmenopausal women sub - optimally adherent with oral daily or weekly bisphosphonate therapy , who switched to dmab or monthly bisphosphonate treatment , reported greater satisfaction in all four domains of tsqm in both treatment groups at 6 and 12 months , but that these positive changes were significantly greater in patients in the dmab group compared to those in patients in the monthly bisphosphonate group at all post - baseline time points.29 whereas patient preference to 6-monthly dmab injections versus oral weekly or monthly bisphosphonates was not surprising in relation to the more acceptable route of administration and the less frequent dosing regimen of the 6-monthly treatment option , patient preference between dmab and another long - acting injectable therapy , such as zoledronic acid , could be less obvious . however , while several studies clearly demonstrated that patients preferred once yearly intravenous infusion of zoledronic acid rather than oral weekly bisphosphonates,3133 a direct comparison in terms of patient satisfaction between dmab and zoledronic acid for the treatment of postmenopausal osteoporosis is lacking . a recent retrospective study on a limited cohort of patients reported a statistically similar patient satisfaction between a group of patients treated with dmab and another one treated with zoledronic acid,34 but the small sample size and the design of the study ( ie , each patient experienced only one of the two treatments without any experience of the other treatment ) other parameters closely related to treatment satisfaction and preference , which could influence patient medication - taking behavior , are patient perceptions about a therapy in terms of the perceived necessity of the prescribed medication to treat a specific condition and concerns about potential adverse effects . a validated tool to assess these beliefs and concerns can be found in the beliefs about medicines questionnaire ( bmq ) , which consists of 22 questions in the following major domains : 1 ) the necessity of the prescribed medication to treat osteoporosis in that moment or in the future ; 2 ) concerns about potential side effects of taking the prescribed medication ; and 3 ) preference for one drug over the other.35 at baseline in the daps study,27,28 when women were nave to therapy , necessity and concerns scores were similar between groups . subsequently , subject beliefs about the necessity for the prescribed treatment were significantly higher for dmab than for alendronate at 6 months , but not at the following visits . subject concerns about potential side effects were significantly lower for dmab than for alendronate at the follow - up visits after the cross - over , when patients had experienced both forms of treatment administration , but not at previous time points.27,28 these variations in subject perceptions about treatment resulted in a significantly higher necessity concerns differential ( ncd ) ( ie , how much treatment necessity outweighs treatment concerns ) for dmab compared with alendronate at 6 months for both treatment years.36 finally , the bmq survey in the daps study provided significantly lower mean preference scores for alendronate than for dmab at every visit , consistent with the preference scores of the psq.27,28 many of the studies , which investigated preference for and satisfaction with dmab , also evaluated adherence to the treatment , overall or in comparison with oral bisphosphonates , especially alendronate . unfortunately , studies specifically designed to compare adherence to dmab versus zoledronic acid are still lacking . in the decide and the stand studies , where participants were strictly followed up every 3 months , compliance at 12 months ( both injections received and 80% of the oral tablets ) was 93% and 94% , respectively , with dmab and 91% and 94% , respectively , with alendronate.9,10 in the daps study , adherence , ie , both compliance ( both dmab injections 6 months 4 weeks apart or 80% of alendronate tablets taken ) and persistence ( both dmab injections or greater than two alendronate doses in the last month and completion of the treatment period ) , was assessed separately for each treatment year.27,28 by the end of the first 12 months , 88.1% of postmenopausal women were adherent to dmab and 76.6% of patients were adherent to alendronate , while after the crossover , the adherence rate was 92.5% for dmab and 63.5% for alendronate . a 46% and 80% relative risk reduction of nonadherence was calculated with dmab compared to alendronate in the first and in the second year , respectively.27,28 the increase of nonadherence for alendronate - treated subjects after the crossover from dmab , and conversely , the further decrease of nonadherence for dmab - treated subjects after the crossover from alendronate , suggest a possible treatment sequence effect : a weekly dosing frequency may be more difficult to follow after a biannual dosing frequency than the opposite treatment sequence . daps investigators also examined whether the subjects perception of their osteoporosis treatment and the treatment preferences influenced adherence.36 they found that at the beginning of the second year of treatment participant perception , as measured by bmq scores , was a significant predictor of nonadherence . indeed , as necessity scores increased , the odds of nonadherence decreased , and conversely , as concerns scores increased , the odds of nonadherence increased . indeed , higher ncd scores were significantly associated with lower odds of nonadherence , thus suggesting that positive perceptions of treatment positively influence medication - taking behavior.36 by extension , it seems feasible that understanding the factors that influence patient perceptions of osteoporosis treatments may result in an improved educational effort to increase adherence . in relation to this hypothesis , a successive study , although with several limitations , showed that in osteoporotic patients starting with a first dmab injection , a positive feedback given to the patient already 6 months thereafter , based on the demonstration through a careful medical explanation of a rapid and highly significant bmd increase and on a good safety profile , was able to guarantee in 99% of patients the willingness to accept a second injection , thus reinforcing the role of patient perceptions and of their assessment during doctor patient interactions on adherence to treatment.37 several studies on medication - taking behavior of patients receiving dmab are now ongoing , and data available so far confirm a high adherence to this 6-monthly subcutaneous treatment.38,39 the 12-month interim results of a european noninterventional study involving germany , austria , greece , and belgium showed that 82.7%89.3% of patients received a second dmab injection within 6 months 4 weeks , and therefore , these patients were considered adherent to treatment,38 a proportion of patients significantly greater than that observed in similar studies on bisphosphonates.17,19 in all four countries , these percentages increased as the permissible time window was extended , and up to 95.3% of patients received a second administration within 6 months 8 weeks.38 at baseline , all participants completed the morisky 8-item medication adherence scale ( mmas-8 ) questionnaire , a tool used to measure the probability of adherence.40 however , although the majority of patients had a low or medium score for adherence to prior treatments , their adherence to dmab was high anyway , suggesting that some features of dmab , such as the dosing schedule , may have positively influenced adherence behavior . no baseline variables were found to be significantly associated with persistence in the four countries , probably because of the high percentages observed and because of the different health care systems in the individual countries ; nevertheless , in some countries , several significant associations were identified . indeed , parental history of hip fracture was associated with higher persistence , while increased age , decreased mobility , and increased distance to the clinic were correlated with lower persistence.38 finally , interim results of a 24-month multicenter , prospective , single - arm observational study in the us and canada showed that at 12 months , 81.9% of patients were persistent with dmab ( ie , they received a second dmab injection within 6 months 8 weeks).39 as already described in another study,38 this percentage changed as the window was modified ( from 74.8% of patients with a 4-week window to 84.8% of patients with a 12-week window ) . in this population , several baseline variables were found to be significantly associated with persistence among us patients and others among canadian patients.39 in particular , it is worth signaling that us patients with greater ncd obtained by means of bmq had a higher odds ratio for persistence,32 further confirming the role of patient perceptions of a specific medication in influencing medication - taking behavior , as already described in previous studies.23,36,37 firstly , participants enrolled in a clinical trial may differ from patients seen in real - life clinical practices . this difference may be observable to a greater extent in randomized clinical trials , where patients are regularly followed up by a skilled health care professional according to a precise study protocol . however , the participation in any prospective study , even observational , may influence patients behavior , potentially leading to an overestimation of adherence to and preference for a specific treatment . this observation is supported by the finding that the rates of bisphosphonate adherence observed in the studies cited so far are meaningfully higher than rates observed in previous retrospective observational reports ( less than half in the first year).17,19 the main reasons that may explain this phenomenon are the willingness of subjects to participate in a study and thus to accept the treatment offered , and the awareness of patients that their medication - taking behavior is being monitored . these two factors , differently from real - world behaviors , eliminate primary nonadherence patient behaviors in trials ( ie , the refusal of a medication at first prescription ) . moreover , in the clinical trials , participants are selected according to given inclusion criteria , and this aspect may limit the generalizability of results . secondly , in many of the cited studies,2629,3639 a conflict of interest can not be excluded , and the provision of a drug to study participants by the study sponsor may have concealed the possible influences of treatment cost and accessibility on patient preference and adherence . nevertheless , although several studies suggested that dmab is cost - effective as compared to bisphosphonates,4145 it must be considered that the effect of these aspects may be very difficult to assess since health care and reimbursement systems vary extensively between countries , and thus studies performed in different regions of the world become scarcely comparable . thirdly , the use of 1- or 2-year treatment periods in the cited trials27,28,38,39 may limit conclusions about long - term adherence to treatment , although a previous meta - analysis on bisphosphonate treatment suggests that nonadherence usually occurs shortly after treatment initiation.19 in spite of these limitations , available data suggest that , in comparison with bisphosphonates , postmenopausal women report greater preference to and satisfaction with dmab , both overall and with its dosing frequency and route of administration , and they would choose dmab over bisphosphonates for long - term osteoporosis treatment.2629 moreover , patient beliefs about the necessity of osteoporosis treatment and patient concerns about potential adverse events appear higher and lower , respectively , with dmab than with bisphosphonates . this situation results in greater ncd scores , indicating that in patient perceptions , treatment necessity clearly outweighs concerns about dmab.27,28,36 furthermore , clinical trials showed that adherence among women treated with dmab was consistently > 80% across studies;9,10,13,27,28,3739 therefore , significantly higher adherence was shown in women treated with dmab than in women treated with bisphosphonates , even when bisphosphonates were administered once monthly or intravenously.17,1922 this different medication - taking behavior appears to be even more pronounced in patients previously treated , often sub - optimally , with bisphosphonates.12,13,28,38 although in clinical trials an overestimation of adherence is conceivable , it must be considered that the adherence to dmab requires only a 6-monthly visit , while the adherence to oral bisphosphonates requires the patient self - administration of tablets according to a correct dosing schedule and in the correct way . therefore , it is possible that in clinical practice , the differences between dmab and oral bisphosphonates in term of compliance and persistence may be even higher , although additional real - life studies are needed to confirm this assumption . moreover , patient perception about treatment seems to influence medication - taking behavior,36,39 and during treatment follow - up , positive reinforcement based on the evidence of actual successful treatment outcomes , such as the bmd increase913 or bone turnover suppression,912 could help to further improve patient adherence.37 indeed , due to the asymptomatic nature of osteoporosis , until a fracture occurs or even later , the patient could easily underestimate the importance of osteoporosis medication , resulting in poor adherence and therefore an increased risk of fracture . in conclusion , current evidence underlines the necessity to personalize osteoporosis treatment , taking patient preference into account , especially in regards to frequency and route of administration . current evidence also draws attention to patient beliefs at the initiation of therapy and during follow - up . these efforts are addressed to improve adherence to osteoporosis treatment and , as a consequence , to achieve more successful treatment outcomes , thus positively impacting on the cost - effectiveness of the chosen drug.45 from this perspective , according to the data demonstrating a better adherence to dmab compared to other osteoporosis treatments , especially bisphosphonates , dmab may represent a reasonable and effective alternative to bisphosphonates , particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected . further studies are required in the future to assess long - term adherence and preference to dmab in real - world clinical practices , to evaluate its long - term safety , and to assess its effectiveness as compared head - to - head with bisphosphonates . OUTPUT:

patient adherence to many osteoporosis treatments , primarily bisphosphonates , is generally poor , thus leading to a significant reduction in antifracture efficacy . patient perceptions about the necessity of the prescribed medication to treat osteoporosis and the concerns about the potential adverse effects are important and potentially modifiable determinants of adherence , in addition to other factors , such as difficult dosing regimens and high dosing frequency . denosumab ( dmab ) is a fully human monoclonal antibody against the receptor activator of nuclear factor-b ligand ( rankl ) , which , through the prevention of the rankl / rank interaction , inhibits osteoclast - mediated bone resorption and significantly reduces the risk of vertebral , nonvertebral , and hip fractures . it is administered subcutaneously every 6 months for the treatment of postmenopausal osteoporosis . preference and adherence to dmab treatment were assessed in various clinical trials . although with some limitations , available data suggest that dmab is preferred to bisphosphonates , produces greater satisfaction than bisphosphonates , and would be preferentially chosen for long - term treatment . moreover , patient perceptions about the necessity of dmab treatment clearly outweigh the concerns about the injections , and positive beliefs about treatment positively influence medication - taking behavior . according to these data , dmab may represent a reasonable alternative to bisphosphonates , particularly for osteoporotic women in whom a suboptimal or even poor adherence to oral treatments is expected .

PubMed_Summ6509

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the motor system is a dynamic network of cortical and subcortical areas interacting through excitatory and inhibitory circuits , modulated by somatosensory input . modifications of cortical excitability enable recovery and reorganization of the remaining motor areas both in animal models [ 4 , 5 ] and in humans [ 1 , 6 ] . transcranial magnetic stimulation ( tms ) and magnetoencephalography ( meg ) have both been applied in stroke patients to reveal cortical excitability changes . motor threshold ( mt ) , that is , the minimal tms intensity eliciting motor evoked potentials ( meps ) , is related to membrane excitability as it is influenced by drugs affecting neuronal ion channels . paired pulse tms ( pp - tms ) reveals short - interval intracortical inhibition ( sici ) , related to the activation of gaba - a receptors and intracortical facilitation ( icf ) attributed mainly to glutamatergic nmda receptor activation ( for references , see ) . in acute stroke , the mt is increased in the lesioned hemisphere ( lh ) whereas in the nonlesioned ( nh ) hemisphere it is normal or decreased one month after stroke . sici is decreased in both hemispheres early after stroke ; icf is stronger in nh in severe than mild strokes [ 1 , 6 ] . finger movements and median nerve or finger stimulation modify spontaneous meg oscillations over the sensorimotor cortex in the beta band ( 1525 hz ) . they are suppressed at 100300 ms after tactile stimulation ( event - related desynchronization ; erd ) , reflecting increased excitability , and increased at 5001000 ms ( event - related synchronization ; ers ) , reflecting removal of excitation [ 12 , 13 ] or reduced excitability . inhibitory gaba - a agonist diazepam increases meg beta activity [ 15 , 16 ] . combined meg and magnetic resonance spectroscopy showed a linear relationship between the beta ers strength and gaba concentration . beta ers has been shown to be significantly weaker in the lh than nh ; stronger ers amplitude was correlated with a better affected hand function up to 3 months after stroke . reduction of beta ers , however , correlated with clinical improvement after physiotherapy of patients with chronic stroke . movement - related beta erd was significantly reduced in lh of stroke patients . the hand representation in the somatosensory cortex ( s1 ) , estimated by somatosensory evoked fields ( sefs ) , is the largest one month after stroke and its increase was correlated with the affected hand function . in tms mapping , hand motor representation expands in the lh up to 1 month . in animal models , somatosensory reorganization is activated immediately after the lesion by diminished gaba - a - related inhibition and by glutamatergic activation after one month . we hypothesized to see correlations between erd and mt related to the early cortical excitability and between ers and sici , both attributed to gaba - a - related processes . moreover , we expected that icf , reflecting glutamatergic activity , would correlate with the somatosensory modifications in meg , as glutamate is associated with late somatosensory plasticity . meg and ntms were recorded from thirteen patients ( age 67.3 11 years , 8 women ) , with first - ever ischemic stroke in the middle cerebral artery territory one ( t1 ) and three months after stroke ( t2 ) . six patients had a subcortical and seven patients had a subcorticocortical or cortical stroke ( table 1 ) . at t1 , one patient used amitriptyline 10 mg / day and another used citalopram 10 mg / day . one patient used zopiclone 7.5 mg for occasional sleeplessness . at t2 , citalopram 10 mg / day was used by one patient . data from these patients has been presented previously [ 18 , 21 , 23 , 24 ] . as the patients having both tms and meg recordings are a subset of the previous patient groups , we recalculated the group - level electrophysiological parameters to show that the present patient group is sufficiently similar to those reported previously ( see supplementary tables 1 and 2 in supplementary material available online at http://dx.doi.org/10.1155/2015/309546 ) . an eximia navigated magnetic stimulator with a coplanar figure - of - eight coil of 70 mm wing radius ( nexstim ltd . , helsinki , finland ) was used for ntms . patients ' mris , required for navigation , were scanned at t1 and used also at t2 . the site was then stimulated by single tms pulses at 110% of mt and by the pp - tms at 90% for conditioning and 110% of mt for test pulses . fifteen single pulses or pairs of conditioning and test pulses were delivered in each stimulation session . the interval between stimuli was 3.3 s and the intersession interval varied between 1 and 3 min . the isi selected for the paired - pulse stimuli was 2 ms for sici and 12 ms for icf . the peak - to - peak amplitudes of meps elicited by pp - tms were normalized by dividing them by the corresponding single - pulse mep amplitude to simplify subject - to - subject comparisons . meg during rest and tactile stimulation of the thumb ( d1 ) , index ( d2 ) , and little finger ( d5 ) were recorded with a 306-sensor neuromagnetometer ( elekta neuromag , helsinki , finland ) in biomag laboratory , right before the ntms measurement . time - frequency representations ( tfr ) in the 1030 hz band were calculated to define the frequency range of beta modulation , which was quantified by the temporal spectral evolution method ( tse ) from signals of 2 to 4 meg sensors showing the strongest reactivity . only the contralateral beta modifications ( the affected hand stimulation for the lh and the unaffected hand for nh ) were analyzed . onset and offset of the erd and ers were defined as a time point when the signal differed 2 sds from the baseline . the absolute erd and ers strengths were calculated from the peak amplitudes and converted into relative values in relation to the 300 ms prestimulus baseline . for sefs , about 120 responses were averaged for stimulation of d2 ( isi 3005 ms ) , and d1 and d5 ( isi 1005 ms ) in separate sessions . the size of the hand representation in the si was determined by calculating the euclidean distance in xyz - space between the equivalent current dipoles ( ecds ) of the earliest responses to d1 and d5 stimulation . multiple comparison correction was carried out according to the number of tests ( n = 32 ) suggested by the four prior hypotheses ( t1 and t2 were tested separately ; lh and nh variations lead to four tests in each case ; n = 442 = 32 ) . we also present significances of correlation values without multiple comparisons and supply all correlation coefficients and corresponding p values ( cf . [ 1 , 9 , 28 ] for a similar approach and for its statistical aspects ) . the differences between ntms and meg values obtained at t1 and t2 were tested with student 's t - test . in the lh , meps were found in 11 patients both at t1 and at t2 and were present in the nh in all patients . mt was higher for lh than nh in 9 patients at t1 ( p < 0.05 , binomial test ) and in 10 patients at t2 ( p < 0.05 , binomial test ) . the mts in the lh and nh correlated strongly both at t1 ( r = .82 , p < .01 ) and at t2 ( r = .78 , p < .01 ) . pp2ms stimulations of nh did not inhibit meps ( disinhibition ; diminished sici ) in 5 patients at t1 and in 3 patients at t2 . pp12ms stimulation of lh facilitated meps ( icf ) in 10 out of 11 patients at t1 and in all patients at t2 . in nh mep amplitudes elicited by pp12ms stimulations were correlated between the lh and nh at t1 ( r = .62 ; p < .05 ) but not at t2 ( supplementary table 2 ) . erd started 140 10 ms after tactile stimulation and peaked at 250 10 ms . the subsequent ers started at 520 40 ms and peaked at 900 70 ms . at t1 , erd was absent in one patient and ers in two patients in the lh ; ers was missing from the nh in one patient . at t2 , ers was smaller in the lh than nh at t1 ( 46 31% versus 63 32% ; p < .05 ) ; at t2 , the difference was nonsignificant . sefs from both hemispheres were detected in 12 patients at t1 and in all patients at t2 . they were smaller in the lh than nh at t1 ( 25 nam versus 32 nam ; p < .04 ) but not at t2 . the si hand representation area was larger in the lh than nh at t1 ( 12 3 mm versus 10 3 mm p < .003 ) but not at t2 ( supplementary table 3 ) . the plots of the most relevant correlations are depicted in figure 1 to show that they were not driven by outliers . all correlations are displayed in table 2 to enable evaluation of significance of our hypotheses against general effects of the lesions . the mt and erd were correlated in the lh at t1 ( r = .66 , p < .03 ) , indicating that small erd was associated with a high mt ( figure 1(a ) ) . at t2 , this correlation was weaker ( r = .58 , p < .06 ) . however , the mt of the lh correlated with the erd of nh ( r = .62 , p < .04 ) , and the mt of the nh correlated with erd of the lh ( r = .65 , p < .02 ) , suggesting that high mt was associated with a small erd in the opposite hemisphere at t2 ( table 2 ) . sici and the ers did not correlate at t1 or in lh at t2 . in the nh , high ers was associated with a strong sici ( r = .59 , p < .04 ; figure 1(b ) ) . in addition to hypothesized correlations , sici of the nh and erd of the lh at t2 were correlated ( r = .82 , p < .001 ) , indicating that strong erd in the lh was associated with a strong sici in the nh . sici in the lh was correlated also with the si amplitude of the lh ( r = .64 , p < .04 ) , indicating that small si amplitude was associated with a weak sici ( table 2 ) . icf and sef parameters did not correlate at t1 . at t2 , icf in the lh correlated with the s1 amplitude of lh ( r = .65 , p in addition , icf in the nh correlated ( r = .82 , p < .001 ) with the si finger representation area of the lh ; this correlation remained significant also after bonferroni correction ( table 2 ) . moreover , icf in the lh at t1 was correlated ( r = .83 ; p < .002 ) with the si finger representation area of lh at t2 ; high icf at t1 resulted in a small hand representation area at t2 ( figure 1(c ) ) . our study is the first to compare meg and ntms excitability parameters during stroke recovery . navigated tms , not applied previously in longitudinal studies of stroke patients , enabled the precise replication of the stimulus site between separate measurements , adding reliability to the follow - up . we found correlations between cortical excitability estimates derived from ntms and meg . as expected , we found correlations between mt and erd , but in only one of the four possible intrahemispheric and two out of four interhemispheric conditions . the sici and beta ers , both attributed to gabaergic mechanisms , were correlated in one of their four possible intrahemispheric conditions ( in the nh at t2 ) . one reason for this may be that various gaba - a receptor subtypes contribute to sici . nonselective gaba - a receptor activators modify sici whereas the gaba - a1 receptor specific zolpidem did not . nonselective gaba - a agonist zopiclone increased meg beta activity whereas zolpidem suppressed beta activity in the vicinity of stroke lesion . moreover , in healthy subjects , diazepam increased meg erd but did not affect ers when the increase of baseline beta activity was taken into account . this nonspecificity could contribute to the correlations of sici with the erd and mt as well . correlations between ntms parameters and meg erd / ers were stronger at t2 than at t1 . analogously , most tms intracortical excitability measures did not correlate with the hand function acutely but did so 3 months after stroke . recovery of sensorimotor fmri activation to digit stimulation from 1 to 3 months was correlated with final motor function , emphasizing the importance of this time period for stroke recovery . is attributed mainly to glutaminergic mechanisms , glutamate may contribute to stroke - induced plasticity . somewhat surprisingly , high icf at t1 correlated with small si hand area at t2 ( figure 1(c ) ) ; thus , the narrowing towards normal hand representation size may be supported by glutaminergic activity . icf did not correlate with the meg erd / ers , and the si hand area and beta erd / ers were not correlated ; this suggests different mechanisms underlying sici and icf ( see for a detailed discussion ) . for example , high mt was associated with a small erd in the opposite hemisphere , and strong erd in the lh was associated with a strong sici in the nh . increased excitability within the unaffected motor cortex may cause imbalance between the homologous cortical motor areas and worsen also the ipsilesional hand coordination ( for references , see ) . thus , some functional correlations may relate to the modified general excitability properties of the motor system , instead of effects in the immediate vicinity of the stroke . tms results give direct information of the changes in the motor output and the immediate effects of tms are relatively local . however , also subcortical and spinal processes affect the meps used to evaluate the tms effects . meg reveals the activity of the whole cortical mantle and enables mapping of network effects generated by stroke . meg source analysis suggests mainly motor cortex origin of beta ers [ 13 , 33 , 34 ] . however , in electrocorticography , recorded directly from the cortex , beta erd and ers appear outside of pre- and postcentral gyri , in supplementary motor cortex , or broadly from pre- and postcentral gyri , frontolateral and medial cortex [ 37 , 38 ] . the widespread cortical generation of the erd and ers may make them resilient to small cortical strokes . multitude of generators may contribute to considerable variability of source locations of beta erd in stroke patients ( cf . ) . multiple sources underlying meg signals may also explain resilience of auditory evoked fields after small strokes . stronger correlations between icf and si parameters than between mt and sici and ers / erd may , in part , result from spatially more limited source areas of s1 responses than those of erd / ers . it can be expected that meg and ntms produce complementary information about the effects of stroke on cortical networks . moreover , meg parameters in the affected hemisphere and ntms indices in the unaffected hemisphere were correlated with the motor performance of the affected hand ( cf . [ 18 , 21 , 24 ] ) . erd in the 822 hz band may reflect downregulation of intracortical inhibition in the human motor cortex , as tms delivered during erd is associated with increased mep amplitudes and reduced sici . however , 1 hz repetitive tms over the motor cortex reduces meps to subsequent single tms pulses , indicating inhibition , but decreases postmovement beta ers , and intermittent theta burst tms facilitates meps but increases postmovement beta ers . beta ers is reduced in patients with myoclonus epilepsy , indicating increased cortical excitability . in line , sici is decreased in myoclonus epilepsy patients ; however , mt is increased [ 44 , 45 ] , and the silent period after the tms pulse , reflecting motor cortical postsynaptic inhibition , is prolonged , indicating prevailing inhibitory cortical tonus . thus , only some aspects of the cortical excitability may be shared in excitability estimates obtained by tms and meg . our results suggest that some tms and meg excitability measures reflect the activity of the same transmitter systems . however , high mt and absence of erd / ers may also correlate because of severely affected sensorimotor connections between the periphery and the cortex . we detected sefs in 12/13 patients and meps in 11/13 patients already at t1 , indicating that both somatosensory and motor pathways were conveying signals . motor function can be maintained despite significant damage to the corticospinal tract , as estimated from mt of stroke patients . moreover , we observed fewer correlations at t1 , when the sensorimotor pathways probably were more affected , than at t2 . however , such spurious correlations should remain stable or decrease during recovery from t1 to t2 but not increase , as in our data . the limitations of our study include the small size of the patient group as the precise features of structural and functional changes may differ among the patients . cortical excitability is modified differently in cortical and subcortical strokes [ 46 , 47 ] . this , however , should not alter our correlations between the tms and meg , as both were recorded from the same patients . possible effects of medication on excitability should go in parallel for meg and ntms , as the patients were tested sequentially during the same day . the patients were not tested in the acute stage with tms , and meg recordings showed most dramatic erd and ers modifications between the acute phase and t1 . although mt in the lh is correlated with the paretic hand function in acute stroke , this correlation , however , weakens during recovery , and tms intracortical excitability parameters correlated with the clinical performance best at 3 months . the 2 ms or 12 ms isis , selected for our paired - pulse stimuli , produce clear sici and icf in healthy subjects and in stroke patients , but we did not test other parameters , which could have produced stronger correlations between ntms and meg . icf and si response amplitude and area size , mt and the erd of the hemisphere harboring the stroke lesion , and sici and ers of the nonlesioned hemisphere are correlated in stroke patients . numerous correlations of the excitability parameters between the lh and nh emphasize the importance of the hemispheric balance of the excitatory - inhibitory properties of the sensorimotor system in analyzing the stroke - related dysfunction during stroke recovery . OUTPUT:

objective . stroke alters cortical excitability both in the lesioned and in the nonlesioned hemisphere . stroke recovery has been studied using transcranial magnetic stimulation ( tms ) . spontaneous brain oscillations and somatosensory evoked fields ( sefs ) measured by magnetoencephalography ( meg ) are modified in stroke patients during recovery . methods . we recorded sefs and spontaneous meg activity and motor threshold ( mt ) short intracortical inhibition ( sici ) and intracortical facilitation ( icf ) with navigated tms ( ntms ) at one and three months after first - ever hemispheric ischemic strokes . changes of meg and ntms parameters attributed to gamma - aminobutyrate and glutamate transmission were compared . results . icf correlated with the strength and extent of sef source areas depicted by meg at three months . the ntms mt and event - related desynchronization ( erd ) of beta - band meg activity and sici and the beta - band meg event - related synchronization ( ers ) were correlated , but less strongly . conclusions . this first report using sequential ntms and meg in stroke recovery found intra- and interhemispheric correlations of ntms and meg estimates of cortical excitability . icf and sef parameters , mt and the erd of the lesioned hemisphere , and sici and ers of the nonlesioned hemisphere were correlated . covarying excitability in the lesioned and nonlesioned hemispheres emphasizes the importance of the hemispheric balance of the excitability of the sensorimotor system .

PubMed_Summ6510

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: although surgery is the current standard treatment for localized surgically operable lesions , many patients with liver metastases can not undergo surgical resection because of associated comorbidities , concerns about their age , the extent of the disease , or the patient 's wishes . alternative treatment approaches for unresectable liver metastasis and primary liver cancer include chemoembolization , radiofrequency ablation , cryotherapy , and the oral multikinase inhibitor sorafenib . treatment choice is guided by the barcelona clinic liver cancer staging system and recommended treatment strategy . stereotactic body radiotherapy ( sbrt ) is a technique that allows the delivery of a precise dose of radiation to a tumor while sparing adjacent normal tissues . however , the movement of intra - abdominal organs due to respiration has hampered the use of sbrt . the insertion of a fiducial marker near to the tumor before radiotherapy allows respiratory motion to be tracked , thus enabling accurate dose delivery while the patient breathes freely . recently , the percutaneous insertion of fiducial markers has been described [ 4 , 5 ] , but experience of such procedures is still limited . this marker is made from gold , which makes it biocompatible and ensures it exhibits good contrast on x - ray images . in this study , we describe our initial experience with this new fiducial marker and evaluate the technical feasibility , clinical efficacy , and safety of sbrt using this marker . this study was part of a prospective sbrt study in which the cyberknife g4 was used to treat liver tumors and was approved by the institutional review board . written informed consent was obtained from all patients . since the patient accrual for this sbrt study was relatively slow , we report our initial experience with a gold flexible linear fiducial marker ( visicoil , radiomed corporation , barlett , tn , usa ) in this article . between july 2012 and february 2015 , 18 patients underwent percutaneous fiducial marker placement under computed tomography ( ct ) fluoroscopic guidance or ultrasonographic guidance before sbrt for liver tumors . their median age was 68 years ( range , 4483 years ) , and all of them were inpatients . first , all patients underwent diagnostic ct scans of their abdomen composed of 35 mm - thick contiguous axial tomographic sections . after reviewing these preliminary images , an appropriate puncture site and the optimal needle guidance method , i.e. ct fluoroscopic or ultrasound guidance , was determined in advance . the marker placement was performed during breath - holding under ct fluoroscopic guidance in 8 cases and under ultrasound guidance in 10 cases . the imaging parameters during ct fluoroscopy included a ct beam width collimated to 3 mm . one patient needed contrast - enhanced ct fluoroscopy during the procedure to delineate the tumor clearly . ultrasonography was performed with a convex probe ( 25 mhz ) . a gold flexible linear marker containing an 18-gauge coaxial needle ( 0.75 mm in diameter and 5 mm in length , fig . local anesthesia was achieved via the subcutaneous administration of 1% lidocaine . after confirming that the needle tip had reached the target lesion , after the procedure , ct or cone - beam ct was performed to determine whether any complications such as pneumothorax or bleeding had occurred . ( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker . ( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker . ( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the gold flexible linear fiducial marker ( visicoil ) . ( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker . ( b ) the gold flexible linear fiducial marker . a 73-year - old man with metastasis from carcinoma of the ampulla of vater . ( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker . ( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the target site was chosen by consensus by an interventional radiologist and a radiation oncologist before the procedure . clinical success was defined as the completion of sbrt without the marker dropping out of position . marker position was checked by ct or cone - beam ct images taken immediately after placement and planning ct images taken before radiotherapy . migration of a marker before radiotherapy was defined as its displacement exceeding 3 mm from the initial position on ct images ; the marker position within or relative to the tumor was evaluated . during radiotherapy , migration of a marker was evaluated by comparing abdominal plain x - ray images at an inspiratory phase in the supine position taken after marker placement with fluoroscopy images taken at an inspiratory phase of the treatment system ; thereby the marker position was evaluated in relation to the rib bones and diaphragm . it was difficult to evaluate subtle displacements of the marker by fluoroscopy images alone , especially once radiotherapy was started , because the size of the tumor and the surrounding tissue could change with treatment . therefore , when migration of the marker that could influence treatment accuracy ( e.g. > 3 mm ) was suspected by fluoroscopy , ct scanning was scheduled for further evaluation to determine whether the displacement was significant or not . first , all patients underwent diagnostic ct scans of their abdomen composed of 35 mm - thick contiguous axial tomographic sections . after reviewing these preliminary images , an appropriate puncture site and the optimal needle guidance method , i.e. ct fluoroscopic or ultrasound guidance , was determined in advance . the marker placement was performed during breath - holding under ct fluoroscopic guidance in 8 cases and under ultrasound guidance in 10 cases . the imaging parameters during ct fluoroscopy included a ct beam width collimated to 3 mm . one patient needed contrast - enhanced ct fluoroscopy during the procedure to delineate the tumor clearly . ultrasonography was performed with a convex probe ( 25 mhz ) . a gold flexible linear marker containing an 18-gauge coaxial needle ( 0.75 mm in diameter and 5 mm in length , fig . local anesthesia was achieved via the subcutaneous administration of 1% lidocaine . after confirming that the needle tip had reached the target lesion , the fiducial marker was deployed , and then the needle was removed ( fig . after the procedure , ct or cone - beam ct was performed to determine whether any complications such as pneumothorax or bleeding had occurred . ( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker . ( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker . ( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the gold flexible linear fiducial marker ( visicoil ) . ( a ) an 18-gauge coaxial introducer needle containing the gold flexible linear fiducial marker . ( b ) the gold flexible linear fiducial marker . a 73-year - old man with metastasis from carcinoma of the ampulla of vater . ( b ) ct image shows the percutaneous insertion of the gold flexible linear fiducial marker . ( c ) ct image shows the successful placement of the gold flexible linear fiducial marker ( arrow ) in the tumor . the target site was chosen by consensus by an interventional radiologist and a radiation oncologist before the procedure . clinical success was defined as the completion of sbrt without the marker dropping out of position . marker position was checked by ct or cone - beam ct images taken immediately after placement and planning ct images taken before radiotherapy . migration of a marker before radiotherapy was defined as its displacement exceeding 3 mm from the initial position on ct images ; the marker position within or relative to the tumor was evaluated . during radiotherapy , migration of a marker was evaluated by comparing abdominal plain x - ray images at an inspiratory phase in the supine position taken after marker placement with fluoroscopy images taken at an inspiratory phase of the treatment system ; thereby the marker position was evaluated in relation to the rib bones and diaphragm . it was difficult to evaluate subtle displacements of the marker by fluoroscopy images alone , especially once radiotherapy was started , because the size of the tumor and the surrounding tissue could change with treatment . therefore , when migration of the marker that could influence treatment accuracy ( e.g. > 3 mm ) was suspected by fluoroscopy , ct scanning was scheduled for further evaluation to determine whether the displacement was significant or not . the characteristics of patients , tumors and fiducial marker placement are summarized in table 1 . the 18 tumors consisted of 5 hepatocellular carcinomas ( 28% ) and 13 liver metastases ( 72% ) . the target sites for marker insertion were as follows : inside the tumor in 11 cases ( 61% ) and near the tumor in 7 cases ( 39% ) . two patients underwent radiofrequency ablation of another lesion after fiducial marker placement ; therefore , their hospitalization period was 5 days . sbrt was successfully performed in all 18 cases , and none of the markers was judged to have dropped out of its position . the median period between marker implantation and sbrt was 16 days ( range : 031 ) . table 1.summary of patients , tumors and fiducial marker placementpatients ( n = 18 ) male / female12/6median age ( range)68 ( 4483)tumors ( n = 18 ) size ( mm ) median of maximum length ( range)35.5 ( 1188)type hepatocellular carcinoma5 liver metastasis ( colon / gastric / others)13 ( 6/2/5)site s1/4/6/7/8/1&8/3&4/4&8/7&81/3/1/1/7/2/1/1/1fiducial marker placement ( n = 18 ) ct fluoroscopic / us guidance8/10 inside / near the tumor11/7s1 = caudate lobe , s3 = ventrolateral segment of the left lobe , s4 = medial segment of the left lobe , s6 = posteroinferior segment of the right lobe , s7 = posterosuperior segment of the right lobe , s8 = anterosuperior segment of the right lobe . summary of patients , tumors and fiducial marker placement s1 = caudate lobe , s3 = ventrolateral segment of the left lobe , s4 = medial segment of the left lobe , s6 = posteroinferior segment of the right lobe , s7 = posterosuperior segment of the right lobe , s8 = anterosuperior segment of the right lobe . no major complications , such as bleeding or marker migration , occurred ( 0% , 0/18 ) . one patient developed mild pneumothorax ; however , the sbrt was performed as planned because the pneumothorax disappeared after a few days ' observation . in sbrt for liver lesions , techniques for controlling tumor motion are required because the bowel and stomach , which have a perforation risk , lie close to the liver . there are two main methods for reducing the uncertainty regarding the positions of liver tumors . one is to minimize tumor motion via the inhalation of oxygen , abdominal compression , learning of regular respiratory patterns , or breath - holding techniques [ 79 ] . the other technique , which is more sophisticated , is target gating or target chasing , during which the movements of the skin surface or other markers are monitored [ 10 , 11 ] . the placement of the gold flexible fiducial markers near or inside a tumor is considered to be the most direct version of this method . in the present study , fiducial markers were inserted before tumor - tracking sbrt ( using a cyberknife g4 ) during abdominal compression to improve the accuracy of localization . percutaneous fiducial marker placement has been widely performed , but some complications such as marker migration ( which might cause delayed or inappropriate treatment ) have been reported [ 4 , 5 ] . for example , a previous study described cardiac embolization due to the migration of a nester embolization coil that was used as a fiducial marker . unlike traditional cylindrical gold seed fiducial markers , for which the migration rate was reported to be 5% , the marker used in this study is flexible and has a coiled design , which might reduce the incidence of fiducial migration . in our study , no marker migration was observed ; thus , this gold flexible linear fiducial marker seems to be superior . however , pneumothorax occurred in one case , and a previous report found that percutaneous insertion of the gold flexible linear fiducial marker into the lungs is associated with a high risk of pneumothorax . in our experience , the needle included with the gold flexible linear fiducial marker is not sharp enough , and it is more difficult to penetrate the pleura and tumors with this needle than with a biopsy needle . ohta et al . previously reported that the transarterial placement of a fiducial marker resulted in a low complications rate ( 2% ) and a high technical success rate ( 100% ) . however , complications such as femoral pseudoaneurysms have also been reported to occur after angiography . in addition , some of the transarterial marker procedures failed , and the outcomes of such procedures were considered to depend on the tumor site and the anatomy of the hepatic artery . celiac artery stenosis makes it difficult to identify the hepatic artery [ 16 , 17 ] . therefore , the tumor site and the anatomy of the hepatic artery should be confirmed with ct and angiography . on the other hand , reported that the complications rate for percutaneous fiducial marker placement in the abdomen or pelvis was 4.3% ( 8/188 ) ; there were five minor complications ( small hematomas in four cases , pneumothorax in one case ) and three major complications ( bleeding in two cases , sepsis in one case ) . the main benefit of percutaneous marker placement is that it is easy to place the marker in the target position and does not take much time . therefore , there is a clear need for additional research to address this issue . at this time , the fiducial marker placement method should be decided based upon a consensus being reached between radiation oncologists and interventional radiologists after consideration of the tumor location and the anatomy of the hepatic artery , which should be confirmed with ct and angiography . however , the deep part of the liver can not be clearly observed using ultrasound . furthermore , the skill of the operator and the efficiency of the ultrasound machine vary among hospitals . therefore , the implantation method should be discussed on an individual basis . three or more fiducial markers were used in the cases described in the literature . in our study , however , only one marker was used based on the consensus of an interventional radiologist and a radiation oncologist . complications such as pneumothorax might occur more frequently when multiple fiducial markers are inserted percutaneously . one marker is considered to be sufficient because the gold flexible linear fiducial marker is less likely to migrate . in this study , no signs of migration were observed , and all patients underwent radiotherapy without any problems . in future , the complications rate and the frequency of recurrence after radiotherapy should be analyzed with respect to the number of markers employed . in conclusion , the new gold flexible linear fiducial marker is useful for percutaneous insertion because of its good stability . in this study , we were unable to determine the local control rate of patients undergoing sbrt with this fiducial marker due to the short follow - up periods involved . it is therefore necessary to observe our patients for a longer period to evaluate the clinical usefulness of this marker . funding to pay the open access publication charges for this article was provided by each of the co - authors in this search . OUTPUT:

the aim of this study was to describe our initial experience with a gold flexible linear fiducial marker and to evaluate the safety and technical and clinical efficacy of stereotactic body radiotherapy using this marker for malignant liver tumors . between july 2012 and february 2015 , 18 patients underwent percutaneous fiducial marker placement before stereotactic body radiotherapy for malignant liver tumors . we evaluated the technical and clinical success rates of the procedure and the associated complications . technical success was defined as successful placement of the fiducial marker at the target site , and clinical success was defined as the completion of stereotactic body radiotherapy without the marker dropping out of position . all 18 fiducial markers were placed successfully , so the technical success rate was 100% ( 18/18 ) . all 18 patients were able to undergo stereotactic body radiotherapy without marker migration . thus , the clinical success rate was 100% ( 18/18 ) . slight pneumothorax occurred as a minor complication in one case . no major complications such as coil migration or bleeding were observed . the examined percutaneous fiducial marker was safely placed in the liver and appeared to be useful for stereotactic body radiotherapy for malignant liver tumors .

PubMed_Summ6511

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: quite often , we come across diseases in various medical specialties that are catalogued in biomedicine as idiopathic , that is to say , diseases with no apparent or known cause . normally , these idiopathic diseases are treated with symptomatic remedies , whose objective is to improve the symptoms that have negative impacts on the normal lifestyle of patients , but without dealing with or solving the causes that provoke them . biomedicine is always searching for the causes for diseases inside the organism , without finding them , when the causes and pathogenesis tend to be outside of the organism , in the environment . often , treatment consists of social modifications that attempt to resolve these pathological processes . environmental factors influence all diseases , but in idiopathic processes are crucial . given the limitations of biomedicine to give clear explanations , and consequently a cure or remedy for certain diseases , a new paradigm is needed that can explain the causes of these pathologies that are considered idiopathic . to this end , it is essential that we integrate different elements through the formation of collaborative groups or health teams , defined by the world health organisation in 1973 as a nonhierarchical group of people with different professional backgrounds but a common objective , which is to provide the most comprehensive care possible to patients and their families , in any situation . currently , collaborative work teams can be found in several different medical specialties such as oncology , geriatrics , and forensic medicine , whose health teams are primarily composed of health care professionals . one striking exception is radiology and traumatology , in which other specialties are starting to be incorporated such as biomedicine , physics , and engineering . within otorhinolaryngology , a medical / surgical specialty that is concerned with the prevention , diagnosis , treatment , and rehabilitation of diseases of the ear and upper respiratory / digestive tracts ( mouth , nose , pharynx , and larynx ) , and the functions derived from these structures ( hearing , respiration , olfaction , taste , swallowing , and phonation : voice and speech ) as well as the cervical and facial structures connected or related to these pathologies and sociology , a science dedicated to the empirical and theoretical analysis of social processes and structures . more specifically , it is the close collaboration between otology , which involves the biological study of diseases and abnormalities of the ear , and health sociology that directly collaborates with doctors and other health professionals , in addition to the syncretic integration of other disciplines such as anthropology and social / clinical psychology . in this manner , the joint labour of otology and sociology gives way to otosociology , a discipline dedicated to the study , intervention , and prevention of organic and functional pathologies of the auditory system with special emphasis on the influence of social factors . in the following sections , we describe how otosociology is capable of explaining both the social consequences and causes of certain diseases identified by otology as idiopathic . in the following section ( diseases , ischaemia , and alterations ) , we describe the process of passing from identification of audiovestibular diseases recognised by otology to discuss these abnormalities as symptoms from the viewpoint of otosociology . in the third section ( otosociology ) , we explain both the training and work focus of otosociologists and the methodologies employed by this new perspective , justifying its use in daily otorhinolaryngological practice . until now , audiovestibular pathologies have been treated by otological medicine , which identifies them exclusively as biological diseases , attempting to situate the aetiopathogenesis in the audiovestibular organ itself , and as a result , the causes and consequences remain hidden , making any treatment strategy strictly palliative in nature . in contrast , otosociology views and treats these pathologies as symptoms of a social problem that affects the biological part of the subject . otosociology , by identifying social problems that cause these symptoms and alterations in the patient 's environment , can apply effective medical treatment and directly address the social consequences ( table 1 ) . the most important otological pathologies are sudden deafness , mnire disease , benign paroxysmal positional vertigo , tinnitus , and hyperacusis , commonly grouped within the category of audiovestibular diseases . these diseases cause patients to seek otological care and are immediately ascribed to the ear and are produced by the ear and are treated as exclusively otic pathologies . many examples of the aetiology , incidence , diagnosis , treatment , and prognosis of these audiovestibular diseases are available in the medical literature and are discussed here . its otological definition is sensorineural or perceptive hearing loss , usually in one single ear , of sudden onset , with a loss of over 30 db , at least three consecutive frequencies , with no previous otological background . otology attempts to discern the causes of sudden deafness in the ear , and several aetiologies have been proposed such as rupture of the cochlear membrane , microangiopathic processes in the ear , viral ear infection , autoimmune diseases of the inner ear , mnire disease , vestibular schwannoma , or meningioma , although none of these theories sufficiently clears up the issue , nor can be applied in all cases . the incidence of sudden deafness has increased over time and is estimated to reach 160 cases per year per 100 000 inhabitants . in japan , where sudden deafness is registered , probable causes of the increase in sudden deafness include increased general awareness of this disease in the japanese population and the presence of diseases correlated with lifestyle , such as hypertension , diabetes , hyperlipidemia , and heart disease , associated with vascular pathologies , with the conclusion that vascular pathologies derived from hypertension and diabetes can lead to alterations in cochlear microcirculation , which leads to sudden deafness from cellular stress . this diagnosis is reached through clinical symptoms , audiometry , and a magnetic resonance of the internal auditory canal through which the auditory nerve passes . medical treatment , which is an idiopathic process , is based on corticosteroids , vasodilators , and antioxidants . the patients with the worst potential prognosis for recovery are those with old age , severe initial hearing loss , vestibular symptoms , late treatment and time to recovery ( the longer it takes to recover , the greater the chance that the patient never will ) , and the presence of tinnitus ( table 2 ) . in otology , mnire disease is defined as an internal ear disorder that affects both balance and hearing , characterised by an abnormal sensation of movement or rotatory vertigo , loss of hearing in one or both ears , tinnitus , sensation of aural fullness , and hyperacusis and occurs in recurring crises . mnire in 1861 described in his mmoire sur des lssions de l'oreille interne donnat lieu des symptmes de congestion crbrale apopectiforme the findings from an autopsy of a woman , in which he observed damaged semicircular canals full of a red , plastic material , resembling a sort of bloody exudation that was only marginally present in the vestibule and nonexistent in the cochlea . seven years after the death of mnire , his student politzer ( 1867 cited by rizzi in 2000 ) published these symptoms as mnire disease in the archives fr ohrenheilkunde . twelve years after the death of mnire , charcot ( 1874 cited by baesly and jones , 1996 ) popularised the name of mnire disease for the symptoms of vertigo , deafness , and tinnitus . mnire disease affects the inner ear with an unknown aetiology , characterised by a dilation of the membranous labyrinth due to increased endolymph ( endolymphatic hydrops ) of an unknown cause . the incidence of this disease ranges between 17/100 000 in japan and 205/100 000 in italy . mnire disease is clinically diagnosed when the patient develops recurrent crises of rotatory vertigo , low - frequency fluctuating sensorineural hearing loss , hyperacusis , and a sensation of blockage in the ear or aural fullness . the committee on hearing and equilibrium of the american academy of otolaryngology - head and neck surgery ( 1995 ) put together a guideline based on clinical histories with four stages : ( 1 ) possible mnire disease ( episodes of vertigo with no hearing loss , fluctuating or fixed sensorineural hearing loss , with disequilibrium but no definitive episodes , excluding other possible causes ) . ( 2 ) probable mnire disease ( one episode of vertigo ; audiometrically documented hearing loss on at least one occasion ; tinnitus or otic pressure ) , ( 3 ) definite mnire disease ( two or more episodes of vertigo lasting at least 20 minutes ; audiometrically documented hearing loss on at least one occasion ; tinnitus or aural fullness of the affected ear ) , and ( 4 ) certain mnire disease ( established disease with histological confirmation ) . since biopsy is not possible without destroying the inner ear , confirmation is only possible through autopsy ; that is to say , no living patient has been diagnosed with certain mnire disease . in mnire disease , the worst symptom for the patient is vertigo , requiring medical treatment with corticosteroids , benzodiazepines , dimenhydrinate , thiethylperazine , or sulpiride . if these medical treatments fail , drugs such as corticosteroids and gentamycin can be administered directly into the inner ear . another therapeutic option is pressotherapy which places pressure on the middle ear that in turn affects the inner ear and can improve the vertigo by affecting the pressure exerted on the liquids in the inner ear . the final alternative for the treatment of vertigo can involve a neurectomy of the vestibular nerve , a labyrinthectomy , or drainage of the endolymphatic sack . benign paroxysmal positional vertigo is defined as a situation in which brief episodes of vertigo are produced by movements of the head . the incidence of this condition is estimated at 4681 cases per 100 000 inhabitants and increases by 38% for every decade of life . the idiopathic variety is twice as common in women as in men and occurs between the ages of 50 and 70 years [ 15 , 16 ] . when the aetiology is trauma or vestibular neuritis it may go unnoticed in daily life and only is recognised when undergoing diagnostic tests . schuknecht ( 1962 ) and schuknecht ( 1969 ) proposed the theory of cupulolithiasis to explain how this vertigo is produced within the inner ear . according to this theory , this vertigo is caused by microscopic stones composed of calcium carbonate and proteins , otoliths , which move within the utricle of the otic vestibular system , that is to say , the interior of the equilibrium centre . for their part , hall and colleagues ( 1979 ) proposed the theory of canalithiasis , stating that these minute particles circulate improperly through the canals of the inner ear labyrinth , altering balance and producing vertigo . dix and hallpike ( 1952 ) [ 2224 ] , who had thoroughly researched vertigo of the ear , developed a diagnostic test for this process , the dix - hallpike test . thus , once the otic mechanisms of this vertigo and how to diagnose it were established , semont and colleagues in 1988 established the treatment of a repositioning manoeuvre to place the calcium deposits in their original place in order to halt the vertigo , known as the semont manoeuvre . in a similar manner , in 1992 , epley described another repositioning manoeuvre for the posterior canal , known as the epley manoeuvre . recently , hilton and pinder ( 2002 , 2004 ) [ 15 , 16 ] performed a review in the prestigious cochrane organisation in which they demonstrate that the epley manoeuvre is effective at repositioning the calcium deposits in the inner ear . the prognosis , from an otological point of view and as its definition indicates , is benign , recurrent but benign . as has been shown , the diagnosis of benign paroxysmal positional vertigo has a perfectly defined set of signs and symptoms , which are always produced , diagnosed , and treated within the inner ear ( table 4 ) . ischaemia is a deficit of blood flow , whether transient or definitive , in an organ or part of it . the concept of ischaemia allows us to make a significant conceptual advancement since the medical viewpoint of the condition starts to look outside of the ear when focusing on its vascularisation , although other factors may be interacting . in recent years , several scientific advancements have been made in this field . with regard to sudden deafness , the ischaemic processes of the inner ear have arisen as a mechanism of pathogenesis . in mnire disease , proposed a model based on haemodynamic disequilibrium that produces transient ischaemia and could have an effect on ph and the proton pump of the inner ear . in this manner , under conditions of ischaemia and metabolic acidity , the activity of the proton pump would create an overload of anions in the endolymph with the result of increased osmolality . this , in turn , leads to the formation of hydrops , an increase in pressure in the endolymph fluid , which causes the fluctuating deafness , vertigo , and tinnitus that are characteristics of mnire disease . it has also been established that endolymph hydrops can be produced without causing vertigo [ 2933 ] . similarly , vertebrobasilar ischaemia is starting to be considered as the pathogenesis of benign paroxysmal positional vertigo . to conclude , it is interesting to point out that currently , several authors consider ischaemia of the nervous system as the pathogenic mechanism of tinnitus [ 3541 ] , a symptom produced in the majority of cases of sudden deafness and mnire disease . this simple change in perspective allows us to extend our focus outside of the auditory organ , a structure specific to the field of otology , in order to offer explanations of these otic pathological processes , favouring the examination of ischaemia as a pathogenic factor and passing from an otological viewpoint to that of otosociology . figure 1 compiles the different aetiopathogenic mechanisms of ischaemia from the stress generated by interactions between the patient 's social and cultural environment and the vulnerability or resiliency of a person . blood analysis of the following substances : endothelin-1 , prolactin , cortisol , adrenaline , noradrenaline , and cholesterol provides the means of an objective analysis of the patient 's evolution . in light of the available literature on the subject that affirms that patients diagnosed with idiopathic sudden deafness have a higher probability of suffering a stroke in the next 5 years [ 42 , 43 ] , an otosociological viewpoint would indicate that otology lacks the necessary tools to consider these conditions from a more global perspective . with a mind - set focused on the ear , it is impossible to contemplate the triggering factors or causes that , of course , are not located within the ear , and so they continue to cause damage . medicine attempts to improve a patient 's health and environment in order to reach a better biological / psychological / social well - being , and so the expanded focus provided by otosociology comprehends the global reality of the patient much better , offering more chances of recovery . otosociology understands that the causes of audiovestibular symptoms that patients describe are produced outside of the ear and even outside of the patient ; that they originate in the patient 's social environment . the social environment in which we carry out our lives implies situations that provoke states of anguish , anxiety , preoccupation , and irritability , as well as the sensation or perception of not being able to successfully confront these situations . this is what we commonly refer to as stress ( figure 2 ) , which can be measured directly through blood levels of certain substances ( endothelin-1 , prolactin , cortisol , adrenaline , noradrenaline , and cholesterol ) , which allows for the objective analysis of its evolution . as we have been discussing , the otologist treats sudden deafness , mnire disease , and benign paroxysmal positional vertigo exclusively as otic diseases , whereas the otosociologist considers them to be symptoms of a cerebral ischaemic pathogenesis produced by psychosocial stress . that is to say , three different symptoms will all lead to the same diagnosis : audiovestibular stroke , with transient ischaemic auditory different studies have started to highlight the importance of lifestyle and stress in the pathophysiological mechanisms of audiovestibular symptoms . stress leads to vasoconstriction , haemoconcentration , and occlusion of the microcirculation that occurs in the inner ear . stress and stressful lifestyles , such as those related to work , social life , and emotional conflicts , as well as personality types that tend towards greater stress , have been correlated with audiovestibular symptoms . more specifically , studies relate situations of psychosocial stress with sudden deafness [ 4749 ] , mnire disease , benign paroxysmal positional vertigo [ 5154 ] , tinnitus [ 5564 ] , and hyperacusis [ 6567 ] . this theory is supported by the findings that social stress can extend itself farther than simply one 's social situation and can even produce physiological damage . in other fields of medicine , many diseases such as gastric ulcer [ 68 , 69 ] , diabetes , hypertension , and acute myocardial infarction have a social component in their origins , whether from previous conditions or sustained stress through time ( chronic stress ) . after providing a detailed description of how otology defines , diagnoses , and treats that which it considers to be audiovestibular diseases , we have introduced the variable of ischaemia as an aetiopathogenic explanation , from the point of view of otosociology , of the true causes of these alterations . alterations , not diseases , that have their origins outside of the ear and are external to the individual because they belong to the social environment . in this manner , we are now ready to expound upon and develop the specific field of otosociology in the following section . we have already established that otosociology is a discipline dedicated to the study , intervention , and prevention of organic and functional pathologies of the auditory system , with special emphasis on the influence of social factors . as we can appreciate , otosociology stems from a holistic viewpoint that not only comprehends the dysfunction of an organ or body part , but rather the person in his / her entirety , including social and cultural environments . as such , it is evident that otosociology does not treat patients or subjects , but people . in this sense , otosociology involves a new theoretical framework with different names , concepts , and research processes from those used in the otological approach . the history of human knowledge is full of situations in which two different people or disciplines come to similar conclusions , in the same period of time , given a certain problem . serendipity , destiny , and chance have been used to describe this phenomenon which , in this case , brought together two different disciplines that researched a common subject ; audiovestibular alterations , but with completely different objectives , methodologies , and points of view . they could even appear to be completely devoid of any connection to each other . in the case of medicine , the issue to be researched is based on finding an explanation for the causes of these alterations with the goal of elucidating an effective treatment ; since viewed solely through the lens of biomedical methodology , the diagnosis is idiopathic and the treatment of symptoms alone is not sufficient to resolve this pathology . in the case of sociology , the common point consists of an unexpected finding in the study of the processes of exclusion of people with sudden deafness . in both cases , researchers were faced with a one - way alley : the causes of audiovestibular alterations were due to factors that were external to the biological states of individuals . they were due , in reality , to the stress produced by the individual 's social and cultural environment . collaboration for field work revealed the same conclusions that had been gained by observing the same individuals with different objectives . thus commenced a scientific dialogue , with the end result of otosociology the tight collaboration between two disciplines that differ significantly in their language , methods , and perspectives requires searching for points of common ground throughout the research process . constant questions and clarifications arise regarding concepts , methodologies , and points of focus that are integral to one discipline but foreign to the other . this tension produced upon the collaboration of these two disciplines has the result of generating new ideas , but also highlights the fact that , in the majority of cases , the two groups are discussing the same issue but with different perspectives and languages . in any case integration of other ways of thinking and analysing problems based on common ground also requires significant effort and a learning curve from both sides , along with an expanded overall perspective and , above all , the possibility of doing the same things in different ways to reach results that , done in a different manner , would not have been achieved . of course , during the process , frustration can arise as often as satisfaction , and many occurrences come to pass that are worth remembering . starting with the very first interviews performed with patients diagnosed with sudden deafness for sociological research , the collaboration commenced with a case by case discussion , providing different points of view and integrating new perspectives and viewpoints with each study interview , testing hypotheses . case by case , and during a year and a half , weekly sessions lasting a mean of 5 hours gave way to the moulding and shaping of what was to become otosociology , which will be described in the following sections . otosociologists must have a thorough understanding of the ear , but more importantly , must properly situate the ear within its surroundings . in this manner , an otosociologist is an otologist with training in sociology that takes into account the influence of social factors in dealing with patients . this involves performing not just an otological examination , but also a biosocial exploration of the patient and his / her condition . training in otosociology , which is given by otologists , sociologists , and psychologists , is directed towards doctors specialised in otorhinolaryngology through a focus on otosociology at the undergraduate or postgraduate level , using b - learning methodologies from sociology faculties , including study materials that delve into sociological theory , methodologies , and research techniques in addition to central themes related to audiovestibular processes . as has been established , medicine involves its own scientific research methods and otologists utilise a series of protocols that they apply rigorously to their daily practice ( figure 3 ) . sociology boasts a qualitative method for investigation involving in - depth interviews , participant observation , and group discussions . it is evident that the protocol currently used by biomedicine does not actually cure patients of what in otosociology we call audiovestibular alterations . it is also evident that the time allotted for a medical consultation is insufficient for applying the traditional qualitative methods employed in sociology . as such , otosociology utilises a hybrid method that combines the clinical and social condition of the patient , which the otosociologist can apply during the time allotted for a consultation . to this end , a pilot study lasting two months tested this hybrid methodology , which has allowed us to elaborate a specific , simplified protocol to be used in daily clinical practice by otosociologists . for the most complicated cases in which the protocol may be insufficient for detecting the causes that have led to the audiovestibular alterations , the otosociologist can seek the express collaboration of a sociologist that is also an expert in otology for an in - depth interview and later analysis . in this pilot study , it was shown that an otologist with proper training in otosociology is capable , in an initial consultation lasting 20 minutes , of performing the normal clinical examination and applying otosociological protocols for arriving at the proper diagnosis and treatment . in cases that were harder to solve or in which the otosociologist had doubts regarding the causes of the alterations , a collaborating sociologist performed an in - depth interview and later compared conclusions with the otosociologist . in all cases , the response from the patient was positive with regard to the medical attention received , the explanations offered , the diagnosis made , and the treatment proposed . the quality of the medical care given undergoes a substantial and objective improvement , and the perception of the patient is very positive . if we assess medical costs , these are considerably reduced by removing the need to prescribe unnecessary medication and repeated consultations . in terms of patient quality of life , we find that this improves immediately upon the consultation . in the patients ' self - evaluation of quality of life , one primary factor is that the person stops feeling like a patient , a sick person , and starts feeling like an individual capable of controlling the alterations that provoked the consultation . additionally , the subject feels released from the years of dependency on medications and medical care , and finally , both he / she and his / her close friends and relatives understand what has occurred and its causes , facilitating over time a recovery from the alterations , whether partial or complete . above all , intervening on the social and cultural causes of the issue removes the possibility that these same causes could repeat themselves in this or any other organ of the body . we have reached a new mutual intellectual understanding through fluid communication and reciprocity . to this end , a positive disposition has been necessary for including other points of view and recognising complementary abilities , that is to say , being open to learning and adapting , maintaining the principle of respect for the capacities and contributions from both sides to concrete points as a whole . secondly we can also affirm that the collaboration between otologists and sociologists in health centres is possible in several different combinations . in an otorhinolaryngology department with one sociologist for every given number of otorhinolaryngologists , the otosociologist can resolve these cases by collaborating with the sociologist in those situations in which the social and cultural causes of the issue and proper interventions to treat it are not clear . thirdly , the integration of a sociologist and the training of otologists in otosociology will benefit all parties involved . the health system will benefit because its principles are centred on the needs of the patient , and the objectives therein are orientated towards promoting health and preventing disease , whether in conditions of treatment , recovery , or palliative care . we can not forget either the economic efficiency in medication , diagnostic tests , and decreased repetition in doctor visits . the objective of the doctor is to cure , but this is often impossible in idiopathic diseases , which constitutes a source of frustration for medical practice . the otosociologist has the opportunity to elucidate the sociocultural causes that produces audiovestibular alterations and can carry out successful interventions to treat it , increasing doctor satisfaction and prestige . for the patient within the health system , otosociology provides high - quality medical care , demedicalisation of the issue , and a consequent recovery of the patient 's identity as an individual , with substantial improvement in his / her condition . this all leads to improved perception of the multidimensional concept referred to as quality of life . by improving a person 's concept of health , to conclude , otosociology has arisen due to the inability of otology to provide effective solutions to the aforementioned audiovestibular symptoms . with this in mind , otosociology provides an aetiopathogenic explanation based on the cultural and social environment of the patient , delivering a correct diagnosis and definitive treatment . OUTPUT:

otology concerns the biological study of ear alterations and diseases , solely . so , the diagnosis of audiovestibular diseases tends to be idiopathic or is based on theoretical concepts such as idiopathic sudden deafness , mnire disease , benign paroxysmal positional vertigo , tinnitus , hyperacusis , or idiopathic facial paralysis . the treatment for these pathologies is symptomatic . otosociology takes the aetiology and pathogenesis of the ear and situates them within the social and cultural environment of the patient . then , audiovestibular disease is based on evidence , and the treatment options seek to solve the causes and consequences produced . otosociology should be considered as a new discipline . otosociology came into being since otology does not provide definitive solutions for the audiovestibular alterations produced from the point of view of the ear , whereas otosociology finds these solutions within the social / cultural environment of the patient . where otology emphasises the diseases of the ear , otosociology deals with social manifestations . where otology deals with idiopathic diseases , otosociology deals with causes and pathogeny produced by interactions in the social and cultural surroundings of the patient . where otology offers symptomatic treatment , otosociology offers treatment of causes and consequences . otosociology can fill significant voids in audiovestibular processes from the perspective of the patient 's social environment .

PubMed_Summ6512

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: crohn 's disease ( cd ) is a chronic inflammatory disorder of the gastro - intestinal tract [ 1 , 2 , 3 ] ; its exact aetiology and pathogenesis is not known . current models of pathogenesis include interactions between genetic factors , environmental factors , and the intestinal flora which lead to dysregulation of the immune response and to inflammation of the wall of the gastro - intestinal tube [ 4 , 5 ] . exacerbations are due to flares of inflammation of the wall of the gastro - intestinal tube . inflammation in cd is transmural and segmental [ 1 , 4 , 6 ] ; thus it spares certain regions and leaves healthy mucosa between the affected , ulcerated sites . transmural inflammation leads to the development of sinus tracts in the organ 's wall , which can lead to phlegmon , fistulas to neighbouring structures , and abscesses . cd can affect any part of the gastro - intestinal tract from the mouth to the anus , but it most often affects the terminal ileum and the colon [ 3 , 4 ] . over 70% of patients have small bowel involvement , usually of the terminal ileum . about 40% of patients have ileo - colic disease , and 30% present with small intestinal disease . cd of the upper gastro - intestinal tract ( oesophagus , stomach , and duodenum ) is much less frequent and most often associated with involvement of more distal parts of the gastro - intestinal tract [ 1 , 7 , 8 ] . further , upper gastro - intestinal disease may be associated with progression and recurrence of intestinal disease [ 6 , 9 ] . the literature shows variable data regarding the prevalence of upper gastro - intestinal involvement ranging from 0.2 to 16% [ 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] . however , isolated oesophageal cd is a very rare condition [ 1 , 2 , 3 , 7 , 10 , 11 ] . the clinical presentation and endoscopic and histologic findings of oesophageal cd are mostly non - specific and share features of more common diseases of the oesophagus . therefore , accurate diagnosis of oesophageal cd can be very challenging [ 9 , 10 , 11 ] and is often made late in its course [ 2 , 10 ] . in the following we report the case of a relapsing para - oesophageal abscess posing a great diagnostic challenge . a 42-year - old male patient with a para - oesophageal abscess and a fistula into the distal oesophagus was referred to our gastroenterology department in september 2012 for further evaluation and treatment . the past medical history consisted of chronic back pain in the context of a lumbar disc herniation , for which he underwent spinal fusion surgery . [ non - steroidal anti - inflammatory drug ( nsaid ) ] and esomeprazole 40 mg q.d . our patient complained of progressive epigastric pain that did not improve after the nsaid had been withdrawn and esomeprazole was increased to 40 mg b.i.d . on admission he was febrile ( 38.3c ) , palpation of the epigastric region was tender , and laboratory studies showed inflammatory changes with a leucocyte count of 15.6 10/l ( normal value 410 10/l ) , a left shift of neutrophils of 28% ( normal value < 16 ) , and an elevated c - reactive protein ( crp ) level of 282 mg / l ( normal value < 5 ) . thoraco - abdominal computed tomography ( ct ) revealed a para - oesophageal abscess with a maximal extension of 6 cm adjacent to the oesophago - gastric junction and a fistula into the distal part of the oesophagus ( fig . 1 ) . upper endoscopy showed the fistula 's porus at 39 cm from the tooth row ; otherwise the mucosa of the oesophagus , stomach , and duodenum was normal . we performed an endoscopic ultrasound ( eus ) that revealed an asymmetrical thickening of the oesophageal wall adjacent to the abscess , which caused a narrowing of the lumen . histologic specimens taken from the oesophagus revealed chronic inflammation with a preponderance of granulocyte infiltration . we continued treatment with the ppi and inserted a naso - duodenal tube for enteral nutrition . further , we started an intravenous antibiotic therapy with amoxicillin 2,000 mg and clavulanic acid 200 mg t.i.d . endoscopy combined with eus confirmed the complete resolution of the fistula and the abscess , whereas the thickening of the oesophageal wall and the enlarged lymph nodes persisted . because of a possible malignancy , a follow - up endoscopy was performed 2 and 5 months after discharge . only a little pseudo - diverticula remained at the site of the former fistula , the thickening of the oesophageal wall had resolved completely , no other mass could be detected , and the mucosa appeared normal . however , more distally , a partial stenosis remained , impeding the passage of the eus endoscope . as the cause of the abscess remained unclear , we supposed the previous treatment with the nsaid as a possible trigger . oesophageal contrast examination revealed stenosis at the oesophago - gastric junction with a lack of relaxation of the lower oesophageal sphincter documented by high - resolution manometry . two balloon dilations ( 30-mm savary balloon ) achieved good control of the complaints in the following months . after a symptom - free period of 18 months , the patient was referred to our emergency department due to a rapidly progressive odynophagia impeding oral intake of food or fluids . on admission the patient was afebrile ( 36.8c ) and in a poor general state ; blood pressure ( 117/75 mm hg ) and heart rate ( 80 bpm ) were within the normal range . bowel sounds were clearly audible , and palpation of the epigastric region provoked tenderness , but there were no signs of peritonism . otherwise , the clinical examination showed normal findings . laboratory studies revealed inflammatory changes with a leucocyte count of 13.2 10/l and an elevated crp level of 139 mg / l . ct scanning of the thorax and the upper abdomen detected a para - oesophageal air - containing fluid collection of 3.5 cm with an enhancing wall at the same location as the previous abscess had been . the histologic specimen of the oesophagus revealed acute - on - chronic inflammation with ulceration and granulation . again , there was no evidence of an eosinophilic oesophagitis , a tumorous growth , or a fungal infection . in the stomach , minimal non - active unspecific inflammation was detected , and the histology of the duodenum had a normal aspect . culture showed a mixed growth of aerobe and anaerobe bacteria as well as some yeast . a serologic examination for human immunodeficiency virus ( hiv ) was negative ( hiv-1/2 antigen - antibody chemiluminescent microparticle immunoassay ) . studies for cytomegalovirus ( cmv ) revealed undetectable cmv igm , and cmv igg was 138 ae / ml ( normal value < 6 ) . also for varicella zoster virus ( vzv ) , igm was negative and vzv igg was 740 serologic studies for herpes simplex virus ( hsv ) types 1 and 2 showed a raised hsv1/2 igg titre of 41,000 ( normal value < 230 ) and an indeterminate testing for hsv1/2 igm . thus the results regarding hsv types 1 and 2 , vzv , and cmv were consistent with a past infection . anti - saccharomyces cerevisiae antibody igg and iga were positive ( igg 10 u / ml , iga 11 u / ml ; normal value < 7 ) . titre of anti - neutrophil cytoplasmic antibody was normal ( normal value < 1 : 20 ) , whereas titre of anti - nuclear antibody was slightly raised ( > 1 : 80 ; normal value < 1 : 80 ) . helicobacter pylori serology was within normal range ( igg < 10 e / ml ; normal value < 10 ) . the histologic specimens of the terminal ileum , colon , and rectum did not show evidence of a chronic inflammatory disease . mri of the small intestine also showed normal findings . based on the current endoscopic , histologic , and also serologic findings and preclusion of other diseases , we made the diagnosis of cd with isolated involvement of the oesophagus complicated by a recurrent para - oesophageal abscess . we started intravenous antibiotic treatment with amoxicillin 2,000 mg and clavulanic acid 200 mg t.i.d . for 20 days and then changed to an oral regimen of amoxicillin 500 mg and clavulanic acid 125 mg t.i.d . the symptoms resolved rapidly , and the leucocyte count and crp level returned to normal . upper endoscopy with eus performed after 2 weeks of treatment showed only a small residual of the abscess . after 3 days . currently , the patient is treated with azathioprine alone and is still in remission . there are only limited data available regarding the prevalence of oesophageal cd , and the prevalence of upper gastro - intestinal involvement is estimated to be 0.216% in patients with co - existing ileo - colic cd [ 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] . not all patients with cd undergo upper endoscopy ; therefore its prevalence might be underestimated [ 8 , 9 , 11 ] . on the other hand , different study populations are analysed , and also different diagnostic criteria are used to define cd involvement of the upper gastro - intestinal tract and oesophagus . furthermore , the prevalence of upper gastro - intestinal involvement has increased since the 1990s compared to older reports [ 1 , 5 , 12 ] . this is probably due to wider use of endoscopy for clinical staging and research as well as better diagnostic tools [ 7 , 12 ] . the clinical presentation of oesophageal cd varies , ranging from asymptomatic [ 1 , 7 , 12 ] to serious illness [ 2 , 3 , 7 , 8 , 9 , 10 , 13 ] . complications include strictures and stenosis [ 1 , 7 , 10 , 11 , 14 ] , abscesses , and fistulas to neighbouring organs [ 2 , 11 ] such as the respiratory tract [ 1 , 13 ] . as reported by our patient , symptoms are often unspecific in oesophageal cd , resembling those of other oesophageal diseases . most often , patients complain of dysphagia , odynophagia , retrosternal pain , or discomfort [ 1 , 2 , 3 , 4 , 7 , 8 , 10 , 11 , 13 ] . since most cases of oesophageal cd occur in patients with known cd or concurrent intestinal cd , diagnostic procedures may lead towards the correct diagnosis . the diagnostic challenge in our case was the fact that there were no findings to support the diagnosis of cd at the time of first presentation . typical symptoms of intestinal cd ( e.g. , crampy lower abdominal pain or change of bowel habits such as diarrhoea or bloody stool ) . at first presentation , upper endoscopy revealed only the fistula 's porus ; apart from that there was no evidence of a diffuse inflammatory process . almost 3 years later , disseminated oesophageal ulcerations became evident for the first time and raised a high suspicion of cd . the endoscopic and macroscopic findings of oesophageal cd described in the literature range from mild mucosal hyperaemia and superficial aphthous ulcers [ 3 , 8 ] in early disease stages to deep ulcerations and erosions , fistulas , and cobblestone appearance in more advanced disease stages [ 1 , 3 , 5 , 7 , 8 , 9 , 10 , 11 , 14 ] . differential diagnosis of oesophageal cd is broad and includes other causes of oesophageal disease like gastro - oesophageal reflux disease and eosinophilic oesophagitis , drug - induced oesophagitis , viral and fungal infections , tuberculosis , epidermolysis bullosa acquisita , connective tissue disease , and vasculitis as well as malignancy [ 1 , 4 , 8 , 11 ] . in our case non - caseating granulomas are considered to be specific to cd ; however , they are found in less than 40% of biopsies taken from the oesophagus [ 3 , 4 , 5 , 7 , 8 , 11 ] . the histologic findings did therefore not allow endorsing or excluding the diagnosis of cd ; however , chronic and acute - on - chronic inflammation is , although not specific , associated with oesophageal cd [ 1 , 2 , 3 , 7 , 8 , 9 , 10 ] . on the other hand , histology allowed us to exclude other possible causes . malignancy and but since the thickening of the oesophageal wall had resolved , no other mass became evident , and repeated histologic specimens never provided evidence of malignant cells or eosinophilic infiltration , malignancy as well as eosinophilic oesophagitis seemed very unlikely to be the underlying cause . our immunologic examinations for hsv , cmv , vzv , and hiv did not show active infection , and histologically there was no evidence of fungal infection or viral cytopathic effects . signs of a multi - system disease such as connective tissue disease or vasculitis were not evident . ileo - colonoscopy and mri - enterography did not reveal chronic intestinal inflammation ; only some cicatrized sites in the terminal ileum were found . whether they represented the residual of a past , somehow asymptomatic or subclinical inflammation remains unclear . in view of the clinical history of relapsing abscess formation and fistulization , the macroscopic aspect of diffuse ulcerative lesions , histologically chronic and acute inflammation , the positive anti - saccharomyces cerevisiae antibody titre as well as the lack of other aetiologies , we established the diagnosis of isolated oesophageal cd . regarding the treatment of oesophageal cd there are no randomized controlled trials ; evidence is based on case series [ 1 , 4 , 7 , 12 ] . the european crohn 's and colitis organization ( ecco ) proposes ppi for the treatment of oesophageal and gastroduodenal cd . depending on the severity of the disease , ppi can be combined with systemic corticoids , thiopurines , or methotrexate . most authors propose dilation with or without steroid injections for strictures [ 1 , 8 , 9 , 11 , 12 ] , and surgery remains an option for refractory strictures as well as fistulas and abscesses which can not be managed otherwise . some concerns exist that ppi as sole treatment might not be sufficient , since the inflammatory process is not inhibited [ 8 , 15 ] . our patient had been under ppi treatment even before he developed the abscess and the stricture . diagnosis of isolated oesophageal cd can be challenging [ 3 , 8 , 9 , 11 ] , since clinical findings often are non - specific . the diagnosis has to be made by integration of symptoms as well as endoscopic , histologic , and serologic findings [ 3 , 8 , 9 , 11 ] . other , more frequent diseases ( e.g. , malignancy , eosinophilic oesophagitis , and viral or fungal infections ) must be ruled out . OUTPUT:

oesophageal involvement in crohn 's disease ( cd ) is uncommon and most often accompanied by involvement of more distal parts . its presentation is mostly non - specific , and therefore a diagnosis , especially in isolated oesophageal disease , is difficult . we present the case of a 42-year - old male patient who was referred to our gastroenterology department because of a para - oesophageal abscess . under antibiotic treatment the abscess healed , but despite great diagnostic efforts , its aetiology remained unclear . three years later the patient was hospitalized again because of an abscess at the same site . endoscopy showed disseminated ulcerations of the lower oesophagus , raising suspicion of cd . after excluding other possible causes , we made the diagnosis of isolated cd of the oesophagus . we review the available literature on this topic and discuss the clinical presentation , symptoms , endoscopic findings , and histology as well as treatment of oesophageal cd .

PubMed_Summ6513

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: complete debridement and effective disinfection of the root canal space is an important prerequisite for achieving long - term success of nonsurgical endodontics . chemomechanical instrumentation reduces majority of infecting bacteria , together with their principal substrate of necrotic pulp debris but retention of microorganisms within the dentinal tubules is thought to be a source of persistent endodontic infection . the use of an intracanal medicament helps in the elimination of bacteria that remain even after cleaning and shaping , thereby making the environment conducive for periapical tissue repair . it is probable that the physiologic state of the cells , particularly in retreatment cases , is closest to the starvation phase . recent studies have also shown that e. faecalis is highly resistant to commonly used intracanal medicaments , such as calcium hydroxide . even 2% chlorhexidine gluconate has been used as an irrigant and intracanal medicament in endodontics . chlorhexidine has a broad spectrum antimicrobial activity targeting both gram - positive and gram - negative microbes . hence , the combination of chlorhexidine and calcium hydroxide as an intracanal medicament has also been tried to achieve the properties of both medicaments but the antimicrobial action of chlorhexidine was found to be reduced . morinda citrifolia , commercially known as noni , is famous as an important folk medicine and as a health drink . the juice of m. citrifolia has a broad range of therapeutic effects , including antibacterial , antifungal , antiviral , antitumor , antihelminthic , analgesic , hypotensive , anti - inflammatory , and immune - enhancing effects . the effectiveness of m. citrifolia with sodium hypochlorite and chlorhexidine gluconate to remove the smear layer from the canal walls of endodontically instrumented teeth was compared by murray et al . and it was concluded that 6% m. citrifolia can be used as an endodontic irrigant ( as per article after usage of irrigant regime it was concluded ) . a gel based on papain , a proteolytic cysteine enzyme , exhibits significant antibacterial and anti - inflammatory properties . it acts only on affected tissues , which lack the 1-antitrypsine plasmatic antiprotease that inhibits proteolysis in healthy tissues . in addition to papain , the chloramines present have the potential of dissolving carious dentin by means of chlorination of the partially degraded collagen . cosmetic and some medicinal products are made from the mucilaginous tissue in the center of the aloe vera leaf and is called as aloe vera gel . there is no study to comparatively evaluate the antimicrobial activity of natural extracts of m. citrifolia , papain , and aloe vera ( all in gel formulation ) , 2% chlorhexidine gel and calcium hydroxide , against enterococcus faecalis . hence , this study was undertaken to evaluate the disinfection of dentinal tubules when contaminated with e. faecalis using m. citrifolia gel , papain gel , and aloe vera when compared with calcium hydroxide and chlorhexidine gel . a rotary diamond disk was used to decoronate the teeth 5 mm below cementoenamel junction and the apical part of the root to obtain 6 mm of the middle third of the root . 3 ( mani inc , tachigi - ken , japan ) in a slow speed handpiece was used to standardize the internal diameter of the root canals . the blocks were treated in an ultrasonic bath of 17% ethylene diamine tetra acetic acid for 5 min followed by 3% naocl for 5 min to remove the organic and inorganic debris . the traces of chemicals used were removed by immersing the blocks in an ultrasonic bath containing distilled water for 5 min . the first cycle was at 121c and the second was with the blocks immersed in 1 ml of tryptone soya ( ts ) broth in individual microcentrifuge tubes . all the blocks were coated externally with paraffin wax . the test organism used for this study was e. faecalis , which is a gram - positive facultative anaerobic bacterium . e. faecalis ( atcc 29212 ) was grown in ts agar for 24 h. the culture was suspended in 5 ml of ts broth and incubated for 4 h at 37c and its turbidity was adjusted to 0.5 mcfarland standard . each dentin block was placed in presterilized microcentrifuge tubes containing 1 ml of the ts broth . fifty microliters of the inoculum containing the e. faecalis was transferred into each of the microcentrifuge tubes . at the end of 24 h purity of the culture was checked by subculturing 5 l of the broth from the incubated dentin blocks in ts broth on ts agar plates . contamination of the dentin blocks were carried out for a period of 21 days . at the end of 21 days the blocks were irrigated with 5 ml of sterile saline to remove the incubation broth . group 1 : saline ( negative control ) group 2 : calcium hydroxide group 4 : m. citrifolia gel group 5 : aloe vera gel group 6 : 2% chlorhexidine gel calcium hydroxide ( sigma aldrich , mumbai , india ) was mixed with sterile saline in a ratio of 1.5:1 ( wt / vol ) to obtain a paste - like consistency . ltd , gujarat , india . ) was used as a thickening agent in the ratio of 2:1 ( vol / wt ) for group 3 ( papain raw extract taken from fruit ) , group 4 ( m. citrifolia raw extract taken from fruit ) , group 5 ( aloe vera raw extract taken from leaf ) , and group 6 ( chlorhexidine ) . hydroxyethyl cellulose is a nonionic , highly inert , and water - soluble agent and has been used in various studies for gel formation . the medicaments were placed inside the canals and sealed at both the ends with paraffin wax . they were incubated in an anaerobic environment for 37c . at the end of 1 , 3 , and harvesting of the dentin was carried out at 2 depths ( 200 and 400 m ) with gates glidden drills no . 4 and 5 , respectively . the collected dentin shavings were transferred into 1 ml of sterile ts broth and incubated in an anaerobic environment at 37c for 24 h. after 24 h , the contents of each tube was serially diluted , 100 l of the broth in 100 l of sterile saline for 5 times . fifty microliters of the dilution was then plated on ts agar plates and incubated for 24 h. colonies were counted and readings were tabulated as shown in table 1 . mean colony counts for different intracanal medicaments at 200 and 400 m depths at different time intervals the data were statistically analyzed with one - way analysis of variance followed by tukey multiple comparison means to check the difference in bacterial inhibition between the groups ( p < 0.05 ) . the paired t test was used to check for differences in growth at different time intervals within groups and for differences at the 2 depths ( p < 0.05 ) . a rotary diamond disk was used to decoronate the teeth 5 mm below cementoenamel junction and the apical part of the root to obtain 6 mm of the middle third of the root . 3 ( mani inc , tachigi - ken , japan ) in a slow speed handpiece was used to standardize the internal diameter of the root canals . the blocks were treated in an ultrasonic bath of 17% ethylene diamine tetra acetic acid for 5 min followed by 3% naocl for 5 min to remove the organic and inorganic debris . the traces of chemicals used were removed by immersing the blocks in an ultrasonic bath containing distilled water for 5 min . the first cycle was at 121c and the second was with the blocks immersed in 1 ml of tryptone soya ( ts ) broth in individual microcentrifuge tubes . the test organism used for this study was e. faecalis , which is a gram - positive facultative anaerobic bacterium . e. faecalis ( atcc 29212 ) was grown in ts agar for 24 h. the culture was suspended in 5 ml of ts broth and incubated for 4 h at 37c and its turbidity was adjusted to 0.5 mcfarland standard . each dentin block was placed in presterilized microcentrifuge tubes containing 1 ml of the ts broth . fifty microliters of the inoculum containing the e. faecalis was transferred into each of the microcentrifuge tubes . at the end of 24 h purity of the culture was checked by subculturing 5 l of the broth from the incubated dentin blocks in ts broth on ts agar plates . at the end of 21 days the blocks were irrigated with 5 ml of sterile saline to remove the incubation broth . group 1 : saline ( negative control ) group 2 : calcium hydroxide group 4 : m. citrifolia gel group 5 : aloe vera gel group 6 : 2% chlorhexidine gel calcium hydroxide ( sigma aldrich , mumbai , india ) was mixed with sterile saline in a ratio of 1.5:1 ( wt / vol ) to obtain a paste - like consistency . ltd , gujarat , india . ) was used as a thickening agent in the ratio of 2:1 ( vol / wt ) for group 3 ( papain raw extract taken from fruit ) , group 4 ( m. citrifolia raw extract taken from fruit ) , group 5 ( aloe vera raw extract taken from leaf ) , and group 6 ( chlorhexidine ) . hydroxyethyl cellulose is a nonionic , highly inert , and water - soluble agent and has been used in various studies for gel formation . the medicaments were placed inside the canals and sealed at both the ends with paraffin wax . they were incubated in an anaerobic environment for 37c . at the end of 1 , 3 , and harvesting of the dentin was carried out at 2 depths ( 200 and 400 m ) with gates glidden drills no . 4 and 5 , respectively . the collected dentin shavings were transferred into 1 ml of sterile ts broth and incubated in an anaerobic environment at 37c for 24 h. after 24 h , the contents of each tube was serially diluted , 100 l of the broth in 100 l of sterile saline for 5 times . fifty microliters of the dilution was then plated on ts agar plates and incubated for 24 h. colonies were counted and readings were tabulated as shown in table 1 . mean colony counts for different intracanal medicaments at 200 and 400 m depths at different time intervals the data were statistically analyzed with one - way analysis of variance followed by tukey multiple comparison means to check the difference in bacterial inhibition between the groups ( p < 0.05 ) . the paired t test was used to check for differences in growth at different time intervals within groups and for differences at the 2 depths ( p < 0.05 ) . contamination of the dentin blocks was confirmed when debris samples harvested from the saline group ( negative control ) yielded positive growth . table 1 shows the antibacterial activity , measured at 2 depths ( 200 and 400 m ) and at 3 time intervals ( 1 , 3 , and 5 days ) . the inhibition of growth in all the groups was statistically significant in comparison to the control group ( saline ) . group 6 ( 2% chlorhexidine gel ) was the most effective against e. faecalis to the depth of 400 m on all days of incubation . intergroup comparison of inhibition between groups 4 and 5 ( m. citrifolia gel and aloe vera gel ) showed no statistical difference on day 1 , but on days 3 and 5 there was a statistically significant difference . inhibition in group 4 ( m. citrifolia gel ) was also statistically significant compared with groups 3 and 2 ( papain gel and calcium hydroxide , respectively ) on all days ( 1 , 3 , and 5 ) . inhibition in group 3 ( papain gel ) was statistically better than group 2 ( calcium hydroxide ) on day 3 , whereas on days 1 and 5 they had similar efficacy . the inhibition of growth of e. faecalis at 200 and 400 m was uniform with no statistically significant difference for all the groups . the inhibition of growth of e. faecalis at the end of days 1 , 3 , and 5 was varied with different medicaments . group 2 ( calcium hydroxide ) showed sufficient antibacterial activity on day 1 , which decreased on day 3 and again increased by day 5.group 3 ( papain gel ) showed a decrease in antibacterial activity at the end of day 5.group 4 ( m. citrifolia gel ) showed constant antimicrobial efficacy on all the days ( 1 , 3 , and 5 days).group 5 ( aloe vera gel ) showed comparable antibacterial activity to m. citrifolia gel on first day , but there was a gradual decrease in the efficacy by the end of day 5 . group 2 ( calcium hydroxide ) showed sufficient antibacterial activity on day 1 , which decreased on day 3 and again increased by day 5 . group 3 ( papain gel ) showed a decrease in antibacterial activity at the end of day 5 . group 4 ( m. citrifolia gel ) showed constant antimicrobial efficacy on all the days ( 1 , 3 , and 5 days ) . group 5 ( aloe vera gel ) showed comparable antibacterial activity to m. citrifolia gel on first day , but there was a gradual decrease in the efficacy by the end of day 5 . to summarize the results , the overall percentage inhibition at 2 depths and different time intervals was , 100% with chlorhexidine gel , 86.02% with m. citrifolia gel , 78.9% with aloe vera gel , followed by 67.3% papain gel and 64.3% with calcium hydroxide [ figure 1 ] . ( abbreviations : mc , morinda citrifolia ; chx , chlorhexidine gel ; ca(oh)2 ; calcium hydroxide ) currently , the use of natural extracts in dentistry has gained importance both to patients and endodontic professionals as the shift is toward natural health remedies . hence the use of an intracanal medicament made of natural extracts is of great significance . the use of a biocompatible intracanal medicament possessing antimicrobial properties between appointments may reduce or eliminate bacteria in the root canal system and significantly increase the success of root canal treatment . the in vitro model developed by haapasalo and rstavik has been used to assess the efficacy of endodontic medicaments in the disinfection of dentinal tubules . lynne et al . modified this model to include quantitative analysis of bacteria in the dentin tubules to define a percentage of reduction in colony forming units in infected dentin before and after the application of intracanal medication preparations . e. faecalis was chosen as the test organism because it has long been implicated in persistent root canal infections and more recently has been identified as the species most commonly recovered from root canals of teeth with post - treatment disease . this study reveals the effect of newer organic intracanal medicaments ( when used as raw extracts ) against e. faecalis . on an average , chlorhexidine gel showed maximum inhibition of e. faecalis at depths of 200 and 400 m followed by m. citrifolia gel ( 86.02% ) , and aloe vera gel ( 78.9% ) . levels of inhibition of papain ( 67.3% ) and calcium hydroxide ( 64.3% ) were somewhat comparable . in the present study , chlorhexidine gel showed 100% inhibition at depths of 200 and 400 m from day 1 to 5 . the reason could be due to the bactericidal dosage of 2% and increased diffusion of the medicament into the dentinal tubules . showed that 2% chlorhexidine gel produced a better antimicrobial action as compared to 0.2% chlorhexidine gel or calcium hydroxide mixed with 0.2% chlorhexidine . m. citrifolia gel showed 86.02% inhibition at depths of 200 and 400 m from day 1 to 5 . claim that the presence of l - asperuloside and alizarin may be responsible for the antibacterial and antimicrobial property of m. citrifolia . this improved performance could be attributed to the increased contact time and physical contact of the gel . these results are in accordance with another study conducted by wang et al . , wherein 2% chlorhexidine solution when converted into gel form performed better than the solution alone . further studies are needed to determine the optimum concentration of m. citrifolia required when used in gel form as an intracanal medicament against e. faecalis . aloe vera showed 78.72% and 80% inhibition at depths of 200 and 400 m from day 1 to 5 . first day results of aloe vera gel were comparable to that of m. citrifolia gel , but the values declined over day 3 and 5 . the possible reason for antimicrobial action of aloe vera could be the presence of 75 potentially active constituents : vitamins , enzymes , minerals , sugars , lignin , saponins , salicylic acids , and amino acids . the pharmacologic actions of aloe vera , as studied in vitro or in animals ( in most cases the total leaf extract was used ) include anti - inflammatory , antibacterial , and hypoglycemic effects . gel based on papain showed 68.05% and 67.28% inhibition at depths of 200 and 400 m from day 1 to 5 . this was probably due to proteolytic cysteine enzyme present in papain , which exhibits antibacterial and anti - inflammatory properties . calcium hydroxide showed 63.82% and 66.22% inhibition at depths of 200 and 400 m from day 1 to 5 . gomes et al . reported that e. faecalis present in the dentinal tubules were resistant to calcium hydroxide intracanal dressing over 10 days . calcium hydroxide had decreased efficacy on day 3 , but had an increased antimicrobial efficacy at day 5 . chlorhexidine gel showed the maximum antimicrobial activity against e. faecalis , whereas calcium hydroxide showed the least . among the natural intracanal medicaments , m. citrifolia gel consistently exhibited good inhibition up to the day 5 followed by aloe vera gel and papain gel . OUTPUT:

aim : a comparative evaluation of the antimicrobial activity of natural extracts of morinda citrifolia , papain , and aloe vera ( all in gel formulations ) , 2% chlorhexidine gel and calcium hydroxide , against enterococcus faecalis an in vitro study.materials and methods : the antimicrobial efficacy was assessed in vitro using dentin shavings collected at 2 depths of 200 and 400 m . the total colony forming units at the end of 1 , 3 , and 5 days were assessed.results:the overall percentage inhibition of bacterial growth ( 200 and 400 m depth ) was 100% with chlorhexidine gel . this was followed by m. citrifolia gel ( 86.02% ) , which showed better antimicrobial efficacy as compared with aloe vera gel ( 78.9% ) , papain gel ( 67.3% ) , and calcium hydroxide ( 64.3% ) . there was no statistical difference between data at 200 and 400 m depth.conclusion:chlorhexidine gel showed the maximum antimicrobial activity against e. faecalis , whereas calcium hydroxide showed the least . among the natural intracanal medicaments , m. citrifolia gel consistently exhibited good inhibition up to the 5th day followed by aloe vera gel and papain gel .

PubMed_Summ6514

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: antiphospholipid syndrome ( aps ) is an autoimmune disease characterized by thrombosis and morbidity , specifically in pregnancy , due to antiphospholipid antibodies . about half of the cases of aps occur as a primary disorder , while the rest arise in association with other autoimmune diseases , such as systemic lupus erythematosus ( sle ) . some diseases , such as pulmonary thrombosis and pulmonary hypertension , are known to be complicated by aps ; however , aps with pleural effusion is extremely rare . here , we present a case of aps complicated by unilateral pleural effusion that responded well to oral corticosteroid therapy . a 75-year - old japanese man was admitted to our hospital for spreading erythema on his trunk and extremities , as well as dyspnea . one year prior to admission , he visited us with a 1-year history of erythema and purpura on his legs , accompanied by intermittent fever . results of laboratory examinations for antiphospholipid antibodies , lupus anticoagulant ( using the phospholipid neutralization test ) , and anticardiolipin antibody had been positive 12 weeks apart . in addition , he showed positive antinuclear antibody ( 1:80 , homogeneous pattern ) , but was negative for anti - dsdna antibody , anti - sm antibody , anti - rnp antibody , anti - ss - a antibody , anti - ss - b antibody , antitopoisomerase i antibody , and anticentromere antibody . mpo - anca , pr3-anca , and cryoglobulin were negative . given the diagnosis of aps , we initiated combination therapy with aspirin ( 100 mg daily ) and warfarin ( target international normalized ratio , 2.03.0 ) , but the skin lesions continued to gradually worsen . violaceous erythema , purpura , and pigmentation were widely noted on his trunk and extremities ( fig . 1 ) ; they were associated with low platelets ( 93,000/l ) and elevated partial thromboplastin time ( 48.4 s ) . a biopsy specimen revealed marked thrombosis in the dermal and subcutaneous small vessels ( fig . 2 ) . there were interface changes of the dermo - epidermal junction and mild inflammatory infiltrates in the perivascular area of the dermis , but mucin deposition and thickening of the basal layer of the epidermis were not apparent . in addition , a chest x - ray and computed tomography demonstrated a large pleural effusion in the left lung ( fig . 3 ) , without evidence of large vessel thrombus . electrocardiogram and echocardiogram were normal . despite serial thoracenteses , effusion recurred . bacterial and fungal cultures , as well as cytology analyses for malignant cells , were all negative . after excluding infectious diseases , malignancies , pulmonary thrombosis , and heart failure , we added oral prednisolone ( 30 mg daily ) to his prior anticoagulant regimen . the skin lesions and the pleural effusion improved rapidly , eventually disappearing without complication ( fig . 4 ) . on follow - up clinical examinations , no symptoms related to sle or other collagen diseases were noted . common causes of pleural effusion include malignancies , infectious diseases , pulmonary embolism , collagen vascular disease , and heart failure . aps - related pleural effusion has rarely been reported , and those cases that have been reported appeared to be complications of accompanying pulmonary embolism , sle , or catastrophic aps [ 4 , 5 , 6 ] . pleuritis , which can induce pleural effusion , is the most common pleuropulmonary manifestation of sle . in the present case , after excluding these differential diagnoses , aps was determined to be the direct cause of the pleural effusion . however , a strong possibility still exists that the pleural effusion may be associated with occult collagen vascular disease , particularly sle or lupus - like disease ( lld ) heretofore undiagnosed . a long - term follow - up study in 128 patients with primary aps demonstrated that 11 patients ( 8% ) developed sle , while 6 ( 5% ) developed lld during a median follow - up period of 8.2 years ( range , 114 years ) . the results of this study suggest that the pleural effusion may be attributed to a coexisting condition like lld , although our patient has not fulfilled american college of rheumatology diagnostic sle criteria to date . this may be supported by the fact that oral corticosteroid therapy was a remarkably effective treatment of the pleural effusion that had previously been unsuccessfully treated by anticoagulant therapy and repeated drainage . corticosteroids and immunosuppressants continue to be the treatment of choice for severe sle complications , including pleural effusion . furthermore , the clinical manifestations of primary aps and aps associated with sle are similar , which makes it more difficult to differentiate these diseases . as pleural effusion can be life - threatening corticosteroids might be an effective choice of treatment for intractable pleural effusion in aps patients . OUTPUT:

antiphospholipid syndrome ( aps ) with pleural effusion is extremely rare . a 75-year - old man was admitted to our hospital for spreading erythema on his trunk and extremities , as well as dyspnea . one year before admission , he had visited us with a 1-year history of erythema and purpura on his legs and occasional fever . given the diagnosis of aps , we initiated a combination therapy of aspirin and warfarin , but the skin lesions had gradually worsened . a biopsy specimen revealed marked thrombosis in the dermal and subcutaneous small vessels . in addition , chest x - ray and computed tomography demonstrated a large pleural effusion in the left lung . he underwent repeated drainage of the pleural effusion but the effusion recurred . we added oral prednisolone 30 mg daily to his prior anticoagulant therapy . the skin lesions and pleural effusion rapidly improved and disappeared without any complication . corticosteroids might be a choice of treatment for intractable pleural effusion in aps patients .

PubMed_Summ6515

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: surgically treated patients with hepatocellular carcinoma ( hcc ) , which represent a highly selected group , have higher survival rates compared to those of medically treated patients at a comparable stage . however , long - term prognosis remains unsatisfactory because of the high incidence of tumor recurrence and metastasis after hepatectomy . thus , identification of markers of poor prognosis is important in order to provide the opportunity for timely intervention . high proliferation rate , a classic hallmark of cancer , is due to the self - sufficiency of growth signals , insensitivity to anti - growth signals , and limitless replicative potential . a variety of methods , including analysis of proliferating cell nuclear antigen , bromodeoxyuridine , argyrophilic nuclear organized regions , ki-67 nuclear antigen , and phosphorylated histone h3 , are used in evaluation of proliferative activity [ 5 - 7 ] . however , many of these methods can not be applied in daily clinical practice . in contrast , the mitotic index , which is a useful and simple method for analysis of cell proliferation , can be easily applied to routine clinical practice . the prognostic role of mitotic index in patient survival has been confirmed in several cancers . in addition , mitotic index has been incorporated in the american joint committee on cancer ( ajcc ) seventh tumor staging system for malignant melanoma , gastrointestinal tumor , and neuroendocrine tumors of the gastrointestinal tract . in hccs , previous studies indicated a potential role of high mitotic index as an adverse prognostic indicator in cohorts of fewer than 200 patients . however , the practical utility of mitotic index as a predictor of prognosis in patients with hcc has not been determined . in this study , we evaluated mitotic index as a possible prognostic marker in a large cohort of 282 patients with primary hcc who received long - term follow - up for 120 months . we also attempted to determine the cutoff value for mitotic index that showed the most significant prognostic role in hcc patients . a total of 290 patients who were pathologically confirmed to have primary hcc and underwent curative resection at samsung medical center , seoul , korea between july 2000 and may 2006 were enrolled in this study . eight patients who received preoperative treatments , including transcatheter arterial chemoembolization , radiofrequency ablation , and radiation therapy , were excluded ; therefore , 282 patients were included in this study . curative resection was defined as complete resection of all tumor nodules with clear microscopic resection margins and no residual tumors on computed tomography scans performed 1 month after surgery . clinical parameters , including age , gender , date of surgery , serum -fetoprotein ( afp ) , and serum albumin , were obtained by reviewing the medical records . when the tumor was less than 3 cm in size , all tumors were sectioned and embedded . when the tumor was larger than 3 cm in size , at least four sections were taken for the pathologic examinations and the mean number of blocks was one for 1 cm of tumor diameter . histopathologic features of hccs , including histologic differentiation , microvascular invasion , major portal vein invasion , intrahepatic metastasis , multicentric occurrence , and non - tumor liver pathology , were reviewed by two pathologists ( s.y.h . and c .- k.p . ) . intrahepatic metastasis and multicentric occurrence were determined according to the criteria of the liver cancer study group of japan . hcc recurrence within the first two years following surgery is mainly due to intrahepatic metastasis , whereas late recurrence usually results from multicentric occurrence . using 2 years as a cutoff , all patients were staged according to the ajcc staging system and barcelona clinic liver cancer ( bclc ) staging classification . during follow - up , serum afp levels were monitored and three phase dynamic computed tomography scan or magnetic resonance imaging was performed every 3 months after surgery . the median follow - up period was 120 months ( range , 14 to 151 months ) for survivors . recurrence - free survival ( rfs ) was measured from the date of surgery until detection of tumor recurrence . disease - specific survival ( dss ) was defined as the interval between the date of surgery and the date of hcc - related death , which was defined as : ( 1 ) the tumor occupying more than 80% of the liver , ( 2 ) portal venous tumor thrombus proximal to the second bifurcation , ( 3 ) obstructive jaundice due to the tumor , ( 4 ) distant metastases , and ( 5 ) variceal hemorrhage with portal venous tumor thrombus proximal to the first bifurcation . two liver pathologists ( s.y.h . and c .- k.p . ) counted the number of mitotic cells in 10 high - power fields ( hpfs ) of hematoxylin and eosin - stained slides , and found areas containing the most mitotic figures , the so - called hot spot . after counting the mitoses in the hot spot , if no hot spot could be found and mitoses were sparse and randomly scattered throughout the lesion , a representative mitosis was chosen and the count began with that field and was extended to adjacent fields . according to the criteria of mitotic figures defined by baak , mitotic cells were counted only if there was complete concordance between the two pathologists using a multi - head microscope . the x - tile statistics package ( yale university , new haven , ct ) was used to determine the optimal cutoff value with the highest level of statistical significance related to patient survival ; cases were dichotomized into low and high mitotic index groups based on the established cutoff value . analysis of the association between mitotic index and clinicopathologic parameters was performed using the chi - square test , fisher exact test , or cochran armitage test . differences in survival rates were assessed using the log - rank test or breslow test . the cox proportional hazard regression model was used to assess the association between clinicopathologic factors and survival time . we examined the proportional hazard assumption graphically to determine whether variables in the cox proportional hazard model were constants that do not depend on time . a total of 290 patients who were pathologically confirmed to have primary hcc and underwent curative resection at samsung medical center , seoul , korea between july 2000 and may 2006 were enrolled in this study . eight patients who received preoperative treatments , including transcatheter arterial chemoembolization , radiofrequency ablation , and radiation therapy , were excluded ; therefore , 282 patients were included in this study . curative resection was defined as complete resection of all tumor nodules with clear microscopic resection margins and no residual tumors on computed tomography scans performed 1 month after surgery . clinical parameters , including age , gender , date of surgery , serum -fetoprotein ( afp ) , and serum albumin , were obtained by reviewing the medical records . when the tumor was less than 3 cm in size , all tumors were sectioned and embedded . when the tumor was larger than 3 cm in size , at least four sections were taken for the pathologic examinations and the mean number of blocks was one for 1 cm of tumor diameter . histopathologic features of hccs , including histologic differentiation , microvascular invasion , major portal vein invasion , intrahepatic metastasis , multicentric occurrence , and non - tumor liver pathology , were reviewed by two pathologists ( s.y.h . and c .- k.p . ) . intrahepatic metastasis and multicentric occurrence were determined according to the criteria of the liver cancer study group of japan . hcc recurrence within the first two years following surgery is mainly due to intrahepatic metastasis , whereas late recurrence usually results from multicentric occurrence . using 2 years as a cutoff , all patients were staged according to the ajcc staging system and barcelona clinic liver cancer ( bclc ) staging classification . during follow - up , serum afp levels were monitored and three phase dynamic computed tomography scan or magnetic resonance imaging was performed every 3 months after surgery . the median follow - up period was 120 months ( range , 14 to 151 months ) for survivors . recurrence - free survival ( rfs ) was measured from the date of surgery until detection of tumor recurrence . disease - specific survival ( dss ) was defined as the interval between the date of surgery and the date of hcc - related death , which was defined as : ( 1 ) the tumor occupying more than 80% of the liver , ( 2 ) portal venous tumor thrombus proximal to the second bifurcation , ( 3 ) obstructive jaundice due to the tumor , ( 4 ) distant metastases , and ( 5 ) variceal hemorrhage with portal venous tumor thrombus proximal to the first bifurcation . two liver pathologists ( s.y.h . and c .- k.p . ) counted the number of mitotic cells in 10 high - power fields ( hpfs ) of hematoxylin and eosin - stained slides , and found areas containing the most mitotic figures , the so - called hot spot . after counting the mitoses in the hot spot , if no hot spot could be found and mitoses were sparse and randomly scattered throughout the lesion , a representative mitosis was chosen and the count began with that field and was extended to adjacent fields . according to the criteria of mitotic figures defined by baak , mitotic cells were counted only if there was complete concordance between the two pathologists using a multi - head microscope . the x - tile statistics package ( yale university , new haven , ct ) was used to determine the optimal cutoff value with the highest level of statistical significance related to patient survival ; cases were dichotomized into low and high mitotic index groups based on the established cutoff value . analysis of the association between mitotic index and clinicopathologic parameters was performed using the chi - square test , fisher exact test , or cochran armitage test . differences in survival rates were assessed using the log - rank test or breslow test . the cox proportional hazard regression model was used to assess the association between clinicopathologic factors and survival time . we examined the proportional hazard assumption graphically to determine whether variables in the cox proportional hazard model were constants that do not depend on time . the median patient age was 53 years ( range , 17 to 76 years ) ; 234 patients were males , and 48 were females . two hundred and eighteen patients ( 77.3% ) were infected with hepatitis b virus , and 26 ( 9.2% ) with hepatitis c virus . two hundred and three patients ( 72.0% ) suffered from tumor recurrence ; 153 patients ( 54.3% ) from early recurrence , and 50 patients ( 17.7% ) from late recurrence . twenty - nine of the 127 deaths were due to non - hcc related causes . seventeen of the 29 deaths were due to hepatic failure ; eight were due to non - hepatic causes , and four were due to unknown causes . the mean mitotic index was 7.75 ( 95% confidence interval , 6.47 to 9.03 ) and the median value was 3.00 ( range , 0 to 60 ) . using the x - tile package , mitotic index was graded as low ( 4 or less mitoses per 10 hpfs ) or high ( 5 or more mitoses per 10 hpfs ) ( fig . high mitotic index showed significant association with younger age ( p < 0.001 ) , larger tumor size ( p=0.022 ) , higher edmondson grade ( p < 0.001 ) , microvascular invasion ( p < 0.001 ) , major portal vein invasion ( p=0.026 ) , intrahepatic metastasis ( p < 0.001 ) , higher afp level ( p < 0.001 ) , hepatitis b virus etiology ( p=0.012 ) , and liver cirrhosis ( p=0.016 ) . as the ajcc t - stage or bclc stage increased , the frequency of high mitotic index also showed a significant increase ( p < 0.001 and p < 0.001 , respectively ) . the 3- , 5- , 7- , and 9-year rfs rates for 282 hcc patients were 43.5% , 37.2% , 31.1% , and 30.0% , respectively . the 3- , 5- , 7- , and 9-year dss rates were 75.1% , 67.1% , 59.6% , and 53.4% , respectively . patients with high mitotic index had shorter dss ( p < 0.001 ) and tended to have shorter rfs ( p=0.112 ) ( fig . 2 ) . by applying the breslow test , which attributes greater weight to earlier events , patients with high mitotic index had shorter rfs ( p=0.003 ) . in subgroup analysis among patients with a larger tumor size ( > 5 cm ) , microvascular invasion , intrahepatic metastasis , higher ajcc t - stage , and higher blcl stage , high mitotic index showed unfavorable influences on dss ( p=0.001 , p=0.008 , p=0.003 , p=0.012 , and p < 0.001 , respectively ) ( fig . larger tumor size , edmondson grade iii , microvascular invasion , major portal vein invasion , intrahepatic metastasis , higher ajcc t - stage , higher bclc stage , lower albumin level , and higher afp level showed unfavorable influences on both rfs and dss . in addition , we found that high mitotic index showed an unfavorable influence on dss ( p < 0.001 ) ( table 2 ) . because ajcc t - stage and bclc stage were associated with vascular invasion , to avoid potential bias we did not perform multiple analyses using these indices . in multivariate analysis , intrahepatic metastasis and lower albumin level larger tumor size and high mitotic index ( p=0.004 ) were found to be independent predictors of shorter dss . patients with high mitotic index were more likely to suffer from disease - specific death compared to those with low mitotic index ( hazard ratio , 1.818 ) ( table 3 ) . multivariate analysis of rfs with mitotic index could not be performed , because the survival curves according to mitotic index were crossed and the proportional hazard assumption was violated . the median patient age was 53 years ( range , 17 to 76 years ) ; 234 patients were males , and 48 were females . two hundred and eighteen patients ( 77.3% ) were infected with hepatitis b virus , and 26 ( 9.2% ) with hepatitis c virus . two hundred and three patients ( 72.0% ) suffered from tumor recurrence ; 153 patients ( 54.3% ) from early recurrence , and 50 patients ( 17.7% ) from late recurrence . twenty - nine of the 127 deaths were due to non - hcc related causes . seventeen of the 29 deaths were due to hepatic failure ; eight were due to non - hepatic causes , and four were due to unknown causes . the mean mitotic index was 7.75 ( 95% confidence interval , 6.47 to 9.03 ) and the median value was 3.00 ( range , 0 to 60 ) . using the x - tile package , mitotic index was graded as low ( 4 or less mitoses per 10 hpfs ) or high ( 5 or more mitoses per 10 hpfs ) ( fig . high mitotic index showed significant association with younger age ( p < 0.001 ) , larger tumor size ( p=0.022 ) , higher edmondson grade ( p < 0.001 ) , microvascular invasion ( p < 0.001 ) , major portal vein invasion ( p=0.026 ) , intrahepatic metastasis ( p < 0.001 ) , higher afp level ( p < 0.001 ) , hepatitis b virus etiology ( p=0.012 ) , and liver cirrhosis ( p=0.016 ) . as the ajcc t - stage or bclc stage increased , the frequency of high mitotic index also showed a significant increase ( p < 0.001 and p < 0.001 , respectively ) . the 3- , 5- , 7- , and 9-year rfs rates for 282 hcc patients were 43.5% , 37.2% , 31.1% , and 30.0% , respectively . the 3- , 5- , 7- , and 9-year dss rates were 75.1% , 67.1% , 59.6% , and 53.4% , respectively . patients with high mitotic index had shorter dss ( p < 0.001 ) and tended to have shorter rfs ( p=0.112 ) ( fig . 2 ) . by applying the breslow test , which attributes greater weight to earlier events , patients with high mitotic index had shorter rfs ( p=0.003 ) . in subgroup analysis among patients with a larger tumor size ( > 5 cm ) , microvascular invasion , intrahepatic metastasis , higher ajcc t - stage , and higher blcl stage , high mitotic index showed unfavorable influences on dss ( p=0.001 , p=0.008 , p=0.003 , p=0.012 , and p < 0.001 , respectively ) ( fig . larger tumor size , edmondson grade iii , microvascular invasion , major portal vein invasion , intrahepatic metastasis , higher ajcc t - stage , higher bclc stage , lower albumin level , and higher afp level showed unfavorable influences on both rfs and dss . in addition , we found that high mitotic index showed an unfavorable influence on dss ( p < 0.001 ) ( table 2 ) . because ajcc t - stage and bclc stage were associated with vascular invasion , to avoid potential bias we did not perform multiple analyses using these indices . in multivariate analysis , intrahepatic metastasis and lower albumin level larger tumor size and high mitotic index ( p=0.004 ) were found to be independent predictors of shorter dss . patients with high mitotic index were more likely to suffer from disease - specific death compared to those with low mitotic index ( hazard ratio , 1.818 ) ( table 3 ) . multivariate analysis of rfs with mitotic index could not be performed , because the survival curves according to mitotic index were crossed and the proportional hazard assumption was violated . in the current study , we elucidated the prognostic significance of mitotic index in a large cohort of patients with primary hcc who received long - term follow - up . we attempted to establish a cutoff value for mitotic index that showed the most significant prognostic role in hcc patients . low mitotic index was defined as four or fewer mitoses per 10 hpfs , and high mitotic index as five or more . high mitotic index showed correlation with larger tumor size , higher edmondson grade , microvascular invasion , major portal invasion , intrahepatic metastasis , higher ajcc t - stage , higher bclc stage , higher afp level , hepatitis b virus etiology , and liver cirrhosis . in addition , patients with high mitotic index had shorter dss and tended to have shorter rfs . the mean time gap between recurrence and death in the high mitotic index group was significantly lower than in the low mitotic index group ( 30.5 months vs. 43.8 months , p=0.004 ) . treatment modality after recurrence did not differ statistically between low versus high mitotic index group ( p=0.38 ) ( supplementary table 1 ) . it is assumed that the high mitotic index group had poorer response to the salvage treatment after recurrence than the low mitotic index group . only a few studies on the prognostic role of mitotic index in hcc haratake et al . , who divided mitotic index into three groups ( 0 - 4/10 hpfs , 5 - 9/10 hpfs , 10 and more/10 hpfs ) , observed a better prognosis for patients with hcc who exhibited low mitotic activity . they reported that longer survival periods were observed in some patients with larger tumors if the mitotic indices were low . ouchi et al . showed that mitotic index was an independent significant variable , influencing the overall survival of 40 patients with hcc following hepatic resection . in addition , they found that hcc with a high mitotic index ( 5/10 hpfs ) was associated with multiple tumors and advanced tumor stage . they also reported a highly significant correlation between mitotic index and ki-67 labelling index ( r=0.870 ) . nanashima et al . also reported correlation of high mitotic index ( 5/10 hpfs ) with overall survival in 81 patients with hcc by univariate analysis . they also found a significant association of high mitotic index with vascular invasion , poor histologic differentiation , and recurrence rate . interestingly , the criteria of mitotic index used in previous studies are the same as those applied in our study , which were determined statistically for the strongest prognostic effect . to the best of our knowledge , this is the first report to show that high mitotic index is an independent predictor of shorter dss . hcc recurrence within the first 2 years following surgery is mainly due to intrahepatic metastasis , whereas recurrence after 2 years following surgery usually results from multicentric occurrence of hcc . it is assumed that the high mitotic index group did not show shorter rfs after 48 months following surgery , because recurrence after 48 months following surgery was mainly due to newly developed hcc . the most outstanding finding of this study is that subgroup analysis among patients with larger tumor size , microvascular invasion , intrahepatic metastasis , higher ajcc t - stage , and higher blcl stage showed unfavorable influences of high mitotic index on dss . counting mitotic cells is a simple , rapid , and inexpensive method which can be routinely performed in daily practice . our data show , for the first time , that high mitotic index is an independent predictor of shorter dss in surgically resected hccs . prospective studies are needed to further investigate the role of mitotic index as a prognostic factor in hcc . OUTPUT:

purposehigh proliferation rate is a hallmark of cancer . the mitotic index is a useful and simple method for analysis of cell proliferation . however , the practical utility of mitotic index as a predictor of prognosis in patients with hepatocellular carcinoma ( hcc ) has not been determined . therefore , we examined mitotic index as a prognostic marker in hcc patients.materials and methodswe counted the number of mitotic cells in 10 high - power fields of the tumor area on hematoxylin and eosin stained slides representing 282 surgically resected hccs . the highest number of mitotic cells was defined as the mitotic index.resultshigh mitotic index was observed in 127 of 282 hccs . high mitotic index showed significant association with younger age , larger tumor size , higher edmondson grade , microvascular invasion , major portal vein invasion , intrahepatic metastasis , higher american joint committee on cancer ( ajcc ) t - stage , higher barcelona clinic liver cancer ( bclc ) stage , higher alpha - fetoprotein level , hepatitis b virus etiology , and liver cirrhosis . patients with high mitotic index had shorter disease - specific survival ( dss ) ( p < 0.001 ) and tended to have shorter recurrence - free survival ( p=0.112 ) . in subgroup analysis among patients with a larger tumor size , microvascular invasion , intrahepatic metastasis , higher ajcc t - stage , and higher blcl stage , high mitotic index showed unfavorable influences on dss ( p=0.001 , p=0.008 , p=0.003 , p=0.012 , and p < 0.001 , respectively ) . in addition , high mitotic index was an independent predictor of shorter dss ( p=0.004).conclusionhigh mitotic index may be a novel predictor of dss in patients with hcc and may have utility as an auxiliary prognostic factor in hcc .

PubMed_Summ6516

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: prostate cancer is the most common cancer diagnosed in new zealand ( nz ) males and the third most common cause of male cancer deaths.1 generally prostate cancer is a slow growing cancer with relatively good prognosis , with 80% of patients with localised disease being still alive at 15 years.2 around 70% of men in nz are identified with low - grade prostate cancer with a good prognosis.3 unfortunately , some men present with advanced disease and their first symptoms may be due to metastases . the stage and grade of cancer will obviously influence treatment options , as will the presence of various co - morbidities.4 men with metastatic prostate cancer may be offered pharmacologic androgen deprivation therapy ( adt ) , specific chemotherapeutic medication or be treated with orchidectomy.5 in new zealand , mori men are less likely to be diagnosed with prostate cancer but have a 70% increased risk of dying compared with non - mori men.6 moreover , mori men diagnosed with non - localised prostate cancer have a threefold risk of dying from the disease compared with non - mori men.7 variation in treatment may be one of the reasons for the observed survival disparities . in the uk , increased use of adt has been linked to the trend of decreasing mortality.8 it is possible that variation in the use of adt also contributes to the survival differences between mori and non - mori men with non - localised prostate cancer . however , little information is available on the use of adt and chemotherapeutic agents in prostate cancer patients in new zealand . the aim of this study was to ascertain the patterns of dispensing adt , including anti - androgens and luteinising hormone - releasing hormone ( lhrh ) analogues , and chemotherapeutic agents in new zealand men within the first year after prostate cancer diagnosis . we also explored the effect of age , ethnicity , year of diagnosis and orchidectomy on pharmacologic adt use . this nationwide audit of androgen deprivation therapy and chemotherapy treatment for prostate cancer was undertaken in new zealand , a nation of 4.5 million people with a universally subsidised health system that includes free public hospital and pharmaceutical care . we identified a cohort of men diagnosed with prostate cancer between 1 january 2006 and 31 december 2011 from the new zealand cancer registry ( nzcr , http://www.health.govt.nz/nz-health-statistics/national-collections-and-surveys/collections/new-zealand-cancer-registry-nzcr ) , which collects data on all new cases of malignant cancers in nz excluding squamous cell carcinoma and basal cell carcinoma of the skin . for each patient nzcr data included date of diagnosis , extent of disease at diagnosis , age at diagnosis , and ethnicity . the extent of cancer at diagnosis is coded in the nzcr as follows : b ( localised ) , c ( invasion of adjacent tissues or organs ) , d ( invasion of regional lymph nodes ) , e ( distant metastases ) , and f ( unknown ) . for the purpose of our study , only about one - quarter of prostate cancer cases have an extent at diagnosis listed in the nzcr , and the accuracy of the extent has not been assessed yet . therefore , the extent of prostate cancer at diagnosis used in this study needs to be understood as that recorded in the nzcr , and may potentially differ from the actual extent at diagnosis . data for the cohort of men identified from the nzcr were linked to the pharmaceutical collection by a unique encrypted number derived from the national health index ( nhi ) number , which is unique for every public health system user in new zealand . the pharmaceutical collection is an administrative claims database that contains information from pharmacists on dispensing subsidised medications . once a funded prescription is dispensed in new zealand the data are collected in a national repository and available for analysis . in addition to prescriber details , the medication name , strength , quantity and dosage are recorded . for our study , data were extracted on androgen deprivation therapy , including anti - androgens ( flutamide , bicalutamide , cyproterone ) and lhrh analogues ( goserelin , leuprorelin ) , and also on chemotherapeutic agents ( doxorubicin , epirubicin , paclitaxel , mitozantrone , docetaxel ) . the information included chemical i d , indicating the primary active chemical ingredient , and the therapeutic group level 1 - 3 ( more detail on http://www.pharmac.health.nz/tools-resources/pharmaceutical-schedule ) . in addition , registration data were linked to the national minimum dataset ( national collection of public and private hospital discharge information on inpatients and day patients ) to identify men treated with orchidectomy . men with prostate cancer morphology not consistent with adenocarcinoma ( 67 ) , men with unknown ethnicity ( 1478 ) and those diagnosed at death ( 374 ) were excluded from the analysis . in addition , 17 men were excluded because their domicile was listed as overseas . we examined the frequency of adt and chemotherapy use in the first year after the initial diagnosis by patients ' age ( < 60 years , 60 - 69 years , 70 - 79 years , 80 + years ) , ethnicity ( mori , pacific and non - mori / non - pacific ) , and extent of disease at diagnosis . differences between distributions were tested using the or fisher exact test ( when sub - group sample sizes were small ) . probability ( p ) multivariate logistic regression models were constructed to assess the likelihood of use of adt for patients with advanced ( regional spread and metastatic ) prostate cancer , adjusting for age , ethnicity , year of diagnosis and orchidectomy . the final study population included 15,947 men diagnosed with prostate cancer in new zealand in the six years between 2006 and 2011 . table 1 summarises the demographic information ( age and ethnicity ) by extent of prostate cancer at diagnosis . most men were diagnosed between the ages of 60 and 79 years ( 68.2% ) . there were 908 ( 5.7% ) mori men , 445 ( 2.8% ) pacific men , and 14,594 ( 91.5% ) non - mori / non - pacific men in the sample . the proportion of mori men in the 2006 census total nz male population of 50 + years ( since most prostate cancer cases occur in men aged 50 + ) was 7% , while pacific males comprised 3% , and non - mori / non - pacific men 90% . in total , 15.0% of men were recorded as having localised extent at diagnosis , 7.6% regional spread , 5.8% metastases , and 71.7% were recorded with unknown extent . androgen deprivation therapy ( flutamide , bicalutamide , cyproterone , goserelin , leuprorelin ) or chemotherapeutic agents ( doxorubicin , epirubicin , paclitaxel , mitozantrone , docetaxel ) were dispensed for 4978 ( 31.2% ) men in the first year following their initial diagnosis . most of the patients received doxorubicin ( 11 ) , with docetaxel being the second most common agent used ( 5 ) . due to such a small sample size , patients with chemotherapy were not considered in the regression analysis . within the first year post - diagnosis , pharmacologic adt was dispensed for 47 patients with localised prostate cancer at diagnosis ( 1.9% of all men with localised disease recorded in the nzcr ) , 266 patients with regional spread ( 22.1% ) and 664 patients with distant metastases ( 71.8% ) . due to the small number and proportion of patients with localised disease who received adt within one year post - diagnosis , further analysis focused on patients with regional and metastatic prostate cancer . figures 1 and 2 show the frequency of types of pharmacologic adt by age , ethnicity and extent of disease at diagnosis ( regional spread , distant metastases , and all extent ( including localised , regional , distant and unknown extent ) . in patients with metastatic cancer , anti - androgens ( 60.1% ) were used more commonly than lhrh analogues ( 50.1% ; p<0.0001 ) . by contrast , overall ( all extents ) , more patients received lhrh analogues ( 25.5% ) than anti - androgens ( 20.6% ; p<0.0001 ) as did patients with regional spread ( 18.8% v. 14.8% ; p=0.008 ) . men younger than 70 years overall and specifically those diagnosed with regional prostate cancer were less likely to receive adt compared with older men ( 21.3% v. 44.5% ; p<0.0001 ; 17.0% v. 37.8% ; p<0.0001 , respectively ) . however , in men diagnosed with metastatic cancer those aged under 70 were more likely to receive adt than older men ( 80.4% v. 69.0% ; p=0.001 ) . overall , adt was less likely to be dispensed for non - mori / non - pacific men than for mori and pacific men ( 30.5% v. 38.5% ; p<0.0001 , and v. 38.9% ; p<0.0001 , respectively ) . in men with regional disease , pacific men were more likely to receive adt compared to non - mori / non - pacific men ( 44.0% v. 21.4% ; fisher exact test p=0.01 ) and they were also more likely to receive anti - androgens than non - mori / non - pacific and mori men ( 40.0% v. 14.1% ; fisher exact test p=0.002 , and v. 16.4% ; fisher exact test p=0.03 , respectively ) . in men with metastatic prostate cancer , mori men were more likely to receive anti - androgens than non - mori / non - pacific men ( 72.5% v. 58.2% ; fisher exact test p=0.02 ) . similarly to anti - androgens and lhrh analogues , orchidectomy can be used to achieve reduction of testosterone levels and thus reduce prostate cancer growth.5 in our sample , 3.3% of patients ( 165 out of 4968 who were prescribed anti - androgens or lhrh analogues ) underwent orchidectomy within the first year after initial diagnosis . the majority of these men ( 77.6% ) received either anti - androgens or lhrh analogues but not both in that year . in addition , there were 202 men who underwent orchidectomy but did not receive pharmacologic adt ( 1.8% of men with prostate cancer not on pharmacologic adt ) in the first year post - diagnosis . since our further analyses focus on men with advanced ( regional spread or metastatic ) prostate cancer , table 2 shows distribution of orchidectomy by age , ethnicity , and pharmacologic adt use separately for all patients and for those with advanced cancer . men older than 70 years with advanced cancer were treated more commonly by orchidectomy only ( 10.0% v. 1.8% ; fisher exact test p<0.0001 ) , and they were also more likely to undergo orchidectomy overall compared with men younger than 70 ( 7.8% v. 3.2% ; fisher exact test p<0.0001 ) . mori men with any extent were more likely to be treated by orchidectomy compared to non - mori / non - pacific men ( 3.4% v. 2.2% ; p<0.0001 ) . in order to assess the use of adt from the clinical point of view , patients with advanced cancer were categorised into three groups , i.e. those who received anti - androgens only , those who received lhrh analogues only and those who received both anti - androgens and lhrh analogues within the first year post diagnosis . in men with advanced cancer , 53.2% ( out of all men on adt ) received both anti - androgens and lhrh analogues within the first year post - diagnosis , followed by those who received anti - androgens only ( 25.8% ) and those who received lhrh analogues only ( 21.0% ) . table 3 shows the distribution of anti - androgens and lhrh analogues use individually and in combination in men with advanced disease . a significantly larger proportion of men older than 70 years at diagnosis received anti - androgens only compared with men younger than 70 ( 29.4% v. 19.4% ; fisher exact test p=0.001 ) , while a significantly larger proportion of non - mori / non - pacific men received lhrh analogues only compared with mori and pacific men ( 22.7% v. 11.7% ; fisher exact test p=0.03 , and v. 6.5% ; fisher exact test p=0.009 , respectively ) . multiple logistic regression models were used to assess the effect of age at diagnosis , ethnicity , year of diagnosis , and orchidectomy on the use of adt ( anti - androgens and lhrh analogues alone or combined ) in men with advanced cancer at diagnosis . six different models were built : model i included age only ; model ii age and ethnicity ; model iii age , ethnicity and year of diagnosis ; model iv age and orchidectomy ; model v age , ethnicity and orchidectomy ; and model vi included age , ethnicity , year of diagnosis and orchidectomy ( table 4 ) . in all models , age was a contributing factor , with older men with advanced cancer being more likely to receive adt . mori and pacific men ( compared with non - mori / non - pacific men ) were approximately 2.1- and 3.1-fold more likely to receive pharmacologic adt when adjusting for age and combinations of age , year of diagnosis and orchidectomy . however , year of diagnosis and orchidectomy in the same year did not seem to pose as confounders and did not significantly contribute to the models . the aim of this study was to assess the frequency of use of adt and chemotherapeutic agents for nz men in the first year after cancer diagnosis , particularly for metastatic patients for whom adt should be prescribed immediately.9 therefore , we have not followed up the cohort for a longer period of time . seventy two percent of men recorded as having metastatic disease at diagnosis received pharmacologic adt ( anti - androgens and/or lhrh analogues ) . whilst a small number of men with prostate cancer had an orchidectomy ( 2% ) , it seems that a quarter of men with advanced prostate cancer did not receive hormonal treatment . since management guidelines for locally advanced and particularly metastatic prostate cancer clearly include use of androgen deprivation therapy as part of the treatment pathway5,10 , there is a need for improvement in this area in new zealand . in comparison , in the usa 95% patients diagnosed between 1994 and 2002 with stage iv disease received either surgical or pharmacologic adt , while 16% received chemotherapy.11 in our sample , chemotherapeutic agents were used very rarely in the first year post - diagnosis . some of the chemotherapeutic agents , such as docetaxel were first subsidised in 2011 , so they would not appear in the pharmaceutical collection previously . there seems to be a greater potential for the use of these agents and newer treatments in men with hormone - refractory advanced prostate cancer.5 older men with metastatic disease in particular were less likely to receive pharmacologic adt . a larger proportion of men older than 70 years at diagnosis received anti - androgens only compared to men younger than 70 . contrary to our expectations mori and pacific men were more likely to receive adt than non - mori / non - pacific men . mori men were more likely to be treated with orchidectomy , while they were less likely to receive lhrh analogues when compared with non - mori / non - pacific men . the dispensing of pharmacologic adt and use of orchidectomy for reduction of testosterone levels in advanced prostate cancer was influenced mainly by patients ' age and ethnicity . men with advanced prostate cancer were more likely prescribed both anti - androgens and lhrh analogues in the first year as opposed to anti - androgens or lhrh analogues alone . data from other countries showed that physician preference has an important influence on the use of adt4 , as do the presence of subsidies12 , patient 's age and tumour grade at diagnosis.13 thus the solution to improved dispensing is likely to involve a greater understanding of the barriers to prescribing from the physicians ' perspective but also of patients ' views on adt use . the strength of this study is that we used data linkage to assess use of adt nationally . men registered with prostate cancer in the new zealand cancer registry were identified and this information was linked to the national dataset of pharmaceutical dispensings as well as to the national minimum dataset to ensure that the use of orchidectomy did not introduce a bias into our analysis . this allowed us to undertake a large - scale pharmaco - epidemiological study on the dispensing of adt and chemotherapeutic agents , which is quite unique internationally . studies from other countries investigated the use of adt in certain patient groups , such as medicare beneficiaries or patients visiting specialist services , but to our knowledge none were population - based.11,14 - 18 in addition , several of the most recent studies were restricted to prostate cancer patients with localised disease . these studies highlighted the benefits of using adt as primary or adjuvant therapy , particularly in high - risk patients.14 - 17 the main weakness of our study is that 72% of men registered with prostate cancer had the extent of disease recorded as unknown . this may have reduced the power of the study and introduced bias if men with advanced disease with known extent in the nzcr were treated differently than men with advanced disease at diagnosis whose extent was recorded as unknown . prostate cancer is similar to bladder and liver cancer with respect to the low recording of extent at diagnosis . although the proportion of incident prostate cancer cases with known extent at diagnosis slightly improved from 25.7% to 28.1% between 2006 and 2010 , for further research into prostate cancer on national level it will be essential to at least achieve proportions of known extent similar to colorectal and breast cancer , where more than 80% of cases have known extent recorded.6 the new zealand cancer control council is currently reviewing the reporting of all cancers in an effort to improve the availability of data in the nzcr , including extent at diagnosis.19 another weakness may be potentially incomplete information linkage either due to incomplete coverage of nhi numbers or deficiencies in reporting . however , the use of nhi numbers across the country was on average 95% during the study period , and more than 95% of all prescriptions recorded in the pharmaceutical collection have had an nhi attached . in addition , the reporting of pharmaceutical cancer data by district health boards was voluntary until july 2008 , which may have affected data linkage in the first years of the study . however , the frequency of adt use in the first year after diagnosis was 70.2% for men diagnosed with distant metastases in 2006 - 2007 and 70.9% for those diagnosed in 2009 - 2010 . therefore , even if changes in data recording within this period might have had an impact , it does not appear to be substantial . this audit showed that there is a clear under - utilisation of adt and particularly chemotherapeutic agents in nz men with advanced prostate cancer . particularly in men with distant metastases OUTPUT:

purpose : to assess the patterns of use of androgen deprivation therapy ( adt ) and chemotherapeutic agents in new zealand men with prostate cancer.methods : men diagnosed with prostate cancer between 2006 and 2011 were identified from the new zealand cancer registry . through data linkage with the pharmaceutical collection and the national minimum dataset information on subsidised anti - androgens , luteinising hormone - releasing hormone ( lhrh ) analogues , chemotherapeutic agents , and orchidectomy was retrieved . the frequency of adt and chemotherapy use in the first year post - diagnosis was assessed by patients ' age , ethnicity , and extent of disease at diagnosis.results : the study population included 15,947 men diagnosed with prostate cancer , of whom 4978 ( 31% ) were prescribed adt or chemotherapeutic agents . adt was dispensed for 72% of men with metastatic disease . only 24 ( 0.2% ) men received chemotherapeutic agents . men with advanced ( regional or metastatic ) disease older than 70 were more likely to receive anti - androgens only and to be treated with orchidectomy compared with younger men . mori and pacific men ( compared with non - mori / non - pacific men ) were more likely to receive pharmacologic adt , and mori men were also more likely to be treated with orchidectomy.conclusions : it was expected that all men diagnosed with metastatic prostate cancer should be using adt in the first year post - diagnosis . however , for more than one - fourth of men neither anti - androgens nor lhrh analogues were dispensed within this period . chemotherapeutic agents were used very rarely , so it seems that both pharmacologic adt and chemotherapy is under - utilised in new zealand patients with advanced prostate cancer .

PubMed_Summ6517

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: to describe the surgical technique and initial experience with a single - port retroperitoneal renal biopsy ( sprrb ) . a single 1.5 cm incision was performed under the 12th rib at mid - axillary line , and an 11 mm trocar was inserted . after lower pole exposure , a laparoscopic biopsy forceps was introduced through the nephroscope working channel to collect a renal tissue sample . the mean operative time was 32 minutes , and mean estimated blood loss was less than 10 ml . the hospital stay of all patients was two days because they were discharged in the second postoperative day , after remaining at strict bed rest for 24 hours after the procedure . sprrb is a simple , safe and reliable alternative to open and videolaparoscopic approaches to surgical renal biopsy . image - guided percutaneous renal biopsy is the most widely used method to sample renal parenchyma for the evaluation of malignancy or diffuse renal disease . the risks of this procedure are minimal and the overall success rate of all renal biopsies varies from 70 to 100% ( 1 ) . its major indications rest on diagnosis and follow - up of several systemic and nephrological conditions that lead to glomerular damage and renal function impairment , providing useful data for treatment and prognosis . it may also be used for evaluation of solid renal masses and cystic renal lesions ( 1 ) . however , this method has absolute and relative contraindications that may hamper or preclude it , such as the presence of a solitary kidney , uncontrolled arterial hypertension , coagulation disorders , renal artery aneurysm , previous percutaneous needle biopsy failure and obesity . bleeding and inadequate amounts of renal tissue for diagnosis are not infrequent , and constitute potential disadvantages of the procedure . in addition , children may be unable to cooperate , requiring general anesthesia . in these settings , open and laparoscopic approaches are well - established alternatives and should be considered , although with a higher level of invasiveness and complexity . in search for an alternative that could minimize surgical aggressiveness of these procedures and hence spread its use , we outlined a renal biopsy technique through a single retroperitoneal laparoscopic access using standard urological instruments . the aim of this paper is to describe the technique now standardized in our institution and our initial experience with the single port retroperitoneal renal biopsy ( sprrb ) . after receiving general anaesthesia , orogastric and bladder catheterization , the patient is usually positioned in the left flank position , as the kidney is more easily accessible at the right side due to its lower position . a 1.5 cm incision is carried out just below the tip of the 12th rib , at the mid - axillary line , and is followed by blunt access to the retroperitoneum space . an initial digital dissection is done aiming to identify the lower renal pole , while also displacing the peritoneum anteriorly . during this step , care must be taken in order to avoid peritoneal tearing , as the pneumoperitoneum resulting from gas insufflation would hamper the maintenance of adequate retroperitoneal working space . next , a rubber balloon is positioned between the kidney and the posterior abdominal wall , and is filled with 300 - 400 cc of saline , creating a virtual cavity . the saline is drained after a few minutes , to achieve hemostasis , and the balloon is then removed . an 11 mm trocar is inserted and carbon dioxide is used to maintain pneumoretroperitoneum at 12 to 15mmhg . retroperitoneal inspection and identification of the psoas muscle and the lower pole of the kidney are now performed with a standard 26 french nephroscope , as shown in figure-1 . it is frequently possible to expose the renal surface bluntly , by using gentle movements of the tip of the scope to drag the perirenal fat away from the intended site of biopsy . alternatively , standard laparoscopic surgical aspirator , scissors or hooks can be inserted through the working channel of the nephroscope , and then be used to dissect , cut and coagulate nearby structures , allowing a clear renal surface to be assessed . once the biopsy site is cleared from fat , one or two samples are taken with the aid of a toothed biopsy forceps , also through the nephroscope ( figure-2 ) . bleeding is expected to be negligible , as the injury caused by the forceps is shallow ( figure-3 ) , but the parenchyma can be coagulated with the same instruments , and a cellulose hemostatic bolster can be applied , if needed . finally , the pneumoretroperitoneum is evacuated and , if no bleeding is observed , the trocar is removed and the access port is closed . figure 2sampling renal parenchyma with a toothed biopsy forceps , through the nephroscope working channel . figure 3aspect of kidney surface after a tissue sample was taken , with only minimal bleeding . at our institution , laparoscopic retroperitoneal renal biopsy is currently often performed for pediatric patients with nephrological conditions ( 2 ) . as the surgical team s experience progressed and the procedure was standardized , however , we felt that it should be even less invasive , especially for this very young population . additionally , in order to spread and popularize its execution , we devised how to use instruments that are already present in a regular urological operating room , such as the nephroscope and laparoscopic scissors and forceps , in a different fashion . a similar approach has been described previously , in pediatric surgery , for appendectomies and varicocelectomies , but with only one case of renal biopsy ( 3 ) . between january and april/2013 , five children underwent sprrb in our hospital , referred from the nephrology clinic for renal biopsy . informed consent was previously obtained from parents , respecting our institution s ethics committee recommendations and approval . the procedure was successfully performed with the technique above described , by a supervised resident in - training . the overall mean operative time was 32 minutes , and mean estimated blood loss was less than 10 ml . no open conversion was needed . the hospital stay of all patients was two days because they were kept in absolute bed rest for 24 hours after the procedure , before being discharged home . pain and analgesics use were low , and there were no significant detected complications . regarding the obtained samples , the average number of glomeruli present in the specimens was 31 , and the histopathological findings showed focal proliferative lupus glomerulonephritis in two cases , diffuse mesangial proliferative glomerulonephritis in another two , and nephritis related to henoch - schnlein purpura in one child . these results are comparable to those previously shown by us , with laparoscopic renal biopsy in children , regarding operative time , blood loss , hospital stay and success in obtaining adequate samples ( 2 ) . table 1clinical features of patients submitted to single - port retroperitoneal renal biopsy.patientgenderage ( years)bmi ( kg / m)ot ( min.)bl ( ml)gndiagnosiscomplications1m0723.625423diffuse mesangial proliferative glomerulonephritisnone2f0924.5371338nephritis related to henoch - schnlein purpuranone3f1121.827530focal proliferative lupus glomerulonephritisnone4m1024.0401743diffuse mesangial proliferative glomerulonephritissmall skin ecchymosis5f1232.031621focal proliferative lupus glomerulonephritisnoneaverage-9.825.1832931 - - bmi = body mass index ( kg / m ) ; ot = operative time ( minutes ) ; bl = blood loss ( milliliters ) ; gn = number of glomeruli per biopsy . bmi = body mass index ( kg / m ) ; ot = operative time ( minutes ) ; bl = blood loss ( milliliters ) ; gn = number of glomeruli per biopsy . although it is likely that the same approach could be used in adult patients as well . our experience with this very initial group was composed entirely of children , and sprrb has been shown to be a very simple , safe and reliable alternative to other laparoscopic approaches . the use of a nephroscope , instead of a regular laparoscope , obviates the need to place an additional trocar for using an auxiliary instrument to dissect the perirenal fat , as is the standard practice ( 4 , 5 ) . its working channel finely substitutes that , sparing one incision , the cost of another trocar and also surgical time to place it . because a second trocar traditionally would be only 5 mm wide , it may seem that the benefit here is not strongly relevant in terms of postoperative pain or cosmetic results , but it is our understanding that no technical difficulty was added whatsoever , by using only one access . moreover , especially children could benefit the most even of a small effect , and coincidently they constitute the majority of patients requiring a surgical renal biopsy in our hospital . mini - perc nephroscopes are not available at our institution at this time , but its use could be a step forward , in this regard , and further decrease the required size of the access port incision . additionally , the ease for urologists in using regular urological equipment , and the possibility that the surgeon simultaneously controls both the camera and laparoscopic scissor / biopsy forceps , are other advantages of this alternative method . in our hospital , retroperitoneal laparoscopy is the procedure of choice for renal biopsy in children and the sprrb is an even less invasive option for these patients , performed through a single incision and with very satisfactory results and only minor pain . OUTPUT:

objective to describe the surgical technique and initial experience with a single - port retroperitoneal renal biopsy ( sprrb).materials and methods between january and april 2013 , five children underwent sprrb in our hospital . a single 1.5 cm incision was performed under the 12th rib at mid - axillary line , and an 11 mm trocar was inserted . a nephroscope was used to identify the kidney and dissect the perirenal fat . after lower pole exposure , a laparoscopic biopsy forceps was introduced through the nephroscope working channel to collect a renal tissue sample.results sprrb was successfully performed in five children . the mean operative time was 32 minutes , and mean estimated blood loss was less than 10 ml . the hospital stay of all patients was two days because they were discharged in the second postoperative day , after remaining at strict bed rest for 24 hours after the procedure . the average number of glomeruli present in the specimen was 31.conclusion sprrb is a simple , safe and reliable alternative to open and videolaparoscopic approaches to surgical renal biopsy .

PubMed_Summ6518

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: cystic fibrosis ( cf ) is the most common autosomal recessive disorder among caucasians with an incidence rate of 1 in 2,500 individuals . the epithelial cells of several organs , including respiratory tract , exocrine pancreas , intestine , vas deferens , hepatobiliary system and also exocrine sweat glands are involved in cf . therefore several clinical features , including suppurative lung disease , pancreatic insufficiency , neonatal bowel obstruction ( meconium ileus ) , multifocal biliary cirrhosis , absent vas deferens to malabsorbtive condition and growth retardation could be seen in affected patients [ 2 , 3 ] . high sweat electrolytes ( chloride and sodium ) concentration , which is seen in cf patients became basis for sweat chloride test since 1949 . the measurement of sweat electrolyte concentrations was established as a standard procedure for diagnosis of cf and remained the gold standard test for the diagnosis of cf . the diagnosis of cf could easily be made in the majority of cases based on typical clinical features and abnormal sweat chloride values . in such situations , genetic analysis of cystic fibrosis transmembrane conductance regulator ( cftr ) gene is not necessary . however , it may be useful in confirming the diagnosis , which also enables carrier testing and prenatal diagnosis [ 6 , 7 ] . the universally accepted reference intervals for sweat chloride concentrations regardless of age or sex are > 60 mmol / l , which is considered diagnostic of cf ; 4060 mmol / l is considered borderline , whilst < 40 in addition to sweat chloride concentrations , sweat sodium is also usually measured , as there is little difference between sweat sodium and chloride concentrations [ 810 ] in order to ensure accurate results from a quantitative sweat test using filter paper , a minimum sweat rate of 1g / m / min corresponding to 75 mg collected in 30 minutes is required ( for a 22 inch filter paper ) . conventionally , it takes around 45 minutes to collect proper volume ( 50400 mg ) sweat for accurate test , which makes the classic sweat test as a time consuming procedure . indeed many local laboratories in developing countries have not been approved to do the test for both techniques of sweat gathering and also electrolytes measuring . forming of salt crystallization of perspiration described by ferre calvete et al could be considered as a useful and alternative test for easy detecting cf patients in these regions . therefore , we designed this study to compare the results obtained by these two methods . in this study , 60 children with clinical signs suggestive of cf , who were referred to the children 's medical center , pediatrics center of excellence in iran , were investigated . the study protocol was approved by the research ethics board of the childrens medical center , tehran university of medical sciences . classic sweat tests ( gibson and cooke sweat test ) and crystallization test were performed for each subject for at least two times in the referral laboratory of the hospital . localized sweating was produced by iontophoresis of pilocarpine nitrate ( gibson and cook method ) using wescor gel discs [ 5 , 12 ] a copper electrode was then attached and a weak electrical current of about 3 milli - amperes ( ma ) was generated using a 9-volt battery for 5 minutes to stimulate sweating . immediately following stimulation , a preweighed filter paper was placed directly over the site of the positive electrode . at the end of the collection about one hour later , the filter paper was removed and the weight was determined . the test was repeated for two or three times in all subjects to confirm the results . meanwhile one drop of each sample was put on lamella and heated by the light of microscope for 5 minutes . sixty children ( 29 females and 31 males ) with age range of 9 months to 2 years had taken part in this study . meq / l , while it was 49.81meq / l in the male group without any significant difference between genders ( p>0.05 ) . cf was diagnosed for the remaining 29 patients who showed positive values of sweat classic test . 1 ) , which provided the test with 100% sensitivity ( ci : 93.1100 ) . only one of 31 subjects without cf ( 17 males and 14 females ; aged 9 months to 2 years ) had positive crystallization test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) . crystal formation in sweat sample of cystic fibrosis patients cystic fibrosis ( cf ) is one of the most frequent ( 1 in 2500 ) autosomal recessive diseases characterized by substantial clinical heterogeneity recent studies have begun to identify chromosomal locations that identify specific genes contributing to this variation . over the past several decades , there has been substantial progress toward diagnostic tools of cf . determination of chloride concentration in sweat is the current diagnostic gold standard for cf . the conventional sweat test with elevated sweat sodium and chloride concentration after iontophoresis of pilocarpine is the standard laboratory test for cf . an accurate sweat test relies on coordination of several factors . technical error of instrument calibration and result reporting the tests should be performed by expert personnel to ensure sufficient sweat volumes and proper use of equipment . the centers doing such tests should follow standard guidelines to reduce complexity in interpreting a variety of result ranges [ 14 , 15 ] advanced equipments and experienced personnel which are necessary for accurate classic sweat test made this test unavailable for many centers , especially in developing countries . although sweat studies became standard diagnostic strategy for diagnosis of cf , it has some limitations whilst it may be unreliable due to not enough collected sweat or borderline values . indeed genetic studies to detect cftr mutation(s ) take time and may even find no useful information . therefore selecting the best cost - benefit method with high sensitivity and specificity is needed for diagnosis of cf . for this reasons nanoduct as a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes is also introduced as a reliable diagnostic tool . nanoduct has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion , diagnosis or suspicion of cf . sands and his colleagues indicated that simultaneous bilateral sweat testing with two different methods ( concentration and conductivity or nonoduct ) provides an extra quality control system , allowing more time efficient organization of the diagnostic and training procedures . forming of salt crystallization of perspiration seems as an attractive and alternative test for easy detecting cf patients . in this study , we have shown that looking for salt crystals in just one drop of sweat could diagnose cf , since crystal formation of sweat under light microscope was detected in a significant number of cf patients . comparing these two methods of sweat test showed good positive predictive value of 96.7% and the negative predictive value of 100% with specificity and sensitivity of 96.7% and 100% , respectively . therefore , the test could be a very useful alternative test , whenever the classic test is not accessible . since the classic sweat test measuring chloride levels with the use of acceptable methods ( gibson - cooke or wescor macroduct ) should be performed in centers that conduct sweat tests frequently with properly documented controls , we recommend sweat crystallization test as an alternative test for cf diagnosis at least in areas where neither classic sweat test nor genotyping are accessible . limitations : there were some limiting factors to consider in interpreting the study 's result . first , this study was conducted on a relatively small sample size . ideally , a larger and more popular sample size would perhaps delineate more suitable differences between the two methods of cf diagnosis in children with cystic fibrosis . second , this study compared two kinds of test in children whose first presentation was compatible with cystic fibrosis , although this would not be statistically a problem . as further study , comparing two methods of the mentioned tests between cf patients and normal children could be more helpful . this study demonstrates the validity of sweat crystal formation test to support a diagnosis of cf in children whenever conventional sweat test is unavailable . in this study , 60 children with clinical signs suggestive of cf , who were referred to the children 's medical center , pediatrics center of excellence in iran , were investigated . the study protocol was approved by the research ethics board of the childrens medical center , tehran university of medical sciences . classic sweat tests ( gibson and cooke sweat test ) and crystallization test were performed for each subject for at least two times in the referral laboratory of the hospital . localized sweating was produced by iontophoresis of pilocarpine nitrate ( gibson and cook method ) using wescor gel discs [ 5 , 12 ] a copper electrode was then attached and a weak electrical current of about 3 milli - amperes ( ma ) was generated using a 9-volt battery for 5 minutes to stimulate sweating . immediately following stimulation , a preweighed filter paper was placed directly over the site of the positive electrode . at the end of the collection about one hour later , the filter paper was removed and the weight was determined . the test was repeated for two or three times in all subjects to confirm the results . meanwhile one drop of each sample was put on lamella and heated by the light of microscope for 5 minutes . sixty children ( 29 females and 31 males ) with age range of 9 months to 2 years had taken part in this study . meq / l , while it was 49.81meq / l in the male group without any significant difference between genders ( p>0.05 ) . cf was diagnosed for the remaining 29 patients who showed positive values of sweat classic test . 1 ) , which provided the test with 100% sensitivity ( ci : 93.1100 ) . only one of 31 subjects without cf ( 17 males and 14 females ; aged 9 months to 2 years ) had positive crystallization test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) . cystic fibrosis ( cf ) is one of the most frequent ( 1 in 2500 ) autosomal recessive diseases characterized by substantial clinical heterogeneity recent studies have begun to identify chromosomal locations that identify specific genes contributing to this variation . over the past several decades , there has been substantial progress toward diagnostic tools of cf . determination of chloride concentration in sweat is the current diagnostic gold standard for cf . the conventional sweat test with elevated sweat sodium and chloride concentration after iontophoresis of pilocarpine is the standard laboratory test for cf . technical error of instrument calibration and result reporting are major factors that affect the results . the tests should be performed by expert personnel to ensure sufficient sweat volumes and proper use of equipment . the centers doing such tests should follow standard guidelines to reduce complexity in interpreting a variety of result ranges [ 14 , 15 ] advanced equipments and experienced personnel which are necessary for accurate classic sweat test made this test unavailable for many centers , especially in developing countries . although sweat studies became standard diagnostic strategy for diagnosis of cf , it has some limitations whilst it may be unreliable due to not enough collected sweat or borderline values . indeed genetic studies to detect cftr mutation(s ) take time and may even find no useful information . therefore selecting the best cost - benefit method with high sensitivity and specificity is needed for diagnosis of cf . for this reasons nanoduct as a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes is also introduced as a reliable diagnostic tool . nanoduct has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion , diagnosis or suspicion of cf . sands and his colleagues indicated that simultaneous bilateral sweat testing with two different methods ( concentration and conductivity or nonoduct ) provides an extra quality control system , allowing more time efficient organization of the diagnostic and training procedures . forming of salt crystallization of perspiration seems as an attractive and alternative test for easy detecting cf patients . in this study , we have shown that looking for salt crystals in just one drop of sweat could diagnose cf , since crystal formation of sweat under light microscope was detected in a significant number of cf patients . comparing these two methods of sweat test showed good positive predictive value of 96.7% and the negative predictive value of 100% with specificity and sensitivity of 96.7% and 100% , respectively . therefore , the test could be a very useful alternative test , whenever the classic test is not accessible . since the classic sweat test measuring chloride levels with the use of acceptable methods ( gibson - cooke or wescor macroduct ) should be performed in centers that conduct sweat tests frequently with properly documented controls , we recommend sweat crystallization test as an alternative test for cf diagnosis at least in areas where neither classic sweat test nor genotyping are accessible . limitations : there were some limiting factors to consider in interpreting the study 's result . ideally , a larger and more popular sample size would perhaps delineate more suitable differences between the two methods of cf diagnosis in children with cystic fibrosis . second , this study compared two kinds of test in children whose first presentation was compatible with cystic fibrosis , although this would not be statistically a problem . as further study , comparing two methods of the mentioned tests between cf patients and normal children could be more helpful . this study demonstrates the validity of sweat crystal formation test to support a diagnosis of cf in children whenever conventional sweat test is unavailable . OUTPUT:

objectivesweat chloride measurement is considered a standard diagnostic tool for cystic fibrosis ( cf ) . this study was performed to compare sweat chloride values obtained by quantitative pilocarpine iontophoresis ( classic test ) with sweat crystallization detected by direct observation of a drop of perspiration under light microscopy in patients with and without cf.methodsthe tests using both techniques were performed simultaneously in patients with and without cf . cutoff values of 60 mmol / l of chloride concentration for the classic sweat test was considered for diagnosis of cf . in crystallization method , observation of typical dendritic forms of salt crystals under light microscopy was interpreted positive.findingssixty patients suspected to cf ( 31 males and 29 females ) with age range of 9 months to 2 years underwent the sweat test using both techniques . median sweat chloride values was 26.13 + 10.85 in group with negative and 72.76 + 12.78 mmol / l in group with positive sweat test , respectively . all the patients who had positive sweat test in classic method showed typical dendritic forms of salt crystal in sweat crystallization test , which provided the test with 100% sensitivity ( 95%ci : 93.1100 ) . only one of the 31 subjects with negative results for classic sweat test had positive result for crystallization sweat test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) . time spent to perform the crystallization test was significantly shorter than the classic method whereas its cost was also lower than the second method.conclusionthere was a good correspondence between two studied methods of sweat test . these results suggested the sweat crystallization test as an alternative test for detecting cf disease with high sensitivity and specificity .

PubMed_Summ6519

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: an important aspect of any research is the use of appropriate methodologies either to control or to reduce the effects of potential confounding factors . a matter of great concern that can influence the results of epidemiological studies of dental caries is the variation in disease diagnosis between two or more examiners ( interexaminer error ) and for the same examiner in two or more occasions ( intraexaminer error ) . therefore , it is very important that data collection measures are standardized in order to minimize measurements variations1 . the calibration process including the determination of reliability , with both previous and ongoing epidemiological survey , is a basic step to understand and standardize the examination criteria , and also to evaluate the interexaminer variability in order to ensure accurate results15,17 . the assessment of reliability is the most employed measure in dental caries surveys during the examiners ' calibration . reliability is related to the extent to which examiners agree in their evaluations16 . the most used measures to assess reliability in epidemiological studies of dental caries are the overall percentage of agreement and the kappa statistics11 . kappa test is a measurement of reliability that takes into consideration the agreement among raters by chance , providing better evaluation of interexaminer disagreement during calibration processes5 . the purposes of this study were : a ) to evaluate interexaminer reliability in caries detection considering different diagnostic thresholds and b ) to indicate , by using kappa statistics , which is the best way of measuring interexaminer agreement during the calibration process in dental caries surveys . the epidemiological examinations were initiated after approval of the study design by the research ethics committee of the dental school of piracicaba , state university of campinas , brazil ( protocol no . the volunteers ' parents signed an informed consent form authorizing the enrollment of the children in the study . dentists with previous experience in epidemiological surveys examined schoolchildren at baseline , 3 and 6 months after initial training , using two diagnostic thresholds on dental caries : who criteria , traditionally used in epidemiological surveys17 and who+il including the diagnostic of initial caries lesions ( il , white spot lesions ) , after being calibrated by a " gold standard " examiner , a dentist who routinely uses the who criteria for exams and had been previously trained and calibrated in il diagnosis . eleven dentists with previous experience in epidemiological surveys of dental caries were invited to participate in this study . schoolchildren aged 6 - 7 years from two public schools in piracicaba , sp , brazil , were selected by a dentist , according to their caries activity . the dentists used mirror , cpi probe , air - drying for examination after the children brushed their teeth . the exclusion criteria were : use of fixed orthodontic device , presence of severe fluorosis and/or hypoplasias , and severe systemic diseases . for each training or calibration period of training , 10 to 13 different children were selected . two diagnostic thresholds were used to record dental caries : 1 ) who threshold ( dmft index ) following the who codes and criteria17 , in which a tooth is considered as decayed when a cavitation is present ; 2 ) who+il threshold , in which active initial lesions were also recorded following criteria adapted from nyvad , et al.13 and fyfee , et al.6 . an il was defined as an active carious lesion which , upon visual assessment by a calibrated examiner , presented intact surface , no clinically detectable loss of dental tissue , with a rough , whitish / yellowish colored area of increased opacity presumed to be carious ( when the cpi probe was used , its tip should be moved gently across the surface ) . il locates close to gingival margin in smooth surfaces or extending along walls of fissure in occlusal surfaces . each examiner was helped by a recorder during the study . a benchmaker examiner ( " gold standard " ) conducted the training processes with both theoretical and practical activities , which lasted 20 hours ; and the calibration exercises , which lasted 8 hours at each phase : baseline , 3 and 6 months after initial training . the training and calibration processes were conducted by the gold - standard examiner using two diagnostic thresholds on dental caries , as described in previous studies2,3 . during theoretical discussions , the benchmaker examiner showed the examiners some photographic slides with clinical examples of each criterion that would be used in the study , in order to determine the examiners ' knowledge about epidemiological diagnosis , to instruct them on the criteria and examination method to be used , and finally , to achieve an initial standardization among them . the clinical training consisted of 4 periods of 4 hours each , and was conducted in an outdoor setting . each dentist examined 10 to 13 children , with distinct caries activity and prevalence , per period . during this phase , examiners discussed clinical diagnosis , study codes and criteria , recording and other errors in order to reach an acceptable level of agreement ( kappa>0.8517 ) . the calibration exercises , in which the examiners did not discuss their findings , were carried out in 2 periods of 4 hours each , with a 1-week interval . these were also undertaken after 3 and 6 months , after the first calibration phase ( baseline ) . the epidemiological examinations were carried out in an outdoor setting , under conditions such as natural light , with dental mirror and ball - ended cpitn probes with a diameter of 0.5 mm ( to remove debris , assess the presence of fissure sealants and , in case of doubt , to check the surface texture of il ) . toothbrushing with fluoridated dentifrice was performed by the children , under supervision of a dental hygienist , following the bass modified technique during approximately two minutes . tooth air - drying ( approximately 5 seconds per tooth ) was performed by using compressed air delivered by a dental compressor ( wetzel : medical line 3.6/30 0.5 hp ) . a program using microsoft excel has been developed by the department of community dentistry of fop - unicamp to calculate the interexaminer reliability by means of the kappa statistics7 that has been recommended by the who17 and the british association of community dentistry15 for evaluation of agreement among examiners in oral health surveys . the code recorded for each dental unit or surface was entered for each examiner , in accordance with the different diagnosis thresholds ( who ; who+il ) used in the three calibration phases . the objective of the statistical analysis was to assess interexaminer reliability under different caries diagnostic thresholds and different ways of analysis . thus , interexaminer reliability was calculated by using kappa statistics , according to two diagnosis thresholds ( who ; who+il ) and considering : a ) the entire dentition ; b ) upper / lower jaws ; c ) sextants : upper / lower right / left , upper / lower anterior ; d ) each teeth individually . for each evaluation , codes from examination made by each examiner were compared to those of other examiners , ( example : 1x2 , 1x3 1x11 ; 2x3 . 2x11 ; 10x11 ) . the epidemiological examinations were initiated after approval of the study design by the research ethics committee of the dental school of piracicaba , state university of campinas , brazil ( protocol no . the volunteers ' parents signed an informed consent form authorizing the enrollment of the children in the study . dentists with previous experience in epidemiological surveys examined schoolchildren at baseline , 3 and 6 months after initial training , using two diagnostic thresholds on dental caries : who criteria , traditionally used in epidemiological surveys17 and who+il including the diagnostic of initial caries lesions ( il , white spot lesions ) , after being calibrated by a " gold standard " examiner , a dentist who routinely uses the who criteria for exams and had been previously trained and calibrated in il diagnosis . eleven dentists with previous experience in epidemiological surveys of dental caries were invited to participate in this study . schoolchildren aged 6 - 7 years from two public schools in piracicaba , sp , brazil , were selected by a dentist , according to their caries activity . the dentists used mirror , cpi probe , air - drying for examination after the children brushed their teeth . the exclusion criteria were : use of fixed orthodontic device , presence of severe fluorosis and/or hypoplasias , and severe systemic diseases . for each training or calibration period of training , 10 to 13 different children were selected . two diagnostic thresholds were used to record dental caries : 1 ) who threshold ( dmft index ) following the who codes and criteria17 , in which a tooth is considered as decayed when a cavitation is present ; 2 ) who+il threshold , in which active initial lesions were also recorded following criteria adapted from nyvad , et al.13 and fyfee , et al.6 . an il was defined as an active carious lesion which , upon visual assessment by a calibrated examiner , presented intact surface , no clinically detectable loss of dental tissue , with a rough , whitish / yellowish colored area of increased opacity presumed to be carious ( when the cpi probe was used , its tip should be moved gently across the surface ) . il locates close to gingival margin in smooth surfaces or extending along walls of fissure in occlusal surfaces . each examiner was helped by a recorder during the study . a benchmaker examiner ( " gold standard " ) conducted the training processes with both theoretical and practical activities , which lasted 20 hours ; and the calibration exercises , which lasted 8 hours at each phase : baseline , 3 and 6 months after initial training . the training and calibration processes were conducted by the gold - standard examiner using two diagnostic thresholds on dental caries , as described in previous studies2,3 . during theoretical discussions , the benchmaker examiner showed the examiners some photographic slides with clinical examples of each criterion that would be used in the study , in order to determine the examiners ' knowledge about epidemiological diagnosis , to instruct them on the criteria and examination method to be used , and finally , to achieve an initial standardization among them . the clinical training consisted of 4 periods of 4 hours each , and was conducted in an outdoor setting . each dentist examined 10 to 13 children , with distinct caries activity and prevalence , per period . during this phase , examiners discussed clinical diagnosis , study codes and criteria , recording and other errors in order to reach an acceptable level of agreement ( kappa>0.8517 ) . the calibration exercises , in which the examiners did not discuss their findings , were carried out in 2 periods of 4 hours each , with a 1-week interval . these were also undertaken after 3 and 6 months , after the first calibration phase ( baseline ) . the epidemiological examinations were carried out in an outdoor setting , under conditions such as natural light , with dental mirror and ball - ended cpitn probes with a diameter of 0.5 mm ( to remove debris , assess the presence of fissure sealants and , in case of doubt , to check the surface texture of il ) . toothbrushing with fluoridated dentifrice was performed by the children , under supervision of a dental hygienist , following the bass modified technique during approximately two minutes . tooth air - drying ( approximately 5 seconds per tooth ) was performed by using compressed air delivered by a dental compressor ( wetzel : medical line 3.6/30 0.5 hp ) . a program using microsoft excel has been developed by the department of community dentistry of fop - unicamp to calculate the interexaminer reliability by means of the kappa statistics7 that has been recommended by the who17 and the british association of community dentistry15 for evaluation of agreement among examiners in oral health surveys . the code recorded for each dental unit or surface was entered for each examiner , in accordance with the different diagnosis thresholds ( who ; who+il ) used in the three calibration phases . the objective of the statistical analysis was to assess interexaminer reliability under different caries diagnostic thresholds and different ways of analysis . thus , interexaminer reliability was calculated by using kappa statistics , according to two diagnosis thresholds ( who ; who+il ) and considering : a ) the entire dentition ; b ) upper / lower jaws ; c ) sextants : upper / lower right / left , upper / lower anterior ; d ) each teeth individually . for each evaluation , codes from examination made by each examiner were compared to those of other examiners , ( example : 1x2 , 1x3 1x11 ; 2x3 . for both diagnostic thresholds , high mean values of kappa were obtained ( tables ) . moreover , interexaminer agreement was constant when considering the entire dentition , jaws and sextants ( tables 1 and 2 ) . kappa values above 0.85 were obtained by analysis of sextants according to who threshold . however , when considering the who+il threshold , the values for posterior sextants decreased ( tables 1 and 2 ) . the results of interexaminer reliability considering each tooth individually showed that the main difficulty was related to caries diagnosis in posterior teeth , especially the permanent first molars , for both thresholds with , in general , lower values for the who+il threshold ( tables 3 and 4 ) . e1 = exercise at baseline ; e2= exercise after 3 months ; e3= exercise after 6 months . e1=exercise at baseline ; e2= exercise after 3 months ; e3= exercise after 6 months . the process of examiners ' calibration is an important aspect in planning and conducting oral health surveys . brazilian surveys4,10 have shown that training and calibration of examiners have been an aspect of great concern for measuring interexaminer agreement , according to the recommendations of the who , which has indicated the use of kappa statistics17 . kappa test provides a better evaluation of disagreement among examiners during calibration processes since it is a measurement of adjusted agreement by taking into consideration the ratio of chance agreement5 . analysis of variance and post - hoc tests , such as scheff , have also been used to assess significant differences in caries indices among examiners9 . the present study showed , in general , high means of interexaminer reliability for both diagnosis thresholds when considering the entire dentition , the upper / lower jaws and sextants ( tables 1 and 2 ) . on the other hand , lower kappa values were observed for dental units ( each tooth individually ) , especially when considering the most sensitive diagnosis threshold ( who+il ) ( tables 3 and 4 ) . as a consequence , good interexaminer agreement for the entire dentition may not be as real as if one considers separately the posterior teeth , in which cavitated and non - cavitated carious lesions are concentrated8 . moreover , considering the current epidemiological profile of dental caries , the higher number of sound teeth ( fewer errors in diagnosis ) in comparison to carious teeth ( more errors in diagnosis ) may dilute the errors attributed to carious teeth , leading to a positive vision of the results achieved in examiners ' calibration14 . therefore , one may speculate that the analysis of kappa values considering the entire dentition rather than each tooth individually may not be the best way to evaluate interexaminer reliability , especially in areas with low caries prevalence . it may be suggested the need for future reformulations in conducting examiners ' calibration , paying more attention to diagnosis of posterior teeth and selecting children of distinct caries activity and prevalence1 . low kappa values under the who+il threshold can also be explained by the inherent difficulty in diagnosing il , especially in surveys1 . although the examinations were carried out in sunny days under high luminosity conditions , the use of artificial light could generate an increase in interexaminer agreement by facilitating the view of posterior teeth . further studies are needed to determine the relevance of using artificial light in dental caries surveys , mainly for detecting initial lesions . in general , the use of more detailed measures to determine interexaminer agreement , such as the evaluation by dental unit ( each tooth individually ) , improves the calibration process by showing which teeth are leading to great disagreements and indicating the possible need for greater efforts in training examiners14 . however , it must be emphasized that the method of evaluating interexaminer agreement also depends on the study design and objectives , the desired degree of accuracy and the available resources . as an example , the calibration process using more rigorous statistical measures , such as the analysis by dental units , would be indicated in either clinical trials or case - control studies , in which the effect of preventive measures on the reduction of caries levels , including the detection of initial lesions , must be evaluated . therefore the kappa statistics considering reliability values according to each code / clinical condition can be employed12 . on the other hand , in order to know and evaluate the epidemiological profile of dental caries in an underprivileged community , for instance , these more robust measures could be dispensed . it is important to mention that the present study , which is part of a 12-month longitudinal study on examiners ' calibration , presents some limitations , such as lack of validity results by comparing the examiners ' results to those from the gold - standard examiner , and lack of intraexaminer errors . such measures were not taken into consideration because the main goal of this study was to evaluate interexaminer reliability by using different diagnostic thresholds for caries detection as well as to verify the behavior of kappa statistics in order to indicate the most adequate way to measure reliability during the examiners ' calibration process in dental caries surveys . the results of this study showed that the interexaminer reliability and its maintenance for six months were possible , under both caries diagnosis thresholds . nevertheless , great disagreement was observed for the posterior teeth , especially when the who+il criteria were used . the analysis considering dental elements individually was the best way of detecting disagreements among examiners during the calibration sections . OUTPUT:

objectivesa ) to evaluate the interexaminer reliability in caries detection considering different diagnostic thresholds and b ) to indicate , by using kappa statistics , the best way of measuring interexaminer agreement during the calibration process in dental caries surveys.methodseleven dentists participated in the initial training , which was divided into theoretical discussions and practical activities , and calibration exercises , performed at baseline , 3 and 6 months after the initial training . for the examinations of 6 - 7-year - old schoolchildren , the world health organization ( who ) recommendations were followed and different diagnostic thresholds were used : who ( decayed / missing / filled teeth dmft index ) and who + il ( initial lesion ) diagnostic thresholds . the interexaminer reliability was calculated by kappa statistics , according to who and who+il thresholds considering : a ) the entire dentition ; b ) upper / lower jaws ; c ) sextants ; d ) each tooth individually.resultsinterexaminer reliability was high for both diagnostic thresholds ; nevertheless , it decreased in all calibration sections when considering teeth individually.conclusionthe interexaminer reliability was possible during the period of 6 months , under both caries diagnosis thresholds . however , great disagreement was observed for posterior teeth , especially using the who+il criteria . analysis considering dental elements individually was the best way of detecting interexaminer disagreement during the calibration sections .

PubMed_Summ6520

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: dna microarray analysis has gained widespread application and a wide variety of methods have been developed to analyze the large and complex datasets generated by this technology ( 1 ) . due to the sheer volume of data , and the high number of sources of potential error , quality control and quality assurance since error may be the result of many factors at multiple steps , a number of qc / qa measures have been proposed to monitor specific sources of error . most of these methods focus on individual spots or spots within a single array ( 3 ) . other methods monitor an individual array as a whole during the experimental process using classification methods ( 4 ) or by comparison of the statistical features of an array with the same statistical features based on historical data ( 5 ) . here we report an r function ( www.rproject.org ) named microarray outlier filter ( mof ) , which was designed to screen outliers at the whole array level by using the arrays from the current experiment and those from the historical archive that meet defined criteria . our lab now routinely applies this software to the qa of our microarray experiments ( 6 ) . in essence , mof examines the consistency of arrays in a large scale experiment ( multiple arrays ) . arrays , as a whole , are inspected to reveal those arrays that are obviously different from most others . these few abnormal arrays are most likely failed arrays that may contain unreliable data . this analysis is based on two assumptions : first , that all samples are similar in gene expression profile ( that is , technical or biological replicates ) and that they have been subjected to the same experimental procedure ( in principle , the results should be similar between arrays since expression levels should be uniform for the majority of the probes ) ; second , that data from most of the arrays are of good quality , resulting in only a few unusual arrays being labeled as potentially failed ones . otherwise , it is possible for a systematic experimental error to result in the few good arrays being suspected as failures because they are identified as abnormal by mof . note that historical arrays satisfying these two criteria can be included to generate a larger dataset for analysis of the outliers . an outlier data point is defined in the context of all the data points for the same specific probe , across all the arrays . the resistant z - score is used to tag an outlier data point , which is defined as : zi = xixswhere x and s are the median and median absolute deviation values , respectively , for each probe across all arrays . a data point is designated as an outlier if its resistant z - score falls outside a preset threshold , which may be 3 , 4 or 5 in our experience . the percentage of outliers among all data points in consideration from an array is used as an indicator of the quality of the array . this is based on our observation that an outlier array , which is largely different from the majority of comparable arrays in its gene expression profile , tends to have more data points distributed at extremes . the other statistical index is the pearson correlation coefficient , expressed as : r=i=1k(xix)(yiy)(n1)sxsywhere x and y are two variables of the signal intensities from the two arrays , n is the number of probes included , x and y stand for means , sx and sy stand for standard deviations of two variables , respectively . the correlation coefficient between two arrays is computed by a function provided in the r package . each array is represented by a collection of data points in the same order of probes . thus , the correlation coefficient reflects the similarity of the two arrays in regard to the expression levels for all the probes collectively . if an array displays apparently low correlation or even reverse correlation to many other arrays , it is flagged as an unusual array merit closer review for failure . therefore , mof can be used to assist in the detection of potentially failed arrays . as an r function , mof is a ready - to - use tool for listing the arrays by the possibility of failure . it does not mean that there must be failed arrays in each batch of arrays . thus it is very important for the user to further verify that the outlier arrays are actually failed arrays by other means , such as scatter plots , clustering , etc . , starting from the worst outlier arrays . in our experience , the two lists determined by the mof indices often show the same unusual arrays , thus confirming each other . however , since these two indices do not reflect exactly the same properties of the data , they may detect different abnormalities in the arrays and thus complement each other . again , additional validation is critical to identify the truly failed arrays and the underlying causes . the input text file is a matrix containing preprocessed microarray data with rows as probes and columns as arrays . for maximum reliability , data points with expression levels close to the background or within the scanner saturation range should be discarded . the output is three text files and two heat maps . in the first text file , two lists of arrays are ordered according to the average correlation coefficient to the rest of the arrays and percentage of outlier spots , respectively . a correlation coefficient table containing the correlation coefficients for all pairs of arrays is found in the second text file . a heat map is generated to provide a general visualization of this table ( figure 1a ) as a guide for the utilization of the data for additional detailed analysis . similarly , percentages of outlier spots for all the arrays are also given as a table in a text file and a corresponding heat map ( figure 1b ) . in essence , mof examines the consistency of arrays in a large scale experiment ( multiple arrays ) . arrays , as a whole , are inspected to reveal those arrays that are obviously different from most others . these few abnormal arrays are most likely failed arrays that may contain unreliable data . this analysis is based on two assumptions : first , that all samples are similar in gene expression profile ( that is , technical or biological replicates ) and that they have been subjected to the same experimental procedure ( in principle , the results should be similar between arrays since expression levels should be uniform for the majority of the probes ) ; second , that data from most of the arrays are of good quality , resulting in only a few unusual arrays being labeled as potentially failed ones . otherwise , it is possible for a systematic experimental error to result in the few good arrays being suspected as failures because they are identified as abnormal by mof . note that historical arrays satisfying these two criteria can be included to generate a larger dataset for analysis of the outliers . an outlier data point is defined in the context of all the data points for the same specific probe , across all the arrays . the resistant z - score is used to tag an outlier data point , which is defined as : zi = xixswhere x and s are the median and median absolute deviation values , respectively , for each probe across all arrays . a data point is designated as an outlier if its resistant z - score falls outside a preset threshold , which may be 3 , 4 or 5 in our experience . the percentage of outliers among all data points in consideration from an array is used as an indicator of the quality of the array . this is based on our observation that an outlier array , which is largely different from the majority of comparable arrays in its gene expression profile , tends to have more data points distributed at extremes . the other statistical index is the pearson correlation coefficient , expressed as : r=i=1k(xix)(yiy)(n1)sxsywhere x and y are two variables of the signal intensities from the two arrays , n is the number of probes included , x and y stand for means , sx and sy stand for standard deviations of two variables , respectively . the correlation coefficient between two arrays is computed by a function provided in the r package . each array is represented by a collection of data points in the same order of probes . thus , the correlation coefficient reflects the similarity of the two arrays in regard to the expression levels for all the probes collectively . if an array displays apparently low correlation or even reverse correlation to many other arrays , it is flagged as an unusual array merit closer review for failure . therefore , mof can be used to assist in the detection of potentially failed arrays . as an r function , mof is a ready - to - use tool for listing the arrays by the possibility of failure . it does not mean that there must be failed arrays in each batch of arrays . thus it is very important for the user to further verify that the outlier arrays are actually failed arrays by other means , such as scatter plots , clustering , etc . , starting from the worst outlier arrays . in our experience , the two lists determined by the mof indices often show the same unusual arrays , thus confirming each other . however , since these two indices do not reflect exactly the same properties of the data , they may detect different abnormalities in the arrays and thus complement each other . again , additional validation is critical to identify the truly failed arrays and the underlying causes . the input text file is a matrix containing preprocessed microarray data with rows as probes and columns as arrays . for maximum reliability , data points with expression levels close to the background or within the scanner saturation range should be discarded . the output is three text files and two heat maps . in the first text file , two lists of arrays are ordered according to the average correlation coefficient to the rest of the arrays and percentage of outlier spots , respectively . a correlation coefficient table containing the correlation coefficients for all pairs of arrays is found in the second text file . a heat map is generated to provide a general visualization of this table ( figure 1a ) as a guide for the utilization of the data for additional detailed analysis . similarly , percentages of outlier spots for all the arrays are also given as a table in a text file and a corresponding heat map ( figure 1b ) . using mof requires setting proper thresholds for the two statistics to flag problematic arrays . in our practice we set the cut - offs at 0.8 , 3 , and 6% for pearson correlation coefficient , z - value , and the outlier percentage , respectively . then , common arrays on the two lists reported by mof satisfying the thresholds respectively can be considered primary candidates of problematic arrays . another way to set the threshold is to take the top 15%20% worst arrays as indexed in the two lists , and then identify common arrays . we would like to caution that the user needs to adjust the threshold based on their experience and the available resources . for reference , we report here two scenarios in using mof , illustrated with experimental data generated by our core facility . in one scenario , a couple of problematic arrays are so different from the rest of the arrays that the two statistics effectively singled them out . for example , we have a dataset composed of 35 arrays using the universal human reference ( uhr ) rna sample ( stratagene , la jolla , usa ) , both indices flagged the same 3 arrays as outlier arrays ( figure 1 ) . each of the 3 arrays had a distinctly lower average correlation coefficient and higher percentage of outlier spots than other arrays . in details , pearson correlation coefficients were 0.22 , 0.30 , and 0.49 for the top 3 arrays , and > 0.76 for the rest ; taking |z|=3 , the same 3 arrays contained outliers of 28%42% , with the fourth showing 11% and the rest showing 5% or less . two of these three arrays were confirmed by the laboratory as failed experiments with reasons identified . in another scenario , there is a lack of outstanding problematic arrays and on the two lists reported by mof the statistical index changes relatively smoothly , from low to high for pearson correlation coefficient or from high to low for z - score reported outlier percentages . for example , in a dataset composed of 185 arrays of human blood samples ( 30 controls and 155 patients with breast disease ) , following the thresholds we have about 30 arrays from either reported list to work on . 12 arrays were common in the top 30 arrays on both lists and were later verified to have obvious problems by scatter plots . mof has been successfully applied to our in - house microarray data as a routine qa measure ( 6 ) . however , users should note that in order to apply mof to any microarray datasets , the two assumptions mentioned above must be met . in our practice , when applying mof to a mouse dataset from different tissue types , tissue specific clusters were generated apparently due to the differences in gene expression profiles between tissue types . in such a case , the first of the two assumptions was not satisfied and thus mof was not applicable . as an additional note , the percentage of outliers changes when using different z - scores . selecting different z - scores may make some arrays to stand out with apparently higher percentages of outlier data points . therefore , the relative level of percentage of outliers is a more meaningful characteristic for judgment than the absolute value itself . users are encouraged to identify more realistic cut - offs in their specific settings using our thresholds as guidance . although a minimal of three arrays is required for correlation coefficient to pick out an outlier array , we recommend that mof should be used on datasets comprised of ten or more arrays . historical data obtained with the same technology on the same tissue type can be used in the analysis to increase the normal array base . OUTPUT:

we developed an r function named microarray outlier filter ( mof ) to assist in the identification of failed arrays . in sorting a group of similar arrays by the likelihood of failure , two statistical indices were employed : the correlation coefficient and the percentage of outlier spots . mof can be used to monitor the quality of microarray data for both trouble shooting , and to eliminate bad datasets from downstream analysis . the function is freely avaliable at http://www.wriwindber.org / applications / mof/.

PubMed_Summ6521

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: tsp-1 is the best - studied member of the thrombospondin ( tsp ) family , which consists of five extracellular calcium - binding multifunctional proteins : tsp-1 , tsp-2 , tsp-3 , tsp-4 , and tsp-5 . tsp-1 and tsp-2 are structurally similar , and they are expressed on the cell surface during physiological events . a variety of normal cells , including endothelial cells , fibroblasts , adipocytes , smooth muscle cells , monocytes , macrophages , and transformed cells such as malignant glioma cells , secrete tsp-1 [ 2 , 3 ] . tsp-1 binds to protein components of the extracellular matrix , such as fibronectin . by this way , tsp-1-specific domains bind to proteoglycans , membrane proteins such as integrins , and other matrix proteins expressed by a variety of cells [ 4 , 5 ] . tsp-1 contains an n - terminal globular domain that binds heparin , the type i , type ii , and type iii repeats , and a terminal globular domain . the nh2-terminal , heparin - binding domain of tsp-1 interacts with low - density lipoprotein receptor - related protein ( lrp1 ) . this tsp-1 domain also binds heparin sulfate proteoglycans and a number of integrins that have an important function in angiogenesis , chemotaxis adhesion , and cell motility . all five members of the tsp family have the repeat domains type ii and iii , but only tsp-1 and tsp-2 contain the type i repeats . type i repeats , also called thrombospondin structural homology repeats ( tsrs ) , inhibit angiogenesis by activating cd36 and inducing apoptosis in endothelial cells . cd36 ( also known as fatty acid translocase , fat ) is a glycosylated protein member of the class b scavenger receptor family . it plays an important role in multiple processes such as fatty acid and glucose metabolism . cd36 is found on the surface of diverse cell types and binds to many ligands , including tsp-1 [ 10 , 11 ] . it has been reported that upon binding with tsp-1 , cd36 dimerizes , becoming actively involved in signal transduction . however , activation of cd36 as a monomer has also been reported . the adhesive and antiangiogenic functions of tsp-1 have been mainly attributed to its interaction with cd36 . other domains of tsp-1 can , however , impact these functions by interacting with other key receptors as it will be discussed in succeeding sections . tgf1 mediates wound healing , cell proliferation , extracellular matrix formation , and the immune response . this multifunctional cytokine is secreted to the extracellular matrix in its inactive form , by virtue of its noncovalent association with the latency - associated peptide ( lap ) . the activating function of tsp-1 is due to the amino acid sequence rfk located in the tsr [ 1416 ] . tsp-1 releases tgf1 from its latent form when it interacts with the n - terminal region of lap and binds the mature tgf1 . this interaction results in the formation of a complex that involves conformational changes in tgf1 , making it accessible to its receptor . lap is crucial for tgf1 activation and regulates many of its functions ; additionally , lap has functions in inflammation independently of tgf1 , such as the induction of chemotaxis of monocytes to injured tissues . they contain amino acid sequences that interact with the neutrophil elastase , and upon this binding these repeats activate neutrophils [ 18 , 19 ] . these type 3 repeats also inhibit the binding of fibroblast growth factor to endothelial cells , reducing angiogenesis . the cooh - terminal domain of tsp-1 binds to cd47 , also known as integrin - associated protein . this domain also interacts with integrins such as 1 and v6 integrins and actively binds to proteoglycans allowing cell adhesion and spreading . these and other interactions significantly affect angiogenesis , cell proliferation , and immune responses . tsp-1 binding with cd47 also regulates nitric oxide ( no ) , a biogas , quite important in both normal and pathological events . by modulating the effects of no , the carboxy - terminal domain of tsp-1 has important function in vasodilation and chemotaxis . this receptor inhibits no as well as all its vascular functions even when tsp-1 is present at very low ( physiological ) concentrations . analysis of wound bed vascularity at 72 hours after skin grafting from tsp-1 and cd47 null mice shows significant increased numbers of blood vessels . most recently it has been reported that cd47 associates with the receptor of vascular endothelial growth factor , vegfr2 . however , the binding of cd47 with tsp1 or other ligands inhibits vegfr2 phosphorylation and further angiogenesis . this paper focuses on well - known interactions of tsp-1 with key receptors and growth factors during the initial inflammatory events throughout the chronic inflammatory processes . new developments are also herein discussed , showing the involvement of tsp-1 in pivotal transcriptional pathways related to inflammation and inflammation - induced carcinogenesis . the inflammatory acute process begins when cells sense the injury , and they release chemical mediators called cytokines . local macrophages express surface membrane receptors called toll - like receptors ( tlr ) that recognize specific types of antigens . once activated , tlr triggers the release of more cytokines promoting inflammation and attracting white blood cells . cytokines will promote leukocytosis by inducing factors favoring the rapid release of neutrophils from the red bone marrow . neutrophils enter the blood stream , and by diapedesis they emigrate outside the blood vessels . chemotactic agents accelerate the migration of leukocytes to the site of injury such as monocytes , which later become macrophages , engulfing any on - site cell debris or pathogens . in addition , mast cells ( producing histamine ) , injured tissue cells , phagocytes , lymphocytes , basophils , and blood proteins are all sources of inflammatory mediators . tsp-1 is transiently released early during the acute phase of inflammation , and multiple factors seem to modulate the release of tsp-1 during this process . tsp-1 is strongly expressed in neutrophils , inducing an intense chemotactic response to injured tissues . tsp-1 is secreted in response to inflammation , promoting the resolution of the inflammatory process and facilitating phagocytosis of damaged cells [ 25 , 26 ] . thus , enhanced production of tsp-1 could be a compensatory mechanism for controlling the immune response and protecting tissues from excessive damage . this receptor is coexpressed with tsp-1 in macrophages and endothelial cells , and , by binding with cd36 ( figure 2 ) , tsp-1 induces apoptosis in endothelial cells . by activating cd36 , tsp-1 also controls blood flow and leukocyte infiltration modulating the action of the no pathway in injured tissues . no is a gas produced when l - arginine is converted to l - citruline by the enzyme nitric oxide synthase ( nos ) . there are four different isoforms of nos , neuronal ( nnos ) , endothelial ( enos ) , mitochondrial ( mtnos ) , and the inducible isoform ( inos ) . the first two are secreted during normal physiological events , but only inos is expressed upon inflammatory stimuli . the effects of no in inflammation have been extensively recognized in a variety of studies . no can modulate leukocyte adhesion in a dose - dependent manner . at low doses , no is anti - inflammatory and antiangiogenic but , after inflammatory stimuli , high levels of no are secreted promoting angiogenesis and leukocyte adhesion to the endothelium . tsp-1 could inhibit the soluble guanylyl cyclase system in endothelial cells and consequently the activation of no by interacting with cd36 and cd47 . through this mechanism , tsp-1 inhibits inflammation by blocking adhesion and activation of leukocytes to the endothelium and diminishing angiogenesis [ 22 , 30 , 31 ] . another factor interacting with tsp-1 during early inflammation is the peroxisome proliferator - activated receptor ( ppar ) . ppar greatly enhances the proapoptotic effects of the tsp-1-derived peptide abt510 ( abbott laboratories ) [ 33 , 34 ] . this peptide corresponds to the tsr of tsp-1 and induces vascular apoptosis in vitro and in vivo through its interaction with cd36 . by using a ppar agonist , the expression of cd36 in endothelial cells the tsp-1 receptor cd47 is critical for the migration of leukocytes through endothelial and epithelial barriers . cd47 is strongly expressed in polymorphonuclear cells , and its activation enhances the expression of tsp-1 in leukocytes . cd47 can directly cause apoptosis through mitochondrial mechanisms , or by activation of the fas / cd95 pathway . expression of cd47 in apoptotic granulocytes can influence the phagocytic functions of the macrophages in inflammatory sites suggesting a critical role of this factor in the resolution of the process ( figure 2 ) . acute inflammation could advance to a resolution , progress to the formation of an abscess , walling off by fibrotic capsule , or evolve as scar upon tissue destruction , fibrin and collagen deposition . chronic inflammation is characterized by infiltration of mononuclear cells , macrophages , lymphocytes , and plasma cells . chronically inflamed tissues have fibroblast proliferation , angiogenesis , tissue destruction , and fibrosis . they invade the injured area during the acute process but , if the cause is not eliminated , infiltration by macrophages persists for long periods of time . the continued secretion of chemotactic factors allows the constant supply of monocytes from the blood and their conversion to macrophages . these cells are key for further lymphocyte infiltration , fibroblast proliferation , tissue destruction , and fibrosis . lymphocytes arise from the hemoblasts of the bone marrow , and later they develop immunocompentence and self - tolerance . plasma cells or b lymphocytes produce antibodies against antigens persisting in the area and therefore provide humoral immunity . included in this group are dendritic cells ( dcs ) , which internalize antigens and present antigenic determinants on their surface for recognition by t lymphocytes . they are part of the adaptive immune system that recognizes something as foreign and acts to immobilize and remove it . during the early stages of injury and inflammation , high levels of tsp-1 can modulate inflammation by inhibiting or enhancing the secretion of the cytokine interleukin 10 ( il10 ) , by this way , tsp-1 can also regulate the functions of dc . in addition , after adding il-6 , il-10 , or tgf1 to cultured dc , they become immune tolerant and show upregulation of intracellular tsp-1 . tsp-1 also inhibits the function of apc by suppressing their capacity to sensitize t - cells in the host . this is demonstrated in a corneal transplantation model , in which most of the corneal tsp-1 null allografts are rejected . cd47 has also a crucial role in t - cell activation [ 42 , 43 ] . interaction of tsp-1 with cd47 promotes the activation of thymus - derived cd4 + cd25 + t regulatory cells ( tregs ) . through this mechanism suppression of cd47 or tsp-1 expression in dc by using small interfering rna ( sirna ) technique actually protects newborn mice against bacterial ( escherichia coli ) meningitis . again , the loss of cd47 activity prevents the maturation of the dcs and the production of inflammatory cytokines . in conclusion , cd47 seems to have pivotal functions in inflammation and provides a major mechanistic pathway for the functions of tsp-1 in that process . cd36 mice exhibit an impaired early proinflammatory response to infection , elevation of cytokines , and higher mortality [ 45 , 46 ] . these findings suggest that cd36 is quite critical for the recognition and clearance of pathogens in acute and chronic infections . by binding to this receptor , tsp-1 could modulate the inflammatory process by activating macrophages and favoring phagocytosis . during chronic inflammation , these adaptive immune mechanisms provide defense against disease and are regulated by cellular interactions and cytokines . b lymphocytes secrete antibodies that bind to infectious agents and label them for destruction or elimination . once inside a cell , a pathogen becomes inaccessible to those antibodies and cytotoxic t cells could destroy them by inducing apoptosis of the cell host . regulatory t cells can modulate the secretion of cytokines enhancing the functions of macrophages and b - lymphocytes . tsp-1 has been reported to decrease immune responses by inhibition of t - cell effectors , or by directly inducing t cell apoptosis [ 47 , 48 ] . in addition , by binding to 41 integrin tsp-1 promotes t - cell adhesion and chemotaxis . tgf1 activation is a crucial element in intestinal homeostasis . in the intestinal tract , an abnormal response to the normal gut flora is a characteristic of the pathogenesis of inflammatory bowel disease ( ibd ) . mucosal t cells from patients with ibd express high levels of smad7 , an inhibitor of tgf1 signaling . by this mechanism , tgf1 mediates intestinal healing and susceptibility to injury [ 5053 ] . however , by activating tgf1 , tsp-1 also enhances fibrosis and compromises organ function [ 54 , 55 ] ( figure 3 ) . during the immune response , leukocytes produce reactive oxygen species ( ros ) that include free radicals and peroxides . ros are quite important for the killing of pathogens , but they can also produce cell damage . tgf1 favors the formation of ros , and , as a cycle , ros can also activate tgf1 promoting apoptosis and fibrosis . angiogenesis is an active component of chronic inflammatory diseases such as rheumatoid arthritis , atherosclerosis , diabetic retinopathy , airway inflammation , and others . tsp-1 exerts a powerful antiangiogenic effect , and this function has a significant impact in chronic inflammation . activated endothelial cells secrete cytokines , chemokines , matrix metalloproteinases , and growth factors that can greatly influence the inflammatory reaction and promote carcinogenesis . tsp-1 deficient mice display extensive acute pneumonia , leukocytosis , pancreatitis , and inflammatory infiltrates in the lacrimal glands [ 26 , 58 , 59 ] . this phenotype suggests that tsp-1 has a significant role in inflammation , a role that has not been exhaustively analyzed . tsp-1 has anti - inflammatory and proinflammatory effects observed in several diseases and animal models . these contrasting functions in inflammation are possible due to interactions with multiple receptors or to the presence of specific matricellular proteins in injured tissue . in addition , tsp-1 might act by a biphasic or dose - dependent mechanism . tsp-1 enhances fibrosis and renal damage by its interaction with tgf1 , while lskl , a peptide antagonist of tsp-1 , reduces renal interstitial fibrosis in a rat experimental model of kidney disease . this effect is attributed to the competitive properties of lskl that prevents tsp-1-mediated activation of tgf1 . tsp-1 is also expressed in glomerulopathies and is considered an early marker of inflammation and fibrosis . the development of diabetic nephropathy is attenuated in tsp-1-deficient mice as demonstrated by a significant reduction of glomerulosclerosis , glomerular matrix accumulation , podocyte injury , renal infiltration with inflammatory cells , and alterations of renal functional parameters . as an activator of tgf1 , tsp-1 could modulate the functions of tgf1 in cardiovascular diseases , atherosclerosis , and obesity . inflammatory cells secrete tsp-1 during the acute phase of the healing process in myocardial infarction . in addition , tsp-1 is selectively expressed in the infarcted border suggesting that tsp-1 might inhibit the expansion of the inflammation by activating tgf1 . in the inflammatory processes leading to atherosclerosis , tsp-1 deficiency enhances inflammation by accelerating plaque maturation and necrosis in apoe - deficient mice . however , tsp-1 expression is increased in response to high glucose in the wall of large vessels and accelerates atherosclerosis and other pathological events observed in diabetes . this correlation is explained by the tsp-1-dependent tgf1 activation that leads to upregulation of plasminogen activator inhibitor 1 ( pai-1 ) gene expression . elevated circulating pai-1 levels mice lacking tsp-1 or the integrin 6 subunit ( tsp-1 and itgb6 mice , resp . ) the inflammation is not as severe as the one found in tgfb1 mice , which develop marked infiltrates of activated t cells in multiple organs and die soon after weaning . tsp-1 null mice have a more severe course of acute induced colitis ; they display increased bleeding and colonic inflammation compared to wt mice controls . tsp-1-deficient mice under multiple cycles of 2.5% of dextran sodium sulfate for induction of colitis die before the cycles are completed . these mice show high incidence of megacolon and peritonitis due to the deeper infiltration of leukocytes into the muscularis and intestinal perforation . in order to increase survival , the use of the tsp - mimetic peptide abt510 drastically reduces intestinal inflammation and angiogenesis and enhances the expression of cd36 , which suggests that cd36 modulates inflammation in this model . additionally , the interaction of tsp-1 with the no pathway seems to be involved in the antiangiogenic mechanisms mediated by the abt510 in cancers [ 31 , 69 ] , and it might also explain the anti - inflammatory effects of this peptide in the colitis model . similarly , in a rat model with bleomycin - induced lung injury , a cd36 peptide also decreases inflammation and fibrosis in the lungs . a synthetic peptide derived from the tsp-1 type 3 repeats ( figure 1 ) also diminishes inflammation and angiogenesis in an experimental model of erosive arthritis . this peptide decreases angiogenesis , leukocyte infiltration , and thickening of the synovial lining of the joint . in the spleen and liver , this peptide significantly reduces the formation of granulomas . however , tsp-1 is upregulated in monocytes , and tissues from patients with rheumatoid arthritis ( ra ) [ 74 , 75 ] and high plasmatic levels of tsp-1 are correlated with proinflammatory cytokines in these patients . tsp-1 also exerts proinflammatory effects in certain types of myositis [ 77 , 78 ] . the chemotactic effect of tsp-1 in leukocytes by its binding to cd47 perpetuates the muscle inflammation in response to high levels of tnf - alpha . in transplantation research , most of the corneal tsp-1 null allografts are rejected , suggesting a protolerogenic function [ 41 , 79 ] . interestingly , when tsp-1 is inhibited by sirna - transfection in pancreatic islet cells , improved revascularization and function are observed in the pancreatic grafts . antiangiogenic compounds , such as tsp-1 , might be useful for achieving a better perfusion and oxygenation in organ transplants . it is involved in many biological processes such as inflammation , immunity , differentiation , cell growth , tumorigenesis , and apoptosis . phosphorylation and subsequent degradation of ib releases nf-b and allows it to be translocated to the nucleus . once inside the nucleus , this transcription factor induces its target genes , thereby inhibiting apoptosis , promoting inflammation , angiogenesis , and carcinogenesis . importantly , nf-b activates the transcription of genes such as tnf - alpha and il-6 , which have major roles in regulating the immune response . recently , it has been reported that blocking the activation of nf-b upregulates tsp-1 expression in rat granulation tissue . tsp-1 has a major role in wound healing , and a significant delay of the healing process is observed in tsp-1 mice . the link between tsp-1 and nf-b seems to be closely related to mechanisms of angiogenesis and carcinogenesis . tsp-1 enhances the binding of nf-b to dna inhibiting angiogenesis , and these events are reverted by blocking the nf-b pathway . activation of nf-b by oxidized low - density lipoprotein ( oxldl ) , a specific ligand of cd36 , is reduced in macrophages of patients with cd36 deficiency . studies in prostate cancers indicate that the combined decrease of nf-b and increase of tsp-1 , modulated by the expression of the androgen receptor , exert antitumor effects . the tsp-1-derived peptide angiocidin has antitumor effects and induces the differentiation of monocytes to macrophages by activating the nf-b pathway . in response to cytokines and growth factors , members of the stat family are phosphorylated by receptor - associated kinases forming homo- or heterodimers . the lack of stat3 , the most important member of this family , actually leads to embryonic lethality . stat3 mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in many cellular processes such as cell growth and apoptosis . the binding of il-6 to the gp130 receptor triggers the phosphorylation of stat3 by jak2 [ 90 , 91 ] . it has been reported that downregulation of tgf1 in epithelial cells inhibits the secretion of il-6 . by this mechanism furthermore , activated stat3 has been recently reported as crucial for intestinal carcinogenesis in colitis - associated cancer . in addition , protein profiling of head and neck squamous carcinomas shows a significant decrease of several proteins such tsp-1 and tgf1 with concomitant increase of stat3 . in a model of angiogenesis , higher levels of il-6 are secreted by tsp-1 aortic explants , and similar results are found in a mouse model of colitis . the higher levels of il-6 are lowered upon activation of tgf1 only in wt aortas . the activity of il-6 was specifically examined through the stat3 pathway in colonic tissues evaluating the status of the phosphorylated forms of stat3 ( p - stat3 ) . interestingly , p - stat3 expression is highly expressed in tsp-1 colons and almost abolished in colons from mice treated with a new tsp-1-mimetic abt-898 ( abbott laboratories ) . these data suggest that this mimetic peptide directly binds to tsp-1 receptors such as cd36 or indirectly interacts with other membrane domains to downregulate stat3 pathway , thereby depressing the immune response . therefore , activation of this pathway is critical for further activation of stat3 in colitis . tsp-1 interacts with a variety of factors in a synergistic way , playing a crucial role in many stages of the inflammatory response . we discussed herein the interactions of tsp-1 with well - known partners such as cd36 , cd47 , no , and tgf1 . we also reviewed recent developments explaining how tsp-1 and its derived peptides directly or indirectly regulate inflammatory events in animal models and human diseases . leukocytes migrate to areas of injury or infection in elevated numbers ; similarly , tsp-1 is secreted at high levels in some areas in order to activate specific mechanisms for regulating the inflammatory response . in some cases finally , new insights about key signaling pathways such as nf-b and stat3 were discussed . because chronic inflammation is linked with tumor development , further studies analyzing the role of tsp-1 in these pathways could elucidate the similar contradictory functions of tsp-1 in cancer . the unraveling of these mechanisms will make possible the development of new and more effective therapies for controlling inflammation and blocking carcinogenesis . OUTPUT:

inflammation is a defensive process against tissue injury . once this self - protective strategy is initiated , an effective resolution of the process is crucial to avoid major and unnecessary tissue damage . if the underlying event inducing inflammation is not addressed and homeostasis is not restored , this process can become chronic and lead to angiogenesis and carcinogenesis . thrombospondin-1 ( tsp-1 ) is a matricellular protein involved in angiogenesis , cancer , and inflammation . the effects of tsp-1 have been studied in many preclinical tumor models , and mimetic peptides are being tested in cancer clinical trials . however , the molecular mechanisms explaining its role in inflammatory processes are not well understood . this paper will discuss the role of tsp-1 in inflammation and its interaction with key receptors that may explain its functions in that process . recent literature will be reviewed showing novel mechanisms by which this multifaceted protein could modulate the inflammatory process and impact its resolution .

PubMed_Summ6522

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: dentistry is a mostly a social interaction between a dentist and the patient in their limited job setting and with personal characteristics . a healthy dentist is one of the most important components in a successful dental practice . like all other professionals , dentists are exposed to occupational health hazards which predispose them to develop a multitude of health problems . maintaining the steady hand and posture by the dentist comes at a cost to the health of the dentist . high frequency of musculoskeletal disorders ( msds ) in dentists has been reported in the literature . a recent review of the literature that examined the prevalence and risk factors of msds in dentists reported that the prevalence of general musculoskeletal pain in dental professionals ranges between 64% and 93% . there are many factors that contribute to msds in dental professionals , including repetitive motion , pinch - grasp , vibration , force , and awkward positions , sitting for a long period of time , operator position , poor posture , lack of flexibility and strength , poor ergonomics , and insufficient work breaks . it is generally agreed that the physical posture of the dentist should be relaxed while they work . dentists can , and do , experience illnesses and problems that can disrupt or impair their practice . career and job satisfaction are the indicators that may have an influence on career longevity . change in the work environment of the dentist might increase his / her career longevity . complementary and alternative medicine ( cam ) , as defined by national centre for complementary and alternative medicine ( nccam ) , is a group of diverse medical and health care systems , practices , and products that are not presently considered to be part of conventional medicine . a large number of patients using cam are those who suffer from chronic musculoskeletal pain . many studies have reported cam therapies , including yoga , ayurveda , homeopathy , reiki , acupressure , massage , prayers , and acupuncture , to be effective in managing chronic musculoskeletal pain and other discomforts in the general population . there are currently no reports that link musculoskeletal pain , cam , and career satisfaction among dentists working in western india . since a large number of dentists all over the world report msds , this study was conducted in western india with an aim to determine if dentists are using cam therapies to manage their msds and , if so , to determine if cam therapies are associated with their job satisfaction and longevity , compared with conventional therapy users . the survey was conducted with the approval of the institutional review board of teerthankar mahaveer university ( tmu ) . dentists registered under indian dental association ( ida ) were recruited to complete an 21-item questionnaire under 5 domains . a pilot study was conducted among dentists working in the teerthankar mahaveer dental college and research centre . following these pilot tests , the questionnaire was further modified and was uploaded on the web - based survey software . all dentists of western india who are current members of the ida were recruited to participate . the final version of the questionnaire was formatted using web - based survey software for electronic distribution . this study included all registered dentists residing in western india with their e - mail addresses ( n = 2166 ) . dentists were sent the link to their e - mail address for competing the survey . dentists who participated in the pilot study , dental students , members of the general public , dental hygienists , dental assistants , and others who were not registered dentists were excluded . the questionnaire consisted of five domains : demographic profile of the dentist , experience with musculoskeletal pain , use of conventional therapies or use of cam therapies for its management , opinions about cam and conventional therapies , and job / career satisfaction related to cam . univariate and bivariate analyses were performed to determine the demographic information , frequently reported areas of location of pain , the number of respondents that used cam or conventional therapies , types of cam or conventional therapies frequently used , work disruption caused by msds , and job satisfaction by using cam and conventional therapies . association between conventional therapy and cam use in relation to career variables was assessed using odds ratio ( or ) . independent samples t - tests were used to determine the opinions about cam and conventional therapies for msd management . univariate and bivariate analyses were performed to determine the demographic information , frequently reported areas of location of pain , the number of respondents that used cam or conventional therapies , types of cam or conventional therapies frequently used , work disruption caused by msds , and job satisfaction by using cam and conventional therapies . association between conventional therapy and cam use in relation to career variables was assessed using odds ratio ( or ) . independent samples t - tests were used to determine the opinions about cam and conventional therapies for msd management . a total of 2166 survey e - mails were sent electronically , with a response rate of 73% ( n = 1581 ) . the nonrespondents were assumed to be similar to the respondents based on the notion that the group under study was somewhat a homogeneous group . findings of the demographic status of the dentists showed that a majority of the study population was males ( 75.7% ) and worked primarily in their own private dental clinics ( 85.7% ) . a total of 79% ( n = 1249 ) reported having msds , with the mean duration of pain being 8.3 years ( median = 3.5 ) . neck and lower back were the most common sites , followed by shoulders , upper back , wrist , elbow / arm , knee , hips , and legs . demographic characteristics of the dentists percentage of dentist reported pain by location figure 2 shows work disruption among dentists as a result of msds . when comparison was made between individuals who used cam therapies or conventional therapy alone and those individuals who used both cam and conventional therapies , the latter group had 4 times lower odds of temporarily quitting work for longer than 1 month [ or = 3.4 , 95% confidence interval ( ci ) = 1.7 - 17.8 ] . work disruption among dentist due to msd figure 3 depicts the use of cam modalities by dentists . about 81% ( n = 1012 ) dentists reported using both cam and conventional therapies most frequently to manage msds . also , of the 1249 individuals who reported msds , 31% ( n = 388 ) used cam therapies alone , 19% ( n = 238 ) used conventional therapies alone , and 3% ( n = 38 ) did not use any therapy . dentists degree of pain improved significantly after using cam therapies versus conventional therapies ( p = 0.004 ) . dentists who suffered from musculoskeletal pain agreed 3 times more that cam therapies were acceptable for msd management ( or = 3.7 , 95% ci = 2.7 - 3.9 ) than those with no pain , and were 3 times more likely to use cam therapies for msd management ( or = 3.4 , 95% ci = 1.4 - 5.9 ) . table 2 depicts the job / career satisfaction among dentists who used cam therapies and conventional therapies . dentists who believed in cam therapies and used them alone had significantly higher odds of agreeing that they were satisfied with their career as a dentist ( or = 3.2 , 95% ci = 1.5 - 5.7 ) and that it contributed to career longevity ( or = 1.92 , 95% ci = 1.4 - 7.3 ) , increased overall health ( or = 1.67 , 95% ci = 1.11 - 6.1 ) , and improved the working efficiency ( or = 2.37 , 95% ci = 1.1 - 7.3 ) , and thus were satisfied with the job ( or = 1.51 , 95% ci = 1.7 - 7.3 ) when compared to users of conventional therapies . older dentists had significantly high rate of cam usage than younger dentists ( or = 2.17 , 95% ci = 1.157 - 1.007 ) . dentists who never used cam reported poorer general health when compared to cam users ( or = 1.16 , 95% ci = 1.06 - 2.4 ) . there were no statistically significant differences when controlling for race , type of degree earned , and number of years of practice . cam use among dentist with msd association between conventional therapy and cam usage with job / career satisfaction many different types of cam therapies , including whole medical systems ( homeopathic and naturopathic medicine ) , mind body medicine ( meditation , prayer , and mental healing ) , biologically based practices ( ayurveda / herbal products ) , manipulative and body - based medicine ( chiropractic care and massage ) , and energy medicine ( reiki and therapeutic touch ) are practiced worldwide . many plants are used in various formulations such as decoctions , powders , medicated oils , paste , etc . ayurvedic drugs like zingiber officinale , ( shng jing ) , ricinus communis , commiphora mukul , boswellia serrata , nyctanthes arbor - tristis , etc . modern research scientists have conducted many scientific researches to assess the safety , efficacy , and anti - inflammatory potential of these drugs . deep breathing exercises involve slow , deep breaths through the nose for 10 sec , followed by a complete exhalation for 10 sec for at least 5 cycles . meditation is a practice in which an individual attempts to keep the mind clear and free from any other thoughts . massage therapist uses the technique of massage to adjust the muscles , which helps in relaxation . yoga practitioners had less muscle weakness than compared to non practitioners .. acupuncture may also be sometimes used for treating msds . it involves using thin , metallic needles to penetrate the skin at different anatomical points of the body . even in optimal seated postures , more than one - half of the body 's muscles are contracted statically and there is little movement of the vertebral joints . this may result in damaging physiological changes that can lead to back , neck , or shoulder pain or msds . the term musculoskeletal disorder is used to describe a wide range of injuries to the tendons , ligaments , nerves , and supporting structures . chronic musculoskeletal pain appears after only a few years of clinical practice , or even during second or third year of undergraduate training . cam therapies have been effective in reducing the risk of and treating musculoskeletal pain in the general population for several decades . in our study , individuals who used cam therapies alone were less likely to report temporarily quitting work . therefore , a dentist who uses cam therapies may reduce work interruptions caused by musculoskeletal pain . according to the present study , dentists who do not suffer from musculoskeletal pain experience higher job satisfaction when compared to those who suffer from msds ( dentist using cam therapies alone had greater career satisfaction compared to those who used conventional therapies alone . therefore , dentists using cam therapies for msd management experienced higher satisfaction and longevity when compared to those using conventional therapies . the most favored cam therapies among participants in the current study were massage , herbal supplements , and yogic exercises . therefore , no effective gender comparison can be made . to date , no studies have examined the use of cam for msds among dentists and its association with career satisfaction ; therefore , the results of this study can not be compared with any other similar study . similar to other studies , our study also reported maximum musculoskeletal complaints in the neck and lower back region . most of the dentists ( 81% ) reported use of both cam and conventional therapies in a complementary way for the treatment of musculoskeletal problems . the hectic schedule of the dentists leaves them with no time to practice mind body techniques and other cam - related modalities to treat their musculoskeletal pain . various researches have been conducted on the characteristics of cam users and the determinants of cam use . some researches show that utilization of cam is influenced by an individual 's personality , family and friends , and socioeconomic factors such as race / culture , education , and economic level . dentists must practice some sort of exercise in their day - to - day routine , including yoga , to be relieved from the problem of musculoskeletal pain . dentists using cam therapies reported they had greater overall health and more life satisfaction compared to conventional therapy users . cam education should be incorporated in the dental curriculum to train the budding dentists about better management of msds . education and additional research are needed to promote an understanding of the complexity of the problem and to address the problem 's multifactorial nature . knowledge and training of alternative therapies is very much required among professionals , especially dentists , so that they can use these therapies as a preventive and treatment modality for chronic pain emerging in day - to - day life and prolong their career . OUTPUT:

musculoskeletal problems have become a significant issue in the profession of dentistry . there are currently no recommended effective disease - preventing and modifying remedies . high prevalence rates for musculoskeletal disorders ( msds ) among dentists have been reported in the literature . complementary and alternative medicine can be helpful in managing and preventing the msds . the purpose of this study was to determine if dentists in the western part of india are using complementary and alternative medicine therapies for msds , and also to find if those who use complementary and alternative medicine therapies have greater job / career satisfaction compared to conventional therapy ( ct ) users . dentists of western india registered under the dental council of india ( n = 2166 ) were recruited for the study . data were analyzed using univariate and bivariate analyses and logistic regression . a response rate of 73% ( n = 1581 ) was obtained , of which 79% ( n = 1249 ) was suffering from msds . the use of complementary and alternative medicine or ct was reported by 90% ( n = 1124 ) of dentists with msds . dentists using complementary and alternative medicine reported greater health ( p < 0.001 ) and carrier satisfaction ( p < 0.001 ) and were able to work as many hours they wanted ( p < 0.001 ) compared to ct users . complementary and alternative medicine therapies may improve the quality of life and enhance job satisfaction for a dentist who suffers from msds .

PubMed_Summ6523

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: transcatheter aortic valve implantation ( tavi ) has gained wide acceptance for the treatment of severe aortic stenosis among patients deemed to be at increased risk for surgical aortic valve replacement . expansion of tavi to lower risk patients is critically dependent on the refinement of earlygeneration devices to further reduce the risk of paravalvular regurgitation , device malposition , atrioventricular ( av ) conductance disturbances , accesssite complications , and periinterventional bleeding . newergeneration devices feature external cuffs or internal skirts to seal the prosthesis to the aortic annulus and reduce the risk of paravalvular regurgitation . atraumatic , precurved , and steerable delivery catheter systems aim for a reduction of plaque embolization , and smaller catheter diameters mitigate the risk of access site complications and bleeding.1 the lotus valve system ( boston scientific , natwick , ma ) is a novel , fully repositionable tavi prosthesis that permits evaluation of the final configuration of the deployed valve , the degree of aortic regurgitation , as well as reduced coronary flow before detachment . singlearm registries of the lotus valve showed high rates of procedural success and suggested substantially lower rates of paravalvular regurgitation compared with earlygeneration devices2 , 3 , 4 ; conversely , rates of av conduction disturbances were relatively high , resulting in permanent pacemaker implantation in 1 in every fourth patient up to one in every third patient.2 , 3 the safety and effectiveness of the fully repositionable lotus valve system as compared with other newergeneration tavi devices have not been evaluated to date . we therefore performed an adjusted comparison of the lotus valve system with the balloonexpandable edwards sapien 3 prosthesis in patients with aortic stenosis undergoing tavi within the nationwide swiss transcatheter aortic valve implantation registry ( nct01368250 ) . all patients undergoing tavi procedures performed in switzerland are consecutively captured in a nationwide , prospective cohort study ( clinicaltrials.gov nct01368250).5 for the purpose of the present analysis , we investigated all patients with severe aortic stenosis treated with the edwards sapien 3 prosthesis or the lotus valve system . selection of tavi candidates , device allocation , and periprocedural management was left to the discretion of the operators . all data were recorded in a webbased database held at the clinical trials unit of the university of bern , switzerland . the swiss tavi registry has been approved by the local cantonal ethics committee and the institutional review boards of all participating sites . the lotus valve system consists of a single nitinol wire that is braided into a stent frame upon foreshortening and mechanical expansion . the prosthesis is attached to the delivery system with 3 coupling fingers ; buckles at the distal end connect to posts located at the commissures of the 3 leaflets upon shortening , and lock the valve in its final configuration . the stent frame accommodates a bovine pericardial valve and comes in 3 prosthesis sizes ( 23 mm , 25 mm , and 27 mm ) fitting an annulus diameter ranging from 20 mm to 26 mm . an adaptive seal in the distal portion of the prosthesis and an outer sleeve have been designed to reduce paravalvular regurgitation . the lotus prosthesis is fully repositionable and allows for an assessment of the final result before detachment of the valve from the coupling fingers of the delivery system . the precurved delivery catheter has a diameter of 18 f to 20 f and is not steerable . the valve can be implanted without rapid ventricular stimulation and predilatation is not necessary in all cases . the lotus valve system received ce mark approval on october 28 , 2013 , and on july 14 , 2014 , for its 23/27 mm and 25 mm prosthesis , respectively , and since then has become available for commercial use and implantation in switzerland . the edwards sapien 3 valve ( edwards lifesciences , irvine , ca ) is the fourth iteration of the first balloonexpandable transcatheter aortic valve prosthesis . the stent frame houses a valve made of 3 modified pericardial tissue leaflets , and accommodates annulus sizes from 18 mm to 28 mm using 3 device sizes ( 23 mm , 26 mm , 29 mm ) . an outer sealing skirt in the distal portion of the prosthesis complements the inner pet skirt and aims at a reduction of paravalvular aortic regurgitation . the prosthesis is loaded on the delivery balloon in the abdominal aorta rendering the delivery catheter compatible with 14 f to 16 f. the commander delivery catheter is steerable and has a wheel to fineadjust valve positioning.6 the edwards sapien 3 valve was introduced in switzerland for implantation on january 27 , 2014 , and completely replaced the previously available edwards sapien xt prosthesis . patients underwent transthoracic echocardiography before hospital discharge , and were contacted for clinical followup at 30 days . standardized interviews , documentation from referring physicians , and hospital discharge summaries were used for the collection of clinical end points . all end points were defined according to the updated version of the valve academic research consortium ( varc2 ) definitions.7 an independent clinical event committee adjudicated all events . the prespecified end point was the varc2 early safety outcome , a composite of allcause mortality , stroke , lifethreatening bleeding , acute kidney injury stage 2 or 3 , coronary obstruction requiring intervention , major vascular complication , and valverelated dysfunction requiring repeat procedure . continuous data are reported as meansd , and categorical variables are reported as number ( percentage ) of patients . events are reported as counts of first occurrence per ( sub)type of event within 30 days of followup ( % of all patients ) . event rates at 30 days were compared for patients treated with the lotus versus the edwards sapien 3 bioprosthesis using cox regressions , censoring patients at death or lost to followup . reported are crude hazard ratios ( hrs ; with 95% cis ) with p values from wald chisquare tests , or continuity correct risk ratios with p values from fisher exact tests in case of zero events . multiple imputation of missing data was performed using chained equations ( n=20 data sets generated ) before the adjusted analyses . reported are adjusted hrs ( 95% cis ) , with the two valves compared , adjusting for age , dyslipidemia , peripheral vascular disease , aortic regurgitation moderate or severe , aortic valve area , new york heart association class iii or iv , and society of thoracic surgeons ( sts ) predicted risk of mortality score . the estimates of adjusted hrs from 20 data sets after multiple imputation of missing values were combined using rubin 's rule and presented with adjusted p values . twosided p values < stratified analyses of the following subgroups were performed : age ( 83 years versus < 83 years median ) , sex ( female versus male ) , left ventricular ejection fraction ( 40% versus > 40% ) , peripheral vascular disease ( yes versus no ) , sts risk score ( > 4 versus 4 ) , and p value for the interaction between subgroups and valve type . all analyses were performed with stata version 14 ( statacorp , college station , tx ) . all patients undergoing tavi procedures performed in switzerland are consecutively captured in a nationwide , prospective cohort study ( clinicaltrials.gov nct01368250).5 for the purpose of the present analysis , we investigated all patients with severe aortic stenosis treated with the edwards sapien 3 prosthesis or the lotus valve system . selection of tavi candidates , device allocation , and periprocedural management was left to the discretion of the operators . all data were recorded in a webbased database held at the clinical trials unit of the university of bern , switzerland . the swiss tavi registry has been approved by the local cantonal ethics committee and the institutional review boards of all participating sites . the lotus valve system consists of a single nitinol wire that is braided into a stent frame upon foreshortening and mechanical expansion . the prosthesis is attached to the delivery system with 3 coupling fingers ; buckles at the distal end connect to posts located at the commissures of the 3 leaflets upon shortening , and lock the valve in its final configuration . the stent frame accommodates a bovine pericardial valve and comes in 3 prosthesis sizes ( 23 mm , 25 mm , and 27 mm ) fitting an annulus diameter ranging from 20 mm to 26 mm . an adaptive seal in the distal portion of the prosthesis and an outer sleeve have been designed to reduce paravalvular regurgitation . the lotus prosthesis is fully repositionable and allows for an assessment of the final result before detachment of the valve from the coupling fingers of the delivery system . the precurved delivery catheter has a diameter of 18 f to 20 f and is not steerable . the valve can be implanted without rapid ventricular stimulation and predilatation is not necessary in all cases . the lotus valve system received ce mark approval on october 28 , 2013 , and on july 14 , 2014 , for its 23/27 mm and 25 mm prosthesis , respectively , and since then has become available for commercial use and implantation in switzerland . the edwards sapien 3 valve ( edwards lifesciences , irvine , ca ) is the fourth iteration of the first balloonexpandable transcatheter aortic valve prosthesis . the stent frame houses a valve made of 3 modified pericardial tissue leaflets , and accommodates annulus sizes from 18 mm to 28 mm using 3 device sizes ( 23 mm , 26 mm , 29 mm ) . an outer sealing skirt in the distal portion of the prosthesis complements the inner pet skirt and aims at a reduction of paravalvular aortic regurgitation . the prosthesis is loaded on the delivery balloon in the abdominal aorta rendering the delivery catheter compatible with 14 f to 16 f. the commander delivery catheter is steerable and has a wheel to fineadjust valve positioning.6 the edwards sapien 3 valve was introduced in switzerland for implantation on january 27 , 2014 , and completely replaced the previously available edwards sapien xt prosthesis . patients underwent transthoracic echocardiography before hospital discharge , and were contacted for clinical followup at 30 days . standardized interviews , documentation from referring physicians , and hospital discharge summaries were used for the collection of clinical end points . all end points were defined according to the updated version of the valve academic research consortium ( varc2 ) definitions.7 an independent clinical event committee adjudicated all events . the prespecified end point was the varc2 early safety outcome , a composite of allcause mortality , stroke , lifethreatening bleeding , acute kidney injury stage 2 or 3 , coronary obstruction requiring intervention , major vascular complication , and valverelated dysfunction requiring repeat procedure . continuous data are reported as meansd , and categorical variables are reported as number ( percentage ) of patients . events are reported as counts of first occurrence per ( sub)type of event within 30 days of followup ( % of all patients ) . event rates at 30 days were compared for patients treated with the lotus versus the edwards sapien 3 bioprosthesis using cox regressions , censoring patients at death or lost to followup . reported are crude hazard ratios ( hrs ; with 95% cis ) with p values from wald chisquare tests , or continuity correct risk ratios with p values from fisher exact tests in case of zero events . multiple imputation of missing data was performed using chained equations ( n=20 data sets generated ) before the adjusted analyses . reported are adjusted hrs ( 95% cis ) , with the two valves compared , adjusting for age , dyslipidemia , peripheral vascular disease , aortic regurgitation moderate or severe , aortic valve area , new york heart association class iii or iv , and society of thoracic surgeons ( sts ) predicted risk of mortality score . the estimates of adjusted hrs from 20 data sets after multiple imputation of missing values were combined using rubin 's rule and presented with adjusted p values . twosided p values < stratified analyses of the following subgroups were performed : age ( 83 years versus < 83 years median ) , sex ( female versus male ) , left ventricular ejection fraction ( 40% versus > 40% ) , peripheral vascular disease ( yes versus no ) , sts risk score ( > 4 versus 4 ) , and p value for the interaction between subgroups and valve type . all analyses were performed with stata version 14 ( statacorp , college station , tx ) . between february 4 , 2014 , and september 29 , 2015 , 140 patients were treated with the lotus valve system and 815 patients with the edwards sapien 3 prosthesis in 12 centers across switzerland . age , sex , medical history , and cardiovascular risk factors were well balanced between the two treatment arms . compared with patients treated with the lotus valve system , patients treated with the edward sapien 3 prosthesis more commonly had peripheral vascular disease ( 15.5% versus 7.9% , p=0.01 ) and higher estimated surgical risk as assessed by the logistic euroscore ( 18.914.8% versus 15.08.6% , p=0.018 ) and sts score ( 5.03.8% versus 4.12.4% , p=0.005 ) . baseline characteristics values are expressed as means with sds ( p value from t tests ) or counts ( % of all patients ; p value from fisher or chisquare tests ) . ccs indicates canadian cardiovascular society ; nyha , new york heart association ; sts , society of thoracic surgeons . procedural characteristics are shown in table 2 . although procedure time was comparable , the amount of contrast media was greater with the lotus valve system compared with the edwards sapien 3 prosthesis ( 17777 ml versus 15393 ml , p=0.004 ) . patients treated with edwards sapien 3 more commonly underwent femoral surgical access ( 12.6% versus 5.7% , p=0.018 ) and predilatation with balloon valvuloplasty ( 81.8% versus 31.4% , p<0.001 ) . device success was 77.1% among patients treated with the lotus valve and 75.7% among patients treated with the edwards sapien 3 prosthesis ( p=0.713 ) . there were no significant differences between the two devices with regards to transprosthetic gradient , patient prosthesis mismatch , or postprocedural aortic valve area , respectively ( table 3 ) . patients treated with the lotus valve more commonly had no aortic regurgitation after intervention ( 71.4% versus 53.2% , difference 18.3% ; 95% ci , 9.427.1 ) ( table 2 ) . whereas 7 patients ( 0.9% ) treated with the edwards sapien 3 prosthesis underwent valve in series implantation due to malpositioning , no case of valve malpositioning was reported in the lotus cohort ( p=0.271 ) . procedural characteristics values are expressed as means with standard deviations ( p values from t tests ) or counts ( % of all patients ; p values from fisher tests or chisquare tests ) . clinical outcomes at 30 days depicted are the number of first events within 30 days with percentage of all patients . cox regressions reporting hazard ratios ( hrs ; with 95% cis ) or continuity corrected risk ratios ( 95% cis ) in case of zero events with fisher exact p values . adjusted hr from cox regressions , adjusting for age , dyslipidemia , peripheral vascular disease , aortic regurgitation moderate or severe , aortic valve area , new york heart association class iii or iv , and society of thoracic surgery risk score ( combining the estimates of 20 data sets using rubin 's rule because of missing data ) . multiple imputation of missing data was performed using chained equations ( n=20 data sets generated ) . mi indicates myocardial infarction ; tia , transient ischemic attack ; varc2 , valve academic research consortium . the early varc2 safety end point occurred in 14.3% of patients treated with the lotus and 14.6% of patients treated with the edwards sapien 3 prosthesis with no difference in crude ( hr , 0.97 ; 95% ci , 0.611.56 [ p=0.915 ] ) and adjusted ( hr , 1.03 ; 95% ci , 0.641.67 [ p=0.909 ] ) analyses ( figure 1 ) . allcause mortality at 30 days was 2.2% among patients treated with the lotus valve system , and 2.8% among patients treated with the edwards sapien 3 valve ( adjusted hr , 0.75 ; 95% ci , 0.222.51 [ p=0.636 ] ) . estimated and observed mortality are illustrated in figure 2 . there were no significant differences between the two devices with regard to mortality , cerebrovascular accidents , myocardial infarction , vascular access site , and bleeding complications . while none of the patients in the lotus group experienced periprocedural myocardial infarction , 7 patients treated with the edwards sapien 3 prosthesis did ( 0.9% ) ( hr , 0.39 ; 95% ci , 0.026.79 [ p=0.602 ] ) . meier estimates of the valve academic research consortium 2 ( varc2 ) early safety composite outcome at 30 days . the blue line relates to the lotus valve system ; the red line relates to the edwards sapien 3 valve . bar graph of estimated and observed mortality at 30 days . society of thoracic surgeons ( sts ) risk scores were used to estimate mortality at 30 days . despite a higher amount of contrast used in patients treated with the lotus valve the number of permanent pacemaker implantations was higher in patients treated with the lotus ( 34.3% ) as compared with the edwards sapien 3 prosthesis ( 14.1% ) ( hr , 2.76 ; 95% ci , 1.973.87 [ p<0.001 ] ) ( figure 3 ) . in a stratified analysis for the varc2 early safety outcome , there were no significant interactions across major subgroups , with the exception of a positive effect for treatment with the lotus valve among patients 83 years and older ( p for interaction=0.030 ) ( figure 4 ) . the blue line relates to the lotus valve system ; the red line relates to the edwards sapien 3 valve . stratified analysis for the valve academic research consortium 2 early composite safety outcome ( based on crude hazard ratios ) . between february 4 , 2014 , and september 29 , 2015 , 140 patients were treated with the lotus valve system and 815 patients with the edwards sapien 3 prosthesis in 12 centers across switzerland . age , sex , medical history , and cardiovascular risk factors were well balanced between the two treatment arms . compared with patients treated with the lotus valve system , patients treated with the edward sapien 3 prosthesis more commonly had peripheral vascular disease ( 15.5% versus 7.9% , p=0.01 ) and higher estimated surgical risk as assessed by the logistic euroscore ( 18.914.8% versus 15.08.6% , p=0.018 ) and sts score ( 5.03.8% versus 4.12.4% , p=0.005 ) . baseline characteristics values are expressed as means with sds ( p value from t tests ) or counts ( % of all patients ; p value from fisher or chisquare tests ) . ccs indicates canadian cardiovascular society ; nyha , new york heart association ; sts , society of thoracic surgeons . procedural characteristics are shown in table 2 . although procedure time was comparable , the amount of contrast media was greater with the lotus valve system compared with the edwards sapien 3 prosthesis ( 17777 ml versus 15393 ml , p=0.004 ) . patients treated with edwards sapien 3 more commonly underwent femoral surgical access ( 12.6% versus 5.7% , p=0.018 ) and predilatation with balloon valvuloplasty ( 81.8% versus 31.4% , p<0.001 ) . device success was 77.1% among patients treated with the lotus valve and 75.7% among patients treated with the edwards sapien 3 prosthesis ( p=0.713 ) . there were no significant differences between the two devices with regards to transprosthetic gradient , patient prosthesis mismatch , or postprocedural aortic valve area , respectively ( table 3 ) . patients treated with the lotus valve more commonly had no aortic regurgitation after intervention ( 71.4% versus 53.2% , difference 18.3% ; 95% ci , 9.427.1 ) ( table 2 ) . whereas 7 patients ( 0.9% ) treated with the edwards sapien 3 prosthesis underwent valve in series implantation due to malpositioning , no case of valve malpositioning procedural characteristics values are expressed as means with standard deviations ( p values from t tests ) or counts ( % of all patients ; p values from fisher tests or chisquare tests ) . clinical outcomes at 30 days depicted are the number of first events within 30 days with percentage of all patients . cox regressions reporting hazard ratios ( hrs ; with 95% cis ) or continuity corrected risk ratios ( 95% cis ) in case of zero events with fisher exact p values . adjusted hr from cox regressions , adjusting for age , dyslipidemia , peripheral vascular disease , aortic regurgitation moderate or severe , aortic valve area , new york heart association class iii or iv , and society of thoracic surgery risk score ( combining the estimates of 20 data sets using rubin 's rule because of missing data ) . multiple imputation of missing data was performed using chained equations ( n=20 data sets generated ) . mi indicates myocardial infarction ; tia , transient ischemic attack ; varc2 , valve academic research consortium . the early varc2 safety end point occurred in 14.3% of patients treated with the lotus and 14.6% of patients treated with the edwards sapien 3 prosthesis with no difference in crude ( hr , 0.97 ; 95% ci , 0.611.56 [ p=0.915 ] ) and adjusted ( hr , 1.03 ; 95% ci , 0.641.67 [ p=0.909 ] ) analyses ( figure 1 ) . allcause mortality at 30 days was 2.2% among patients treated with the lotus valve system , and 2.8% among patients treated with the edwards sapien 3 valve ( adjusted hr , 0.75 ; 95% ci , 0.222.51 [ p=0.636 ] ) . there were no significant differences between the two devices with regard to mortality , cerebrovascular accidents , myocardial infarction , vascular access site , and bleeding complications . while none of the patients in the lotus group experienced periprocedural myocardial infarction , 7 patients treated with the edwards sapien 3 prosthesis did ( 0.9% ) ( hr , 0.39 ; 95% ci , 0.026.79 [ p=0.602 ] ) . kaplan meier estimates of the valve academic research consortium 2 ( varc2 ) early safety composite outcome at 30 days . the blue line relates to the lotus valve system ; the red line relates to the edwards sapien 3 valve . society of thoracic surgeons ( sts ) risk scores were used to estimate mortality at 30 days . despite a higher amount of contrast used in patients treated with the lotus valve the number of permanent pacemaker implantations was higher in patients treated with the lotus ( 34.3% ) as compared with the edwards sapien 3 prosthesis ( 14.1% ) ( hr , 2.76 ; 95% ci , 1.973.87 [ p<0.001 ] ) ( figure 3 ) . in a stratified analysis for the varc2 early safety outcome , there were no significant interactions across major subgroups , with the exception of a positive effect for treatment with the lotus valve among patients 83 years and older ( p for interaction=0.030 ) ( figure 4 ) . the blue line relates to the lotus valve system ; the red line relates to the edwards sapien 3 valve . stratified analysis for the valve academic research consortium 2 early composite safety outcome ( based on crude hazard ratios ) . the key findings of our analysis can be summarized as follows . in a nationwide prospective registry of patients undergoing tavi , we found no differences for the primary end point , the early composite safety end point within 30 days between patients treated with the fully repositionable lotus valve system versus the balloonexpandable edwards sapien 3 prosthesis.rates of device success were comparable for both devices.more than mild residual aortic regurgitation was exceedingly low with both devices.patients treated with the lotus valve system had a 2 to 3fold increased risk of permanent pacemaker implantation compared with patients treated with the edwards sapien 3 prosthesis . in a nationwide prospective registry of patients undergoing tavi , we found no differences for the primary end point , the early composite safety end point within 30 days between patients treated with the fully repositionable lotus valve system versus the balloonexpandable edwards sapien 3 prosthesis . patients treated with the lotus valve system had a 2 to 3fold increased risk of permanent pacemaker implantation compared with patients treated with the edwards sapien 3 prosthesis . newergeneration tavi devices are characterized by improved device success as compared with earlygeneration devices primarily by a reduction of moderate or severe prosthetic valve regurgitation , which has consistently been associated with increased late mortality.8 , 9 documentation of moderate to severe aortic regurgitation has been reported in up to 14% of patients treated with earlygeneration devices,8 , 9 , 10 and motivated the development of internal skirts and external cuffs to seal the prosthesis to the aortic annulus and reduce paravalvular regurgitation . complimentary to technical refinements of the devices , dedicated imaging tools have been introduced allowing for precise device positioning within the annular landing zone . in the swiss tavi registry , moderate or severe aortic regurgitation was documented in 0.7% and 1.2% of patients treated with lotus and edwards sapien 3 , respectively . our findings are consistent with the repositionable percutaneous replacement of stenotic aortic valve through implantation of lotus valve system : evaluation of safety and performance ( reprise ) ii study and the uk lotus registry , reporting moderate or severe aortic regurgitation in 1% and 0.8% of patients , respectively.2 , 3 reduction of paravalvular aortic regurgitation results from a combination of both , the full repositionability of the lotus valve allowing for an assessment of the result prior to deployment , and the prosthesis design with an adaptive seal in the distal portion and an outer sleeve.6 a similarly low incidence of moderate to severe aortic regurgitation was documented with the edwards sapien 3 valve that has been refined by an external sealing cuff that mimics a parachute . the incidence of more than mild paravalvular regurgitation decreased from 5.3% to 1.3% ( p=0.04 ) as compared with its predecessor in a previous analysis from the swiss tavi registry including almost 600 patients.11 rates of permanent pacemaker implantation amounted to 34% among patients treated with the lotus valve , and were 2 to 3fold higher compared with patients treated with the edwards sapien 3 prosthesis . comparable rates of av conductance disturbances and permanent pacemaker implantation have been consistently reported in the reprise ii study ( 28.6% ) and the uk lotus registry ( 31.8%).2 , 3 the effect of permanent pacemaker implantation after tavi on longterm outcomes remains a matter of debate.12 , 13 no difference in 1year mortality was documented in patients with a previous permanent pacemaker , a new permanent pacemaker , or no pacemaker in a prospective registry of 353 patients from 2 institutions.12 in contrast , permanent pacemaker implantation after tavi was reported to be an independent predictor of 1year mortality in an analysis of the placement of aortic transcatheter valves ( partner i ) trial.13 moreover , permanent pacemaker implantation was associated with a longer duration of hospitalization and higher rates of repeat hospitalization at 1 year.14 the degree of pacemaker dependency accompanied by ventricular dyssynchrony may reconcile the differential in clinical findings between studies . av conductance disturbances along with pacemaker dependency after tavi may be temporary rather than permanent in nature . in a small study of 36 patients with new pacemaker following implantation of a selfexpandable prosthesis , more than half of the patients were pacemaker independent at a median followup of 12 months.15 the rates of the early composite safety end point were comparable between the two devices at 30 days . in line , there were no differences with respect to cardiovascular mortality , myocardial infarction , bleeding , or vascular access site complications . the observed mortality rate ( lotus 2.2% versus sapien 3 2.8% ) was substantially lower as compared with the sts estimates . the overall incidence of stroke was 4.3% and 3.1% of patients treated with the lotus valve system and the edwards sapien 3 prosthesis , respectively . the incidence of stroke at 30 days was 5.9% in the reprise ii study and 3.9% in the uk lotus registry,2 , 3 while large nationwide tavi registries reported stroke rates in the range of 1.5% to 4%.9 , 11 , 16 , 17 , 18 , 19 although the signal has to be interpreted with caution , several reasons may account for a potential difference in cerebrovascular events between the two devices . a significantly lower rate of prior balloon valvuloplasty among patients treated with the lotus valve as compared with the edwards sapien valve may affect the rates of stroke . in a small study of 87 patients , the volume of new cerebral ischemic lesions as assessed by diffusionweighted magnetic resonance imaging was significantly higher among patients without as compared with patients with prior balloon aortic valvuloplasty.20 in contrast , a recent metaanalysis of 18 studies with 2443 patients demonstrated a trend towards a reduced risk of clinically relevant stroke with direct tavi . however , the findings should be interpreted with caution given the limitations of the nonrandomized studies included in the metaanalysis and the unadjusted nature of the summary measures used.21 the effect of predilatation on clinical outcome is currently being investigated in the transcatheter aortic valve implantation without predilatation ( simplify tavi ) study ( nct 01539746 ) and the balloon expandable transcatheter aortic valve implantation without predilatation of aortic valve ( easeit ) study ( nct02127580 ) . moreover , differences in the delivery catheter diameter , flexibility , and steerability may affect the risk of plaque abrasion in the aortic arch . finally , full repositionability of the lotus valve may increase the inclination of repeated prosthesis placement , which , in turn , has been associated with an increased risk of stroke.22 the present analysis has several limitations . first , there was no random allocation to treatment with the lotus valve or the edwards sapien 3 prosthesis , respectively . although baseline characteristics between the two treatment arms were comparable , we can not exclude selection of treatment according to concealed confounders . second , the number of patients included in the analysis was limited , and the duration of followup did not extend beyond 30 days . however , it constitutes the largest series reported to date and data are consistent with previously reported singlearm registries . third , differences in balloon valvuloplasty prior to device implantation may have confounded the clinical results . however , our analysis reflects routine clinical practice with the 2 devices by experienced operators . finally , implantation depth and oversizing have both been associated with an increased rate of conductance disturbances , respectively . first , there was no random allocation to treatment with the lotus valve or the edwards sapien 3 prosthesis , respectively . although baseline characteristics between the two treatment arms were comparable , we can not exclude selection of treatment according to concealed confounders . second , the number of patients included in the analysis was limited , and the duration of followup did not extend beyond 30 days . however , it constitutes the largest series reported to date and data are consistent with previously reported singlearm registries . third , differences in balloon valvuloplasty prior to device implantation may have confounded the clinical results . however , our analysis reflects routine clinical practice with the 2 devices by experienced operators . finally , implantation depth and oversizing have both been associated with an increased rate of conductance disturbances , respectively . in a nationwide registry , no statistical difference was found between the repositionable lotus valve system and the balloonexpandable edwards sapien 3 prosthesis with respect to the varc2 early safety outcome for the treatment . the need for new permanent pacemaker implantation was more frequent among patients treated with the lotus valve . the swiss tavi registry is supported by a study grant from the swiss heart foundation and the swiss working group of interventional cardiology , and is sponsored by unrestricted funds from boston scientific , edwards lifesciences , medtronic , st . the study sponsors had no role in the study design , data collection , data analysis , data interpretation , or writing of the report . jude medical , and received research contracts to the institution from edwards lifesciences and symetis . dr toggweiler is a proctor for symetis and received speakers ' fees from edwards lifesciences and medtronic . jude medical and has received reimbursement for travel expenses from medtronic , boston scientific , and edwards lifesciences . dr roffi received institutional research grants from abbott vascular , boston scientific , biotronik , biosensor , and medtronic . dr windecker has received research contracts to the institution from abbott , boston scientific , biosensors , cordis , medtronic , and st . dr wenaweser serves as proctor for medtronic , edwards lifesciences , and boston scientific and has received an unrestricted grant from medtronic to the institution ( university of bern ) . table s1 . missing baseline characteristics , multiple imputation , and adjusted analyses appendix s1 . collaborators and swiss transcatheter aortic valve implantation registry investigators . OUTPUT:

backgroundthe safety and effectiveness of the fully repositionable lotus valve system as compared with the balloonexpandable edwards sapien 3 prosthesis for the treatment of aortic stenosis has not been evaluated to date.methods and resultsall patients undergoing transcatheter aortic valve implantation with the edwards sapien 3 or the lotus valve system were included into the swiss transcatheter aortic valve implantation registry . an adjusted analysis was performed to compare the early clinical safety outcome according to the valve academic research consortium2 definition . between february 2014 and september 2015 , 140 and 815 patients were treated with the lotus and the edwards sapien 3 valve , respectively . there was no difference in crude and adjusted analyses of the early safety outcome between patients treated with lotus ( 14.3% ) and those treated with edwards sapien 3 ( 14.6% ) ( crude hazard ratio , 0.97 ; 95% ci , 0.611.56 [ p=0.915 ] ; adjusted hazard ratio , 1.03 ; 95% ci , 0.641.67 [ p=0.909 ] ) . more than mild aortic regurgitation was < 2% for both devices . a total of 34.3% of patients treated with lotus and 14.1% of patients treated with edwards sapien 3 required a permanent pacemaker ( hr , 2.76 ; 95% ci , 1.973.87 [ p<0.001]).conclusionsthe repositionable lotus valve system and the balloonexpandable edwards sapien 3 prosthesis appeared comparable in regard to the valve academic research consortium2 early safety outcome , and the rates of more than mild aortic regurgitation were exceedingly low for both devices . the need for new permanent pacemaker implantation was more frequent among patients treated with the lotus valve .

PubMed_Summ6524

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: leptin is an adipose tissue - derived hormone that has been shown to be related to several metabolic , inflammatory , and hemostatic factors involved in the development of hypertension and cardiovascular disease . experimental animal studies suggest that higher leptin levels may cause hyperglycemia , elevations in blood pressure ( mediated through increased sympathetic activity ) , and renal dysfunction . in rat models , leptin has been shown to induce natriuresis which may in turn result in an increase in arterial pressure so as to maintain sodium and water balance . leptin has also been shown to serve as a cofactor of tgf - beta activation , promote renal endothelial cell proliferation , and potentially may play a role in renal glomerulosclerosis [ 57 ] . recent studies have reported that infusion of recombinant leptin into normal rats for 3 weeks fosters the development of focal glomerulos 4.clerosis . however , few human studies have examined the putative association between plasma leptin levels and chronic kidney disease ( ckd ) in humans . in this context , we examined the independent relation between plasma leptin levels and ckd in a multiethnic sample of us adults , after adjusting for main confounding factors . the current study is based on data from the third national health and nutrition examination survey ( nhanes iii ) . detailed description of nhanes iii study design and methods are available elsewhere [ 813 ] . in brief , nhanes iii included a stratified multistage probability sample representative of the civilian noninstitutionalized us population . selection was based on counties , blocks , households , and individuals within households and included the oversampling of non - hispanic blacks and mexican americans in order to provide stable estimates of these groups . subjects were required to sign a consent form before their participation , and approval was obtained from the human subjects committee in the us department of health and human service . the sample included in the current analysis consisted of participants aged greater than 20 years who were randomly assigned to complete an examination in the morning after an overnight fast . we further excluded participants with self - reported cardiovascular disease ( n = 434 ) , missing serum creatinine ( n = 60 ) or who were missing data ( n = 101 ) on covariates included in the multivariable model , including systolic or diastolic blood pressure , body mass index ( bmi ) , or cholesterol levels . serum creatinine was measured using the jaffe kinetic alkaline picrate method performed on a roche hitachi 737 analyzer . serum creatinine values in nhanes iii were calibrated to the standard creatinine values from the cleveland clinic foundation ( ccf ) laboratory who used a roche coupled enzymatic assay method that was traceable to an isotope dilution mass spectrometric method using the following deming regression equation : standard creatinine in mg / dl = 0.960 nhanes measured serum creatinine ( in mg / dl)0.184 . glomerular filtration rate ( egfr ) was estimated from serum creatinine using the 4-variable modification of diet in renal disease ( mdrd ) study equation as follows : egfr = 175 ( serum creatinine in mg / dl ) ( age in years ) ( 0.742 if female ) ( 1.21 if black ) . ckd was defined as an egfr of < 60 ml / min/1.73 m , consistent with national kidney foundation kidney disease outcomes quality initiative ( kdoqi ) stage 3 chronic kidney disease . age , gender , race / ethnicity , smoking status , alcohol intake ( g / day ) , level of education , history of diabetes and oral hypoglycemic intake or insulin administration , and antihypertensive medication use were assessed using standardized questionnaires . individuals who had not smoked 100 cigarettes in their lifetimes were considered never smokers ; those who had smoked 100 cigarettes in their lifetimes were considered former smokers if they answered negatively to the question do you smoke now ? and current smokers if they answered affirmatively . using height and weight measured during the study examination , body mass index ( bmi ) rigorous procedures with quality control checks were used in blood collection and details about these procedures are provided in the nhanes laboratory / medical technologists procedures manual [ 8 , 11 ] . louis , mo , usa . the assay was a radioimmunoassay ( ria ) with a polyclonal antibody raised in rabbits against highly purified recombinant human leptin . the minimum detectable concentration of the assay was 0.5 fg / l leptin , and the limit of linearity was 100 recovery of leptin added to serum is 99104% over the linear range of the assay . within- and between - assay cvs ranged from 3.4% to 8.3% and from 3.6% to 6.2% , respectively [ 11 , 12 ] . serum glucose was measured using the modified hexokinase method at the university of missouri diabetes diagnostic laboratory . diabetes was defined based on the guidelines of the american diabetes association as a serum glucose 126 mg / dl after fasting for a minimum of 8 hours , a serum glucose 200 mg / dl for those who fasted < 8 hours before their nhanes visit , a glycosylated hemoglobin value 6.5% , or a self - reported current use of oral hypoglycemic medication or insulin . seated systolic and diastolic blood pressures were measured using a mercury sphygmomanometer according to the american heart association and seventh joint national committee ( jnc7 ) recommendations . participants were considered to have hypertension if they reported current blood pressure - reducing medication use and/or had systolic blood pressure 140 mm hg and/or diastolic blood pressure 90 mm hg . plasma leptin was analyzed both as a continuous variable as well as a categorical variable . for the analysis as a continuous variable , leptin values were log transformed ( base e ) as a result of their skewed distribution . using the distribution present in the nhanes iii population , we categorized plasma leptin level into quartiles ( 4.3 fg / l , 4.48.7 fg / l , 8.816.9 fg / l , > 16.9 fg / l ) . the multivariable - adjusted odds ratio [ ( or ) ( 95% confidence interval ( ci ) ] of ckd associated with leptin quartile was calculated with the lowest quartile as the referent , using logistic regression models . odds ratios were calculated initially after age and sex adjustment and subsequently after additional adjusting for race / ethnicity ( non - hispanic whites , non - hispanic blacks , mexican americans , and others ) , education categories ( below high school , high school , above high school ) , smoking ( never smoker , former smoker , current smoker ) , alcohol intake ( continuous ) , bmi ( continuous ) , diabetes mellitus ( absent , present ) , hypertension ( absent , present ) , and total serum cholesterol ( continuous ) . trends in the or of ckd across increasing plasma leptin category were determined by modeling median within - quartile leptin level as a continuous variable . to examine the dose - response relationship of the observed association between plasma leptin level and ckd without linearity assumptions , we used flexible nonparametric logistic regression employing the generalized additive modeling approach ( r system for statistical computing , available from comprehensive r archive network [ http://www.cran.r-project.org/ ] ) to calculate odds ratio of ckds mellitus , adjusting for all covariates in the multivariable model ; the predicted odds ratio of ckd was then plotted against increasing leptin levels ( on the log scale ) . previous studies have shown that serum leptin levels are associated with increased systemic inflammation as measured by c - reactive protein levels , hyperglycemia , high insulin levels , and increased systolic blood pressure , factors that have also been shown to be associated with ckd[17 , 21 , 22 ] . therefore , in a supplementary analysis , to examine if the observed association between plasma leptin and ckd was explained by c - reactive protein levels , fasting insulin , glucose levels , or systolic blood pressure , we adjusted for these variables in the multivariable - adjusted model . sample weights that account for the unequal probabilities of selection , oversampling , and nonresponse were applied for all analyses using sudaan ( version 8.0 ; research triangle institute , research triangle park , nc ) and sas ( version 9.2 ; sas institute , cary , nc ) software ; standard errors ( se ) were estimated using the taylor series linearization method . table 1 presents the characteristics of the study population included in the current analysis . overall , this study included a broad age range , multiethnic sample of americans with an approximately equal number of men and women . the mean egfr of the study participants was 94 ml / min/1.73 m , and 3.5% had ckd . a positive association between higher leptin quartiles and ckd was present in the age , sex - adjusted model as well as the multivariable model . when analyzed as a continuous variable after log transformation , a positive association was present between leptin and ckd . table 3 presents the association between plasma leptin levels and ckd within subgroups defined by gender , bmi categories , and diabetes and hypertension . overall , the association between leptin and ckd was consistently present within these subgroups . although some of the ors failed to reach conventional levels of statistical significance due to limited sample size and therefore statistical power , tests for interaction were not statistically significant ( each p > 0.10 for all stratified analyses ) . when we employed nonparametric models to graphically examine the dose - response relationship between plasma leptin levels and ckd without linearity assumptions involved in traditional regression models , we observed an overall positive association between plasma leptin and ckd , consistent with the results in tables 1 , 2 , and 3 . however , there was a steeper association with ckd for plasma leptin levels > 16 fg / l ( figure 1 ) . in a supplementary analysis , to examine if the observed association between leptin and ckd was explained by c - reactive protein , a marker of inflammation , or fasting insulin or glucose levels , or systolic blood pressure , we additionally adjusted for these variables to the multivariable - adjusted model . the positive association between leptin and ckd was attenuated , but still present . compared to quartile 1 of plasma leptin ( referent ) , the multivariable or ( 95% ci ) of ckd was 1.31 ( 0.70 to 2.44 ) in quartile 2 , 1.22 ( 0.57 to 2.62 ) in quartile 3 , and 2.72 ( 1.14 to 6.48 ) in quartile 4 ; p - trend = 0.0475 . in a multi - ethnic , population - based sample of us adults , we found that higher plasma leptin levels were positively associated with ckd . this association appeared to be independent of confounders such as age , race - ethnicity , education , bmi , diabetes , and hypertension and appeared to be consistently present in both men and women . furthermore , the observed association between plasma leptin levels and ckd was present even after adjusting for c - reactive protein and fasting insulin levels , suggesting an association between this adipokine and ckd that is independent of these factors . several lines of recent evidence suggest that an association between leptin and ckd is plausible . this includes the role of leptin in activating the sympathetic nervous system and causing chronic elevations in blood pressure and renal dysfunction , inducing natriuresis which may result in an increase in arterial pressure so as to maintain sodium and water balance , serving as a cofactor of tgf - beta activation , promoting renal endothelial cell proliferation , and subsequent glomerulosclerosis [ 57 ] . it was recently shown that , in rats , infusion of recombinant leptin caused the development of focal glomerulosclerosis . also , leptin is also reported to be related to insulin resistance and high c - reactive protein levels , both of which have been shown to be related to ckd [ 21 , 25 ] . a previous study conducted among women with type 1 diabetes reported that plasma leptin levels are independently related to reduced renal function . in a study from south africa conducted among approximately 300 black subjects , okpechi et al . reported that plasma leptin levels were inversely related to egfr . in another study , common polymorphisms in the lep gene overall , our findings of a positive association between plasma leptin and ckd are in agreement with these previous studies ; in addition , we were able to study a large multiethnic sample that includes both men and women and also adjusts for multiple confounders such as bmi , diabetes , hypertension , lipid levels , and c - reactive protein . the main strengths of our study include its population - based nature , inclusion of a representative multiethnic sample , adequate sample size , and the availability of data on confounders for multivariable adjustment . furthermore , all data were collected following rigorous methodology , including a study protocol with standardized quality control checks . the main limitation of our study is the cross - sectional nature of nhanes , which precludes conclusions regarding the temporal nature of the association between plasma leptin and ckd . second , defining ckd as egfr < 60 ml / min/1.73 m introduces some ascertainment bias . this bias is likely to result in under- or overestimation of odds ratios presented in this report . in summary , in a multiethnic sample of us adults , we found that higher plasma leptin levels are associated with ckd , independent of traditional factors such as age , sex , smoking , alcohol intake , bmi , diabetes , hypertension and serum cholesterol . our results suggest that leptin may explain part of the reported association between obesity and kidney disease . however , future prospective cohort studies are needed to confirm or refute our findings . OUTPUT:

background . leptin is an adipose tissue - derived hormone shown to be related to several metabolic , inflammatory , and hemostatic factors related to chronic kidney disease . recent animal studies have reported that infusion of recombinant leptin into normal rats for 3 weeks fosters the development of glomerulosclerosis . however , few studies have examined the association between leptin and ckd in humans . therefore , we examined the association between plasma leptin levels and ckd in a representative sample of us adults . methods . we examined the third national health and nutrition examination survey participants > 20 years of age ( n = 5820 , 53.6% women ) . plasma leptin levels were categorized into quartiles ( 4.3 fg / l , 4.48.7 fg / l , 8.816.9 fg / l , > 16.9 fg / l ) . ckd was defined as a glomerular filtration rate of < 60 ml / min/1.73 m2 estimated from serum creatinine . results . higher plasma leptin levels were associated with ckd after adjusting for age , sex , race / ethnicity , education , smoking , alcohol intake , body mass index ( bmi ) , diabetes , hypertension , and serum cholesterol . compared to quartile 1 of leptin ( referent ) , the odds ratio ( 95% confidence interval ) of ckd associated with quartile 4 was 3.31 ( 1.41 to 7.78 ) ; p - trend = 0.0135 . subgroup analyses examining the relation between leptin and ckd by gender , bmi categories , diabetes , and hypertension status also showed a consistent positive association . conclusion . higher plasma leptin levels are associated with ckd in a representative sample of us adults .

PubMed_Summ6525

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: thyroid hormones failure leads to significant interferences and malfunctions at different physical , mental and social aspects . according to an investigation performed in colorado state of usa at 2000 , screening of 25000 people showed that nearly 2.6 million people would be apparently afflicted with hypothyroidism in the next 20 years . a thyroid screening investigation in tehran at 2001 revealed that the prevalence of hypothyroidism in people over 20 years old is 3.5 people per thousand and its subclinical feature prevalence is 2.2 people per thousand ; the prevalence of hyperthyroidism is less than one people per thousand and subclinical hyperthyroidism prevalence is 4.2 people per thousand . mental health is considered as one of the most important indicators of the health and hygiene of a society and is mainly affirmed by the psychologists and other scientists of behavioral and social sciences ; this has developed a background for evaluating and assessing mental disorders caused by hypothyroidism . the purpose of mental health is a person s complete ability to perform his / her daily affairs , communicate with his / her family and environment properly , and show no adverse behaviors culturally and socially . mental health is very important because it is correlated with a person s individual and social performance . in fact , providing mental health can lead to increased efficiency in both personal and social aspects . many studies have reflected that duration of treatment will be prolonged in patients with lower mental health levels and these patients can be prepared through necessary interventions in order to achieve more adaptation and encounter to the tension of the disease . a study has indicated that psychiatric disorders are usually common in patients with acute hypothyroidism and these disorders are ( to some extent ) recovered along with the treatment of the causative disease . the effect of hypothyroidism on increase of depression parameters in older people has been proved in another study . hypothyroidism can also affect the conceptive ( perceptive ) and temperamental ( behavioral ) functions of the patient . mental signs , stress , tension , memory loss ( par amnesia ) , and physical dysfunctions are the factors that cause quality of life deterioration . quality of life is the state of our good or bad feeling about our own life . effect of auto - immunity thyrotoxicosis on the quality of life of patients with auto - immune hypothyroidism has been determined . the results of another study have determined that men with hypothyroidism have weaker physical conditions than hypothyroid women . another study surveying the relationship between the quality of life and hypothyroidism has revealed that the quality of life of most of the patients with hypothyroidism was at an intermediate level . anyway , psychological factors affect the occurrence of all diseases and the fact that whether their role is related to the beginning , progression , severity or recurrence of the disease or predisposing or reaction to the disease has been a controversial issue and it is variable among different diseases . generally , the importance of quality of life and mental health in hypothyroid patients is considerable . changes in mental health condition of these patients have been approved . also , mental health is one of the most important factors affecting the quality of life . therefore , in the present study , the mental health condition and the quality of life level of patients with hypothyroidism have been compared with the normal people in order to perform appropriate care programs to increase these patients mental health condition and quality of life . therefore , the purpose of present study was to compare the quality of life and mental health of hypothyroid patients with normal people referring to motahari clinic , affiliated to shiraz university of medical sciences . this study is a descriptive - analytic investigation performed in motahari clinic of shiraz city . research samples were 95 patients ( more than 20 years old ) with hypothyroidism confirmed by specialists ; they referred to motahari clinic and were selected through convenience sampling method . recruitment was performed by attendance of the researcher at the motahari clinic and selection of the patients based on inclusion and exclusion criteria , between october 2014 and august 2015 . a control group of 95 normal people was assigned among the relativesof the other patients and also the personnel of the clinics by convenience sampling method . then , the sample volume was calculated and determined using med - calc statistical software with 5% error rate and 80% statistical power ( attrition of 20% ) as 190 cases . n=(z1-2)2(12+22)(2-1)2 =0.05 , =0.10 , 1=20.1 , 2=19.6 , sd1=2.95 , sd2=2.8 , z1-a/2=1.96 , z1-b/2=0.85 . age more than 20 years old and ability to write and read or to participate in the interview were the inclusion criteria . exclusion criteria were lack of willingness to participate and cognitive disorders or chronic diseases . eligible patients with hypothyroidism referring to motahari clinic of shiraz university of medical sciences were placed in the test ( patients ) group . normal people ( control group ) were the eligible relative of the other patients ( except patients with hypothyroidism ) with or with no other diseases except hypothyroidism referring to the motahari clinic without any direct relationship or affinity to patients with hypothyroidism . after approval of the ethics committee of shiraz university of medical sciences ( no 93 - 01 - 08 - 8062 ) and coordination with the clinic , the researcher attended the clinic on all working days of the week and at two work shifts of morning and afternoon and selected the eligible samples . the purpose of the research was explained to the participants , written consent forms were obtained , and they were ensured about the privacy of the data . then , the individual questionnaire , general health questionnaires ( ghq ) and the quality of life questionnaire were delivered to the study units . if the participants were not able to fill the questionnaire , the questions were read to them by the researcher and their answers were recorded completely . data collection tool in this study was a 3 part questionnaire . in the first part , the demographic information was gathered through 5 questions ( age , sex , marital status , level of education and occupation ) and in the second part , the questions of ghq through 28 questions in 4 domains of physical signs , anxiety , social dysfunction and depression on the basis of a 4- choice likert scale ( not at all , normally , more than usual and much more than usual ) . reliability coefficient of the whole test were reported as 0.88 and those of the fields were 0.77 , 0.81 , 0.50 and 0.58 , respectively . ( 2001 ) evaluated the ghq-28 psychometric properties ; the coefficients of test - retest and split half and chorenbach alpha were obtained as 0.70 , 0.93 and 0.90 , respectively . the simultaneous validity was obtained 0.55 through midlex questionnaire and the construct validity was reported 0.72 to 0.87 . the third part was about the questions of whoqol - bref questionnaire , evaluating the quality of life generally and totally ; this part consisted of 26 questions in 4 fields of physical health , mental health , social relations and environmental health ( 3 , 6 , 7 and 8 questions for each field respectively ) and 2 other miscellaneous questions surveying the health condition and quality of life level in a general manner . each field was given a score range of 4 - 20 , scoring 4 representing the worst and score 20 the best condition in the related field . evaluated the reliability of whoqol - bref questionnaire in iranian community with test - retest of all domains ; physical health , mental health , social relations and environmental health respectively 0.77 , 0.77 , 0.75 , 0.84 . also , internal consistency of all domains using alpha cronbach between patients and healthy subjects was reported 0.52 - 0.84 . data were analyzed in spss software version 19 ( spss statistics ; ibm corporation , chicago , illinois , usa ) using descriptive statistical methods and independent t- test , pearson correlation coefficient and anova and p<0.05 was considered statistically significant . frequencies and percentages were calculated for categorical variables , means and standard deviations for continuous variables . independent t - test was performed to examine mental health , quality of life and quantitative demographic information . then , the sample volume was calculated and determined using med - calc statistical software with 5% error rate and 80% statistical power ( attrition of 20% ) as 190 cases . n=(z1-2)2(12+22)(2-1)2 =0.05 , =0.10 , 1=20.1 , 2=19.6 , sd1=2.95 , sd2=2.8 , z1-a/2=1.96 , z1-b/2=0.85 . age more than 20 years old and ability to write and read or to participate in the interview were the inclusion criteria . exclusion criteria were lack of willingness to participate and cognitive disorders or chronic diseases . eligible patients with hypothyroidism referring to motahari clinic of shiraz university of medical sciences were placed in the test ( patients ) group . normal people ( control group ) were the eligible relative of the other patients ( except patients with hypothyroidism ) with or with no other diseases except hypothyroidism referring to the motahari clinic without any direct relationship or affinity to patients with hypothyroidism . after approval of the ethics committee of shiraz university of medical sciences ( no 93 - 01 - 08 - 8062 ) and coordination with the clinic , the researcher attended the clinic on all working days of the week and at two work shifts of morning and afternoon and selected the eligible samples . the purpose of the research was explained to the participants , written consent forms were obtained , and they were ensured about the privacy of the data . then , the individual questionnaire , general health questionnaires ( ghq ) and the quality of life questionnaire were delivered to the study units . if the participants were not able to fill the questionnaire , the questions were read to them by the researcher and their answers were recorded completely . data collection tool in this study was a 3 part questionnaire . in the first part , the demographic information was gathered through 5 questions ( age , sex , marital status , level of education and occupation ) and in the second part , the questions of ghq through 28 questions in 4 domains of physical signs , anxiety , social dysfunction and depression on the basis of a 4- choice likert scale ( not at all , normally , more than usual and much more than usual ) . reliability coefficient of the whole test were reported as 0.88 and those of the fields were 0.77 , 0.81 , 0.50 and 0.58 , respectively . ( 2001 ) evaluated the ghq-28 psychometric properties ; the coefficients of test - retest and split half and chorenbach alpha were obtained as 0.70 , 0.93 and 0.90 , respectively . the simultaneous validity was obtained 0.55 through midlex questionnaire and the construct validity was reported 0.72 to 0.87 . the third part was about the questions of whoqol - bref questionnaire , evaluating the quality of life generally and totally ; this part consisted of 26 questions in 4 fields of physical health , mental health , social relations and environmental health ( 3 , 6 , 7 and 8 questions for each field respectively ) and 2 other miscellaneous questions surveying the health condition and quality of life level in a general manner . each field was given a score range of 4 - 20 , scoring 4 representing the worst and score 20 the best condition in the related field . nejat et al . evaluated the reliability of whoqol - bref questionnaire in iranian community with test - retest of all domains ; physical health , mental health , social relations and environmental health respectively 0.77 , 0.77 , 0.75 , 0.84 . also , internal consistency of all domains using alpha cronbach between patients and healthy subjects was reported 0.52 - 0.84 . data were analyzed in spss software version 19 ( spss statistics ; ibm corporation , chicago , illinois , usa ) using descriptive statistical methods and independent t- test , pearson correlation coefficient and anova and p<0.05 was considered statistically significant . frequencies and percentages were calculated for categorical variables , means and standard deviations for continuous variables . independent t - test was performed to examine mental health , quality of life and quantitative demographic information . 95 patients ( male and female ) in the patient group and 95 people ( male and female ) in the control group were studied . minimum age in the patient group was 22 years old and maximum age was 70 years . the sample s demographic characteristics different aspects of the quality of life were assessed and compared between the two groups using independent t - test and no significant difference was noted between the test and control groups . in other words , the patients mental health mean score was 59.70 , compared with that of the normal people which was 48.68 ( p>0.001 ) . in fact , the physical signs , anxiety and depression were higher and more severe in the test ( patients ) group . in other words , the mental health condition of hypothyroid patients was lower than the normal people . mean and standard deviation between the quality of life and mental health in hypothyroidism patients and healthy subjects comparison of the mean scores of mental health and quality of life in hypothyroidism patients and normal subjects comparison of demographic data and both of mental health and quality of life showed a significant relationship ( p=0.005 ) just between education and mental health ( table 4 ) . also , evaluation of the relationship between demographic variables and mental health and quality of life revealed that there was a significant difference only between the mental health condition and physical signs ( p>0.001 ) and anxiety ( p>0.001 ) with degree of education . but this significant relationship was not observed in the quality of life and its aspects ( p>0.001 ) . mental health and quality of life based on demographic variables these results also confirm the significant correlation between the mental health and quality of life in hypothyroid patients ( p>0.001 ) . the present study was performed to assess and compare the quality of life and mental health between patients with hypothyroidism and normal people . results showed that hypothyroid patients have significant differences in all aspects of mental health compared with the normal people . it was revealed that these patients have the highest severity of depression , physical signs and anxiety . but there was no significant difference in the quality of life and its aspects between the patients and the normal people . these results regarding the low level of mental health in patients with hypothyroidism compared with the normal people are in agreement with other studies . a study performed to investigate the effect of thyroid disorders on anxiety and depression level of patients showed that anxiety and depression signs in patients with overt hypo- and hyper - thyroidism were more intense than other thyroid disorders . another investigation has noted that anxiety - but not depression- was higher in patients with differentiated thyroid cancer ( dtc ) than normal people . also , another study revealed that neuropsychiatric disorders were very common in hypothyroidism which may be recovered through treatment done regarding the underlying cause ( treatment associated with hypothyroidism ) . because of the considered aspects of mental health have been evaluated and assessed in the mentioned investigations , it can be said that their results confirm our findings to some extent . on the other hand , because the depression feature has the most severity in patients with hypothyroidism , it can be seen that some investigations confirm it too . for example , the results of a study showed that subclinical hypothyroidism can increase the risk of depression . there was also a compatible study which showed the significant relationship between physical condition and anxiety aspects of mental health and patient s education level . those results also showed that there was a direct correlation between hypothyroid patient s education level and their social condition ; this can be because of lower social and individual adaptation skills in patients with lower education levels to withstand the problems of the disease . therefore , patients with higher education levels have better physical conditions and lower anxiety levels . our results are also compatible with other studies results regarding the comparison of the quality of life of patients with hypothyroidism and normal people . the quality of life of patients with different types of thyroid gland cancer undergoing tsh- suppressive thyroxin therapy was assessed in an investigation . these patients were considered as a model of subclinical hyperthyroidism . finally , the results showed that restoration of euthyroidism ( normal function of thyroid gland ) had no effect on the quality of life of these patients . but the results of a similar study comparing the mental health condition and the quality of life of patients with hypothyroidism with the normal people were different . it was seen that the quality of life of these patients was lower than the normal people in the mentioned study . also , another study implied the lower level of quality of life in patients with auto - immune hypothyroidism . this difference can be due to the varieties of the study population , culture and the type of investigation tool . in this regard , the results of a review study on evaluating tools of signs and condition of health and quality of life of hypothyroid patients showed that many of using tools were not appropriate to the purpose of the investigations ; hence , they can increase or alter the results . moreover , there are some compatible studies about the significant correlation between mental health and the quality of life in patients with hypothyroidism . in a study performed to investigate the relationship between mental health and quality of life of patients with coronary arteries disorders , this relationship was reported as significant . unfortunately , in studies performed to compare the quality of life and mental health of patients with multiple sclerosis ( ms ) and irritable bowel syndrome ( ibs ) , only the results of the quality of life comparison and mental health comparison between 2 groups were reported , but no results regarding the existence or otherwise of the relationship between the two mentioned variables in one group were reported . in this study , most of the subjects were male with a mean age of 38.93 . in comparison with this result , the other study reported the prevalence of overt and subclinical hypothyroidism more in female , respectively . this result disagrees with that of the current study and it can be due to the selection of subjects from one center . but another study conducted on hypothyroidism patients over 18 years of age , reported that the mean age of the subjects was 44 years old . therefore , it is recommended that in the future studies in this field , multi - central sampling should be considered . the most important limitation of the present study was the selection of patients from only one specialized clinic ( of course , it is the most active clinic in this field in the south of iran ) . therefore , generalization of the results of this study to larger fields must be performed with caution and in order to increase the extension capability of these findings , the population and sample size must be larger and multiple . also , the use of several diagnostic methods for the selection of normal people in future studies is recommended . with regard to the results of the present study indicating lower levels of mental health in patients with hypothyroidism , holding educational programs and protocols about this disease to improve the mental health is suggested . also , these results indicate the relationship between mental health and quality of life ; therefore , it is necessary to pay attention to their importance in such patient s care and treatment programs design . OUTPUT:

abstractbackground : hypothyroidism is a condition caused by a decrease in the thyroid gland hormones . this disease is very common at all age ranges . regarding its long term therapeutic procedure , this disease can affect the quality of life and the mental health of the patients . the present study aimed to compare the quality of life and mental health in hypothyroid patients and normal people . methods : this descriptive - analytic investigation was performed using convenience sampling on 95 patients with hypothyroidism and 95 normal cases referring to motahari clinic between october 2014 and august 2015 . data were collected through general health questionnaire ( consisted of 4 fields ; physical signs , anxiety , social function disorder , depression ) and quality of life questionnaires . data were analyzed using independent t- test , pearson correlation coefficient and variance analysis . p - values<0.05 were considered as significant . results : both control ( normal ) and test ( patient ) groups were matched in demographic characteristics in this study ( p>0.001 ) . the results showed that there was no significant difference between the quality of life of patients and that of the normal people ( test and control groups ) ( p>0.001 ) . but the comparison of mental health level of patients ( 59.70 ) and normal people ( 48.68 ) showed a significant difference at all aspects ( p<0.001 ) conclusion : considering and improving the mental health status of such patients can be positively effective in their treatment procedure . considering this key point in a country like iran with rich religious backgrounds can be useful in designing self - care and therapeutic programs and even for all people .

PubMed_Summ6526

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: genetic disorders caused by mutations in the -globin gene are widely known as the human -hemoglobinopathies , in which -thalassemia and sickle cell disease ( scd ) are the most prevalent ones , particularly in the mediterranean , africa , and southeast asia , leading to great mortality and morbidity [ 14 ] . the high occurrence of the -thalassemia and scd mutations is due to the reason that both cause mild severity of malarial infection in the heterozygous state [ 57 ] . however , in the homozygous state , these mutations shorten the lives of affected ones . -thalassemia is caused by the inherited mutations in the -globin gene complex , resulting a total absence or severe decrease in the production of -globin chains [ 8 , 9 ] . the lack of -globin chain production leads to the accumulations and precipitations of free intracellular -globin chains , which may consequently result in premature hemolysis of red blood cells and apoptosis of erythroid precursor [ 8 , 10 , 11 ] . therefore , the combining effects of ineffective erythropoiesis , hemolysis , and hypersplenism are the main culprit of severe anemia in -thalassemia patients . it is characterized by the abnormal appearance of the red blood cells which are rigid and sickled . scd is attributed to a point mutation at the coding sequence of the -globin gene which causes the substitution of glutamate by valine in the glutamic acid at the sixth position of -globin protein , and thus forming a sickle hemoglobin ( hbs , 22 ) when incorporating into a hemoglobin tetramer [ 13 , 14 ] . hbs will polymerize inside the red blood cells under hypoxic condition , resulting in the alternation of the shape of red blood cells as well as their function . however , long - term transfusion therapy may cause iron overload in patients from the gradual breakdown of transfused blood which may eventually result in cardiac failure and/or even death . though the advance in iron chelation can help to remove excess iron in patients , the survival rate is greatly dependent on the iron chelation regimens . allogeneic hematopoietic stem cell transplantation ( hsct ) is one of the gene transfer therapies aimed at the underlying molecular causes of scd and -hemoglobinopathies . several hundred scd and thalassemia patients have successfully experienced hsct with promising results [ 16 , 17 ] . nevertheless , there is a great likelihood that hsct will be limited to a small proportion of hemoglobinopathy patients as evidence has shown merely younger patients and those who have not developed significant disease complications have gained the best results in hsct . also , most successful transplantations have to utilize stem cells from matched sibling donors making hsct a challenging therapy for some patients . therefore , hsct may not be applicable to many current patients . transferring of - or -hematopoietic stem cells of patients can be another therapy option for -thalassemia patients . it has taken a long period of time to have the clinical gene transfer protocol being approved since the transduction of human hematopoietic stem cells and gene expression must reach certain efficiency and high level . despite the fact that this approach has successfully passed its initial human trial , previous studies reported the issues regarding low autoploidy recombination , insertional mutagenesis , and effect of inserted vectors on the expression of nearby genes could possibly limit the application [ 21 , 22 ] . apart from gene therapy , fetal hemoglobin reactivation by chemical agents appears promising enough to develop into effective interventions to cure human -hemoglobinopathies . previous studies have revealed that homozygous -thalassemia patients will not suffer severe anemia until fetal -globin genes are silenced and that patients carrying hereditary persistence of fetal hemoglobin ( hpfh ) , meaning fetal hemoglobin ( hbf ) is abnormally persisted at high level in adults , will only suffer mild anemia [ 8 , 13 , 2327 ] . more evidences also supported that hpfh can improve the severity of both -thalassemia and scd . therefore , it have been suggested that increasing the synthesis of fetal hemoglobin ( hbf ) by reactivating fetal -globin gene can be a potential therapy in patients suffering -thalassemia or scd . it is expected that the pharmacological induction of hbf can correct the globin chain imbalance in -thalassemia patients , while inhibit hbs polymerization in scd patients [ 2832 ] . in recent years , much effort has been made to identify the naturally occurring inducers and drug treatments which can increase the synthesis of hbf and promote the expression of fetal -globin gene . some chemotherapeutic agents , for example , 5-azacytidine and hydroxyurea , ( hu ) have been reported due to their ability to enhance hbf production [ 31 , 33 , 34 ] . yet , most of these currently identified hbf - inducing agents exhibit low efficacy and specificity , myelotoxicity , and carcinogenesis as well as modest responses to treatment which greatly limit their usefulness in the clinical practice [ 5 , 35 , 36 ] . owing to this , ( i ) discovering novel screening platform for identifying potential inducers with high efficiency and accuracy and ( ii ) identifying new hbf - inducing agents from the natural world with the combination of efficacy , safety , and ease of use will be high on the agenda . with the aim of determining the therapeutic potency of the novel inducing compounds and studying the underlying regulatory mechanism of the embryonic and fetal human globin genes expression , various in vitro and in vivo screening platforms have been widely utilized . for in vitro models , there are six human cell lines carrying an embryonic - hbf phenotype ; they are k562 human chronic myelogenous leukemia cells , m - tat , nsmeg , ocim1 , ocmi2 , and as - e2 , while k562 cell line is one of the most well - known and widely used screening platforms for hbf inducers [ 13 , 30 ] . another seven human cell lines which are capable of synthesizing both - and -globin chains are jk-1 , kmoe-2 , ku812 , lama-84 , tf-1 , tn922 , and ap217 ; yet , ku812 cell line is comparatively unique and useful from the others as it can undergo a spontaneous differentiation which can be observed [ 30 , 3739 ] . moreover , human bone marrow cd34 + hematopoietic progenitors drawn from -thalassemia patients and primary erythroid progenitors stem cells ( epscs ) obtained from peripheral blood are also great in vitro models to study the effect of different hbf - inducing agents [ 1 , 13 ] . back to the 1980s , baboons , a nonhuman primate model , have already been used for the study of fetal and adult hemoglobin synthesis during fetal development [ 40 , 41 ] . there was an influential research conducted by de simone and colleagues that the adult baboon has been shown to respond to erythropoietic stress with the reverse hemoglobin switch during which an increase in the number of hbf - containing erythrocytes ( f cells ) and an increase in hbf synthesis can be observed in adult baboon [ 40 , 42 , 43 ] . however , this animal model is expensive to purchase , feed , and maintain in conditions appropriate to modern animal husbandry . in order to understand the influence of hbf synthesis and its induction mechanism , till the 90s , researchers have successfully discovered that transgenic mice carrying human a -globin gene , which can act as a new in vivo model for screening novel pharmaceutical compounds for hbf induction in the adult [ 44 , 45 ] . these inducers can be categorized into several classes based on their mechanisms of action [ 13 , 46 ] as listed in table 1 . some of them are classified as chemotherapeutic agents , for example , hydroxyurea ( hu ) , 5-azacytidine ( 5-aza ) , decitabine , and citarabine . hu is also known as a ribonucleotide reductase inhibitor due to its ability of inhibiting dna analysis , while 5-aza , decitabine and citarabine are dna methyltransferase inhibitors who responsible for the hypomethylation of dna [ 8 , 13 ] . several short - chain fatty acids ( scfas ) specifically stimulate transcription in the -globin gene promoter through histone deacetylase hdac inhibition , resulting in global histone hyperacetylation [ 5 , 47 ] . in contrast , some studies argue that globin histone hyperacetylation induced is not the primary mechanism of scfa ; yet , hdac inhibitors are often potent -globin inducers [ 47 , 48 ] . rapamycin preferentially induce -globin mrna accumulation , while being only minor for -globin and none for -globin mrnas . as its hbf - inducing effect is not related to cytotoxicity and cell growth inhibition , scientists are very interested in further studying if the enhancement of -globin mrna medicated by rapamycin is associated with xmni polymorphism . there are studies showing that k562 cells treated with dna - binding agents , such as mithramycin , have led to erythroid differentiation and sharp enhancement of -globin mrna level . through pcr arrested experiments , it is found that these dna - binding drugs were capable of interacting with -globin promoter of human genomic dna . in recent years , researches have been done on immunomodulatory drugs , such as thalidomide , revlimid , and pomalidomide . their exhibited hbf - inducing activity has been revealed in k562 or primary human erythroid cultures . further study has demonstrated their activity is associated with the increase in histone acetylation at -globin gene promoter . erythropoietin ( epo ) is a cytokine that have been shown to induce hbf production during in vitro differentiation of primary human cells in several trials [ 47 , 5255 ] . it also stimulates red blood cells production , prolongs the survival of erythroid cells , and decreases the incident of programmed cell death . in recent years , scientists have conducted numerous studies in order to identify the natural remedies that could be possibly applied in treating -hemoglobinopathies , including scd and -thalassemia , summarized in table 2 . the extract of aegle marmelos containing bergatene was found to be responsible for the activation of erythroid differentiation and hbf induction in human leukemic k562 cells [ 31 , 69 ] . they are powerful inducers of erythroid differentiation , -globin gene expression and hbf synthesis in human erythroid cells . thus , it is known as a potential therapeutic approach for both -thalassemia and sickle cell anemia . in addition , nicosan ( formerly known as niprisan ) , an ethanol / water extract from nigeria indigenous plants , has successfully demonstrated a significant anti - sickling effects in vitro as well as in vivo [ 70 , 71 ] . there is evidence demonstrating that angelicin is a powerful inducer of erythroid differentiation , enhancement of the hbf synthesis in erythroid progenitors and -globin mrna accumulation of human leukemia k562 cells [ 8 , 73 ] . red wine , especially the skin of grapes , contains resveratrol which mimics the hbf - inducing activity of hu . since -thalassemia cells exhibit a high level of oxidative stress , which eventually shorten the survival of erythroid cells in -thalassemia patients , resveratrol which exhibits both antioxidant activity and hbf inducing property can become a very promising hbf inducer from the natural world . rapamycin is isolated from streptomyces hygroscopicus , a bacterial species being found in the soil of easter island . it has the ability to increase hbf production in cultures of erythroid precursors from -thalassemia patients without cytotoxicity or growth - inhibitory effect [ 8 , 13 ] . it is a dna - binding drug which has the potential to induce -globin mrna accumulation and hbf production in erythroid cells from healthy human subjects as well as -thalassemia patients . recently , it is reported that an indian almond , called terminalia catappa , has long been used as a traditional herbal treatment for sca in nigeria . has then demonstrated terminalia catappa distilled water active fraction ( tcdwf ) from terminalia catappa leaves exhibit a stimulatory effect on the hbf production in primary erythroid prohenitor stem cells ( epscs ) . terminalia catappa consists of flavonoids , alkaloids , and anthraquinones . also , through gas chromatography - mass spectrometry ( gcms ) , it is shown that a group of highly related long - chain fatty acids , for example , hexadecanoic acid , 10-octadecenoic acid , and octadecenoic acid , are present in the tcdwf . yet , further investigation is required in order to confirm the biological activities of these active compounds present in the tcdwf . for the chinese herbal medicine , yisui shengxue granule ( yssxg ) , a complex prescription made up of 11 different kinds of chinese herbal medicines , has shown to be effective in enhancing the hbf expression and inhibiting ineffective hematopoiesis [ 76 , 79 ] . current research has further confirmed this complex prescription has the ability to increase -globin gene expression and alter the expression of genes that involved in the survival , proliferation , and terminal differentiation of erythroid cells . recently , some researchers found that cucurbitacin d ( cud ) in a chinese medicinal herb , called fructus trichosanthis ( ft ) , exhibits a higher potency in hbf induction compared with hydroxyurea since there is evidence showed cud results in a higher fetal cell percentage and greater hbf content in k562 cells with much lower cytotoxicity . scientists have started to put effort on appreciating their underlying molecular mechanisms as well as verifying their target molecules . the first piece of evidence regarding the cell signaling of the hbf induction has suggested that , in k562 cells , butyrate induces erythroid differentiation and hemoglobin production through p38 mapk pathway [ 1 , 80 ] . several years later , another group of scientists has interestingly revealed that , without drug treatment , the -globin mrna level is increased sufficiently solely by overexpressing mapkk3 and mapkk 6 which are the direct upstream activators of p38 in k562 cells . according to mabaera et al . , p38 mapk signaling pathway is critical for the upregulation of the production of hbf . different environmental stresses could activate the p38 mapk signal pathway which will subsequently cause apoptosis , cell growth and erythroid differentiation . various studies have also revealed the effect of numerous hbf - inducing agents , such as butyrate , apicidin , and trichostatin a , are associated with p38 mapk signaling pathway . therefore , they both indicated p38 mapk pathway plays a vital role in promoting -globin gene expression . during the past few years , researchers come up with different mechanistic models of hbf induction while most of the models are generally based on what are thought to be the primary actions of hbf - inducing agents , for instance , global dna hypomethylation induced by dna methyltransferase inhibitors ( dnmt inhibitors ) or global histone hyperacetylation induced by histone deacetylase inhibitors ( hdac inhibitors ) , including scfa derivatives . however , when we come across with the recent key experimental findings , including the fact that 5-aza can promote hbf production without dna hypomethylation , that -globin promoter hypomethylation is inadequate to stimulate gene expression , and that the ability of hdac inhibitors to induce hbf is regardless of the potency of hdac inhibitions , some of these proposed mechanistic models are no longer capable to explain those results . therefore , it is of essence to propose a new model of hbf induction which is valid to most hbf - inducing agents and can adequately account for the recent experimental results . , through integrating recent results of cell - signaling experiments with the stress erythropoiesis model , have proposed a new model called the cell stress signaling model . they suggested that the key effect of most hbf - inducing agents is to activate the cell stress signaling pathways during adult erythropoiesis which subsequently lead to -globin gene expression and hbf production . it is found that certain hbf - inducing agents , such as hu , butyrate ( scfa ) , thalidomide ( imid ) , trichostatin a ( hdac inhibitor ) , and anisomycin , can activate the corresponding cell stress responses , including nitric oxide , oxidative stress ( ros ) , osmotic shock , and protein synthesis inhibition . these cell stress responses will eventually activate the downstream p38 mapk signaling pathway , including downstream kinases and transcription factors , and thus result in -globin gene expression and hbf production . besides p38 mapk signaling pathway , the potential of camp signaling pathway in hbf production has also been mentioned in the cell stress signaling model . there are findings suggested that in primary erythroid cell cultures , camp response element binding protein ( creb ) is activated by camp - activated protein kinase a instead of p38 mapk pathway . the phosphorylated creb will then activate the downstream transcription factors and eventually lead to -globin gene expression . therefore , not only is the cell stress signaling model applicable to most of the hbf - inducing agents but also is able to explain the key findings of some of the previous experiments . in the previous studies , researchers have found out that stimulating erk signaling pathway leads to megakaryocytic differentiation ; contrastingly , suppressing erk signaling pathway results in the enhancement of the erythroid phenotype as well as the -globin mrna expression . moreover , the evidence that erk inhibitor u0126 has the ability to stimulate -globin gene expression and hbf production in human erythroid progenitor cells suggested the inhibition of erk can possibly lead to the promotion of hbf production . the involvement of jnk in erythroid differentiation still remained debatable [ 76 , 8587 ] . it is reported that pretreatment with hu in k562 cells has led to a significant inhibition of jnk . moreover , short chain fatty acid derivatives ( scfad ) , such as butyrate and valproate , did not result in jnk phosphorylation ; thus , there was not any significant changes on jnk pathway in k562 cells [ 76 , 87 ] . nevertheless , in mouse erythroleukemia cells , experimental findings have suggested that activation of jnk is crucial for erythropoietin - induced erythroid differentiation [ 86 , 88 ] . as a result , whether jnk plays a significant role in hbf induction still remains to be investigated in the future . the potential of reactivating fetal hemoglobin via manipulating the gene transcription of - or -globin has been gained much attention recently . there is escalated number of publications regarding the genetic regulatory mechanism of developmental stage - specific expression of -globin genes . the mechanisms accounting for switching globin - genes expression during the development are highly regulated by cis - acting elements and trans - acting factors which include the locus control region ( lcr ) [ 85 , 86 ] . previous studies have also revealed that lcr has an important of enhancing globin - gene switching potently . understanding the fetal - to - adult hemoglobin switching is believed to have a clinical relevance of developing novel approaches of reversal of fetal hemoglobin production from adult hemoglobin in patients . several researchers have applied the knowledge of the regulatory mechanisms of globin - genes expression to design an artificial zinc finger dna - binding domain ( zf - dbd ) with the aim of manipulating the expression patterns of globin - genes [ 85 , 87 ] . therefore , techniques involving small molecule inhibitors or genetic knockdown can be potential applications to reactivate the fetal hemoglobin in the future . interestingly , besides the discovery of the upstream signaling pathway of activating the -globin gene expression , there are findings supporting the fact that posttranscriptional regulation also involves in regulating the -globin gene expression in response to different stimuli [ 89 , 90 ] . weinberg et al . revealed that instead of acting on the transcription rate of -globin gene in patients , butyrate has the ability to enhance the efficiency of translation of -globin mrna . moreover , there is evidence proving that the key effect of gtp and doxorubicin derivatives is the elevation of the amount of -globin in patients , at least partially , by enhancing the stability of -globin mrna [ 91 , 92 ] . liu et al . also suggested that , similar to gtp and doxorubicin derivatives , cud can therapeutically induce the production of hbf due to its ability of increasing -globin mrna stability . they have showed even though the change in the half - life of -globin mrna is small , it leads to remarkable changes in the total amount of stable -globin mrna and consequently the amount of functional -globin present in the cell . therefore , the control of -globin mrna stability can be known as a significant regulatory mechanism of -globin gene expression . in -thalassemia , due to the precipitation of excess -globin chains , rapid cellular apoptosis of early erythroblasts and red blood cell membrane damage are well characterized [ 9496 ] . 5-azacytidine , hydroxyurea , myleran , and butyrate had long been applied in clinics for -thalassemia treatment with the aim of stimulating hbf production [ 97100 ] . despite the ability of inducing the production of hbf in -thalassemia , a large portion of identified hbf - inducing agents , such as 5-azacytidine and hydroxyurea , are chemotherapeutic agents which inhibit cell proliferation and cause cell growth arrest . further , due to their cytotoxic nature , the dose limiting myelotoxicity and potential carcinogenicity have always led to concerns . therefore , in order to correct the pathophysiology of -thalassemia , it is of essence to improve the underlying erythroid cell survival and proliferation , with the intention that hbf - inducing agents can exert their effect on stimulating the fetal globin expression prior to the activation of irreversible programmed cell death pathway . owing to this issue , perrine et al . ( 2002 ) have conducted a pilot study revealing the combination of butyrate and rhu - erythropoietin ( epo ) , the hematopoietic growth factor that stimulates erythroid proliferation , decreases apoptosis , and prolongs erythroid cell survival and differentiation , has addictive effects in inducing hematologic responses in any -thalassemia patients . this result further suggested that definitive treatment to correct -thalassemia will likely require more than one type of therapeutic regimen ; in other words , hematopoietic growth factor , such as exogenous epo will be required for -thalassemia patients in order to respond optimally to any hbf - inducing agent . hydroxyurea ( hu ) was first approved by the food and drug administration ( fda ) for the treatment of sickle cell disease ( scd ) in 1996 ; yet , hu only increases hbf production in approximately half of scd patients and is even less effective in enhancing the hbf level for -thalassemia patients [ 104106 ] . additionally , there is a recent clinical trial conducted to assess the therapeutic potential of hqk-1001 , an oral butyrate derivative 2,2-dimethylbutyrate sodium salt to treat -thalassemia patients . although results revealed hqk-1001 exhibits a stimulatory effect on hbf production and -globin gene expression , further study is needed to find out if the surge of hbf production is sufficient to alleviate the complications of -thalassemia including anaemia , chronic haemolysis , and so forth . nevertheless , up to date , there is no such pharmacological agent(s ) has been officially approved by fda for treating patients with -thalassemia . the underlying reason of this is that for pharmacological hbf induction therapy in patients with thalassemia major , it requires the production of -globin chains ( plus -globin chains in thalassemia major ) reaches 50% of the production of -globin chains in order to result in optimal therapeutic correction of the anemia in patients with -thalassemia ; while for that in patients with scd , it only requires the production of hbf reaches 2030% of total circulating hemoglobin for sufficient prevention of sickling effect in scd . therefore , it is necessary to identify novel pharmacological hbf inducer or alternate therapeutic approaches which can effectively enhance the hbf production to the optimal level and sufficiently reduce the chain imbalance in homozygous -thalassemia . in recent years , ( 2008 ) have proposed p38 mapk cell stress signaling pathway and other stress - related pathways may be the keys to understanding hbf induction , owing to the fact that most hbf - inducing agents are , as mentioned before , cytotoxic and many activate the p38 mapk cell stress signaling pathway . this stress signaling model predicts a variety of diverse hbf - inducing compounds and stimuli will activate cell stress signaling pathway which will then activate similar response genes , such as the -globin genes . it is supported by several observation and evidence , for example , the stimulation of -globin gene expression and hbf production in human primary erythroid cells by 5-azacytidine is closely related to p38 mapk phosphorylation and this stimulation is inhibited when treated with p38 mapk inhibitor sb203580 . on the other hand , based on the stress signaling model , mabaera and colleagues ( 2008 ) have also made some predictions which require further investigation , for example , the members of stress signaling pathways , ranging from the sensors of cellular stress to the activated transcription factors that bind to the -globin gene promoters , are needed for activating the -globin gene expression as well as hbf production . nevertheless , concerns have been raised about the possibility of triggering rapid cellular apoptosis in erythroid cells and consequently leading to low blood count when patients , especially those with thalassemia , are receiving chemotherapeutic agents including 5-azacytidine , decitabine , hu and butyrate . comparing with scd patients , -thalassemia patients are more susceptible to chemotherapeutic agents because treating with chemotherapeutic agents may further encourage rapid cellular apoptosis which has already been well - characterized in -thalassemia patients even they are not exposed to the agents . also , as mentioned before , accelerated cellular apoptosis of erythroid progenitors in -thalassemia is a significant barrier to definitive therapy because there is a high possibility that the programmed cell death will be established earlier before hbf - inducing agents act its beneficial effect on the globin chain balance in cells . consequently , chemotherapeutic agents , such as hu , butyrate and 5-azacytidine , may not be the best hbf - inducer for -thalassemia due to the fact that the hbf - inducing property of those agents are largely dependent on the activation of cell stress signaling pathway . in contrast , those chemotherapeutic agents may have beneficial effect on activating -globin gene expression and hbf production in scd ; yet , the dose of inducing agents must be strictly monitored in order to ensure it is high enough to activate stress signaling pathway but not too high to trigger cell - cycle arrest or apoptosis in hematopoietic precursor cells that will result in dangerously low blood counts . in light of the lack of promising hbf - inducing agents for -thalassemia treatment , up to now , different research groups have paid lots of effort on identifying the existing or novel natural chinese herbal medicines which have the possibility to effectively induce hbf synthesis without any apparent growth - inhibitory effects . yisui shenxu granule ( yssxg ) , a complex prescription consisting of 11 chinese herbal medicines , had been used for treating -thalassemia for more than over 20 years [ 76 , 79 ] . recently , effort has been put on investigating the efficacy and safety of yssxg by a randomized single - blinded trial . result has demonstrated it has obvious clinical efficacy , while hepatauxe and splenomegaly were relieved and no adverse reaction was observed . the underlying mechanism for the effect of yssxg is possibly by activating the expression of -globin gene and increase hbf production in order to compensate for the functional deficiency of -globin gene . zhang and wu have found out that stimulating the gene expression of -globin , epor , spi , and fklf , while hindering the gene expression of ckit , gata1 , and gata2 , could promote the -globin gene expression and alter the expression of gene which is responsible for the regulation of -globin gene expression and the expression of other genes that are participated in the survival , proliferation , and terminal differentiation of erythroid cells . ( 2011 ) have presented the first piece of evidence on the hbf - inducing property of ethanol extract of fructus trichosanthis ( ft ) , one of the most frequently used chinese herbal medicine . their study has demonstrated ft has the ability to enhance the -globin gene expression as well as hbf synthesis through activating p38 mapk and inhibiting erk signaling pathway . despite the promising result shown , acute and chronic toxicity test in vivo is strongly required in the future in order to ensure the ethanol extract of ft is safe for clinical use on human . also , the efficacy of the extract should be examined in clinical evaluation before actual clinical practice . during the same year , another group of researchers have identified cucurbitacin d ( cud ) , a chemical inducing agent that can be found in fructus trichosanthis , is a novel therapeutic agent for treating -thalassemia . there are evidences suggesting that cud could act as a good hbf - inducing agent for -thalassemia patient comparing with hu since cud exhibits a higher amplitude and rapidity in enhancing the hbf production than hu does in k562 cells , and , unlike hu , cud does not show any growth - inhibitory effect even when it is at its optimal activity . taken all together , natural herbal medicines , which exhibit a higher potency in hbf induction compared with chemotherapeutic agents and have much lower cytotoxicity , will definitely be the novel therapeutic candidates for -thalassemia by targeting the activation of -globin gene expression ; yet , some of the candidates are still required further investigation on their safety and efficacy . chemotherapeutic agents , such as 5-azacytidine , hydroxyurea , myleran , and butyrate , had long been used for -thalassemia treatment by stimulating hbf synthesis ; yet , cytotoxicity , growth - inhibitory effect , fear of long - term carcinogenesis , and only modest hbf - inducing activity have limited the clinical usage of these agents in -thalassemia and scd treatment . also , through understanding the pathology of -thalassemia , it is revealed that most of the identified hbf - inducing agents have limitation on treating -thalassemia . it is because the rapid cellular apoptosis of erythroid progenitors in -thalassemia causes a significant obstacle that overstimulating the cell stress signaling pathway by the hbf inducer may possibly lead to irreversible cellular apoptosis before -globin gene expression and hbf synthesis can be stimulated . with the advancement of biotechnologies , increasing number of studies will be done to explore and optimize new interventions and nature remedies to reactivate hbf synthesis for -thalassemia patients . in the future , it is expected that increasing number of hbf inducing agents could be found from natural remedies and folk medicines all over the world . in this context , further studies are required with the aim of exploring more natural herbal medicines as well as studying the efficacy and safety of from the laboratory to clinical use for the individuals with -hemoglobinopathies . OUTPUT:

for the treatment of -thalassemia and sickle cell disease ( scd ) , pharmacological induction of fetal hemoglobin ( hbf ) production may be a promising approach . to date , numerous studies have been done on identifying the novel hbf - inducing agents and understanding the underlying mechanism for stimulating the hbf production . in this review , we have summarized the identified hbf - inducing agents by far . by examining the action mechanisms of the hbf - inducing agents , various studies have suggested that despite the ability of stimulating hbf production , the chemotherapeutic agents could not be practically applied for treating -hemoglobinopathies , especially -thalassemia , due to the their cytotoxicity and growth - inhibitory effect . owing to this therapeutic obstacle , much effort has been put on identifying new hbf - inducing agents from the natural world with the combination of efficacy , safety , and ease of use . therefore , this review aims to ( i ) reveal the novel screening platforms for identifying potential inducers with high efficiency and accuracy and to ( ii ) summarize the new identified natural remedies for stimulating hbf production . hopefully , this review can provide a new insight into the current status and future perspectives in fetal hemoglobin reactivation for treating -thalassaemia and scd .

PubMed_Summ6527

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: a girl weighing 3,190 g was delivered by a caesarean section at 38 weeks and five days of gestation . at the time of birth , a systolic murmur was noted during a physical examination , and transthoracic echocardiography revealed a peri - membranous ventricular septal defect ( vsd ) with a septal aneurysm , a small patent foramen ovale ( pfo ) , and a small right - sided patent ductus arteriosus ( pda ) from the innominate artery . the vsd was measured as having a diameter of 3.5 mm and a shunt flow less than 2.5 m / sec . due to the presence of neonatal hyperbilirubinemia , echoencephalography was conducted , and no abnormalities were found . five months later , the patient was referred to konkuk university medical center for vsd and pda . her body weight was 6,700 g ( 25th percentile ) , and her height was 61.6 cm ( 10th percentile ) . transthoracic echocardiography revealed a vsd approximately 6 mm in size with a minimal aneurysm , a left - sided pda 3.6 mm in diameter from the right aortic arch and an aberrant left subclavian artery . a subsequent computed tomographic scan demonstrated isolation of the left subclavian artery with a right aortic arch , a left pda , and a vsd ( fig . the intraoperative findings were a perimembranous vsd , a pfo , a mildly patent right ductus arteriosus , and isolation of the left subclavian artery connected to the left pulmonary artery via a left pda . the left subclavian artery was disconnected from the left pulmonary artery and reimplanted to the left common carotid artery by end - to - side anastomosis with monofilament polypropylene 6 - 0 sutures ( fig . ductus arteriosus is usually located on the left side , between the descending aorta and the junction of the main pulmonary artery and left pulmonary artery . however , ductus arteriosus may also be present on the right side or , very rarely , may occur bilaterally in association with aortic arch anomalies or conotruncal anomalies . in such aortic arch anomalies , isolation of the left subclavian artery with right aortic arch is also uncommon . here , isolation refers to the fact that the left subclavian artery connects to the pulmonary artery via either the ligamentum arteriosum or a patent ductus arteriosus without any connection to the aorta . isolation of the left subclavian artery with a right aortic arch is known to be commonly associated with congenital heart disease , but may also occur with normal intracardiac anatomy , although few such cases have been described . isolation of the left subclavian artery with a right aortic arch may be related to the 22q11 deletion . bilateral ductus arteriosus and isolation of the left subclavian artery with a right aortic arch can be explained through the hypothetical double aortic arch plan suggested by edward . regression takes place on two levels in the double aortic arch plan : on one level , regression occurs between the left common carotid artery and the left subclavian artery ; and on the other level , regression occurs at the left dorsal aortic root distal to the left ductus arteriosus . and then right ductus arteriosus remains persistent , left ductus arteriosus connects the left subclavian artery to the left pulmonary artery ( fig . however , the right ductus arteriosus regressed , and only the left ductus arteriosus remained patent . if the left ductus arteriosus is patent , blood may be supplied to the left subclavian artery via the left ductus arteriosus . if the left ductus arteriosus regresses , the blood supply to the left subclavian artery may involve a mediastinal , thoracic anastomosis , or vertebral pathway . isolation of the left subclavian artery usually presents with no apparent symptoms in neonates , but it may present with congenital pulmonary steal syndrome , subclavian steal syndrome , or may even present in adults with late symptoms due to sporadic progression . hayabuchi et al . reported the case of a three - month - old girl with cerebral atrophy and an underdeveloped left arm . reported the case of a 15-year - old boy with an underdeveloped left arm . due to these symptoms and signs , the therapeutic management of isolation of the left subclavian artery remains controversial , especially when it is associated with complicated congenital heart disease . some authors have suggested that adequate collateral circulation must be ensured , meaning that reconstruction of the isolated subclavian artery is optional , regardless of the symptoms and signs . successful results have been reported after ligation or device closure of the pda and ligation of the left subclavian artery . however , reconstruction of the left subclavian artery due to pulmonary steal syndrome after right pda closure in bilateral pda has been reported . in one report , ischemic symptoms in the left arm and vertebrobasilar insufficiency occurred years after ligation of the left subclavian artery . hokari et al . reported that a man with peutz - jeghers syndrome presented with his first vertigo attacks due to subclavian steal syndrome at 29 years of age . our patient presented with no symptoms and signs related to subclavian or pulmonary steal syndrome , and had shown normal findings on an echoencephalography study conducted at our medical center due to neonatal hyperbilirubinemia . however , brain computed tomography angiography performed after surgery revealed hypoplasia of the left vertebral artery . we suggest that this hypoplasia would have led to vertebrobasilar insufficiency or underdevelopment of the left arm without surgical reconstruction . since surgical reconstruction of the isolated left subclavian artery leads to antegrade flow in the left subclavian artery , it can prevent hypoplasia of the left vertebral artery and subclavian / pulmonary steal syndrome . our case shows that early surgical reconstruction is reasonable , regardless of the symptoms , in cases of isolation of the left subclavian artery . OUTPUT:

right aortic arch with isolation of the left subclavian artery is a rare anomaly . the incidence of bilateral ductus arteriosus is sporadic , and a right aortic arch with isolation of the left subclavian artery in association with bilateral ductus arteriosus is therefore extremely rare . since the symptoms and signs of isolation of the left subclavian artery can include the absence or underdevelopment of the left arm , subclavian steal syndrome , or pulmonary artery steal syndrome , the proper therapeutic approach is controversial . we report a case in which surgical reconstruction was used to treat isolation of the left subclavian artery with right aortic arch in association with bilateral ductus arteriosus and a ventricular septal defect .

PubMed_Summ6528

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: in 2015 , an estimated 477.9/100,000 cases of esophageal cancer ( ec ) were diagnosed in china , and approximately 375/100,000 people died from this disease [ 1 , 2 ] . in china , ec occurs in 50.3% ( 161.3/320.8 ) of patients aged 60 - 74 , and in 19.6% ( 62.9/320.8 ) of patients over 75 years of age in [ 1 , 2 ] . a radiation therapy oncology group study ( rtog 8501 ) demonstrated a survival benefit of the addition of platinum - based chemotherapy to radiation , compared to radiation alone for patients with nonsurgical ec [ 3 , 4 ] . rtog 8501 only included about 23.1% ( 28/121 ) of elderly patients ( 70 years ) . thus , management of elderly patients with ec remains a therapeutic challenge , and the most relevant treatment modalities are still being debated . although survival improvement has been observed over the past decade , ec treatment continues to be significantly influenced by age . moreover , it has also been reported that elderly patients have undergone less surgery , radiotherapy , and chemotherapy than younger patients . to our knowledge , no specific data have been published regarding therapeutic strategies in elderly patients with ec . despite progress in surgical practice , esophagectomy is associated with significant morbidity and mortality , and 75 years is often considered as the age limit for surgery . external beam radiation therapy ( ebrt ) was an important treatment strategy for elderly patients . however , a few published results indicate that ebrt combined with brachytherapy in elderly patients with ec . californium-252 ( cf ) is a neutron - emitting radionuclide , and cf - based neutron brachytherapy ( nbt ) has only been implemented in china very recently . neutron brachytherapy is a form of high linear energy transfer ( let ) radiotherapy , which has been proven to be effective for treating intracavitary cancers of the cervix when used in combination with ebrt [ 9 , 10 ] . we performed a retrospective cohort study of 191 patients older than 69 years who were diagnosed with locally advanced esophageal squamous cell cancer ( escc ) , treated with radiation therapy . the main objective was to assess the overall survival and local control rates after ebrt plus neutron brachytherapy for elderly escc patients . we also evaluated the impact of age on treatment tolerance , prognostic factors , and patterns of failure . from january 2001 until november 2012 , a total of 191 consecutive patients older than 69 years with localized , advanced escc were referred to our department at the changzhi cancer hospital for radiotherapy and cf nbt . the reasons were as follows : 30 patients were medically inoperable ( 6 patients were diabetic , 11 had chronic obstructive pulmonary disease , and 13 patients had a prior or concurrent malignancy ) ; 34 patients rejected surgery ; 76 patients were too old ( 75 years or older , 33 of 85 had t4 lesion ) ; and 85 patients had unresectable lesions . of these , 191 patients were treated with ebrt combined with brachytherapy . patients with good performance status ( at least able to care for himself or herself ) and adequate hepatic , renal , and hematologic functions were selected for curative treatment . the patients clinical stage was diagnosed by barium examination , endoscopy , endoscopic ultrasonography , or tumor histology . megavoltage radiation therapy units were used with a minimum source - to - axis distance of 100 cm . the radiation field extended at least 3 cm superior and inferior to the tumor , with a lateral margin of at least 2 cm . the field included the lesser curvature and bottom of stomach if the tumor invades gastroesophageal junction . multi - field techniques were used to limit the maximum dose to the spinal cord to 45 gy . the initial anterior - posterior parallel - opposed fields received 30 gy , and the off - cord fields received 20 - 30 gy , for a total dose of 40 - 54 gy in 20 - 27 fractions in 4 - 5.5 weeks . neutron brachytherapy with a one - balloon applicator ( figure 1 ) was used in conjunction with the cf lzh-1000 remote after - loading system ( linden science and technology co. , shenzhen , china ) . the physical characteristics of the cf neutron , the characteristics of the applicator , and the process of nbt were described in detail by liu [ 12 , 13 ] . the nbt dose was prescribed to the reference point , which was located at 10 mm from the center point of the source capsule in the transverse direction . figure 1 is an x - ray image taken while the applicator and the simulator source were both inserted into the esophagus of a patient . the source applicator is a custom - made catheter , which not only allows the source wire to travel inside , but also includes a water balloon surrounding the source . the water balloon is 12 cm long , and its diameter can vary depending on the amount of water injected into it . that are eccentric with respect to the axis of the esophagus , the water balloon can be inflated accordingly to keep the source close to the tumor but away from the adjacent normal epithelium . in figure 1 , the water balloon can clearly be seen as it is filled with an x - ray contrast agent . the total nbt dose ( to the reference point ) given to each patient varied between 8 and 25 gy - eq in two to five fractions , with 4 - 5 gy - eq per fraction per week . images ( a - d ) showing a 75 years male patient , middle site esophageal squamous cell cancer . the tumor regression conditions before each of the four neutron brachytherapy treatments under an x - ray treatmentplanning simulator from a - d the patients were examined weekly during the ebrt . weekly blood tests were obtained , and any admission for treatment - related complications was recorded . all adverse events were graded according to the national cancer institute s common terminology criteria for adverse events , version 3.0 . the patients usually underwent follow - up examinations every 3 - 4 months after the completion of treatment . tumor response and nodal disease were evaluated with repeated computed tomography ( ct ) scans , barium swallow studies , and endoscopy . the objectives of the study were to evaluate overall acute toxicity and local - regional control rates . survival was calculated from the date of consultation until death or last follow - up evaluation . the pattern of failure ( local and/or regional vs. distant ) was defined as the first site of failure . the time to first failure , time to any local failure , and time to any distant metastases were calculated from the date of consultation . local and regional recurrence included the primary tumor and regional lymph nodes . overall survival and local - regional control were estimated using the kaplan - meier method . pearson s test was used to assess measures of association in the frequency data . from january 2001 until november 2012 , a total of 191 consecutive patients older than 69 years with localized , advanced escc were referred to our department at the changzhi cancer hospital for radiotherapy and cf nbt . the reasons were as follows : 30 patients were medically inoperable ( 6 patients were diabetic , 11 had chronic obstructive pulmonary disease , and 13 patients had a prior or concurrent malignancy ) ; 34 patients rejected surgery ; 76 patients were too old ( 75 years or older , 33 of 85 had t4 lesion ) ; and 85 patients had unresectable lesions . of these , 191 patients were treated with ebrt combined with brachytherapy . patients with good performance status ( at least able to care for himself or herself ) and adequate hepatic , renal , and hematologic functions were selected for curative treatment . the patients clinical stage was diagnosed by barium examination , endoscopy , endoscopic ultrasonography , or tumor histology . megavoltage radiation therapy units were used with a minimum source - to - axis distance of 100 cm . the radiation field extended at least 3 cm superior and inferior to the tumor , with a lateral margin of at least 2 cm . the field included the lesser curvature and bottom of stomach if the tumor invades gastroesophageal junction . multi - field techniques were used to limit the maximum dose to the spinal cord to 45 gy . the radiation treatments were delivered 5 days / week at 2 gy / fraction . the initial anterior - posterior parallel - opposed fields received 30 gy , and the off - cord fields received 20 - 30 gy , for a total dose of 40 - 54 gy in 20 - 27 fractions in 4 - 5.5 weeks . neutron brachytherapy with a one - balloon applicator ( figure 1 ) was used in conjunction with the cf lzh-1000 remote after - loading system ( linden science and technology co. , shenzhen , china ) . the physical characteristics of the cf neutron , the characteristics of the applicator , and the process of nbt were described in detail by liu [ 12 , 13 ] . the nbt dose was prescribed to the reference point , which was located at 10 mm from the center point of the source capsule in the transverse direction . figure 1 is an x - ray image taken while the applicator and the simulator source were both inserted into the esophagus of a patient . the source applicator is a custom - made catheter , which not only allows the source wire to travel inside , but also includes a water balloon surrounding the source . the water balloon is 12 cm long , and its diameter can vary depending on the amount of water injected into it . the water balloon is an essential part of the applicator . for tumors that are eccentric with respect to the axis of the esophagus , the water balloon can be inflated accordingly to keep the source close to the tumor but away from the adjacent normal epithelium . in figure 1 , the water balloon can clearly be seen as it is filled with an x - ray contrast agent . the total nbt dose ( to the reference point ) given to each patient varied between 8 and 25 gy - eq in two to five fractions , with 4 - 5 gy - eq per fraction per week . images ( a - d ) showing a 75 years male patient , middle site esophageal squamous cell cancer . the tumor regression conditions before each of the four neutron brachytherapy treatments under an x - ray treatmentplanning simulator from a - d weekly blood tests were obtained , and any admission for treatment - related complications was recorded . all adverse events were graded according to the national cancer institute s common terminology criteria for adverse events , version 3.0 . the patients usually underwent follow - up examinations every 3 - 4 months after the completion of treatment . tumor response and nodal disease were evaluated with repeated computed tomography ( ct ) scans , barium swallow studies , and endoscopy . the objectives of the study were to evaluate overall acute toxicity and local - regional control rates . survival was calculated from the date of consultation until death or last follow - up evaluation . the pattern of failure ( local and/or regional vs. distant ) was defined as the first site of failure . the time to first failure , time to any local failure , and time to any distant metastases were calculated from the date of consultation . overall survival and local - regional control were estimated using the kaplan - meier method . pearson s test was used to assess measures of association in the frequency data . age of the escc patients who were treated with radiation therapy ( nbt and ebrt ) ranged from 70 to 84 years ( median : 75 years ) . there were 115 patients aged 70 - 74 , and 76 patients aged > 74 years . the cancer stages were categorized according to the 6 edition of the ajcc cancer staging manual , with 72 patients categorized as stage iia , 10 patients categorized as stage iib , and 109 patients were categorized as stage iii . the detailed patient data and log - rank test are provided in table 1 . patient and tumor characteristics rt radiotherapy alone , os overall survival rate , lcr local control rate the duration of follow - up ranged from 6 to 106 months ( median : 30.4 months ) . the median survival time for the 191 patients was 23.6 months , and the 1- , 2- , 3- , and 5-year rates for overall survival ( os ) were 68.5% , 48.2% , 40.3% , and 28.7% , respectively . the 1- , 2- , 3- , and 5-year rates for local - regional control ( lrc ) were 82.2% , 67.0% , 61.8% , and 54.2% , respectively . we used the following nine factors for the univariate analysis of survival rates and local control rate : sex , age , karnofsky score ( kps ) , tumor location , tumor length , tumor t stage , nodal stage , clinical stage , and radiation dose . among them , three ( age , tumor length , and clinical n stage ) were found to have relevance to os ( p = 0.010 , p = 0.016 , and p = 0.009 , respectively ) . age , clinical n stage , and radiation dose were factors that were significantly related to lrc ( p = 0.038 , p = 0.014 , p = 0.014 , respectively ) . in the univariate analysis , the 5-year os ( lrc ) was 37.3% ( 58.6% ) for patients aged 70 - 74 years , and 14.5% ( 47.9% ) for patients aged > 74 years ( p = 0.010 and p = 0.038 , respectively , figure 2a and b ) . in multivariate analysis , age and clinical n stage were associated with os and lrc ( p = 0.011 [ 0.041 ] and p = 0.005 [ 0.005 ] ) ( table 2 ) . results of multivariate cox regression analysis of overall survival and local - regional control ci confidence interval , hr hazard ratio , c clinical comparison of the overall survival rate ( a ) , and local control rate ( b ) between the two treatment groups at the time of the analysis , 80 patients were alive and free of disease , and 5 patients were alive with disease evolution . the main sites of distant metastases were the lung ( n = 9 ) , liver ( n = 5 ) , brain ( n = 2 ) , and bones ( n = 8) . in 14 patients , metastases developed in more than one organ . additionally , 15 patients died of mixed causes , including pneumonia , cerebral hemorrhage , and heart infarction . local - regional recurrence occurred in 59 ( 59/191 , 30.9% ) patients , with 9/59 ( 15.3% ) occurrences outside the radiation fields and 50/59 ( 84.7% ) occurrences inside the radiation fields . none of those patients underwent salvage surgery . in terms of acute toxicity , no perforations dysphagia was relieved after the second or third nbt treatment in 87% of the patients , and a temporary feeding tube was not required in most of the patients . grade 2 esophagitis , expressed by clinical odynophagia , was observed in 64 cases ( 33.5% ) , and it was managed with the early introduction of h2 blockers and surface anesthesia at the initiation of the nbt . in total , eight ( 4.2% ) patients had grade 2 irradiation dermatitis . from the time of treatment completion to the development of local - regional recurrence or death , 5 ( 2.6% ) and 15 ( 7.9% ) patients experienced fistula and massive bleeding , respectively . the median time of incidence was 7.0 ( 3.7 - 55.7 ) months for fistula and 9.5 ( 3.2 - 90.9 ) months for bleeding . as shown in table 3 , the incidence of severe , late complications was related to older age ( p = 0.027 ) , higher nbt dose / fraction ( 20 - 25 gy/5f ) , and higher total dose ( > 66 gy ) . in total , 68.5% of the patients resumed normal swallowing , while 4.2% had some residual dysphagia ( non - malignant ) requiring intermittent dilatation . age of the escc patients who were treated with radiation therapy ( nbt and ebrt ) ranged from 70 to 84 years ( median : 75 years ) . there were 115 patients aged 70 - 74 , and 76 patients aged > 74 years . the cancer stages were categorized according to the 6 edition of the ajcc cancer staging manual , with 72 patients categorized as stage iia , 10 patients categorized as stage iib , and 109 patients were categorized as stage iii . the detailed patient data and log - rank test are provided in table 1 . patient and tumor characteristics rt radiotherapy alone , os overall survival rate , lcr local control rate the duration of follow - up ranged from 6 to 106 months ( median : 30.4 months ) . the median survival time for the 191 patients was 23.6 months , and the 1- , 2- , 3- , and 5-year rates for overall survival ( os ) were 68.5% , 48.2% , 40.3% , and 28.7% , respectively . the 1- , 2- , 3- , and 5-year rates for local - regional control ( lrc ) were 82.2% , 67.0% , 61.8% , and 54.2% , respectively . we used the following nine factors for the univariate analysis of survival rates and local control rate : sex , age , karnofsky score ( kps ) , tumor location , tumor length , tumor t stage , nodal stage , clinical stage , and radiation dose . among them , three ( age , tumor length , and clinical n stage ) were found to have relevance to os ( p = 0.010 , p = 0.016 , and p = 0.009 , respectively ) . age , clinical n stage , and radiation dose were factors that were significantly related to lrc ( p = 0.038 , p = 0.014 , p = 0.014 , respectively ) . in the univariate analysis , the 5-year os ( lrc ) was 37.3% ( 58.6% ) for patients aged 70 - 74 years , and 14.5% ( 47.9% ) for patients aged > 74 years ( p = 0.010 and p = 0.038 , respectively , figure 2a and b ) . in multivariate analysis , age and clinical n stage were associated with os and lrc ( p = 0.011 [ 0.041 ] and p = 0.005 [ 0.005 ] ) ( table 2 ) . results of multivariate cox regression analysis of overall survival and local - regional control ci confidence interval , hr hazard ratio , c clinical comparison of the overall survival rate ( a ) , and local control rate ( b ) between the two treatment groups at the time of the analysis , 80 patients were alive and free of disease , and 5 patients were alive with disease evolution . the main sites of distant metastases were the lung ( n = 9 ) , liver ( n = 5 ) , brain ( n = 2 ) , and bones ( n = 8) . in 14 patients , metastases developed in more than one organ . additionally , 15 patients died of mixed causes , including pneumonia , cerebral hemorrhage , and heart infarction . local - regional recurrence occurred in 59 ( 59/191 , 30.9% ) patients , with 9/59 ( 15.3% ) occurrences outside the radiation fields and 50/59 ( 84.7% ) occurrences inside the radiation fields . in terms of acute toxicity , no perforations were observed during this treatment period . in total , 88 ( 46.1% ) dysphagia was relieved after the second or third nbt treatment in 87% of the patients , and a temporary feeding tube was not required in most of the patients . grade 2 esophagitis , expressed by clinical odynophagia , was observed in 64 cases ( 33.5% ) , and it was managed with the early introduction of h2 blockers and surface anesthesia at the initiation of the nbt . in total , eight ( 4.2% ) patients had grade 2 irradiation dermatitis . from the time of treatment completion to the development of local - regional recurrence or death , 5 ( 2.6% ) and 15 ( 7.9% ) patients experienced fistula and massive bleeding , respectively . the median time of incidence was 7.0 ( 3.7 - 55.7 ) months for fistula and 9.5 ( 3.2 - 90.9 ) months for bleeding . as shown in table 3 , the incidence of severe , late complications was related to older age ( p = 0.027 ) , higher nbt dose / fraction ( 20 - 25 gy/5f ) , and higher total dose ( > 66 gy ) . in total , 68.5% of the patients resumed normal swallowing , while 4.2% had some residual dysphagia ( non - malignant ) requiring intermittent dilatation . to our knowledge , this is the first reported clinical experience of the treatment using nbt and ebrt for elderly patients with escc . we also found that , firstly , nbt + ebrt is safe and beneficial in terms of local control in the radical treatment of elderly patients with escc , and secondly , the os rate was significantly increased , and the late complication rate was significantly decreased in patients aged 70 - 74 years compared to that of patients aged > 74 years . during the treatment period , no severe treatment related complication occurred . definitive conformal radiotherapy ( crt ) is considered a feasible nonsurgical treatment in patients with a locally advanced ec , and approximately a 50 - 65% clinical complete response rate , 17 - 26 months of median overall survival , and 30 - 40% 2-year survival rate [ 15 , 16 , 17 ] . in the current study , the os was similar to the results of prior studies , though without chemotherapy [ 15 , 16 , 17 ] . we believe that there are at least two factors that made the cf - based nbt more effective for local tumor than chemotherapy regimens , particularly in the treatment of locally advanced escc . the first factor is related to the high - let nature of fission neutrons , which made them much more effective ( compared to the low - let x - ray ) in killing the hypoxic tumor cells in the locally advanced cancers . the second factor is related to the fact that water is an effective neutron attenuator that can be conveniently injected into the source applicator during treatment to reduce the neutron dose to the nearby normal tissue . because there is a significant difference in the elasticities of normal tissue and tumor tissue , the proper injection of water into the source applicator can effectively push away the nearby normal tissue while still keeping the tumor tissue close to the source . tougeron reported that age > 74 years was associated with worse creatinine clearance ( p < 0.01 ) and greater chemotherapy dose reduction at treatment onset due to age ( p < 0.01 ) , but this had no influence on total crt dose , or os . in the current study , the incidence of late severe complications was significantly related to the factors of higher total dose and nbt dose . in addition to the dose factors , the patients age also significantly increased the incidence of relevant , late complications . while the normally expected side effects ( shown in table 4 ) seem to be quite acceptable , the number of deaths ( n = 20 or 10.5% ) resulting from fistula , hematemesis , and hemoptysis is high . this may be linked to the late effect of radiation damage , as fatal esophagitis of fistula cases were also observed in the rtog 92 - 07 trial where the ir - based high - dose - rate boost dose of 15 gy in 3 weekly fractions was deemed to be too high . further ct review is needed to compare the pretreatment tumor length , esophageal tumor wall thickness , and association of tumor with surrounding normal structures with subsequent fistula formation . comparative toxicity rates , overall survival and local control of selected series ct chemotherapy , bt brachytherapy , erbt external beam radiotherapy , pts patients , y years , ns not stated , os overall survival ld limited disease , lc local control brachytherapy applied between ebrt the major limitation of our study was that the retrospective analysis might have been based on incomplete medical records . others restrictions were that the study was conducted in a single institution , small sample size , and the lack of predefined factors determining treatment decisions , which were based only on evaluations by the referral doctor and members of a multidisciplinary team . it should nonetheless be recalled that the aim of the study was to retrospectively identify the parameters to be associated with the key therapeutic decision . our results suggest that elderly patients with escc could benefit from nbt + ebrt without major toxicities . patient s age , clinical stage n status , and radiation dose could be used to select the appropriate treatment in an elderly patient . OUTPUT:

purposethe aim of this study was to retrospectively observe and analyze the long - term treatment outcomes of 191 elderly patients with esophageal squamous cell cancer ( escc ) who were treated with californium-252 ( 252cf ) neutron brachytherapy ( nbt ) in combination with external beam radiotherapy ( ebrt).material and methodsfrom january 2002 to november 2012 , 191 patients with escc underwent nbt in combination with ebrt . the total radiation dose to the reference point via nbt was 8 - 25 gy - eq in two to five fractions with one fraction per week . the total dose via ebrt was 50 - 60 gy , which was delivered over a period of 5 to 6 weeks with normal fractionation.resultsthe median survival time for the 191 patients was 23.6 months , and the 5-year rates for overall survival ( os ) and local - regional control ( lrc ) were 28.7% and 54.2% , respectively . the patients age was a factor that was significantly associated with os ( p = 0.010 ) , according to univariate analysis . the 5-year os ( lrc ) was 37.3% ( 58.6% ) for patients aged 70 - 74 years and 14.5% ( 47.9% ) for patients aged > 74 years ( p = 0.010 and p = 0.038 ) . in multivariate analysis , age and clinical n stage were associated with os and lrc ( p = 0.011 [ 0.041 ] and p = 0.005 [ 0.005 ] ) . from the time of treatment completion to the development of local - regional recurrence or death , 5 ( 2.6% ) patients experienced fistula and 15 ( 7.9% ) experienced massive bleeding . the incidence of severe late complications was related to older age ( p = 0.027 ) , higher nbt dose / fraction ( 20 - 25 gy/5 fractions ) , and higher total dose ( > 66 gy).conclusionsthe clinical data indicated that nbt in combination with ebrt produced favorable local control and long - term survival rates for elderly patients with escc , and that the side effects were tolerable . patient s age , clinical stage n status , and radiation dose could be used to select the appropriate treatment for elderly patients .

PubMed_Summ6529

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: aggregatibacter actinomycetemcomitans is an inhabitant of the oral cavity and periodontal pathogen . in periodontal disease , the bacterium infects and proliferates within the periodontal pocket , between the gingival tissue and the tooth . the presence of bacteria and their products such as secreted proteins and lps induce an inflammatory response by the host . inflammation leads to tissue damage and alveolar bone loss that is characteristic of periodontal diseases . a. actinomycetemcomitans has been highly associated with a rapidly progressing form of periodontal disease known as localized aggressive periodontitis ( lap ) that occurs in adolescents . this bacterium has also been reported to cause non - oral infections such as pneumonia , endocarditis , pericarditis , bacteremia , septicemia , osteomyelitis , synovitis , infectious arthritis , skin infections , urinary tract infections and brain abscesses [ 46 ] . a major virulence factor of a. actinomycetemcomitans is the secretion of leukotoxin ( ltxa ) , which induces apoptosis in white blood cells ( wbc ) from humans and old world primates [ 710 ] . apoptosis induction by ltxa occurs via different pathways such as a mitochondrial signaling pathway that results in collapse of the mitochondrial membrane potential and arrest of oxidative phosphorylation [ 1113 ] or by activation of caspase 1 . furthermore , ltxa has been shown to induce g2/m cell cycle arrest and apoptosis in mouse b - cell hybridoma hs-72 cells . however , the molecular pathway that leads to ltxa induced cellular apoptosis and cell cycle arrest is not well understood . ltxa is believed to play a crucial role in evasion of the host immune response by the bacterium . ltxa likely exerts its effects within the periodontal pocket where polymorphonuclear leukocytes and other immune cells infiltrate to control the infection . the receptor for ltxa on wbcs is leukocyte function antigen-1 ( lfa-1 ; cd11a / cd18 ) [ 1618 ] . lfa-1 is expressed only on wbcs and is normally involved in migration of wbcs to infected and injured tissues . when presented in its activated or exposed state , lfa-1 binds intercellular adhesion molecule-1 ( icam-1 ) on the surface of vascular endothelial cells resulting in adhesion of wbcs to the endothelial lining and subsequent extravasation . recently , we reported that ltxa preferentially targets immune cells expressing the activated form of lfa-1 , resulting in selective depletion of host cells . while studying the interaction between wbcs and vascular endothelial cells , we found that relatively high doses of ltxa irreversibly damaged endothelial cells and caused changes in expression levels of endothelial adhesion molecules . this work provides a novel mechanism for a. actinomycetemcomitans - induced tissue damage during infection . leukotoxin ( ltxa ) was purified from culture supernatants of a. actinomycetemcomitans strain nj4500 as previously described . the storage buffer for the purified toxin was 20 mm tris hcl , ph 6.8 , 250 mm nacl , and 0.2 mm cacl2 . the typical yield was 0.5 mg/100 ml starting culture . for long - term storage ( greater than one month ) , protein was lyophilized in sterile glass vials and stored at 80 c . samples were reconstituted in sterile distilled water prior to use and we found that when stored in this manner , ltxa was stable for at least 6 months . all toxin preparations were filtered through a 0.22 m filter prior to use . for experimental setup heat inactivation ( 65 c for 20 min ) has been shown effectively abolishing all toxic effects of ltxa . human microvascular endothelial cells ( immortalized cell line hcmec / d3 were used at a passage number 2832 . hcmec / d3 were grown in ebm-2 medium ( lonza cc-3156 ) , supplemented with 5% fetal bovine serum , 1.4 m hydrocortisone , 5 g / ml ascorbic acid , 1% chemically defined lipid concentrate , 10 mm hepes , and 1 ng / ml human basic fibroblast growth factor . after trypsinization , cells were seeded in 96-well plates pre - coated with 0.3% collagen ( 5000 cells / well ) . medium was supplemented with ltxa at concentrations of 5 g / ml , 500 ng / ml or 50 ng / ml or corresponding to the highest dosage ltxa - buffer alone was added . after 24 , 48 , 72 , 96 and 144 h , proliferation was quantitated using the cck-8 assay , based on the mitochondrial reduction of tetrazolium salt ( fluka 96992 ) . briefly , medium was removed and 100 l of fresh medium and 10 l of cck-8 solution was added . absorbance was measured after 4 h of incubation with a bmg fluostar optima spectrofluorophotometer . , between 50,000 and 60,000 cells were seeded per well in a collagen coated 12-well plate without treatment or with immediate addition of ltxa - buffer , or ltxa at 5 g / ml , 500 ng / ml , 50 ng / ml or 5 ng / ml . seventy - two or 96 h after seeding with or without treatment , cells were trypsinized , washed and counted in a malassez haematocytometer in triplicates and results were expressed as cells / cm . hcmec / d3 cells were grown in pre - coated 12-well plates without treatment , with ltxa - buffer or with ltxa at doses ranging from 5 g / ml to 5 ng / ml for 24 , 72 or 96 h. cells were harvested by trypsinization , washed in rpmi containing 10% fcs , then washed in ice - cold pbs and resuspended in 1 ml 80% ethanol . ethanol was removed after centrifugation and cells were stained in pbs , containing 0.05% triton - x , 0.1 mg / ml rnase a and 15 l propidium iodide for 1 h on ice . after this , cells were resuspended in 3 ml pbs , pelleted by centrifugation and resuspended in 500 l pbs for flow cytometric analysis , performed in duplicates ( except 24 h experiment ) , repeated 34 times . for analysis of apoptosis , cells were grown in 6-well plates without changing of medium for 48 or 72 h without treatment , with ltxa - buffer or with ltxa at doses ranging from 5 g / ml to 5 ng / ml . the pan - caspase inhibitor , z - vad - fmk , at a final concentration of 25 m was added to high concentrations of ltxa ( 5 g / ml and 500 g / ml ) to evaluate apoptosis via caspase activation . cells were then stained in binding buffer for annexin v - fitc ( beckman coulter aposcreen ) and 7-aad ( bd ) for 15 min at room temperature . another 100 l of binding buffer was added and cells were directly analyzed by flow cytometry ( beckman coulter fc-500 ) . , cells were grown on tissue culture dishes with cover glass bottom ( fluorodish fd 35 - 100 ) . cells were either untreated or treated with 5 g / ml ltxa . after 72 h cells were washed with pbs and stained with hoechst 33258 ( 0.01 mg / ml ) for 20 min . cells were washed again and images were taken directly afterwards at 40 magnification ( olympus ix-71 ) . hcmec / d3 cells were grown in 6-well plates for 48 h without changing of medium and in the presence or not of ltxa 5 ug / ml to 5 ng / ml or ltxa - buffer . after 24 h and 48 h 90 l of supernatant was removed and stained for annexin v ( aposcreen beckman coulter ) according to combes et al . . analysis of annexin v positive mp was performed in triplicates , repeated 3 times . for analysis of long - term effects of ltxa , hcmec / d3 cells were seeded in collagen - coated 24-well or 12-well plates with or without ltxa at 5 g / ml , 500 ng / ml , 50 ng / ml , 5 ng / ml or ltxa - buffer . medium was changed every other day and cells were grown until untreated wells were confluent ( three to four days ) . for short - term ltxa effect evaluation , hcmec / d3 were grown in collagen - coated 24-well or 12-well plates until confluence and then treated for 16 h with ltxa at 5 g / ml , 500 ng / ml , 50 ng / ml , 5 ng / ml , ltxa - buffer or medium alone . cells were stained for cd54 ( mab from beckman coulter im1239u ) and cd106 ( mab from ebioscience 12 - 1069 - 73 ) and analyzed by flow cytometry in duplicates , repeated 34 times . comparison between treatment groups at different time points were performed by two - way anova and bonferroni post test between groups . 1a ) . to confirm that our preparation contained only ltxa and not other products that could potentially affect cells ( eg . lps , cytolethal distending toxin , endotoxin ) , ltxa ( 5 g / ml ) was incubated with hl-60 cells and k562 cells . k562 cells are a white blood cell line that does not express lfa-1 and are therefore resistant to ltxa - mediated cytotoxicity . nearly all the hl-60 cells were annexin v positive , indicating they were undergoing apoptosis ( fig . in contrast , k562 cells did not stain with annexin v after ltxa treatment and the buffer- and ltxa - treated curves were superimposable . thus , cytotoxicity was due to ltxa in our purified preparation . to assess the effect exerted by purified ltxa ( fig . 1 ) on human brain endothelial cells ( hcmec / d3 ) proliferation , cells were treated once with increasing concentrations of ltxa ( 5 ng / ml5 g / ml ) and grown for up to six days . every day a tetrazolium - salt - based assay ( cck-8 ) was performed as well as cell counts . proliferation was irreversibly abrogated by a single treatment of high dose ltxa ( 5 g / ml ) . at 500 ng / ml a significant decrease in proliferation was observed whereas lower ltxa concentrations or ltxa - buffer had no effect ( fig . 2 ) . whereas untreated cells as well as ltxa - buffer and low dosage ltxa treated cells quintupled after 96 h , 5 g / ml ltxa reduced cell numbers by half , and 500 ng / ml ltxa resulted only in a duplication of cell numbers at 96 h. as shown in fig . 6 , hcmec / d3 cells presented with dramatic morphological changes when treated with a single dose of 5 g / ml ltxa . monolayer formation and even generation of cell cell contacts seemed to be inhibited by ltxa treatment and could not be observed . hcmec / d3 cells were treated once with increasing concentrations of ltxa ( 5 ng / ml5 g / ml ) and cell cycle analysis was performed at different time points ( 24 , 72 , and 96 h ) . treatment with ltxa dose - dependently increased the proportion of cells in the g2/m phase but decreased the proportion in the g1 phase ( fig . 54% of untreated or ltxa - buffer treated cells were in the g1 phase and 26% in the g2/m phase , compared to 21% of cells in the g1 phase and 70% in the g2/m phase when treated with 5 g / ml ltxa ( p < .001 , p < .001 , respectively ) . the s phase was reduced from 18% in untreated or ltxa - buffer treated cells to 3% in ltxa treated cells ( p < .05 ) . single dose ltxa treatment ( 5 g / ml ) significantly increased numbers of apoptotic cells ( annexin v positive , 7-aad negative ) after 48 h and 72 h ( fig . 4 ) . after 72 h a mean of 1.9% of hcmec / d3 stained positively for annexin v and were therefore considered apoptotic , compared to a mean of 18% in ltxa 5 g / ml treated cells ( p < .001 ) and 5.9% in ltxa 500 ng / ml treated cells ( ns ) . addition of the pan - caspase inhibitor z - vad - fmk ( 25 m ) to the 5 g / ml ltxa treatment for 72 h reduced apoptotic cell proportions to 9.8% ( p < experiments with z - vad - fmk were only performed for 5 g / ml and 500 ng / ml ltxa treatment or untreated cells for 72 h. after 48 h and 72 h , ltxa treatment ( 500 ng / ml ) significantly increased numbers of annexin v and 7-aad double positive cells ( after 72 h 13.7% in 5 g / ml [ p < .001 ] and 5.2% [ ns ] in 500 ng / ml ) were found , compared to untreated ( 3.2% ) , ltxa - buffer treated ( 1.9% ) or ltxa in lower concentrations ( 2.2% in 50 ng / ml , and 2% in 5 ng / ml , respectively ) . treatment with z - vad - fmk concomitantly with to ltxa 5 g / ml or 500 ng / ml did not reduce numbers of necrotic cells ( 16.4% and 5.2% , respectively , untreated 3.2% ) . since cellular microparticles positively staining for annexin v are considered markers of early apoptosis we evaluated numbers of endothelial microparticles after 24 h and 48 h incubation with ltxa at increasing concentrations and ltxa - buffer . after 24 h and 48 h increased numbers of annexin v positive microparticles at 5 g / ml ltxa treatment ( both p < .001 ) were found , indicating early signs of apoptosis and/or cellular activation already after 24 h ( fig . 5 ) . after 72 h apoptotic endothelial cells , exhibiting the characteristic chromatin condensation were observed by hoechst staining and fluorescence microscopy ( fig . 7 , hcmec / d3 cells either seeded with or without a single dose of ltxa ( long - term ) in increasing concentrations ( 5 ng / ml to 5 g / ml ) or treated with ltxa for 16 h after forming a confluent monolayer ( short - term ) , expressed increased levels of both icam-1 ( cd54 ) and vcam-1 ( cd106 ) . percentages of icam-1 positive cells as well as mean fluorescence intensity ( mfi ) were comparably and dose - dependently upregulated in both long- and short - term treatments . after short - term treatment of a confluent monolayer 87.2% of untreated cells compared to 95.3% of ltxa 500 ng / ml and 99% of ltxa 5 g / ml treated cells expressed icam-1 ( long - term icam-1 positive cells untreated 87.2% , ltxa 500 ng / ml 94.2% and ltxa 5 g / ml 96.9% ) . mean icam-1 mfi of untreated cells was 28.9 and 119.9 ( long - term mfi untreated 30.7 vs. ltxa 5 g / ml 126 ) after ltxa 5 g / ml treatment . vcam-1 expression was dose - dependently higher when hcmec / d3 confluent monolayers were treated for a short - term period ( 16 h ) . after a 16 h ltxa treatment 6.9% ( mfi 9.2 ) of untreated cells expressed cd106 compared to 26.9% ( mfi 11.4 ) of ltxa 500 ng / ml and 43.7% ( mfi 26.9 ) of ltxa 5 g / ml treated cells . when cells were grown in the presence of ltxa 5.7% ( mfi 8.2 ) of untreated cells and 8.6% ( mfi 10.3 ) of ltxa 500 ng / ml or 18.8% ( mfi 9.7 ) of ltxa 5 g / ml treated cells expressed cd106 ( fig . many pathogenic bacteria produce toxins that amplify or suppress the host immune response by altering cell signaling or transcriptional responses . evidence to date suggests that a. actinomycetemcomitans ltxa disrupts the host immune response mainly by killing of host immune cells . our present findings of ltxa - induced apoptosis and activation of microvascular endothelial cells , never previously reported , amplify the spectrum of pathogenetic mechanisms of a. actinomycetemcomitans and provide further explanation for tissue destruction in localized aggressive periodontitis and other diseases associated with this bacterium . as the interface between circulation and site of infection , the vascular endothelium plays a pivotal role in recruitment of leucocytes and launch of immune responses , as well as in the basic function of blood circulation and tissue maintenance . we found that a single dose of purified ltxa administered to human microvascular endothelial cells ( hcmec / d3 ) importantly and irreversibly inhibits cell proliferation by g2/m cell cycle arrest . in addition ltxa induces apoptosis , which is partially caspase - dependent . both decreased cell viability and apoptotic cell death of endothelial cells due to ltxa impairment of the endothelial barrier function would facilitate tissue invasion and distribution of a. actinomycetemcomitans and ltxa . indeed , loesche postulated that ltxa is the causative agent of local tissue destruction during lap associated with a. actinomycetemcomitans . in addition , intact blood perfusion of tissue surrounding the sites of inflammation is crucial for an effective host immune response . damage to the endothelial lining of microvessels by ltxa could severely compromise circulation and impair host defense to infection , further contributing to the pathogenic nature of the bacterium . however , in our study endothelial cells were only affected by ltxa in a relatively high dose rage from 500 ng / ml to 5 g / ml , whereas lfa-1 bearing cells such as macrophages or human pbmcs were already affected at 110 ng / ml and minimal amounts of ltxa have been shown to induce a rapid proinflammatory reaction in human macrophages , already at a ratio of 1 bacterium / macrophage . to our knowledge concentrations of ltxa locally present in patients with lap is not known , however , currently it is not evaluable if higher dosage as used in our experiment do have important clinical relevance . already after 24 h of ltxa treatment in the highest concentration , hcmec / d3 cells shed significantly increased amounts of annexin v positive microparticles into the cell culture supernatant . therefore , our finding of increased endothelial microparticle numbers is a clear sign of cell activation and/or apoptosis as an immediate reaction to ltxa treatment . it has been reported that apoptosis of endothelial cells in vitro is associated with the establishment of a pro - inflammatory milieu leading to paracrine induction of icam-1 and vcam-1 and , in turn , increased adhesiveness resulting in adhesion and transmigration of monocytic cells into the vessel wall . in our study , we found that levels of icam-1 and vcam-1 increased on endothelial cells upon treatment with ltxa . leukocyte recruitment form the circulation to sites of inflammation and infection involves a multistep cascade consisting of leukocyte rolling , firm adhesion , and , ultimately , transmigration . a key step in this process is the interaction of icam-1 with its leukocyte counter receptor , lymphocyte function - associated antigen-1 ( lfa-1 ) [ 3234 ] . whereas under physiological conditions vascular endothelium expresses low levels of icam-1 , inflammatory stimuli can significantly increase icam-1 surface expression . in acute and chronic inflammatory diseases , endothelial cells become activated and express increased levels of icam-1 , in addition to vcam-1 and e - selectin [ 3537 ] . vcam-1 is implicated in the control of leukocyte rolling in the beginning of leukocyte recruitment process whereas icam-1 accounts for firm arrest . this might be reflected by our results of vcam-1 up - regulation in short - term stimulation whereas icam-1 was upregulated in short- and long - term stimulation . whether the upregulation of icam-1 and vcam-1 upon ltxa treatment is directly induced by ltxa or caused by paracrine induction due to a pro - apoptotic milieu caused by the toxin however , other pro - inflammatory effects of ltxa such as the activation and secretion of interleukin-1 beta have already been described . it is therefore tempting to speculate that an autocrine stimulation of endothelial cells by their own il-1 could play a role in the observed cam upregulation . epidemiologic and clinical studies suggest a connection between poor oral health and increased risk of cardiovascular disease ( cvd ) . perodontopathogens have been found in atherosclerotic plaques and a. actinomycetemcomitans periodontitis has been linked to a higher risk of cardiovascular diseases and atherosclerosis . recently described elevated icam-1 expression in the aorta of mice which have been systemically challenged with a. actinomycetemcomitans . endothelial icam-1 upregulation is of special interest since it is one of the basal mechanisms associated with atherosclerotic plaque formation and subsequentially development of cvd . since endothelial cells do not express lfa-1 , a 2 integrin receptor and the natural receptor for ltxa , it is not clear how ltxa may interact with this cell type . however endothelial cells do express 1 and 3 heterodimers on their cell surfaces . while no significant amino acid homology between 1/3 and 2 integrins is known , a certain amount of structural homology does exist . therefore , even though the toxin does not bind with a high affinity to 1 or 3 as it does to 2 high ltxa dosage might be enough binding stimulus to trigger cell activation and/or cell death . interestingly , a. actinomycetemcomitans has the ability to invade vascular endothelial cells using platelet - activating factor as its receptor although the bacterial adhesin mediating this interaction is not known . gangliosides are glycoshingolipids on the surfaces of many cell types and are involved in signaling and membrane protein regulation . we proposed that ltxa may have gained the ability to bind to gangliosides on red blood cells ( rbc ) because of the similarity of their sugar moieties and structure to the carbohydrate modification of lfa-1 . similar to our observations on endothelial cells , rbc lysis requires significantly higher doses of ltxa than needed for wbc killing . hence , it is possible that ltxa interacts with gangliosides on the surface of endothelial cells in a manner similar to that seen in rbcs . in conclusion , we demonstrate that ltxa significantly increased expression levels of icam-1 and vcam-1 in endothelial cells further corroborating pro - inflammatory effects of ltxa . additionally , ltxa has important anti - proliferative as well as pro - apoptotic effects on microvascular endothelial cells and induces a g2/m phase cell cycle arrest . the presented work underlines not only the important function of ltxa in tissue destruction during a. actinomycetemcomitans infection but also its relevance in cvd . OUTPUT:

aggregatibacter actinomycetemcomitans is a human pathogen that produces leukotoxin ( ltxa ) as a major virulence factor . in this study the effect of ltxa on microvascular endothelial cell viability and phenotype was studied . high doses of single ltxa treatment ( 500 ng / ml to 5 g / ml ) significantly and irreversibly decreased cell proliferation and induced apoptosis , as assessed by tetrazolium salt and annexin v assay , respectively . apoptosis was partially inhibited by the pan - caspase inhibitor , z - vad - fmk . ltxa caused a cell cycle arrest in the g2/m phase after 72 h. between 500 ng / ml and 5 g / ml , after long- or short - term stimulation ltxa increased the expression of icam-1 and vcam-1 , as well as the percentages of endothelial cells expressing these adhesion molecules . thus , a. actinomycetemcomitans ltxa has substantial pro - inflammatory effects on human brain endothelial cells by upregulation of icam-1 and vcam-1 . furthermore , ltxa in higher concentration was found to decrease proliferation and induces apoptosis in microvascular endothelial cells .

PubMed_Summ6530

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: osteoporosis is one of the most serious public health problems for elderly people and also a major cause of the bedridden state . this condition / disease has threatened the quality of life in old age and increased medical costs . in particular , the potential for developing osteoporosis increases dramatically after menopause in females , and estrogen deficiency causes rapid bone loss of trabecular regions in hip or lumbar spine . estrogen deficiency is also associated with decrease in intestinal ca absorption which results in further acceleration of bone loss . although it is well known that decrease in intestinal ca absorption is attributable to estrogen deficiency , it remains unclear what actions other gonadal hormones have for the association between bone mass and intestinal ca absorption in the estrogen deficiency state . dehydroepiandrosterone ( dhea ) , secreted mainly from the adrenal gland and ovary , plays a critical physiological role for maintaining steroidogenesis by being used as the available precursor converted to testosterone and estrogens in various peripheral tissues such as bones , liver , brain , and skeletal muscles . dhea concentration in the blood decreases the following ovariectomy in animals . on the other hand , dhea replacement improves bone mineral density ( bmd ) , especially a trabecular site , in the ovariectomized ( ovx ) animals [ 6 - 8 ] . we previously observed that dhea replacement increased e2 ( estradiol ) centration in the blood . the presence of estrogen receptors in the intestinal mucosa and estrogen stimulates intestinal calcium absorption via an estrogen receptor . however , to our knowledge , the effect of dhea administration on intestinal ca absorption in estrogen deficiency state has not been studied yet . accordingly , we hypothesized that dhea administration would increase intestinal ca absorption via increasing e2 concentration in the blood and prevent trabecular bone loss caused by estrogen deficiency . in the present study , we examined bone mass in a trabecular abundant site of lumbar spine and ca balance such as intestinal ca absorption and ca accumulation in ovx rats after 8 weeks of dhea administration . seventeen female sprague - dawley rats , 6 weeks old , were surgically ovariectomized and randomized into two groups : ovx control rats ( oc , n = 8) and ovx rats with dhea treatment ( od , n = 9 ) . briefly , all rats were fed a diet with 1.05% calcium and 1.01% phosphate purchased from clea japan ( ce-2 , clea japan , inc . , dhea dissolved in sesame oil was administered to the od group intraperitoneally at 20 mg dhea / kg body weight for 8 weeks beginning one week after ovariectomy while the oc group was treated with vehicle only ( sesame oil , 0.5 ml ) . rats were not treated with dhea or vehicle every fourth day ( i.e. , they were treated for 3 consecutive days ) . the rats were kept in individual cages ( 15 25 19.5 cm ) and allowed access to food and distilled water ad libitum . food consumption and body weight gain the room temperature was maintained at 24 1c , and the humidity at 50 5% . fluorescent lights were turned on from 8:00 a.m. to 8:00 p.m. animal care and experimental procedures were approved by the animal experimental committee of the university of tsukuba . the lumbar spine , left , and right tibiae of each rat were isolated by dissection , and all the muscle and connective tissue was carefully removed . thereafter , bmc and bmd value for the l3-l6 lumbar spine were measured by dual - energy x - ray absorptiometry ( dxa ; aloka dcs-600r instrument ) . in the present study , we used young ovx rats whose growth of bone is considerably influenced by body mass . therefore , we normalized body weight for bmc to evaluate the effect of dhea on bone mass . at the each dissection after the adhering connective tissues had been trimmed off , the femoral wet weight was measured . thereafter , the femoral length , long width , and short width were measured with a caliper . length was measured from the proximal tip of the femur head to the distal tip of the medial condyle . the mediolateral ( long width ) and anteroposterior ( short width ) dimensions were measured at the midpoint of the femur diaphysis . the bone strength of the middle diaphysis of the femur was then tested by measuring the mechanical strength , breaking force with an iio dyn-1255 instruments . the force necessary to produce a break at the center of the femur was measured under the following conditions ; the sample space was 1.0 cm , the plunger speed was 100.0 mm / min , the load range was 50.0 kg , and the chart speed was 120.0 cm / min . in this study , two balance studies were carried out to determine the rate of intestinal ca absorption and ca accumulation . animals were placed in individual metabolic cages ( 24 20 18 cm ) . the first phase was carried out on the 4th and 5th day after starting the experimental diets period ( metabolic cage phase 1 : mc 1 ) . the next phase ( mc 2 ) was carried out at the end of the experimental period . at each phase , urine was collected under acidic conditions by using 2ml 2n hydrochloric acid , thus preventing ca precipitate and putrefaction . all urine was centrifuged at 2,500 rpm for 15 min to eliminate refuse . in the fecal determination , all daily feces were burnt to ash at 550 - 600 for approximately 18 hours , and the resulting ash was dissolved in 1n nitric acid . the level of serum ca was measured by the inductively coupled plasma atomic emission spectroscopy ( icap - aes - 575 v nippon jarrell - ash ) . intestinal ca absorption and ca accumulation were calculated using the amount of ca intake , the fecal ca excretion and the urinary ca excretion . statistical significance ( p < 0.05 ) was determined using an unpaired student s t - test between groups . two - way analysis of variance ( anova ) was used for determining the effects of time and group on intestinal ca absorption and accumulation . statistical analysis was carried out by one - way anova followed by fisher`s f - test for multiple comparisons among four points in intestinal ca absorption and accumulation . statistical analysis was performed using spss for windows ( version 20.0 j ; spss inc . , seventeen female sprague - dawley rats , 6 weeks old , were surgically ovariectomized and randomized into two groups : ovx control rats ( oc , n = 8) and ovx rats with dhea treatment ( od , n = 9 ) . briefly , all rats were fed a diet with 1.05% calcium and 1.01% phosphate purchased from clea japan ( ce-2 , clea japan , inc . , dhea dissolved in sesame oil was administered to the od group intraperitoneally at 20 mg dhea / kg body weight for 8 weeks beginning one week after ovariectomy while the oc group was treated with vehicle only ( sesame oil , 0.5 ml ) . rats were not treated with dhea or vehicle every fourth day ( i.e. , they were treated for 3 consecutive days ) . the rats were kept in individual cages ( 15 25 19.5 cm ) and allowed access to food and distilled water ad libitum . food consumption and body weight gain the room temperature was maintained at 24 1c , and the humidity at 50 5% . fluorescent lights were turned on from 8:00 a.m. to 8:00 p.m. animal care and experimental procedures were approved by the animal experimental committee of the university of tsukuba . the lumbar spine , left , and right tibiae of each rat were isolated by dissection , and all the muscle and connective tissue was carefully removed . thereafter , bmc and bmd value for the l3-l6 lumbar spine were measured by dual - energy x - ray absorptiometry ( dxa ; aloka dcs-600r instrument ) . in the present study , we used young ovx rats whose growth of bone is considerably influenced by body mass . therefore , we normalized body weight for bmc to evaluate the effect of dhea on bone mass . after the adhering connective tissues had been trimmed off , the femoral wet weight was measured . thereafter , the femoral length , long width , and short width were measured with a caliper . length was measured from the proximal tip of the femur head to the distal tip of the medial condyle . the mediolateral ( long width ) and anteroposterior ( short width ) dimensions were measured at the midpoint of the femur diaphysis . the bone strength of the middle diaphysis of the femur was then tested by measuring the mechanical strength , breaking force with an iio dyn-1255 instruments . the force necessary to produce a break at the center of the femur was measured under the following conditions ; the sample space was 1.0 cm , the plunger speed was 100.0 mm / min , the load range was 50.0 kg , and the chart speed was 120.0 cm / min . in this study , two balance studies were carried out to determine the rate of intestinal ca absorption and ca accumulation . animals were placed in individual metabolic cages ( 24 20 18 cm ) . the first phase was carried out on the 4th and 5th day after starting the experimental diets period ( metabolic cage phase 1 : mc 1 ) . the next phase ( mc 2 ) was carried out at the end of the experimental period . at each phase , urine was collected under acidic conditions by using 2ml 2n hydrochloric acid , thus preventing ca precipitate and putrefaction . all urine was centrifuged at 2,500 rpm for 15 min to eliminate refuse . in the fecal determination , all daily feces were burnt to ash at 550 - 600 for approximately 18 hours , and the resulting ash was dissolved in 1n nitric acid . the level of serum ca was measured by the inductively coupled plasma atomic emission spectroscopy ( icap - aes - 575 v nippon jarrell - ash ) . intestinal ca absorption and ca accumulation were calculated using the amount of ca intake , the fecal ca excretion and the urinary ca excretion . all the data are expressed as mean se . statistical significance ( p < 0.05 ) was determined using an unpaired student s t - test between groups . two - way analysis of variance ( anova ) was used for determining the effects of time and group on intestinal ca absorption and accumulation . statistical analysis was carried out by one - way anova followed by fisher`s f - test for multiple comparisons among four points in intestinal ca absorption and accumulation . statistical analysis was performed using spss for windows ( version 20.0 j ; spss inc . , chicago , il , usa ) . the body weight gain , food intake , and food efficiency are presented in table 1 . the initial body weight did not differ between the groups . the final body weight and the body weight gain were significantly lower in the od group than in the oc group . the bmc normalized by body weight of the lumbar spine ( trabecular - abundant region ) in the od group was found to be significantly higher compared to that in the oc group . to eliminate the effect of body weight on growing bone , we normalized body weight for bmc for evaluating the effect of dhea on bone mass . the bmd of the lumbar spine in the od group tended to be higher compared to that in the oc group , but it did reach statistically significant levels . the femoral wet weight normalized by body weight in the od group was found to be significantly higher compared to that in the oc group , but the long and short width and length of femur did not differ between the groups ( table 2 ) . the breaking force at femoral diaphysis site ( cortical boneabundant ) did not differ between the groups ( table 2 ) . the intestinal ca absorption , rate of intestinal ca absorption , ca accumulation , and rate of ca accumulation decreased from mc 1 ( the 4th and 5th of the experimental diet period ) to mc 2 ( the end of the experimental period ) , but the interaction of time and group was not observed . in both mc1 and mc2 , all parameters did not differ between the groups . the present study demonstrated that dhea administration increased the bone mass of lumbar spine in ovariectomized rats . on the other hand we found that the bone mass of lumbar spine ( trabecular abundant site ) was increased after 8 weeks of dhea administration . this result is similar to the result of our previous study and turner et al.s study which showed increase in trabecular bone mass of tibia . dhea particularly may have a positive effect on trabecular bone mass but not in cortical areas in the diaphysis region . the reason for this site - specific effect remains unclear yet , but our result further supported that dhea administration may be effective for preventing the reduction of trabecular abundant bones at which fracture frequently occurs for postmenopausal women with osteoporosis . in the present study , femoral weight normalized by body weight was higher in rats treated with dhea than in control rats . the reason for the higher femoral weight would be supported by martel et al. study that the total bmc of femur increased by dhea administration in ovariectomized rats . also , we measured the femoral strength . to our knowledge , no studies have examined the effect of dhea treatment on the bone strength of diaphysis site . however , we did not observe any effect of dhea on the bone strength at the midpoint of the femur diaphysis . the lack of effect of dhea on the bone strength might be partly influenced by the non - effect of dhea on the bone mass at the diaphysial area . our previous study showed that e2 concentration in the blood was higher in ovariectomized rats treated with dhea than in ovariectomized control rats . although evidence of a direct effect of estrogen promoting intestinal ca absorption has been reported , our results revealed that deha administration may have no effect on intestinal ca absorption . as reason for the lack of dhea effect , intestinal ca absorption might have increased by dhea administration in an earlier phase during 8 weeks of the experimental period . ca accumulation at the end point of the present experiment did not differ between the groups , meaning that the effect of dhea on bone had already reached its ceiling peak level . as another possible reason for the lack of dhea effect , we used 1.05% ca diet which is an enough ca amount for maintaining the bone health of ovariectomized rats . some studies related to examining intestinal ca absorption used to use 0.3 - 0.5% ca diet condition which can lead to bone loss and induce higher ca absorption . as the result of our previous study , the serum dhea concentration was approximately 9-fold higher in dhea - treated rats than in control rats . thus , we cautiously assumed that ca absorption would have increased if we treated lower dose of dhea than that in the present study . therefore , future research that focuses on the dose - dependent effect of dhea administration is necessary . in addition , we observed that dhea administration increased bmc normalized body weight even though it did not increase bmd . during the growing phase , bmd sometimes may not precisely reflect the alteration of bone mass since growth of bone is considerably influenced by body mass . because bmd is calculated by dividing the bmc with area ( cm ) , the bmd measurement by dxa did not provide the details of bone parameters such as cortical width and periosteal circumferences . thus , the parameters should be examined in detail by using the methods of pqct , ct , or bone morphometry in future studies , especially when using animals in the growing phase . the present study confirmed the positive effect of dhea on trabecular bone mass of lumbar spine in ovariectomized rats . on the other hand , dhea administration did not affect intestinal ca absorption . we suggest that dhea administration might have limited impact on intestinal ca absorption in estrogen deficiency state . OUTPUT:

[ purpose]the effect of dehydroepiandrosterone ( dhea ) administration on intestinal calcium ( ca ) absorption in estrogen deficiency state has not been studied yet . we examined the bone mineral content ( bmc ) of lumbar spine and ca balance such as intestinal ca absorption and ca accumulation in ovariectomized ( ovx ) rats after 8 weeks of dhea administration.[methods]seventeen female sprague - dawley rats , 6 weeks old , were randomized into two groups : ovx control rats ( oc , n = 8) and ovx rats with dhea treatment ( od , n = 9 ) . dhea was administered to the od group intraperitoneally at 20 mg dhea / kg body weight for 8 weeks while the oc group was treated with vehicle only.[results]the bmc normalized by body weight of the lumbar spine ( trabecular - abundant region ) in the od group was found to be significantly higher compared to that in the oc group . the femoral wet weight normalized by body weight in the od group was significantly higher compared to that in the oc group . the intestinal ca absorption , rate of intestinal ca absorption , ca accumulation , and rate of ca accumulation decreased from the 4th and 5th of the experimental diet period to the end of the experimental period , but interaction of time and group was not observed . in both periods , all parameters did not differ between the groups.[conclusion]the present study confirmed the positive effect of dhea on trabecular bone mass in ovariectomized rats . on the other hand , dhea administration might have limited the impact on intestinal ca absorption in estrogen deficiency state .

PubMed_Summ6531

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: chronic hepatitis b virus ( hbv ) infection is a potentially life - threatening liver disease with serious complications such as cirrhosis and hepatocellular carcinoma . the prevalence of hbv infection varies widely , with rates ranging from 0.1% to 20% worldwide . iran is an area of intermediate endemicity and the prevalence of chronic hepatitis b infection is reported to be 1.7% in general population . it has been demonstrated that some hbs - ag negative individuals with positive anti - hbc continue to replicate hbv . thus , the absence of hbs - ag in the blood of apparently healthy individuals may not be sufficient to ensure an hbv - free status . anti - hbc can be detected throughout the course of both acute and chronic hbv infection . it persists longlife after resolution , therefore the routine blood donor screening for anti - hbc has been implemented in some countries , resulting in a decrease in the risk of post - transfusion hbv infection . in iran , the reported rates range from 5.1% in hamadan and 6.5% in shiraz to as high as 34% in sistan - balouchestan . nevertheless , the associated figures for isoalted anti - hbc prevalnce in other studies were as low as 0.56% in the united kingdom to as high as 76% in ghana however , most of previous studies reported isolated anti - hbc rates between 2 - 5% . despite this fact , iranian health policy makers have not introduced anti - hbc screening among blood donors , partly because of the lack of empirical data on the benefit of introducing anti - hbc screening in a donor population with low prevalence of hbv . on the other hand , the indefinite deferral of donors with false - positive anti - hbc is a major disappointing side effect of anti - hbc screening in countries with low endemicity of hbv infection . it is of utmost importance to differentiate whether isolated anti - hbc is due to false positive results or the prior exposure to hbv , because individuals with false - positive anti - hbc can benefit from vaccination and their blood can be safely transfused . to distinguish between the aforementioned conditions , evaluation of response to hb vaccination has been proposed . in the present study , we investigated the anti - hbs seroconversion in 2 groups of blood donors with isolated anti - hbc and their controls after hb vaccination . we also attempted to find the predictors of non - response status among individuals with isolated anti - hbc . ninety individuals with isolated anti - hbc positive test and 100 healthy persons with negative serological markers of hepatitis b were recruited in the study as case and control groups , respectively . the exclusion criteria were : age > 64 years , previous hbv vaccination , organ transplantation , immunodeficiency disorders , hemodialysis , immunosuppressive therapy , contraindication for hbv vaccination ( i.e. prior history of anaphylactic reaction to vaccine ) , positive results for hbs - ag , anti - hbs , anti - hcv , or anti - hiv tests and aspartate aminotransferase ( ast ) or alanine aminotransferase ( alt ) levels above 3 times normal cutoff values . also , none of the participants were positive for signs and symptoms of chronic hepatitis and cirrhosis . prior to intervention , informed consents were obtained from all the participants , in accordance with the guidelines established by the ethics committee of zahedan university of medical sciences . all the participants were tested for hbv - dna by qualitative polymerase chain reaction ( pcr ) ( cinna gen inc . , tehran , iran ) that could detect as low as 100 copy / ml of viral genome . the following reagents were added to each tube on ice : 1x pcr mixture 15 ul and taq - dna polymerase 0.4 ul . then the tubes were shaken and spun thoroughly . the pcr mixture contained primers amplifying 353 bp of the region of the core gene . one drop ( 20 - 25 ul ) of mineral oil was also added to each tube . then , 10 ul dna ( with the use of specified pipette for sampling of dna ) was added to the mixture and spun on microfuge for 3 - 5 seconds . the tubes were transferred to preheated thermocycler with the following program : 1 cycle of 60 seconds at 93c , 20 seconds at 61c and 40 seconds at 72c , followed by 35 cycles of 93c , 61c , and 72c for 20 , 20 , and 40 seconds , respectively . finally , 10 iu / ml of amplified samples were directly analyzed in a 2% agarose gel without adding loading buffer . afterwards , all subjects received three doses of 20 g of hepatitis b recombinant vaccine ( heberbiovac hbr , havana , cuba ) at 0 , 1 , and 6 months , if applicable ( see below ) . the vaccine was injected intramuscularly into the deltoid muscle . in order to quantify anti - hbs antibodies , individuals with high titer anti - hbs response ( anti - hbs > 50 miu / ml ) did not receive additional doses of the vaccine . however , others completed the vaccination course , and another blood sample was collected 30 days after the third dose to measure anti - hbs level . anti - hbs titer 10 miu / ml 30 days after the first vaccination was considered as early primary response . also , late primary response was defined as anti - hbs titer 10 miu / ml 30 days after the third dose of vaccines . non - responders were individuals with < 10 miu / ml anti - hbs titers after receiving three doses of hb vaccine . data were analyzed using spss for windows software , version 11.5 ( spss inc . , odd s ratios ( ors ) were chosen to measure the association between dichotomous variables , and the results were adjusted for potential confounders by multivariate logistic modeling . table 1 presents the demographic and important risk factors of the participants , comparing those with isolated anti - hbc to controls . 1 ) abnormal level was defined as levels > 1.5 times upper than normal limit 2 ) ns : not significant 3 ) linear by linear association ( chi - squared for linear trend ) ; exact method participants of the case group were significantly older , and mostly married . the case group had also higher male / female ratio , and more history of transfusion and tattoo ( p<0.05 ) . however , history of infection in spouse , familial history of hbv infection , and serum ast and alt levels was not significantly different between cases and controls . totally , 19 ( 21.1% ) cases and 3 ( 3% ) controls did not seroconvert ( non - responder ) after three doses of hb vaccine ( p<0.0001 ) . however , primary response was observed in 43 ( 47.8% ) isolated anti - hbc positive cases and 92 ( 92% ) controls ( p<0.0001 ) , of whom 15 cases and two controls seroconverted after the first dose of hb vaccine ( early responder ) . furthermore , anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine was significantly higher among cases ( 31.1% vs. 5% , p<0.0001 ) . two ( 2.2% ) cases with positive isolated anti - hbc had detectable hbv dna and were therefore , excluded from the analysis . both of these two hbv dna positive cases did not seroconvert after receiving 3 doses of vaccination . none of the cases and controls showed adverse effects after receiving recombinant hb vaccine . table 2 compares non - responders ( excluding 2 hbv dna positive cases ) with primary responders ( including early and late responders ) . according to univariate analysis , serum anti - hbc positivity , age , and marital status were significantly different between the two groups ; however , in multivariable analysis , only anti - hbc positivity and age remained independently associated with non - responding status . indeed , anti - hbc positive subjects were 12.2 times ( 95% ci : 3.2 - 46.4 , p<0.0001 ) more likely to fail seroconversion . similarly , age 50 years was 3.6 times more likely to lead in non - responsive state ( 95% ci : 1.0 - 12.3 , p<0.04 ) . also , anti - hbc positive participants were more likely to develop anti - hbs titer 50 miu / ml 30 days after receiving the first dose of vaccine ( table 3 ) . 1 ) abnormal level was defined as levels > 1.5 times upper than normal limit 2 ) ns : not significant 3 ) linear by linear association ( chi - squared for linear trend ) ; exact method . * participants with anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine and those with positive hbv dna were excluded as noted earlier , early response ( anti - hbs titer 10 miu / ml 30 days after the first vaccination ) was found in 17 subjects . we compared early responders to late responders ( the table is not included ) and found a trend toward a higher seroprotective response rate after the first vaccination in the subjects with abnormal baseline alt levels and those aged>50 years ( ors : 6.9 and 8 , p<0.02 and p<0.001 , respectively ) . data were analyzed using spss for windows software , version 11.5 ( spss inc . , odd s ratios ( ors ) were chosen to measure the association between dichotomous variables , and the results were adjusted for potential confounders by multivariate logistic modeling . table 1 presents the demographic and important risk factors of the participants , comparing those with isolated anti - hbc to controls . 1 ) abnormal level was defined as levels > 1.5 times upper than normal limit 2 ) ns : not significant 3 ) linear by linear association ( chi - squared for linear trend ) ; exact method participants of the case group were significantly older , and mostly married . the case group had also higher male / female ratio , and more history of transfusion and tattoo ( p<0.05 ) . however , history of infection in spouse , familial history of hbv infection , and serum ast and alt levels was not significantly different between cases and controls . totally , 19 ( 21.1% ) cases and 3 ( 3% ) controls did not seroconvert ( non - responder ) after three doses of hb vaccine ( p<0.0001 ) . however , primary response was observed in 43 ( 47.8% ) isolated anti - hbc positive cases and 92 ( 92% ) controls ( p<0.0001 ) , of whom 15 cases and two controls seroconverted after the first dose of hb vaccine ( early responder ) . furthermore , anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine was significantly higher among cases ( 31.1% vs. 5% , p<0.0001 ) . two ( 2.2% ) cases with positive isolated anti - hbc had detectable hbv dna and were therefore , excluded from the analysis . both of these two hbv dna positive cases did not seroconvert after receiving 3 doses of vaccination . none of the cases and controls showed adverse effects after receiving recombinant hb vaccine . table 2 compares non - responders ( excluding 2 hbv dna positive cases ) with primary responders ( including early and late responders ) . according to univariate analysis , serum anti - hbc positivity , age , and marital status were significantly different between the two groups ; however , in multivariable analysis , only anti - hbc positivity and age remained independently associated with non - responding status . indeed , anti - hbc positive subjects were 12.2 times ( 95% ci : 3.2 - 46.4 , p<0.0001 ) more likely to fail seroconversion . similarly , age 50 years was 3.6 times more likely to lead in non - responsive state ( 95% ci : 1.0 - 12.3 , p<0.04 ) . also , anti - hbc positive participants were more likely to develop anti - hbs titer 50 miu / ml 30 days after receiving the first dose of vaccine ( table 3 ) . 1 ) abnormal level was defined as levels > 1.5 times upper than normal limit 2 ) ns : not significant 3 ) linear by linear association ( chi - squared for linear trend ) ; exact method . * participants with anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine and those with positive hbv dna were excluded as noted earlier , early response ( anti - hbs titer 10 miu / ml 30 days after the first vaccination ) was found in 17 subjects . we compared early responders to late responders ( the table is not included ) and found a trend toward a higher seroprotective response rate after the first vaccination in the subjects with abnormal baseline alt levels and those aged>50 years ( ors : 6.9 and 8 , p<0.02 and p<0.001 , respectively ) . in our setting , we vaccinated isolated anti - hbc as well as healthy blood donors and monitored their response to hbv vaccination . a total of 19 ( 21.1% ) cases and 3 ( 3% ) controls did not seroconvert after receiving 3 doses of hb vaccine . prior investigators reported a wide range of non - responding state , sunbul 9.1% , coz yatacho 9.7% . therefore , at least 20% of isolated anti - hbc positive cases may suffer from occult hepatitis b infection , for whom a diminished ability to mount an anti - hbs response is proposed . furthermore , in our study , anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine was developed in 28 ( 31.1% ) cases and 5 ( 5% ) controls . scanty studies have addressed anamnestic rates ; however , in a study reported by sunbul and colleagues , out of 33 ( 42.4% ) subjects with isolated anti - hbc showed rapid high seroconversion , while in a report by ural and co - workers , this rate was 41.7% ( 20 out of 48 ) . our lower rate could in part be explained by lower prevalence of hbv in our region . in such patients , further vaccination may not be necessary . finally , 43 ( 47.8% ) subjects with isolated positive anti - hbc and 92 ( 92% ) controls showed primary response after the vaccination protocol . nevertheless , most of previous researchers assigned their subjects in two groups of responders ( either primary or anamnestic ) and non - responders . accordingly , our cumulative responder rate would be 78.9% among subjects with isolated positive anti - hbc , which is in agreement with reports by koh ( 70.6% ) , kabir ( 79.8% ) , and silva ( 80% ) , but lower than what reported by ural ( 89.6% ) , pereira ( 90% ) , yatacho ( 90.3% ) and sunbul ( 90.9% ) . , discrepancies in response rate to hb vaccination among isolated anti - hbc subjects can be explained by serologic kit sensitivity , defining cut off points , and inclusion criteria for borderline results . therefore , in our region , nearly 80% of isolated anti - hbc subjects can be safely included in the donor pool , simply based on a vaccination protocol . notably , the isolated anti - hbc subjects with false positive results ( 47.8% in our setting ) are susceptible to hepatitis b infection and should receive a complete course of hb vaccine . however , they may lose hb vaccination because of misinterpretation of anti - hbc results . on the other hand , our results revealed that individuals with isolated positive anti - hbc were significantly older , mostly married , had higher male / female ratio , history of transfusion , tattoo and abnormal serum ast and alt levels when compared with controls . the higher rate of anti - hbc positivity among older subjects mirrors a cohort effect of hbv infections acquired decades ago when hbv was moderately endemic in iran and hbv national vaccination program had not been commenced . furthermore , only two ( 2.2% ) isolated anti - hbc positive cases had detectable hbv dna . recent studies suggest that 1 - 2% of anti - hbc reactive units contain low levels of hbv dna . however , in studies conducted on 4930 healthy blood donor volunteers in fars and hamadan provinces , 6.5% and 5.1% were isolated anti - hbc positive cases , among whom 16 ( 12.3% ) and 3 ( 1.2% ) were hbv dna positive , respectively . having compared non - responders to primary responders ( table 2 ) , anti - hbc positivity , age , and marital status showed significant differences in univariable analysis . however , in multivariable analysis , only anti - hbc positivity and age ( > 50 years ) remained independently associated with non - responding status . on the other hand , when we compared primary responders with those who developed anti - hbs titer 50 miu / ml 30 days after the first dose of vaccine ( table 3 ) , positivity for anti - hbc and age > 50 years were the most relevant factors in developing higher anti - hbs titers to hbv vaccine . therefore , isolated anti - hbc subjects aged > 50 years would more likely either develop anti - hbs titers 50 miu / ml 30 days after receiving the first dose of vaccine or never respond to hb vaccine . as a result , one month after the first dose of hb vaccine in isolated anti - hbc subjects aged > 50 years , we can make a decision regarding whether to advise a strict follow - up ( occult hbv infection ) or assure the patient that he / she has a resolved hbv infection . interestingly , when we compared the early and late responders ( the table is not included ) , anti - hbc positivity , abnormal alt level , and age > 50 years were associated with a higher probability of early response . therefore , anti - hbc positive subjects aged > 50 years with abnormal alt levels should be offered the first dose of hb vaccine and evaluated one month later in order to decide for their future follow - up . various molecular modalities have been developed to determine if isolated anti - hbc subjects could transmit hbv infection . however , they will further increase the testing costs and require trained personnel and equipment , which may not be possible in many blood banks around the country . thus , studying the cost effectiveness of monitoring the response to hb vaccination could be worth of considering as a diagnostic tool . we also suggest future studies focusing on evaluating the short - course vaccination protocols such as double - dose / double - time vaccination in order to make sooner decision . in conclusion ; using vaccination , we found that half of the subjects with isolated positive anti - hbc were falsely positive for the test and more than 75% of subjects with isolated positive anti - hbc could benefit from vaccination and could be included in donor pool . moreover , one - fifth of subjects were non - responders and may have occult hbv infection . because at least 5% of the donor population in iran is anti - hbc positive , blindly rejecting anti - hbc positive donors would cause the exclusion of a consistent number of donors , most of whom could safely be included in the donor pool . therefore , hb vaccination may be used as a diagnostic tool for clarifying the situation of the subjects with isolated anti - hbc and can help in reducing the blood supply problems . this study was financially supported by zahedan university of medical sciences and iranian blood transfusion organization research center ( zahedan branch ) . OUTPUT:

background it is important to differentiate whether isolated anti - hbc is due to false positive results or the prior exposure to hepatitis b virus , because individuals with false - positive anti - hbc can benefit from vaccination and their blood can be safely transfused . to distinguish between these two conditions , we evaluated the serologic response to hepatitis b vaccine . methods ninety subjects with isolated anti - hbc ( cases ) and 100 subjects with totally negative hepatitis b serologic markers ( controls ) were recruited to receive three doses of hepatitis - b ( hb ) vaccine . thirty days after the first dose of the vaccine , anti - hbs titers were checked and individuals with anti - hbs titer > 50 miu / ml did not receive additional doses of the vaccine . however , others completed the vaccination course , and another blood sample was collected 30 days after the third dose to measure anti - hbs level . results nineteen ( 21.1% ) cases and three ( 3% ) controls had no sero - conversion ( anti - hbs titers < 10 miu / ml ) 30 days after the third dose ( p<0.0001 ) . primary response , defined as the development of anti - hbs antibody titers 10 miu / ml 30 days after the third dose , was observed in 43 ( 47.8% ) cases and 92 ( 92% ) controls ( p<0.0001 ) . also , 31.1% of cases developed anti - hbs titers 50 miu / ml 30 days after the first dose of vaccine , but the rate was significantly lower ( 5% ) in the control group ( p<0.0001 ) . furthermore , half of the individuals with positive isolated anti - hbc developed protective levels of anti - hbs after three doses of hb vaccination . conclusion more than 75% of individuals with positive isolated anti - hbc can benefit from vaccination and can be included in donor pool . also , one fifth seemed to have occult hbv infection . so hb vaccination may be used as a diagnostic tool for clarifying the situation of the subjects with isolated anti - hbc .

PubMed_Summ6532

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: we searched medline ( between 1966 and 2007 ) and the cochrane library central registry of controlled trials ( between 1984 and 2007 ) for relevant publications using the following medical subject heading terms : diabetes and ( food or diet ) . we examined reference lists of those publications to identify additional studies suitable for our purpose . we searched for studies of the effects of two kinds of prescribed diets differing according to proportions of carbohydrate and fat under conditions that the prescribed total energy and protein intake did not differ significantly between groups of patients with type 2 diabetes . we designated one diet as the lfhc diet , which was defined as having a relatively high c / f ratio , and the other as the hflc diet , which had a relatively low c / f ratio . as shown in detail in table 1 , in examining these studies , we found that the c / f ratio ranged from 0.60 to 1.56 for the hflc diets and from 1.67 to 7.30 for the lfhc diets . descriptive statistics of studies included in the meta - analysis c / f / p , proportion of carbohydrate / fat / protein to total energy of the prescribed diet ; n / a , not assessed . among the studies identified , we included only randomized controlled trials with measurements of fasting plasma glucose ( fpg ) and fasting insulin and intervention periods of 1 week . studies that included an intervention with a change in the content or quality of carbohydrate such as an increase in fiber and whole grains were excluded because such diets are high in fiber , which in itself ameliorates glycemia and lipemia regardless of changes in the c / f ratio ( 3,4 ) . studies of very - low - calorie or enteral ( not oral ) diets and those in which the dosage of hypoglycemic agents was changed during the intervention period were also excluded . one of three reviewers extracted all studies that met the eligibility criteria , and a second reviewed all extracted data . extracted data included features of the study design ( i.e. , crossover or parallel design and presence of a washout period ) , intervention periods , characteristics of patients ( mean age , bmi , percent men , and percent those using hypoglycemia agents ) . other extracted data regarded the characteristics of each diet , such as macronutrient composition ; a weight - loss diet , which was defined as caloric restriction resulting in weight reduction ; a weight - maintenance diet , which was defined by a weight change of 1 kg during the intervention period , and a monounsaturated fat ( mufa ) diet within the hflc - diet group , which was defined as the addition of mufa to the hflc diet . we also extracted baseline and final means and statistical dispersions of each group for the following metabolic profiles : a1c , fpg , fasting insulin , total cholesterol , fasting triglycerides , ldl cholesterol , hdl cholesterol , and 2-h postprandial levels of glucose and insulin . if vldl cholesterol but not triglyceride data were provided , the triglyceride value was calculated by multiplying vldl cholesterol 5 according to the friedewald formula ( 5 ) . also , if hba1 but not a1c data were provided , a1c was estimated by the relation between hba1 and a1c concentrations according to the methodology of kilpatrick et al . ( 6 ) . if necessary , measures of means and dispersion were approximated from figures in the articles using an image scanner ( canoscan lide 500f [ resolution 600 dpi ] ; canon , tokyo , japan ) . ( 7 ) , with each included trial evaluated according to randomization , double blinding , withdrawals , and dropouts . the effect on each metabolic profile , which is expressed as the mean difference between lfhc- and hflc - diet groups in individual studies , was calculated by subtracting the change from baseline to final values in the hflc - diet group from that in the lfhc - diet group . the se of the change from baseline values was directly extracted from the reported data or estimated from the ses of the baseline and final values in the lfhc- and hflc - diet groups , assuming a correlation of 0.5 between the baseline and final measures within each group , according to the formula of follmann et al . ( 8) , as follows : we chose the percent change from baseline values because the mean baseline and final values in patients in each study were highly skewed . to estimate percent change , we divided each change from baseline values and its se by the baseline value . when no baseline value was reported , as in some crossover studies , we summarized the intervention effect by the ratio of the difference in final values between lfhc- and hflc - diet groups to the final value in the hflc - diet group and assumed that the baseline se was equal to the final se . this method of estimating percent change has limitations , especially in studies without washout periods . therefore , we performed a sensitivity analysis to examine the effect of these studies on the results . all percent changes were firstly pooled with a fixed - effects model ( 9 ) . for each outcome measure , influence analysis was conducted to detect an outlier ( i.e. , a single estimate with an extreme result ) , which influenced overall outcome . if heterogeneity was significant , the percent changes were secondarily re - pooled with a random - effects model ( 9 ) . publication bias was assessed using two formal methods : begg 's test ( 10 ) and egger 's test ( 11 ) . the trim - and - fill technique ( 12 ) was used to investigate the impact of any suggested bias . we also calculated the weighted mean difference ( wmd ) in individual trials by multiplying each percent change by the inverse of its se squared . we ecologically examined the mutual association among each metabolic effect of the lfhc diet compared with the hflc diet by spearman 's correlation analyses among wmds . to investigate the effect of study characteristics , stratified analyses were performed for the following possible confounders : study design ( i.e. , whether each trial used a crossover design and , if so , whether the trial had a washout period or data on baseline values ) , intervention period ( < 4 vs. 4 weeks ) , percent the study of female sex ( < 50 or 50% ) , mean age ( < 55 vs. 55 years ) , bmi ( < 28 vs. 28 kg / m ) , percentage using hypoglycemia agents ( zero vs. above zero ) , c / f ratio in the lfhc ( > 3 vs. 3 ) and hflc ( > 1 vs. 1 ) groups , prescription of the mufa diet ( yes vs. no ) , and prescription of a weight - loss or weight - maintenance diet . we additionally conducted linear multivariable regression analyses to determine whether the characteristics of the patients were independent predictors that influenced the effect of the lfhc diet versus that of the hflc diet . in this analysis , age , bmi , and the carbohydrate proportion in the lfhc and hflc diets were entered as continuous variables . all analyses were performed with stata software version 10 ( stata corporation , college station , tx ) . of 2,203 potentially relevant publications based on search terms and 22 references obtained from manual searches , 19 ( 1331 ) met the inclusion criteria . four articles ( 19,20,24,31 ) included two trials in one study , and two articles ( 27,28 ) used the same cohort . studies included in the current analysis had intervention periods ranging from 10 days to 6 weeks and patient numbers ranging from 8 to 42 . means between - study sds for the mean study characteristics from 22 trials were as follows : age 55 5 years , percent men 63 23 , bmi 28 3 kg / m , percent using hypoglycemia agents 52 31 , and diabetes duration 6 1 years . ten studies ( 15,1821,2326,31 ) described the number of dropouts , and nine ( 13,14,16,17,22,2730 ) did not . none of the 19 articles described methods of randomization , which led to a low quality score for the trial . a crossover design was used in 17 studies ( 1318,20,21,2331 ) ( with 19 trials ) , whereas a parallel design was used in two studies ( 19,22 ) with three trials . median carbohydrate / fat proportion of total energy ( c / f ratio ) in the lfhc and hflc diets was 58%/24% ( 2.4 ) and 40%/40% ( 1.0 ) , respectively . three studies ( 19,22,26 ) with 4 trials prescribed a weight - loss diet , and 11 studies ( 13,14,1719,21,2325,27,28 ) with 11 trials provided a mufa diet to the hflc - diet group . there were no significant differences in the reduction in a1c , total cholesterol , and ldl cholesterol between the lfhc and hflc diets . however , the lfhc diet produced significant increases in fasting insulin and triglycerides levels of 8.4% ( p = 0.02 ) and 13.4% ( p < 0.001 ) , respectively , and a significant reduction in hdl cholesterol compared with that associated with the hflc diet . two - h glucose and insulin values were higher in the lfhc - diet group than in the hflc - diet group by 10.3% ( p < 0.001 ) and 12.8% ( p < 0.001 ) , respectively . overall percent changes resulting from lfhc versus hflc diet on metabolic profiles and data on publication bias and their likely effect on the estimates * studies ( n ) added by the trim - and - fill method . percent change after adjustment for publication bias by the trim - and - fill method . begg 's , begg 's adjusted rank correlation test ; egger 's , egger 's regression asymmetry test . influence analyses indicated that there were a few outliers for percent change in total ( 22 ) , hdl ( 22 ) , and ldl ( 29 ) cholesterol ( see online appendix tables a1 and a2 , available at http://care.diabetesjournals.org/cgi/content/full/dc08-1716/dc1 ) . when these trials were omitted from the analyses , percent change in total cholesterol , hdl cholesterol , and ldl cholesterol significantly changed from 0.0% ( 95% ci 2.1 to 2.0 ) to 1.6% ( 4.5 to 1.3 ; p = 0.03 ) , from 10.4% ( 12.2 to 8.6 ) to 5.6% ( 2.9 to 8.4 ; p < 0.001 ) , and from 3.0% ( 6.3 to 0.4 ) to 0.1% ( 4.1 to 3.8 ; p = 0.001 ) , respectively . these outlying trials comprised a large part of study heterogeneity in percent change in total , hdl , and ldl cholesterol ( 22.2 , 59.1 , and 53.0% , respectively . ) therefore , they were excluded from the following analyses for the outcome that they affected . after omission of these outliers , there was no evidence of significant study heterogeneity ( p > 0.4 for all outcomes ) . ecological analyses showed trends indicating that the wmd in fpg was positively associated with that in fasting insulin ( r = 0.45 ; p = 0.04 ) and triglycerides ( r = 0.59 ; p = 0.004 ) and that the wmd in fasting insulin and triglycerides was mutually associated ( r = 0.43 ; p = 0.04 ) . these associations remained significant after adjustment for whether a weight - loss diet was prescribed ( fpg vs. fasting insulin , r = 0.58 and p = 0.004 ; fpg vs. triglycerides , r = 0.44 and p = 0.04 ; and fasting insulin vs. triglycerides , r = 0.44 and p = 0.04 ) . table 2 also shows data on publication bias and its likely effect on estimates of outcome according to the trim - and - fill method ( 12 ) . there was a relatively strong suspicion of publication bias for hdl cholesterol ( egger 's test , p = 0.08 for hdl cholesterol ; recommended level of significance , p 0.10 [ ( 32 ) ] ) . according to results of the compensatory trim - and - fill method , the effect of publication bias would slightly underestimate the adverse effect of the lfhc diet . results of our stratified analysis to detect characteristics of studies and patients included in our analyses that might have modulated study outcomes are shown in table 3 . of the 17 studies with a crossover design , 9 with 10 trials ( 1416,21,2326,29 ) did not include a washout period , which could lead to an underestimation due to a carryover effect ( 33 ) . however , the effect of these nine studies on results was not significant for any of the measures . stratified analysis to examine the effects of characteristics of studies and patients on each metabolic profile * studies having neither a washout period nor baseline data . parallel study design or cross - sectional design studies that have a washout period and/or baseline data . the elevation in fasting insulin was remarkable ( 17.1% ; p = 0.001 ) in lfhc diets with a c / f ratio 3 ( in this case , an lfhc diet with 60% carbohydrate and 20% fat of total energy ) while the c / f ratio in the lfhc diet did not influence triglycerides . there was a greater elevation in triglycerides ( 21.0% ; p<0.001 ) with the lfhc diet when the lfhc diet and mufa diet were compared ; i.e. , mufa was replaced with carbohydrate . however , the magnitude of the elevation in fasting insulin did not differ between the mufa diet and non - mufa diet ( i.e. , regardless of dietary fat quality ) . whereas a larger elevation in triglycerides was observed in trials limited to weight - maintenance diets , the lfhc diet did not significantly elevate triglycerides compared with the hflc diet when only trials with weight - loss diets were examined ( i.e. , diets for weight loss ) ( p = 0.48 ) . the elevation in fasting insulin was greater in younger and leaner patients in response to the lfhc diet compared with that in response to the hflc diet . moreover , mean age and bmi were independent predictors of percent change in fasting insulin . multiple regression analysis indicated that every 1 kg / m of bmi and 1 year of age were independently associated with a greater elevation in fasting insulin by 2.6% ( p = 0.002 ) and 1.7% ( p = 0.005 ) , respectively . for patients not taking antihyperglycemic drugs , however , because only a few studies included patients not receiving antihyperglycemic drugs , the results should perhaps be interpreted with caution . of 2,203 potentially relevant publications based on search terms and 22 references obtained from manual searches , 19 ( 1331 ) met the inclusion criteria . four articles ( 19,20,24,31 ) included two trials in one study , and two articles ( 27,28 ) used the same cohort . studies included in the current analysis had intervention periods ranging from 10 days to 6 weeks and patient numbers ranging from 8 to 42 . means between - study sds for the mean study characteristics from 22 trials were as follows : age 55 5 years , percent men 63 23 , bmi 28 3 kg / m , percent using hypoglycemia agents 52 31 , and diabetes duration 6 1 years . ten studies ( 15,1821,2326,31 ) described the number of dropouts , and nine ( 13,14,16,17,22,2730 ) did not . none of the 19 articles described methods of randomization , which led to a low quality score for the trial . a crossover design was used in 17 studies ( 1318,20,21,2331 ) ( with 19 trials ) , whereas a parallel design was used in two studies ( 19,22 ) with three trials . median carbohydrate / fat proportion of total energy ( c / f ratio ) in the lfhc and hflc diets was 58%/24% ( 2.4 ) and 40%/40% ( 1.0 ) , respectively . three studies ( 19,22,26 ) with 4 trials prescribed a weight - loss diet , and 11 studies ( 13,14,1719,21,2325,27,28 ) with 11 trials provided a mufa diet to the hflc - diet group . there were no significant differences in the reduction in a1c , total cholesterol , and ldl cholesterol between the lfhc and hflc diets . however , the lfhc diet produced significant increases in fasting insulin and triglycerides levels of 8.4% ( p = 0.02 ) and 13.4% ( p < 0.001 ) , respectively , and a significant reduction in hdl cholesterol compared with that associated with the hflc diet . two - h glucose and insulin values were higher in the lfhc - diet group than in the hflc - diet group by 10.3% ( p < 0.001 ) and 12.8% ( p < 0.001 ) , respectively . overall percent changes resulting from lfhc versus hflc diet on metabolic profiles and data on publication bias and their likely effect on the estimates * studies ( n ) added by the trim - and - fill method . percent change after adjustment for publication bias by the trim - and - fill method . begg 's , begg 's adjusted rank correlation test ; egger 's , egger 's regression asymmetry test . influence analyses indicated that there were a few outliers for percent change in total ( 22 ) , hdl ( 22 ) , and ldl ( 29 ) cholesterol ( see online appendix tables a1 and a2 , available at http://care.diabetesjournals.org/cgi/content/full/dc08-1716/dc1 ) . when these trials were omitted from the analyses , percent change in total cholesterol , hdl cholesterol , and ldl cholesterol significantly changed from 0.0% ( 95% ci 2.1 to 2.0 ) to 1.6% ( 4.5 to 1.3 ; p = 0.03 ) , from 10.4% ( 12.2 to 8.6 ) to 5.6% ( 2.9 to 8.4 ; p < 0.001 ) , and from 3.0% ( 6.3 to 0.4 ) to 0.1% ( 4.1 to 3.8 ; p = 0.001 ) , respectively . these outlying trials comprised a large part of study heterogeneity in percent change in total , hdl , and ldl cholesterol ( 22.2 , 59.1 , and 53.0% , respectively . ) therefore , they were excluded from the following analyses for the outcome that they affected . after omission of these outliers , there was no evidence of significant study heterogeneity ( p > 0.4 for all outcomes ) . ecological analyses showed trends indicating that the wmd in fpg was positively associated with that in fasting insulin ( r = 0.45 ; p = 0.04 ) and triglycerides ( r = 0.59 ; p = 0.004 ) and that the wmd in fasting insulin and triglycerides was mutually associated ( r = 0.43 ; p = 0.04 ) . these associations remained significant after adjustment for whether a weight - loss diet was prescribed ( fpg vs. fasting insulin , r = 0.58 and p = 0.004 ; fpg vs. triglycerides , r = 0.44 and p = 0.04 ; and fasting insulin vs. triglycerides , r = 0.44 and p = 0.04 ) . table 2 also shows data on publication bias and its likely effect on estimates of outcome according to the trim - and - fill method ( 12 ) . there was a relatively strong suspicion of publication bias for hdl cholesterol ( egger 's test , p = 0.08 for hdl cholesterol ; recommended level of significance , p 0.10 [ ( 32 ) ] ) . according to results of the compensatory trim - and - fill method , the effect of publication bias would slightly underestimate the adverse effect of the lfhc diet . results of our stratified analysis to detect characteristics of studies and patients included in our analyses that might have modulated study outcomes are shown in table 3 . of the 17 studies with a crossover design , 9 with 10 trials ( 1416,21,2326,29 ) did not include a washout period , which could lead to an underestimation due to a carryover effect ( 33 ) . moreover , none of these studies had baseline data . however , the effect of these nine studies on results was not significant for any of the measures . stratified analysis to examine the effects of characteristics of studies and patients on each metabolic profile * studies having neither a washout period nor baseline data . parallel study design or cross - sectional design studies that have a washout period and/or baseline data . p < 0.05 . the elevation in fasting insulin was remarkable ( 17.1% ; p = 0.001 ) in lfhc diets with a c / f ratio 3 ( in this case , an lfhc diet with 60% carbohydrate and 20% fat of total energy ) while the c / f ratio in the lfhc diet did not influence triglycerides . there was a greater elevation in triglycerides ( 21.0% ; p<0.001 ) with the lfhc diet when the lfhc diet and mufa diet were compared ; i.e. , mufa was replaced with carbohydrate . however , the magnitude of the elevation in fasting insulin did not differ between the mufa diet and non - mufa diet ( i.e. , regardless of dietary fat quality ) . whereas a larger elevation in triglycerides was observed in trials limited to weight - maintenance diets , the lfhc diet did not significantly elevate triglycerides compared with the hflc diet when only trials with weight - loss diets were examined ( i.e. , diets for weight loss ) ( p = 0.48 ) . the elevation in fasting insulin was greater in younger and leaner patients in response to the lfhc diet compared with that in response to the hflc diet . moreover , mean age and bmi were independent predictors of percent change in fasting insulin . multiple regression analysis indicated that every 1 kg / m of bmi and 1 year of age were independently associated with a greater elevation in fasting insulin by 2.6% ( p = 0.002 ) and 1.7% ( p = 0.005 ) , respectively . for patients not taking antihyperglycemic drugs , the lfhc diet could be more harmful for fasting insulin than the hflc diet . however , because only a few studies included patients not receiving antihyperglycemic drugs , the results should perhaps be interpreted with caution . although central to mnt , the influences of various dietary c / f ratios on glycemic control and lipid profiles in patients with type 2 diabetes have not been systematically reviewed . our meta - analysis is the first to quantify the effect of the lfhc diet compared with that of the hflc diet on each metabolic outcome . our results fundamentally support current dietary guidelines ( 1 ) stating that replacing fat with carbohydrate significantly elevates postprandial glucose and insulin levels when total energy intake is consistent . we additionally found that the lfhc diet significantly elevated fasting insulin compared with the hflc diet , with marked elevations noted when the c / f ratio was 3 . moreover , there were significantly positive relationships among the change in fpg and the magnitude of the elevation in fasting insulin and triglycerides , independent of energy restriction for weight control . postprandial hyperglycemia with postprandial hyperinsulinemia and failure to maintain glucose homeostasis are often clustered in insulin - resistant individuals , who are representative of those with type 2 diabetes ( 34 ) . this suggests that an lfhc diet is unfavorable compared with an hflc diet for insulin - resistant patients , at least when energy intake is consistent . however , our findings do not support the benefit of an extremely high - fat diet because the carbohydrate proportion in the hflc diets included in our analyses was 50% . moreover , we can not comment on the possible benefit of a high - carbohydrate diet with a high - fiber component because we excluded studies investigating the effect of such a diet . moreover , there is concern that increased fat intake ad libitum may promote weight gain ( 35 ) . it is worth repeating that total caloric intake and nutritional content must be appropriate for metabolic control regardless of macronutrient proportions ( 1 ) . changes in fpg and a1c did not differ between the two diets despite significant elevations in 2-h and fasting insulin with the lfhc diet . one possible explanation is that the elevation in postprandial glucose level was overcompensated for by increased insulin secretion . however , only three studies concurrently assessed a1c , fasting insulin , and fpg values , with an intervention period of , at most , 6 weeks . therefore , we could not conclude whether the elevation in postprandial glucose and insulin level achieved by raising the dietary c / f ratio leads to the deterioration of glycemic control represented by elevations in fpg and a1c . a previous meta - analysis suggested that replacing carbohydrate with mufa reduced fasting triglycerides in patients with type 2 diabetes on weight - maintenance diets ( 36 ) ; this was supported by our results . however , it is uncertain whether the effect on triglycerides was caused by the c / f ratio or the ratio of energy from mufa to total energy . moreover , whether the effect of this replacement was independent of that of a weight - loss diet has not been investigated . according to our stratified analyses , no dose - response relationship between the c / f ratio in the lfhc diet and the elevation in triglycerides was indicated , although replacement of the mufa diet with the lfhc diet induced a greater elevation in triglycerides . moreover , the lfhc diet did not significantly elevate triglycerides compared with the hflc diet when a weight - loss diet was prescribed . therefore , controlling total caloric intake and the quality of dietary fat appear to be more important than carbohydrate and fat composition in improving triglycerides levels . in other words , these findings suggest that a high - carbohydrate diet has little harmful effect on triglycerides levels if such a diet provides sufficient energy restriction for weight control . first , although we omitted studies investigating the effect of high - carbohydrate diets that were also high in dietary fiber , it is possible that the additional phytochemicals ( including fiber itself ) , which are inevitably accompanied by a substantial amount of carbohydrate , influence the metabolic effects regardless of the change in c / f ratio . second , we assumed that energy intake from the two diet groups would be similar if a weight - maintenance diet was equal to an isocaloric diet based on evidence of the meta - analysis by bravata et al . ( 37 ) that indicated that weight change was associated with restriction of caloric intake but not reduced carbohydrate content . however , some recent studies showed that low - carbohydrate diets resulted in greater weight loss than low - fat diets despite their similar energy content ( 38 ) , as is often the case with high - fiber diets ( e.g. , whole grains ) ( 39 ) . more investigation is needed to determine whether the relationship between change in energy intake and body weight is independent of the proportions of dietary carbohydrate and fat . third , few studies investigated long - term effects ( e.g. , > 2 months ) of changing the proportions of carbohydrate and fat on metabolic profiles in patients with type 2 diabetes . actually , a larger elevation in fasting insulin in association with the lfhc diet was observed for an intervention period of < 4 weeks compared with 4 weeks but without statistical significance ( p = 0.10 ) . possibly , a prolonged intervention involving changes in macronutrient composition causes some adaptation of insulin metabolism . fourth , most studies provided insufficient data about baseline glucose and lipid levels , and few focused on black or asian patients . therefore , the current meta - analysis provides limited suggestions on identifying patients for whom a low - fat or low - carbohydrate diet is especially effective in terms of their circumstances or metabolic profiles ( 1 ) . future studies focused on the following are suggested : 1 ) providing a possible explanation for the greater adverse effect on the fasting insulin by the lfhc diet than by the hflc diet , especially in younger and leaner individuals ; 2 ) identifying the long - term effect of a low - carbohydrate diet on factors other than metabolic effects ( e.g. , adaptation in glucose and lipid metabolism , ad libitum energy intake in patients with type 2 diabetes or obesity [ ( 40 ) ] ) and the safety of such a diet ( e.g. , with regard to the digestive system ) ; and 3 ) addressing whether a subject 's medication status and the characteristics of diabetes drugs could influence the effect of changing the dietary c / f ratio in patients with type 2 diabetes . in conclusion , replacement of dietary fat with carbohydrate is not recommended for improvement of insulin resistance in patients with type 2 diabetes under conditions whereby total energy and protein intake and the content of carbohydrate are similar and the proportion of carbohydrate to total energy is 30% . we found that younger and leaner patients had higher fasting insulin responses with the lfhc diet , although the biological mechanism was not fully investigated . the lfhc diet also adversely affects triglycerides and hdl cholesterol compared with the hflc diet . however , energy restriction and dietary fat quality seemed more important for lowering the triglyceride concentration than the proportion of carbohydrate and fat . OUTPUT:

objectivethe effects of dietary macronutrient composition on metabolic profiles in patients with type 2 diabetes have been inconsistent . this meta - analysis aimed to elucidate the effect of replacing dietary fat with carbohydrate on glucose and lipid parameters in patients with type 2 diabetes.research design and methodswe searched for randomized trials that investigated the effects of two kinds of prescribed diets ( a low - fat , high - carbohydrate [ lfhc ] diet and a high - fat , low - carbohydrate [ hflc ] diet ) ; in these studies , energy and protein intake did not differ significantly between the two dietary groups . nineteen studies that included 306 patients met our inclusion criteria . median diet composition of carbohydrate / fat in the lfhc and hflc diets was 58%/24% and 40%/40% , respectively.resultschanges in values for a1c , fasting plasma glucose ( fpg ) , and total and ldl cholesterol did not differ significantly between the lfhc and hflc groups . however , the lfhc diet significantly increased fasting insulin and triglycerides by 8% ( p = 0.02 ) and 13% ( p < 0.001 ) , respectively , and lowered hdl cholesterol by 6% ( p < 0.001 ) compared with the hflc diet . there were positive associations among the magnitude of changes in fpg , fasting insulin , and triglycerides for the diets analyzed . however , stratified analysis indicated that the increase in triglycerides was insignificant when accompanied by energy intake restriction.conclusionsour findings suggested that replacing fat with carbohydrate could deteriorate insulin resistance while the adverse effect on triglycerides from the lfhc diet could be avoided by restricting energy intake to a degree sufficient for the attainment of weight reduction .

PubMed_Summ6533

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: mindfulness refers to an awareness that emerges by paying attention to purpose and to the present moment and nonjudgmentally focusing on the unfolding of one 's immediate experience . more recently , mindfulness has been proposed as a cognitive behavior , rather than physiological , paradigm for meditation . mindfulness aims to develop enhanced awareness of the moment - to - moment experience of perceptible mental processes and forms an important component of meditation practices . initially , a meditator engages in focused concentration or attention over an object and as one grows in his practice , he leans towards the attentional disengagement or open monitoring . meditation imbibes an initial phase of mindfulness , making mindfulness a key determinant of meditation practice . during the last decade , several studies have been conducted across the globe to report the development of mindfulness and its effects on health and well - being . one such study conducted on a martial art technique aikido using a mindfulness attention awareness scale ( maas ) concluded that consistent practice of aikido leads to development of mindfulness . another study on insomnia in menopausal women reported that postmenopausal women with insomnia are less mindful than women without insomnia , thereby concluding that mindfulness - based interventions , such as meditation , may be beneficial for postmenopausal insomnia . a study assessing the health risk behavior in adolescents concluded that mindfulness possibly shields against decision - making processes that place adolescents at risk for smoking . there are several others studies looking at the effects of mindfulness on neurological and psychiatric diseases and also assessing the levels of mindfulness in normal and diseased individuals . one of the studies reviewing the instruments of measuring mindfulness concluded that the maas was used by most studies ( n = 27 ) and had positive overall quality ratings for most of the psychometric properties reviewed . given the fact that past studies have looked at the levels of mindfulness in various practices , health and disease conditions , we planned the current study to asses the levels of mindfulness in a moving meditation practice . one of the various forms of mindfulness is the practice of a unique technique called cyclic mediation ( cm ) . it was fundamentally designed for novice practitioners and combines the practice of yoga postures with guided meditation . cm is known to induce a quiet state of mind , which is compatible with the description of meditation ( dhyana or effortless expansion ) , according to patanjali . although this moving meditation differs from the classic description of meditation , in which the practitioners remain seated , keeping as still as possible , the mental state in both practices ( moving meditation and seated practices ) is supposed to be comparable . an essential part of the practice of cm is being aware of sensations arising in the body , which emphasize the mindful component . there have been several studies which have proven the beneficial effects of cm . in one of the studies conducted on middle managers , cm program decreased occupational stress levels and baseline autonomic arousal in 26 asymptomatic , studies conducted to ascertain the effects of cm practice reported a decreased oxygen consumption indicating physiological relaxation as in mindfulness . few studies looking at the immediate effects of cm concluded that it improves attention , cognition , enhances slow wave sleep , and reduces anxiety . mindful yoga practices ( like cm ) may generate the state of mindfulness , which , when evoked recurrently through repeated practice , may accrue into trait or dispositional mindfulness . despite several studies on cm , none have reported its mindful component . the current study aimed at investigating the level of mindfulness in experienced cyclic meditators . we also report the correlation between the years of meditation experience and the level of mindfulness . one hundred and thirty - three ( n = 133 ) healthy male volunteers ( 66 meditators and 67 non - meditators ) with ages ranging from 25 to 35 years [ group mean age standard deviation ( s.d . ) , 24.6 4.5 for meditators and 24.1 4.7 for non - meditators ] participated in the study . meditators were selected from s - vyasa yoga university , south india and corresponding non - meditators ( controls ) matched for age , gender , and education were obtained from similar institutes in bangalore , india . meditators had a minimum 3 years experience of meditation ( group mean experience s.d . , 5.12 1.35 years ) . non - meditators had no exposure to any yoga practices and were unaware of the aims of the study . subjects with cognitive deficits ruled out by routine clinical examination were excluded from the study . this study was approved by the institutional ethics committee and a signed informed consent was obtained from all the subjects following explanation of the study . the questionnaire was administered in a classroom setup ( for approximately 30 min ) and two of the project coordinators were present to supervise the administration and to assist the participants where necessary . all the participants filled out the questionnaire , but for whom more than 10% of the items were missing or whose reports were considered unreliable ( i.e. , consistently rated the highest or the lowest scores on all items ) , were excluded from the analyses ( n = 06 ; 4% ) . the subjects participating in this study had higher educational qualifications with almost 90% of the participants being postgraduates . this was a cross - sectional study , where subjects ( meditators ) were recruited from s - vyasa yoga university and other universities ( non - meditators ) by convenience sampling . maas is a 15-item self - reported single - factor scale that is exclusively focused on attention / awareness component of mindfulness construct . this instrument has been independently used to assess individuals either with or without meditation experience . this scale has been widely used for various studies and has reported positive overall quality ratings for most of the psychometric properties reviewed . maas is a brief , easy to administer scale , and has therefore been used in wide range of studies related to assessing mindfulness trait . maas is known to have good reliability ratings and a history of clinical and research use that was developed to assess the core attentional aspect of mindfulness , and the capacity for moment - to - moment attention in particular . the maas consists of 15 items that measure the level of mindfulness ( example items are i could be experiencing some emotion and not be conscious of it until some time later , or i find it difficult to stay focused on what 's happening in the present ) . the items are answered on a six - point scale ( 1 = almost always ; 6 = almost never ) on which higher scores are an indication of higher trait mindfulness . the maas has been validated in various samples of students ( = 0.82 ) and adults from the general community ( = 0.87 ) . the questionnaire was scored by computing a mean of the 15 items in the questionnaire . the data were checked for normality and an independent samples t - test was employed to compare the means of both the groups . we also calculated the partial correlation ( r ) between the years of meditation experience against the levels of mindfulness . for all the analysis , we present 95% confidence intervals and considered p < 0.05 as significant . this was a cross - sectional study , where subjects ( meditators ) were recruited from s - vyasa yoga university and other universities ( non - meditators ) by convenience sampling . maas is a 15-item self - reported single - factor scale that is exclusively focused on attention / awareness component of mindfulness construct . this instrument has been independently used to assess individuals either with or without meditation experience . this scale has been widely used for various studies and has reported positive overall quality ratings for most of the psychometric properties reviewed . maas is a brief , easy to administer scale , and has therefore been used in wide range of studies related to assessing mindfulness trait . maas is known to have good reliability ratings and a history of clinical and research use that was developed to assess the core attentional aspect of mindfulness , and the capacity for moment - to - moment attention in particular . the maas consists of 15 items that measure the level of mindfulness ( example items are i could be experiencing some emotion and not be conscious of it until some time later , or i find it difficult to stay focused on what 's happening in the present ) . the items are answered on a six - point scale ( 1 = almost always ; 6 = almost never ) on which higher scores are an indication of higher trait mindfulness . the maas has been validated in various samples of students ( = 0.82 ) and adults from the general community ( = 0.87 ) . the questionnaire was scored by computing a mean of the 15 items in the questionnaire . the data were checked for normality and an independent samples t - test was employed to compare the means of both the groups . we also calculated the partial correlation ( r ) between the years of meditation experience against the levels of mindfulness . for all the analysis , we present 95% confidence intervals and considered p < 0.05 as significant . maas scores were significantly higher in meditators as compared to with the non - meditators ( independent samples t - test , t = 10.391 , p < 0.001 ) . the 95% confidence interval for the difference in the levels of mindfulness trait between meditators and non - meditators was ( 1.05 , 1.55 ) . we found a positive correlation ( r = 0.620 ) between the years of meditation practice and the levels of trait mindfulness . mean total scores of meditators and non - meditators on the mindfulness attention awareness scale . in the present study , we studied trait mindfulness and its correlation with duration of meditation practice using a maas . we found that meditators had higher levels of trait mindfulness and were positively correlated with the duration of meditation practice . while there are known differences between buddhist views of mindfulness and modern psychological adaptations , there is broad agreement that a clearly formulated mental training , usually referred to as meditation , the practice of cm involves physical postures ( asanas ) , breath work , physical and mental awareness together leading to a state of meditation . according to patanjali , development of meditation ( dhayana ) is a process and takes a series of practices , which together are called ashtanga yoga the eightfold path to reach the highest state of consciousness . one reaches the state of mindfulness or meditation or antaranga yoga as a result of continued and consistent practice of the first six limbs of yoga . our results are very much in accordance with patanajali 's concept of the process of development of mindfulness and meditation . another school of yoga , hatha yoga comprises practices of postures , breath work , and cleansing practices , all aimed at striking a balance between the body and the mind . consistent practice of these hatha yoga techniques transforms the practitioner and establishes him in the state of mindfulness and meditation . the meditation technique practiced in the current study comprises all these components , which justifies the higher levels of mindfulness in the meditation group . also , higher levels of trait mindfulness in cm practitioner can be accredited to the years of cm practice , which would have lead to the development of mindful trait in the meditators as signified by the positive correlation between level of mindfulness and the duration of meditation practice . the findings of the present study are in line with earlier studies on trait mindfulness in meditators . highly experienced zen meditators showed similar trends where levels of mindfulness were found to have strong positive correlation to the years of meditation experience . the results of this study indicate that maas is sensitive to individual differences in levels of mindfulness and suggest that the higher scores among those consciously practicing this skill are due to such training . an 8-week mindfulness - based stress reduction ( mbsr ) program showed increase in the trait mindfulness of the participants , which mediate the effects of training on clinical outcomes . in a similar study , 8 weeks of yoga training resulted in significant increases in trait mindfulness of practitioners . another study with cancer patients undergoing 8-weeks of mbsr , showed improved levels of mindfulness and lowered mood disturbances and symptoms of stress . a similar study like ours , comparing two different meditation techniques concluded that meditation improves the levels of mindfulness regardless of the meditation technique . studies explaining the underlying mechanisms of development of mindfulness have been its stage of infancy . however , if mindfulness is considered to be a component of self - awareness and meditation , one of the studies reports the role of frontal control systems in neuroanatomical models of self - awareness . several neuroimaging and electroencephalograpy ( eeg)/event related potentials ( erp ) studies have shown changes in activation of prefrontal cortex ( pfc ) and the anterior cingulate cortex ( acc ) , as well as significant increases in alpha and theta activity during meditation there is substantial evidence of changes in pfc during mindfulness meditation , which is known to be associated with attention , concentration , and emotion regulation . in another study , individuals with higher levels of mindfulness demonstrated less emotional reactivity in the midbrain ( amygdala , dorsal acc ) , which is likely due to an enhanced ability to engage the pfc . functional magnetic resonance imaging studies comparing experienced mindfulness meditators and novice controls have suggested increased neuronal activity in regions of the brain related to self - awareness ( e.g. , dorsolateral and medial pfc ) , particularly momentary self - awareness / self - reference . majority of the studies on mindfulness meditation and other mindfulness training programs have demonstrated significant changes in the pfc . these findings show promise for the individual 's ability to train the mind , changing not only emotional experiences , but also brain structure and functioning ; moreover , the ability to do so appears to improve over time as experience with meditation increases . one of the limitations of our study is that the meditators participating in this study lived in a yoga institute and practiced other yoga techniques . therefore , we are not sure if the development of higher levels of mindfulness is due to the meditation practice or an influence of other yoga practices . further studies should be conducted on subjects practicing only cm and not adhering to any other yoga practices . another limitation could be the small sample size . given the huge number of yoga practitioners in today 's date , studies with larger sample sizes are warranted . consistent practice of moving meditation practices like cm can lead to development of higher levels of mindfulness . this may positively impact mental states and attention , which can in turn help psychological well - being of individuals . this furthers the scope for clinical trials with cm as an intervention in the management of psychological disorders . OUTPUT:

context : mindfulness forms an important component of meditation practice and has been increasingly popular around the world . there has been growing interest in studying the mindful component of various meditation techniques . one of the various forms of mindfulness is the practice of a unique technique called cyclic mediation ( cm ) . we aimed at ascertaining the level of mindfulness in experienced practitioners of cm using a mindfulness attention awareness scale ( maas).materials and methods : maas was administered anonymously in a classroom setup and two of the project coordinators were present to supervise the administration and to assist the participants where necessary . we executed a cross sectional design . one hundred and thirty - three ( n = 133 ) healthy male volunteers ( 66 meditators and 67 non - meditators ) with ages ranging from 25 to 35 years participated in the study . meditators had a minimum 3 years experience of meditation.results:data were analyzed using ibm spss 20 . the data were checked for normality and an independent samples t - test was employed to compare the means of both the groups . maas scores were significantly higher in meditators as compared with the non - meditators ( p < 0.001 ) . we found a positive correlation ( r = 0.620 ) between the years of meditation practice and the levels of trait mindfulness.conclusions:cm can lead to development of higher levels of mindfulness and may have the ability to positively impact mental states and attention , thereby offering the potential for prevention of clinical levels of psychopathology and improving overall psychological well - being in healthy individuals .

PubMed_Summ6534

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the head and neck posture of an individual can influence soft - tissue relationships in the cervical and shoulder region1 , 2 . a common concern in the modern workplace is upper extremity disorders arising from overhead work , which is associated with neck and shoulder disorders and pain3 . long - term overhead working postures result in strain and fatigue of the shoulder muscles because arm elevation is associated with shoulder muscle fatigue4 , 5 . previous studies have focused on risk factor analysis and the development of therapeutic exercises for overhead work - related disorders rather than prevention6 , 7 . some studies have been performed on postural ergonomic interventions including working techniques for overhead work6 , 7 . however , we found that few studies have focused on protective ergonomic devices for overhead workers . therefore , this study investigated a new neck support tying ( nst ) method that used a thera - band for the prevention of neck and shoulder pain in workers performing overhead work . the new nst method supports the neck during hyperextension and prevents excessive upward rotation of the scapula during overhead work . the purpose of the present study was to investigate the effect of this nst method on cervical rom and shoulder pain after overhead work . the subjects were divided into two groups as follows : a control group consisting of 7 males without nst , and a nst group consisting of 7 males with nst . the initial cervical rom and initial ppts of the ut and mt were not significantly different between the two groups . the initial values of cervical flexion , extension , and right and left lateral flexion in the control group were 63.44.2 , 72.86.0 , 53.92.9 , and 51.35.6 degrees , respectively . the initial values for cervical flexion , extension , and right and left lateral flexion in the nst group were 62.35.1 , 72.53.9 , 53.33.0 , and 52.22.4 degrees , respectively . all participants gave their informed , written consent according to the protocol approved by the human ethics committee of the yonsei university faculty of health science . this study examined a new nst method that uses a thera - band for the prevention of neck and shoulder pain in workers performing overhead work . for the nst method , we used the grey thera - band ( 60 cm length ) which was applied as follows . the midpoint of the thera - band supported the posterior aspect of the neck , and both ends of the thera - band were passed under both axillae , and tied behind the back . the nst provided support for neck hyperextension and prevented excessive upward scapular rotation during overhead work . cervical flexion , extension , and right and left lateral flexion were measured with a cervical range of motion ( crom ) instrument ( performance attainment associates , st . a dolorimeter pressure algometer ( fabrication enterprises , white plains , ny , usa ) was used to measure the pressure pain threshold ( ppt ) of the right side upper trapezius ( ut ) and the lower trapezius ( lt ) muscles . a 1-cm rubber plate delivers pressure from the probe to the body , and the pressure is read from a needle gauge . all subjects performed one trial of overhead work with their arms over their heads for 15 min . the overhead work was performed at a height of 25 cm above each subject 's head . differences in cervical rom and ppt between the nst and control groups after the overhead work were tested with the independent t - test using the spss statistical package ( version 18.0 ; spss , chicago , il , usa ) . the cervical flexion , extension , and lateral flexion angles of the nst group were significantly larger than those of the control group ( p < 0.05 ) . the cervical flexion , extension , and right and left lateral flexion of control group were 50.48.2 , 64.711.3 , 41.77.9 , 43.29.2 degrees , respectively . the cervical flexion , extension , and right and left lateral flexion of nst group were 61.511.2 , 69.46.9 , 48.75.6 , 49.86.7 degrees , respectively . the ppt of ut of the nst group ( 7.21.8 lb ) was significantly higher than those of the control group ( 6.32.0 lb ) ( p < 0.05 ) . the ppt of mt of the nst group ( 5.81.4 lb ) was significantly higher than those of the control group ( 5.01.2 lb ) ( p < 0.05 ) . repeated and sustained working with elevated arms is known to lead to neck and shoulder pain8 . this study proposed a new neck support tying method using thera - band and investigated its effect on cervical rom and shoulder pain after overhead work . reductions in rom have implications for the safety and efficiency of functional activities , and lead to a loss of corrective or protective reactions1 , 9 . rom losses can occur from inactivity and structural changes of the tissues in the cervical spine , and result in an increase in connective - tissue density , shortening of collagen tissue , and muscle fibrosis1 , 9 . in this study , the cervical flexion , extension , and lateral flexion angles of the nst group shoulder forward flexion with scapular upward rotation requires the activation of the upper trapezius , and overstretches the middle trapezius through scapular protraction3 , 5 , 7 . the ppts of the ut and mt were significantly lower in the nst group than those of the control group . these results indicate that the nst supported the neck and prevented excessive scapular elevation and upward rotation during overhead work . the thera - band , which provides varied resistance through the range of movement , has been used for rehabilitation in combination with therapeutic exercise10 . it is light and portable , has low resistance , and can be adjusted to accommodate various situations11 . the nst method prevented rom reduction and pain in the cervical and shoulder regions . the nst method can be easily and simply applied using a thera - band and is also inexpensive . we suggest that industrial workers could use the nst method when performing overhead work . OUTPUT:

[ purpose ] this study proposed a new neck support tying ( nst ) method using thera - band for the prevention of neck and shoulder pain in workers doing overhead work . the purpose of this study was to investigate the effect of the new nst method using thera - band on cervical rom and shoulder pain after overhead work . [ subjects ] fourteen male subjects were recruited . [ methods ] this study measured the cervical rom and pressure pain threshold ( ppt ) of the upper and middle trapezius ( ut and mt ) muscles after the control and nst groups had performed overhead work . [ results ] the cervical flexion , extension , and lateral flexion angles of the nst group were significantly larger than those of the control group . the ppts of ut and mt of the nst group were significantly higher than those of the control group [ conclusion ] the nst prevented rom reduction and pain in the cervical and shoulder regions .

PubMed_Summ6535

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: rates of diabetes mellitus are rising dramatically across the globe , threatening both individual health as well as the stability of national health systems . in the united states , diabetes is the leading cause of adult blindness , kidney failure , and non - traumatic amputations while also playing a central role in the development of cardiovascular disease , the leading killer of those with the disease . with estimates that diabetes currently affects nearly 24 million people in the us and that this number will rise to over 44 million individuals by 2034 , the staggering $ 245 billion spent annually on diabetes - related healthcare costs is sure to rise dramatically . while these costs are unsustainable in the us where the healthcare infrastructure is robust and relatively well - funded , the burden of diabetes in the developing world may be catastrophic . current projections estimate that 592 million individuals worldwide will have diabetes by 2035 , with 77% of those individuals living in middle- or low - income countries with significantly less developed health systems . to prevent this threat from overwhelming health budgets across the globe , identification and elimination of the factors promoting the last decade has witnessed a proliferation of exciting epidemiological and basic science data suggesting that environmental contaminants play a pathogenic role in the development of metabolic disease ( reviewed in refs . ) . indeed , while initially implicated in perturbations of sex steroid and thyroid hormone signaling , environmental endocrine disrupting chemicals ( edcs ) have now been shown to be associated with or to directly alter body weight and glucose homeostasis after either adult or developmental exposure ( reviewed in refs . ) . such metabolic disruptors include a diverse array of compounds such as bisphenol a , persistent organic pollutants ( pops ) , phthalates , antifouling agents , and pesticides . our own recent work has added to this list a novel class of metabolism - perturbing agents , namely phenylsulfamide fungicides , as exemplified by tolylfluanid ( tf ) . in this work , we ve shown that dietary exposure to tf has the capacity to promote weight gain and increase adiposity despite not altering total food intake ; rather , these changes appear to occur through altered circadian rhythms of food intake . moreover , adult mice exposed to tf exhibited glucose intolerance as well as systemic and adipose - specific insulin resistance , phenotypic features commonly seen in the pathogenesis of type 2 diabetes . this new evidence provides further support to the contention that environmental change may play a critical role in the emergence of chronic diseases ; however , many questions remain regarding the clinical scenarios in which edcs exert their deleterious metabolic effects . under most circumstances , homeostatic mechanisms maintain normal energy metabolism and resist the development of cardiometabolic disease ; however , several factors operating alone or in concert can lower this resistance to metabolic disease ( rmd ) and accelerate the progression of obesity , diabetes , hypertension , dyslipidemia , and cardiovascular disease ( fig . 1 ) . while accidental or intentional ingestions of a single chemical may be sufficient to cause diabetes in select circumstances ( e.g. the rodenticide vacor and the fungicide chlorothalonil ) , it is unlikely that a single chemical will be sufficient to explain the dramatic explosion in global diabetes rates . however , as there are tens of thousands of unique chemicals to which humans are potentially exposed , coordinate exposure to multiple edcs that additively antagonize critical pathways regulating energy metabolism through complimentary mechanisms may be sufficient to promote cardiometabolic dysfunction , whereas a single signaling disruptor in isolation may be insufficient to drive significant disease . these edc edc interactions may be critical for generating metabolic phenotypes from the chronic , low - dose exposures that characterize human contact with environmental toxicants . unfortunately , the experimental complexities of analyzing mixtures of metabolic disruptors are immense ; however , some recent data demonstrate that such mixtures , at environmentally relevant doses , can disrupt energy handling , suggesting that further studies into common co - exposures are warranted . alternatively , the potency of a metabolic disruptor might be enhanced by permissive conditions in specific patients that may predispose those individuals to environmentally - mediated metabolic disease . such factors may include underlying genetics , diet , lifestyle , preexisting diseases , pharmacological treatments , and states of fat redistribution that alter the patient s baseline physiology in such a way as to increase their sensitivity to metabolic disruption . our recent work demonstrates that dietary exposure to tf increases adiposity , promotes glucose intolerance , and decreases insulin sensitivity both globally and at the level of the adipocyte . like many metabolic investigations while we had previously shown that ex vivo exposure to tf induced adipocytic insulin resistance in outbred cd1 mice , inbred c57bl/6 mice , 2 strains of rats , and even human adipose tissue , whether the observed effects on global energy homeostasis are influenced ( either positively or negatively ) by the background genetics of the animal model is not known . in the field of endocrine disruption , this may be particularly relevant as the c57bl/6 strain is known to harbor a polymorphism in the aryl hydrocarbon receptor gene , a molecular target for many putative edcs , including dioxins and dioxin - like polychlorinated biphenyls ( pcbs ) . intriguingly , since a predominant phenotype of exposure to metabolic disruptors is an increase in adiposity , whether mice with a genetic predilection to accrete adipose tissue exhibit divergent metabolic consequences of edc exposure may suggest that underlying genetics modulate the metabolic risk posed by edcs . importantly , because many edcs are hydrophobic , ascertaining whether sequestration in fat is potentially protective may shed new light on the mechanisms and metabolic consequences of adipose expansion under edc exposure . finally , animal models that are resistant to edc - induced metabolic disruption may provide novel insights into detoxification or resistance pathways that may be exploited pharmacologically to treat or prevent edc - induced obesity and diabetes . built upon and supporting the developmental origins of health and disease hypothesis ( dohad ) , recent evidence demonstrates that exposure to various edcs during critical developmental windows can promote metabolic dysfunction in adulthood . the mechanisms by which remote exposures to edcs disrupt energy homeostasis and how these effects can be inherited in a multigenerational or transgenerational manner are not fully understood . although epigenetic alterations are implicated , the molecular targets of these epigenetic modifications are imprecisely known . while genome - wide association studies have been generally disappointing with regard to identifying genetic polymorphisms that may explain type 2 diabetes , genes for which the data are strongest , e.g. , tcf7l2 , should be considered as potential epigenetic targets of edcs that induce metabolic disruption after developmental exposure . more intriguing may be genes implicated in the pathogenesis of neonatal diabetes and maturity onset diabetes of the young ( mody ) . mutations in genes implicated in these conditions are often inherited in an autosomal dominant fashion and elicit robust metabolic phenotypes , suggesting that edc - induced alterations in these genes or regions that regulate their expression may be sufficient to drive the onset of diabetes . intriguingly , the link between mody genes and type 2 diabetes in larger cohorts has recently been established . identifying such potential causes of developmentally - derived diabetes is particularly important since some patients with mody mutations who have historically been treated with insulin can be managed with oral agents ( e.g. , sulfonylureas ) , potentially resulting in both better control and reduced morbidity . determining whether edcs may promote metabolic dysfunction through these pathways is vital as it may provide vital insights into the best approaches to treat patients with environmentally - mediated diabetes . it is clear that the deteriorating quality of our diet plays an important role in promoting the development of obesity and diabetes ; moreover , the exportation of the american diet may be a significant contributor to the global plague of metabolic disease . despite the importance of diet in modulating energy handling , the impact of these global shifts in diet composition on edc action has only recently been interrogated . to date , the interactions between edcs and dietary stressors in the disruption of energy homeostasis has largely been interrogated in the context of high fat feeding . indeed , potentiation of metabolic disruption by a high fat diet has been demonstrated for bisphenol a , perfluorooctane sulfonate , pops , and chemical mixtures . interestingly , our metabolic cage analyses suggest that mice exposed to tf have a preference for fat over carbohydrate utilization during the fed state . this suggests that diets rich in carbohydrates , or the simple sugars enriched in a western diet , may be particularly deleterious in the context of exposure to tf and potentially other edcs . this may be significant as the transformation of the american diet over the last 30 years has been one of increased carbohydrate content , particularly the refined grains and simple sugars found in processed foods . as increased fructose intake has been implicated in the explosion in diabetes rates , understanding how edcs interact with secular trends in dietary carbohydrate content and composition will be important for contextualizing the importance of edcs in the current metabolic disease epidemic . furthermore , as the burden of diabetes spreads to low- and middle - income countries , understanding how edcs interact with specific dietary factors in these countries will be essential for estimating the risk posed by environmental toxicants as drivers of the metabolic disease epidemic in the developing world . an intriguing finding of our work on tf was that adiposity ( fat mass as a fraction of total body mass ) and weight gain were increased in the presence of this edc despite no change in total food intake . we were , however , able to discern an intriguing change in the circadian pattern of food intake , with tf - exposed mice consuming more food during the normally fasting light - phase . this evidence provides some of the first experimental support for edc - induced disruptions in energy homeostasis arising through perturbations in circadian rhythms . in humans , clinically , the timing of food intake has been shown to contribute to weight gain . moreover , individuals who consume more calories at night may have a harder time losing weight . second , do edcs augment the deleterious metabolic effects of disruptions in circadian patterns of food intake that are driven by lifestyle factors that are intentional ( e.g. , night eating ) or forced ( e.g. , shift work ) ? and finally , if alterations in circadian rhythms are wholly or partially responsible for edc - induced obesity and diabetes , will restriction of food intake to the normal feeding period be an appropriate treatment approach ? studies examining the lifestyle factors that exacerbate or antagonize the deleterious effects of edcs on energy homeostasis may provide vital insights into both the mechanisms of edc - induced metabolic dysfunction as well as potential avenues to treat toxicant - mediated metabolic disease . beyond influences of feeding behavior , understanding how edcs modulate central processes such as motivation may help explain difficulties patients have self - regulating food intake and sustaining exercise , as will studies of edc effects on skeletal muscle , which remains an understudied area of metabolic toxicity . some of the early evidence suggesting edcs have the capacity to alter energy metabolism came from studies examining their ability to promote adipocyte differentiation from preadipocytes or mesenchymal stem cells . in many of these studies the 3t3-l1 cell line is used as a model of adipogenesis , with preadipoctye - to - adipocyte differentiation classically induced by exposure to insulin , a glucocorticoid , and an agent to raise camp levels . the capacity of various edcs to amplify adipose development can be studied by triggering adipogenesis with this differentiation cocktail in the presence or absence of the edc of interest . by this approach , many environmental contaminants have been shown to promote adipocyte differentiation ( reviewed in ref . ) . as we have recently dissected for the prototypical obesogen tributyltin , most edcs appear to require one or more components of the differentiation cocktail to induce adipogenesis . as such , it is possible that clinical states that modulate those specific pathways could augment the adipogenic capacity of edcs . for example , hyperinsulinemic states , as observed in prediabetes or early type 2 diabetes , may sensitize mesenchymal stem cells and preadipocytes to edc - induced adipocyte differentiation for chemicals requiring co - exposure to insulin to induce adipogenesis . similarly , clinical states of high adrenergic tone that are predicted to raise intracellular camp levels may potentiate the action of some adipogenic edcs that require pre - activation of camp signaling . one example of this is obstructive sleep apnea ( osa ) , a common disease linked to metabolic dysfunction . likewise , edcs that require glucocorticoids to promote adipocyte development may exhibit enhanced adipogenic capacity in individuals with hyperactivation of the hypothalamic - pituitary - adrenal ( hpa ) axis who exhibit high glucocorticoid levels or enhanced glucocorticoid receptor ( gr ) signaling . such clinical states include cushing s syndrome , pseudo - cushing s syndrome , osa , or even endogenous obesity . we demonstrated that tf activates adipocytic gr signaling both ex vivo and in vivo , suggesting one mechanism by which this novel endocrine disruptor promotes metabolic dysfunction . it remains to be determined whether clinical states of heightened gr signaling potentiate tf action . it is interesting , however , to speculate that other edcs that inhibit the enzymes responsible for glucocorticoid inactivation , 11-hydroxysteroid dehydrogenases , might exhibit enhanced metabolism - disrupting potency in clinical states of glucocorticoid excess ( e.g. , dithiocarbamates and organotins ) . whether an individual s underlying disease state renders them more susceptible to edc - mediated metabolic disruption has not been studied , but knowledge of the mechanisms by which these environmental toxicants disrupt nutrient handling and the development of metabolic tissues may suggest that , under certain clinical scenarios , some individuals may be primed for environmentally - mediated alterations in energy metabolism . reciprocal to the concept that underlying diseases might augment an individual s sensitivity to the deleterious metabolic effects of an edc , disease treatments themselves may generate a permissive environment under which edcs induce metabolic dysfunction . as argued for states of endogenous corticosteroid overproduction , pharmacological treatment with glucocorticoids , as employed in the care of individuals with inflammatory diseases , may potentiate the action of edcs working through or in conjunction with gr signaling . similarly , treatment with adrenergic agonists that raise camp levels may prime preadipocytes for differentiation upon exposure to some edcs . for example , standard treatment approaches to asthma , a highly prevalent lung disease , with 2-adrenergic agonists such as albuterol , may generate a permissive environment for edc - induced adipogenesis . as our knowledge of the mechanisms by which edcs exert deleterious metabolic effects expands , we will be better equipped to predict how various disease states and their treatments may render a subset of patients particularly sensitive to environmental contaminants modulating those pathways . conversely , knowledge of the mechanisms by which edcs induce metabolic disease may suggest therapeutic avenues to treat environmentally - mediated obesity and diabetes or identify individuals whose exposure to certain edcs should be aggressively limited . finally , future studies may take advantage of the known mechanisms by which anti - diabetic medications lower blood sugar ( e.g. , sulfonylurea receptor , peroxisome proliferator - activated receptor- , amp - activated protein kinase , sodium - glucose co - transporter-2 , incretin receptors , etc . ) to : a. ) unravel the molecular mechanisms of metabolic disruption ; b. ) identify potential edc - drug antagonism that limit therapeutic efficacy ; and c. ) develop molecularly - based approaches to treat edc - mediated diabetes in a new era of precision environmental medicine . a core therapy for myriad metabolic diseases is weight loss . whether achieved through dietary interventions , exercise , anti - obesity drugs , or surgery , reductions in body weight have multiple salutary effects on energy metabolism and overall health , effectively raising rmd in the disease progression model ( fig . 1 ) . however , because adipose tissue serves as a reservoir for lipophilic edcs , mobilization of fat with weight loss is accompanied by a repartitioning of these chemicals from adipose tissue into the circulating plasma compartment . this has been shown in several human studies examining caloric restriction with or without a weight loss drug , as well as for patients undergoing bariatric surgery . the precise impact of this release on global energy homeostasis is poorly characterized , but evidence suggests that the subsequent rise in serum organochlorine levels is associated with changes in muscle metabolism that suggest an impairment in energy handling . a similar study also showed an inverse association between the extent of pollutant liberation and insulin levels . it is interesting to speculate that this reduction in insulin levels could be compensation for edc - induced impairments in hepatic gluconeogenesis as we have shown for dioxin - like pcbs . importantly , reductions in total fat mass have also been shown to concentrate pollutant levels in adipose tissue , suggesting that adipocyte physiology may also be deleteriously affected by effective increases in edc concentrations in this important metabolic tissue induced through weight loss . whether this repartitioning of putative metabolic disruptors partially antagonizes further weight loss or its metabolic benefits requires further investigation , as does the hypothesis that adipose expansion itself protects against edc - induced metabolic dysfunction through fat sequestration that limits edc action on non - adipose tissues . finally , the impact of clinical states of altered adipose development , e.g. , congenital and acquired lipodystrophies , on an individual s sensitivity to environmental contaminants necessitates interrogation as individuals with these diseases may be especially vulnerable to edc - induced metabolic dysfunction due to a reduced capacity to safely sequester lipophilic pollutants . an analogous clinical state of edc repartitioning that results from energy shifts and promotes systemic pollutant release is lactation . many studies from diverse geographical regions have demonstrated the presence of various environmental contaminants in breast milk , including pops such as pcbs and organochlorine pesticides . importantly , while edc elimination through lactation may be an important mode by which the total body burden of pollutants is reduced in the mother , the subsequent exposure of the developing newborn to these edcs during this critical developmental period may be especially deleterious for the long - term metabolic health of the child as suggested by the dohad hypothesis . interestingly , while the metabolism - disrupting potency of edcs to which an individual is exposed in adulthood is likely enhanced by that individual s clinical status ( e.g. lifestyle factors , underlying diseases , and medications ) , it is also possible that early life edc exposures potentiate the adverse metabolic consequences of those same clinical factors later in life . improved understanding of the impact of exposure to edcs through breast milk on later life energy homeostasis is of critical importance for both predicting risk and developing novel treatment strategies to address pollutant - induced metabolic dysfunction . our recent work demonstrating that dietary exposure to the phenylsulfamide fungicide tf promotes weight gain , adipose accretion , and glucose intolerance as well as systemic and cellular insulin resistance provides further support to the theory that environmental toxicants likely contribute to the current global epidemic of metabolic disease . while exposure to certain edcs has been shown to be sufficient to initiate the development of diabetes , this occurs rarely . it is more likely that the contribution of edcs to the current epidemic of obesity and diabetes results from coordinate exposures to multiple edcs , each affecting the same or complimentary signaling pathways that regulate energy handling . alternatively , edc - mediated metabolic dysfunction may be enhanced or accelerated by patient - specific parameters that alter an individual s sensitivity to metabolic disruption , including underlying genetics , diet , lifestyle factors , preexisting diseases , pharmaceuticals , and clinical states of fat redistribution . more comprehensive understanding of the complex interplay between these patient - specific variables and edc action will be essential for determining the contribution of environmental pollutants to the current epidemic of metabolic disease and for devising strategies to address the threat of environmental degradation on human metabolic health . OUTPUT:

the global epidemic of metabolic disease is a clear and present danger to both individual and societal health . understanding the myriad factors contributing to obesity and diabetes is essential for curbing their decades - long expansion . emerging data implicate environmental endocrine disrupting chemicals ( edcs ) in the pathogenesis of metabolic diseases such as obesity and diabetes . the phenylsulfamide fungicide and anti - fouling agent tolylfluanid ( tf ) was recently added to the list of edcs promoting metabolic dysfunction . dietary exposure to this novel metabolic disruptor promoted weight gain , increased adiposity , and glucose intolerance as well as systemic and cellular insulin resistance . interestingly , the increase in body weight and adipose mass was not a consequence of increased food consumption ; rather , it may have resulted from disruptions in diurnal patterns of energy intake , raising the possibility that edcs may promote metabolic dysfunction through alterations in circadian rhythms . while these studies provide further evidence that edcs may promote the development of obesity and diabetes , many questions remain regarding the clinical factors that modulate patient - specific consequences of edc exposure , including the impact of genetics , diet , lifestyle , underlying disease , pharmacological treatments , and clinical states of fat redistribution . currently , little is known regarding the impact of these factors on an individual s susceptibility to environmentally - mediated metabolic disruption . advances in these areas will be critical for translating edc science into the clinic to enable physicians to stratify an individual s risk of developing edc - induced metabolic disease and to provide direction for treating exposed patients .

PubMed_Summ6536

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: in this issue of critical care , laporta and coworkers review a multidisciplinary working group 's analysis of a case study on the causes of and solutions for staff turnover in an intensive care unit ( icu ) setting . this issue is of profound significance to health care leaders in western countries because the workforce is shrinking as a result of impending baby boomer retirements and , as the population ages , the demand for intensive care services will grow considerably . these demographic factors are further compounded by the fact that the complexity of care provided in the icu demands professionals who are highly trained and skilled . in this environment , turnover can be costly to the organization because of the significant expenses associated with recruiting and training workers . there are many well documented reasons for staff turnover in the intensive care setting that are highlighted by laporta and coworkers as core reasons . these core reasons include job dissatisfaction due to inflexible scheduling practises , insufficient opportunity for professional development , as well as a lack of collaborative decision making around clinical and practice issues . the authors discuss that data on icu turnover comes from nursing literature and that this research may be applicable to other health care professionals . however , it is important not to assume that reasons for turnover are the same among different groups of health care providers and that staff turnover is something to be avoided at all costs . for example , misra - hebert and coworkers state that one contributor to physician turnover is conflict between the physician 's and organization 's philosophy and goals . physician turnover in this case may be beneficial both to the physician and organization if the two parties can not reconcile their differences and the conflict impacts on the ability of both parties to move forward . there are other important reasons for turnover that should be considered by icu leaders , and these include burnout and generational diversity . burnout is a prevalent phenomenon in icus , and the nursing literature suggests that issues such as moral distress when engaging in futile care contributes to burnout . in the medical literature causes of physician burnout include volume of work , increased expectations of the public , lack of sleep and the possibility of being sued . the consequence of burnout is that there is a negative impact on quality of care and staff morale , which can ultimately cause turnover . for example , gunderson indicates that physicians who are dissatisfied may engage in inappropriate prescribing patterns . neuhauser , furthermore , discusses how environments with rigid systems and attitudes among the leadership will decrease staff morale because staff desire flexible policies and autonomy in decision - making . the generational diversity found in the icu environment can also be a source of turnover of staff . it is well documented that generation x ( born in 19651980 ) and the millennial generation ( born in 19802000 ) have a strong desire for more balanced work life than veterans ( born in 19251945 ) and baby boomers ( born in 19461964 ) . research conducted by lorin and coworkers on internal medicine residents of the millenial generation showed that although 41% considered a fellowship in critical care , only 3.4% chose this training because of lack of leisure time and stress levels among faculty and fellows . clearly , it is important for leaders to be attuned to these generational differences when developing recruitment and retention plans and redesigning the workplace environment . the review from laporta and coworkers also highlights the importance of icu leadership working with frontline staff to create a vision and strategy that addresses the core reasons for turnover . it is essential that this vision be aligned with the vision , mission and values , and strategic plan of the health care organization . furthermore , the team should assess whether their hospital is highly reputable , has high patient satisfaction , and sufficient resources and equipment to provide care . all of these components are signs of a positive work environment , and leadership can build on these attributes to recruit and retain staff . the other key factor in this process is the use of a team work approach . team work training in the areas of conflict resolution , learning styles and giving feedback will help the staff to work together to create and achieve an inspiring vision . although the financial and human resource investments required to engage in this process are considerable , there is substantial evidence in the literature that highly functioning , satisfied teams lead to more efficient patient care and better outcomes . staff turnover is a critical issue that icu leaders need to understand and address in their unit settings . attention to this issue with a systematic , evidence - based approach that focuses on team work and collaboration will not only improve retention but will also make the icu a highly competitive and desirable place to work . OUTPUT:

this commentary discusses laporta and coworkers analysis of a case study on the causes of and solutions for staff turnover in an intensive care setting . staff turnover is a significant issue for health care leaders due to the shrinking workforce in western countries and an increased demand for intensive care services as the population ages . the commentary considers reasons for turnover such as burnout and generational diversity , and highlights the importance of a team work approach to address the issue of turnover .

PubMed_Summ6537

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: due to the widespread use of imaging modalities , such as ultrasonography , computed tomography ( ct ) , and magnetic resonance imaging , the incidences of incidentally found small cortical renal masses ( srms ) and renal cell carcinoma ( rcc ) , have increased during the past years . for decades , the standard therapy for patients with clinically suspected rcc consisted of radical nephrectomy , an invasive surgical procedure with high morbidity . however , in a recently published randomized trial of nephron - sparing surgery ( nss ) in patients with srm yielded comparable oncological outcome with radical nephrectomy . in addition , population - based studies clearly demonstrate an overall survival benefit in patients undergoing nss as a result of preserved renal function [ 4 , 5 ] . nephron - preserving procedures , such as partial nephrectomy and image - guided minimally invasive ablative procedures , have therefore increasingly been applied in patients with srm [ 6 , 7 ] . initially , image - guided ablative procedures were performed in patients who were not suitable candidates for nss based on significant medical comorbidity , advanced symptomatic disease , or refusal of conventional therapy [ 6 , 8 ] . accumulating data on follow - up and oncological safety suggest a broader indication in patients with srm . a particular form of an image - guided ablative procedure is radiofrequency ablation ( rfa ) , which can be performed open or percutaneously . in rfa , an electric current oscillates through an electrode placed centrally in the target tissue . this results in frictional ionic agitation and heat formation in the tissue surrounding the tip of the electrode , causing local protein coagulation and cellular death . compared with open and laparoscopic ( partial ) nephrectomy it is a nephron - sparing therapy with low morbidity and mortality , short hospital stay , and acceptable oncologic outcome [ 8 , 10 , 12 ] . nevertheless , rfa of the kidney can be accompanied by minor and even major complications . several investigators have postulated the occurrence of bowel perforation as a complication of rfa of renal masses due to the close proximity of bowel [ 13 , 14 ] . to our current knowledge , only two articles have described such a case [ 15 , 16 ] . yet in a large series of 100 percutaneously performed renal rfas , none of the patients had colonic injuries . the reported incidence of bowel perforation complicating renal rfa therefore ranges from 0 to 8.3% [ 8 , 15 ] . in this article , we describe the first case of appendiceal perforation as a complication of ct - guided percutaneous rfa of an smr . a 60-year - old male patient was referred to our outpatient clinic with an incidental mass in the right kidney , which was recently diagnosed during work - up of his microscopic hematuria . his previous medical history consisted of kidney stone lithotripsy , hypertension treated with a beta - blocker and diuretic , and two episodes of transient ischemic attack . abdominal ct scan showed a rapidly enhancing , exophytic mass in the lower pole of the right kidney with a maximum diameter of 2.5 cm ( fig . the appendix was noticed in a retrocecal position , at a 1.4-cm distance from the renal mass ( fig . 1b , c ) . based on his mild comorbidity and on the small size of the renal mass , 1a small , exophytic , rapidly enhancing renal mass at the lower pole of the right kidney . b retrocecal position of the appendix on the lateral site of the right kidney in the vicinity of the renal mass ( c ) . * appendix , renal mass a small , exophytic , rapidly enhancing renal mass at the lower pole of the right kidney . b retrocecal position of the appendix on the lateral site of the right kidney in the vicinity of the renal mass ( c ) . * appendix , renal mass our technique of rfa in renal masses has extensively been described in previous articles [ 17 , 18 ] . in short , after the patient received an antibiotic prophylaxis ( 1,500 mg cefuroxim ) and epidural analgesic before the rfa procedure , he was placed in prone position on the ct table . a planning ct scan was performed to locate the renal mass . under fluoroscopic ct guidance , a 17 g cool - tip electrode ( valleylab , covidien , boulder , co ) was placed centrally into the mass . subsequently a 20 g needle was inserted lateral in the anterior pararenal space for injection of dextrose in water to hydrodissect the renal mass from the surrounding vital tissues , such as the colon and appendix . after the hydrodissection and the positions of the needles were checked with a ct scan of the area of interest , ablation was started . final temperature after 15 min was > 75c with adequate roll - offs . the rfa procedure was performed by a highly experienced interventional radiologist ( w.p . ) who at that time had already performed > 180 percutaneous image - guided ablative procedures ( including renal , liver , and lung ) . a 60-year - old male patient was referred to our outpatient clinic with an incidental mass in the right kidney , which was recently diagnosed during work - up of his microscopic hematuria . his previous medical history consisted of kidney stone lithotripsy , hypertension treated with a beta - blocker and diuretic , and two episodes of transient ischemic attack . abdominal ct scan showed a rapidly enhancing , exophytic mass in the lower pole of the right kidney with a maximum diameter of 2.5 cm ( fig . the appendix was noticed in a retrocecal position , at a 1.4-cm distance from the renal mass ( fig . 1b , c ) . based on his mild comorbidity and on the small size of the renal mass , 1a small , exophytic , rapidly enhancing renal mass at the lower pole of the right kidney . b retrocecal position of the appendix on the lateral site of the right kidney in the vicinity of the renal mass ( c ) . * appendix , renal mass a small , exophytic , rapidly enhancing renal mass at the lower pole of the right kidney . b retrocecal position of the appendix on the lateral site of the right kidney in the vicinity of the renal mass ( c ) . our technique of rfa in renal masses has extensively been described in previous articles [ 17 , 18 ] . in short , after the patient received an antibiotic prophylaxis ( 1,500 mg cefuroxim ) and epidural analgesic before the rfa procedure , he was placed in prone position on the ct table . a planning ct scan was performed to locate the renal mass . under fluoroscopic ct guidance , a 17 g cool - tip electrode ( valleylab , covidien , boulder , co ) was placed centrally into the mass . subsequently a 20 g needle was inserted lateral in the anterior pararenal space for injection of dextrose in water to hydrodissect the renal mass from the surrounding vital tissues , such as the colon and appendix . after the hydrodissection and the positions of the needles were checked with a ct scan of the area of interest , ablation was started . final temperature after 15 min was > 75c with adequate roll - offs . the rfa procedure was performed by a highly experienced interventional radiologist ( w.p . ) who at that time had already performed > 180 percutaneous image - guided ablative procedures ( including renal , liver , and lung ) . on the ct images performed during the procedure , the colon and appendix were considered to be a safe distance ( at least 1.0 cm ) from the ablative field as a result of the hydrodissection ( fig . 2 ) . adequate ablation of the kidney tumor was achieved without intraprocedural complications . on the first postprocedural day fluid collection with air configuration on the lateral and anterior side of the renal mass as a result of hydrodissection can be seen . retrocecal appendix ( * ) is in the vicinity of the ablative field patient in left lateral decubitus position during rfa procedure . fluid collection with air configuration on the lateral and anterior side of the renal mass as a result of hydrodissection can be seen . retrocecal appendix ( * ) is in the vicinity of the ablative field five days after the procedure , he presented at our hospital with fever ( 39.5c ) and right lumbar pain . 3 ) showed a large retroperitoneal fluid collection with air configurations , suggesting retroperitoneal abscess formation , on the lateral side of the right kidney . moreover , a direct connection was noticed between the cecum and fluid collection , with contrast material in the retroperitoneal abscess , suggesting perforation at the base of the appendix ( fig . 3 ) . after ct - guided drainage of the abscess and intravenous antibiotic therapy , the patient remained septic . therefore , 2 days later laparotomy was performed . intraoperatively , a retroperitoneally confined abscess was drained . however , due to an extensive local inflammatory reaction affecting the terminal ileum ( fig . 4 ) , the approach had to be extended intra - abdominally to allow necessary resection of the ileocecal region followed by primary anastomosis between the ileum and ascending colon and an omental plasty . during this step , histopathologic examination of the resected specimen showed a perforated appendix based on ulcero - phlegmonous and gangrenous inflammation . on day 18 after the rfa 3leakage of contrast material from the perforated cecum / appendiceal base into the right anterior pararenal space suggesting appendiceal perforation . presence of air configurations in the right anterior pararenal space suggesting abscess formationfig . oversewn cecal perforation at the base of the necrotic appendix leakage of contrast material from the perforated cecum / appendiceal base into the right anterior pararenal space suggesting appendiceal perforation . presence of air configurations in the right anterior pararenal space suggesting abscess formation intraoperative view after abscess drainage . rfa of srm was first applied in 1997 and has proven to be a promising and safe technique since . in a large series of 100 patients with renal tumors treated with rfa , 11 minor and major complications were reported , of which the most common was haemorrhage . . complications of rfa can generally be divided into two categories : ( 1 ) those related to imaging - guided electrode placement and ( 2 ) those related to thermal therapy . the latter are more common in kidney rfa compared with other rfa indications , e.g. , hepatic rfa , as a result of the proximity of other vital structures , such as the bowel and ureter . nevertheless , only two articles so far have reported bowel perforation as a complication of renal rfa [ 15 , 16 ] . the first step in preventing thermal complications is thorough assessment of the tumor location on preprocedural ct scans during the process of patient selection . percutaneous renal rfa can be performed with the patient prone or in lateral decubitus position . in both positions , vital structures in the vicinity of the target mass will be kept away from the ablative zone by way of gravity . third , the rfa electrodes can be used to lift the ablated tumor away from vital structures . examples of invasive methods include hydrodissection with glucose in water or injection of carbon dioxide in between the target tissue and the tissue that needs protection . in our patient , a lateral dissection was performed with glucose in water to dissect the renal mass from the appendix and the colon , which was located caudolateral with respect to the renal mass . unfortunately , in this way the appendix came even closer to the tract of the needle . nevertheless , on the ct images performed during the procedure , the appendix was considered to be at sufficient distance from the ablative field . eventually , this caused the appendiceal perforation . since this complication , we modified our ablative technique . currently we start the hydrodissection before placement of the rfa electrode in the target tissue . in addition , instead of injecting 100 cm fluid during hydrodissection , we attach the needle to a continuous drip system . in conclusion , in this article we described a case of appendiceal perforation leading to retroperitoneal abscess formation as a complication of percutaneous rfa of an srm . although rfa of srm is generally a minimally invasive and safe procedure , one should be aware of the possibility of particular minor and major complications when performing this innovative and promising procedure . if vital structures remain in close vicinity of the ablative field , one should consider treatment options other than rfa . OUTPUT:

percutaneous radiofrequency ablation ( rfa ) has gained wide acceptance as nephron - sparing therapy for small renal masses in select patients . generally , it is a safe procedure with minor morbidity and acceptable short - term oncologic outcome . however , as a result of the close proximity of vital structures , such as the bowel , ureter , and large vessels , to the ablative field , complications regarding these structures may occur . this is the first article describing appendiceal perforation as a complication of computed tomography - guided rfa despite hydrodissection . when performing this innovative and promising procedure one should be aware of the possibility of particular minor and even major complications .

PubMed_Summ6538

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: have all been reported to affect bond strength,3,4 owing to differences in the degree of conversion , contraction stress and physical properties of the materials selected.57 in addition , the type of bur chosen might affect both the etching effect and the penetration of resin monomer since the roughness of the bur influences smear layer thickness.8 it has also been reported that certain environmental conditions , for example , increased temperature and humidity in the oral cavity , significantly reduces the bond strength.9,10 contamination is also a well - known and important factor affecting bonding performance ; in particular , contamination with blood , saliva or gingival crevicular fluid significantly reduces the bond strength1113 due to the inhibition of monomer diffusion , and therefore requires the application of isolation techniques , such as the use of a rubber dam , in the bonding procedure . the routine use of maintenance spray for prolonging the superior performance of dental cutting handpieces is also of importance when considering sources of contamination . maintenance spray must be used before each autoclaving or chemi - claving , and recently almost all dental offices sterilize the handpieces used with patients by autoclaving or chemi - claving for infection control . immediately after spraying , the handpiece is briefly operated for several minutes to remove excess spray ; however , it has been reported that this usual practice of removing excess spray is ineffective for preventing surface contamination.14 some studies have evaluated the influence of maintenance spray on resin bonding to enamel , and almost of those indicated that contamination of maintenance spray had little effect on bonding.1519 on the other hand , the contamination of maintenance spray to dentin has been some reported to affect the lower bond strength.19 however , the reports have been equivocal,20 and further studies should be needed . the purpose of this study was , therefore , to investigate the influence of contamination with two different types of maintenance sprays on the microtensile bond strength ( tbs ) of dentin bonded with a 2-step self - etching adhesive system . the null hypothesis tested was that contamination with maintenance spray does not influence the tbs of the bonded dentin . nine caries - free extracted human molars stored in 0.5% chloramine t solution at 4c was used for tbs study . the teeth were trimmed using a model trimmer ( mt-7 , j morita tokyo mfg . tokyo , japan ) in order to form a long , flat dentin surface at the mid - crown level . the flat dentin surface was then polished with # 600 silicon carbide paper to create a standard smear layer . these specimens were then randomly divided to one of the following three groups , with three teeth in each group : oil - free spray group : dentin surface contaminated with an oil - free maintenance spray for air bearing handpieces ( astron cleaner , j. morita mfg . tokyo , japan ) for approximately 1 s at a distance of 23 cm , rinsed with water spray for 30 s , and then air - dried sufficiently . oil - containing spray group : dentin surface contaminated with an oil - containing maintenance spray for ball bearing handpieces ( intra spray , j morita mfg . corp . ) for approximately 1 s at a distance of 23 cm , rinsed with water spray for 30 s , and then air - dried sufficiently . control group : dentin surface was immediately rinsed with water spray for 30 s and then air - dried sufficiently . all specimens were then treated with a self - etching priming adhesive system ( clearfil se bond , kuraray medical , tokyo , japan ; also known as clearfil megabond in japan ) according to the manufacturer s instructions . the self - etching primer was applied with a three - way syringe to the surfaces for 20 s prior to drying . bonding agent was then applied to the surface and polymerized by quartz - tungsten - halogen light curing unit for 10 s ( new light vl - ii , gc , tokyo , japan ) . after applying the bonding agent to each specimen , resin composite ( clearfil ap - x , shade a2 , kuraray medical ) was built - up incrementally ( in five steps ) to a height of 5 mm . each increment was light - cured for 20 s ( new light vl - ii ) , and the specimens were then stored in distilled water for 24 h at 37c . after storage , each bonded specimen was sectioned into four or five slabs , approximately 0.7-mm thick , perpendicular to the bonded surface using a low - speed diamond saw ( isomet , buehler , lake bluff , il , usa ) under water cooling . the slabs were trimmed using a superfine - grit diamond bur ( sf # 114 , shofu , kyoto , japan ) to an hourglass shape to form a gentle curve along the adhesive interface from both sides , as described by sano et al.21 the width at the narrowest portion was approximately 1.4 mm , and the thickness of the bonded area of each specimen was verified by a digital micrometer ( mitutoyo , tokyo , japan ) . the specimens were then attached to a bencor multi - t testing apparatus ( danville engineering co , san ramen , ca , usa ) with cyanoacrylate adhesive ( model repair ii blue , dentsply - sankin , ohtawara , japan ) connected to a universal testing machine ( tensilon rtc-1150-tsd , orientec , tokyo , japan ) . the specimens were then subjected to tbs testing at a crosshead speed of 1 mm / min until failure occurred . the tensile bond strength was calculated as the load at failure ( n ) divided by the bonded area ( mm ) . bond strength data were analyzed by one - way anova and the tukey - kramer test . statistical analysis was performed using a commercially available statistical package ( statview 5.0j , sas institute , cary , nc , usa ) . to determine the mode of failure , both the dentin and composite halves of all fractured specimens were visually inspected under a light microscope ( ms-803 , moritex , tokyo , japan ) at 210 magnification and further observed using a field - emission scanning electron microscope ( fe - sem ; jsm-6340f , jeol , tokyo , japan ) at 15 kv , under the magnifications of 75 to classify the failure mode of each specimen , and 1000 to observe the details of peculiar images . failure modes were classified as cohesive failure of resin , failure of the adhesive interface ( fracture between the dentin or the hybrid layer and the overlying adhesive in the same sample ) , mixed resin and adhesive ( r&a ) failure ( interfacial and partial cohesive failure of the adhesive only or cohesive failure in the same sample ) , mixed that included the dentin ( failure within the dentin only or mixed failure that included the dentin ) or cohesive failure of dentin , wherever relevant . bonded samples prepared by same procedure as for tbs testing were ground with increasingly finer silicon carbide paper and highly polished with a slurry solution of aluminum polishing suspension ( refine tec , co. , yokohama , japan ) ( 1 m , 0.3 m , 0.05 m ) . the samples were then subjected to 32% phosphoric acid ( uni - etch , bisco , schaumburg , il , usa ) treatment for 30 s and rinsed with tap water for 30 s. the specimens were further treated with 1% sodium hypochlorite solution ( wako pure chemical , osaka , japan ) for 10 min . all specimens were subsequently dehydrated in ascending grades of ethanol ( 50% , 70% , 80% , 90% , 95% , 99% , and 99.9% ) for 10 min each , and were further desiccated in a box with silica gel for 24 h. the dried specimens were placed on an aluminum stub and sputter - coated with au - pd using a cool sputter coater ( sc500a , vg microtech , east sussex , uk ) . the coated specimens were examined using the fe - sem at 15 kv , under the magnification of 4000. nine caries - free extracted human molars stored in 0.5% chloramine t solution at 4c was used for tbs study . the teeth were trimmed using a model trimmer ( mt-7 , j morita tokyo mfg . tokyo , japan ) in order to form a long , flat dentin surface at the mid - crown level . the flat dentin surface was then polished with # 600 silicon carbide paper to create a standard smear layer . these specimens were then randomly divided to one of the following three groups , with three teeth in each group : oil - free spray group : dentin surface contaminated with an oil - free maintenance spray for air bearing handpieces ( astron cleaner , j. morita mfg . tokyo , japan ) for approximately 1 s at a distance of 23 cm , rinsed with water spray for 30 s , and then air - dried sufficiently . oil - containing spray group : dentin surface contaminated with an oil - containing maintenance spray for ball bearing handpieces ( intra spray , j morita mfg . corp . ) for approximately 1 s at a distance of 23 cm , rinsed with water spray for 30 s , and then air - dried sufficiently . control group : dentin surface was immediately rinsed with water spray for 30 s and then air - dried sufficiently . all specimens were then treated with a self - etching priming adhesive system ( clearfil se bond , kuraray medical , tokyo , japan ; also known as clearfil megabond in japan ) according to the manufacturer s instructions . the self - etching primer was applied with a three - way syringe to the surfaces for 20 s prior to drying . bonding agent was then applied to the surface and polymerized by quartz - tungsten - halogen light curing unit for 10 s ( new light vl - ii , gc , tokyo , japan ) . after applying the bonding agent to each specimen , resin composite ( clearfil ap - x , shade a2 , kuraray medical ) was built - up incrementally ( in five steps ) to a height of 5 mm . each increment was light - cured for 20 s ( new light vl - ii ) , and the specimens were then stored in distilled water for 24 h at 37c . after storage , each bonded specimen was sectioned into four or five slabs , approximately 0.7-mm thick , perpendicular to the bonded surface using a low - speed diamond saw ( isomet , buehler , lake bluff , il , usa ) under water cooling . the slabs were trimmed using a superfine - grit diamond bur ( sf # 114 , shofu , kyoto , japan ) to an hourglass shape to form a gentle curve along the adhesive interface from both sides , as described by sano et al.21 the width at the narrowest portion was approximately 1.4 mm , and the thickness of the bonded area of each specimen was verified by a digital micrometer ( mitutoyo , tokyo , japan ) . the specimens were then attached to a bencor multi - t testing apparatus ( danville engineering co , san ramen , ca , usa ) with cyanoacrylate adhesive ( model repair ii blue , dentsply - sankin , ohtawara , japan ) connected to a universal testing machine ( tensilon rtc-1150-tsd , orientec , tokyo , japan ) . the specimens were then subjected to tbs testing at a crosshead speed of 1 mm / min until failure occurred . the tensile bond strength was calculated as the load at failure ( n ) divided by the bonded area ( mm ) . bond strength data were analyzed by one - way anova and the tukey - kramer test . statistical analysis was performed using a commercially available statistical package ( statview 5.0j , sas institute , cary , nc , usa ) . to determine the mode of failure , both the dentin and composite halves of all fractured specimens were visually inspected under a light microscope ( ms-803 , moritex , tokyo , japan ) at 210 magnification and further observed using a field - emission scanning electron microscope ( fe - sem ; jsm-6340f , jeol , tokyo , japan ) at 15 kv , under the magnifications of 75 to classify the failure mode of each specimen , and 1000 to observe the details of peculiar images . failure modes were classified as cohesive failure of resin , failure of the adhesive interface ( fracture between the dentin or the hybrid layer and the overlying adhesive in the same sample ) , mixed resin and adhesive ( r&a ) failure ( interfacial and partial cohesive failure of the adhesive only or cohesive failure in the same sample ) , mixed that included the dentin ( failure within the dentin only or mixed failure that included the dentin ) or cohesive failure of dentin , wherever relevant . to determine the mode of failure , both the dentin and composite halves of all fractured specimens were visually inspected under a light microscope ( ms-803 , moritex , tokyo , japan ) at 210 magnification and further observed using a field - emission scanning electron microscope ( fe - sem ; jsm-6340f , jeol , tokyo , japan ) at 15 kv , under the magnifications of 75 to classify the failure mode of each specimen , and 1000 to observe the details of peculiar images . failure modes were classified as cohesive failure of resin , failure of the adhesive interface ( fracture between the dentin or the hybrid layer and the overlying adhesive in the same sample ) , mixed resin and adhesive ( r&a ) failure ( interfacial and partial cohesive failure of the adhesive only or cohesive failure in the same sample ) , mixed that included the dentin ( failure within the dentin only or mixed failure that included the dentin ) or cohesive failure of dentin , wherever relevant . three human molars were used . bonded samples prepared by same procedure as for tbs testing were ground with increasingly finer silicon carbide paper and highly polished with a slurry solution of aluminum polishing suspension ( refine tec , co. , yokohama , japan ) ( 1 m , 0.3 m , 0.05 m ) . the samples were then subjected to 32% phosphoric acid ( uni - etch , bisco , schaumburg , il , usa ) treatment for 30 s and rinsed with tap water for 30 s. the specimens were further treated with 1% sodium hypochlorite solution ( wako pure chemical , osaka , japan ) for 10 min . all specimens were subsequently dehydrated in ascending grades of ethanol ( 50% , 70% , 80% , 90% , 95% , 99% , and 99.9% ) for 10 min each , and were further desiccated in a box with silica gel for 24 h. the dried specimens were placed on an aluminum stub and sputter - coated with au - pd using a cool sputter coater ( sc500a , vg microtech , east sussex , uk ) . the coated specimens were examined using the fe - sem at 15 kv , under the magnification of 4000. mean and standard deviation ( sd ) tbs for the specimens of all three tested groups are summarized in table 1 . the non - sprayed control showed significantly higher tbs than the two sprayed groups ( p < 0.05 ) . there was no significant difference between the two sprayed groups ( oil - free spray ( n = 14 ) and oil - containing spray ( n = 15 ) ) ( p > 0.05 ) . representative fe - sem micrographs of fractured specimens after the tbs testing are shown in figures 2a , 3a and 4a , and distribution of the failure mode is summarized in figure 5 . most commonly , a mixture of cohesive failure of the resin and failure of the adhesive interface / hybrid layer ( r&a failure ) was observed in each group . failure in the adhesive interface was observed only in the two sprayed groups and not in the control group . the percentage of mixed failure that included the dentin was higher in the control group than in the two sprayed groups . fe - sem micrographs of the cross - sectioned resin - dentin interfaces in each group are shown in figures 2b , 3b and 4b . resin tags were evident in all three groups , with no significant difference among the groups . the purpose of this study was to investigate the influence of contamination with two different types of maintenance sprays on the microtensile bond strength ( tbs ) of dentin bonded with a 2-step self - etching adhesive system , clearfil se bond . some of the previous studies applied the combined spray of lubricant and water running through the handpiece20 in order to simulate the clinical situation . it has been reported that the spray contents was discharged up to at least 240 min , but the amount of discharge was gradually reduced.14 their results suggested that uniform discharging of spray contents into entire the dentin surface might be difficult . in this study , therefore , the spray was applied directly in order to contaminate the dentin surface , referred to rosa et al and matos et al.18,19 powers et al15 and knight et al17 evaluated the handpiece lubrication on bond strength of enamel using two multi - step etch and rinse adhesive systems ( all - bond 2 , bisco ; opti - bond fl , kerr ; and gluma 2000 , heraeus kulzer ) , and they found that the significant difference between the mean bond strengths for the group prepared with a sterilized unlubri - cated handpiece and the group prepared with a lubricated handpiece . however , other studies which evaluate the bondstrengths of oil - contaminated enamel with multi - step etch and rinse adhesives stated that contamination had little effect on bond strength.15,18 rosa et al assumed that etch and rinse adhesive had little effect of oil contamination , because the etchant was efficient in removing much of the oil.18 it has also been some reported about the influence of handpiece lubrication on bond strength , but the results have been equivocal.15,16,19,20 roberts et al investigated using a 2-step etch and rinse adhesive ( single bond , 3 m espe ) , a 2-step self - etch adhesive ( clearfil se bond ) , and a 1-step self - etch adhesive ( one - up bond f , tokuyama dental ) , and resulted that there were no significant differences in dentin bond strength between the non - contaminated control and the spray - contaminated groups regardless of the type of handpiece or use of routine lubrication in each adhesive system.20 on the other hand , matos et al19 reported that the bond strength of clearfil protect bond ( kuraray medical ) , a 2-step self - etching adhesive system which improved on clearfil se bond22 to dentin was lower more than half compared with a non - contaminated group . our study also revealed that contamination of maintenance spray significantly affected to reduce the tbs of bonded dentin . differ to etch and rinse adhesive , it is not needed the water spraying before applying self - etch adhesive . therefore , the adverse effect of maintenance spray on self - etch adhesive might be larger than that on etch and rinse adhesive . in the results of this study , we suggested that the null hypothesis tested in this study that contamination with maintenance sprays does not influence the tbs of dentin bonded with 2-step self - etch adhesive can be rejected . this study also compared two different types of maintenance sprays oil - free spray ( astron cleaner ) and oil - containing spray ( intra spray ) , but no significant difference was found between the sprays . intra spray contains iso - paraffin oil for lubrication , and astron cleaner contains ethanol but do not contain any type of oil . in fe - sem micrographs of the fractured surface , the failure within the hybridized dentin area was mainly observed in the oil - containing spray group , and failure at the adhesive interface was rarely observed . furthermore , the long thick resin tags visible on the fe - sem micrographs of the cross - sectioned resin - dentin interface were the same as those observed in the other groups . these results indicated that the lower tbs in the oil - containing spray group might not be due to the inhibition of resin penetration . since both spray cans contain liquefied petroleum gas as an aerosol propellant , this might be attributable to decrease in the mechanical properties of the adhesive interfacial area . further studies are needed to clarify what component was affected on resin bonding . in order to perform ideal bonding , it should be eliminated the all inhibitors on resin bonding in the clinical situation . as already mentioned , contamination of blood or saliva significantly reduces the bond strength12,13 due to the inhibition of resin penetration . in order to prevent cavity surfaces produced by such contaminants , dentists typically use the rubber dam isolation technique , which is useful for creating a suitable environment for resin bonding since it not only isolates the surface from these fluids , but also reduces intraoral humidity . however , the technique is not able to prevent contamination from handpiece maintenance spray since the spray has been reported to discharge for at least 240 minutes;23 thus , the usual practice of removing excess spray by operating the handpiece for just a few minutes is ineffective in preventing the contamination.14 future work should focus on eliminating the contaminants from maintenance sprays in order to improve bonding performance to dentin . within the limitations of this study , the following conclusions are drawn : contamination from maintenance spray significantly affects the microtensile bond strength to dentin . however , there is no difference between the effects of oil - free and oil - containing maintenance sprays on the reduction in the microtensile bond strength to dentin . OUTPUT:

objectiveto investigate the influence of maintenance spray on resin bonding to dentin.materials and methodsthe crown of extracted , caries - free human molars was transversally sectioned with a model trimmer to prepare the dentin surfaces from mid - coronal sound dentin , and then uniformly abraded with # 600 silicon carbide paper . the dentin surfaces were randomly divided into three groups : oil - free spray group where maintenance cleaner for air bearing handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s ; oil - containing spray group where maintenance cleaner for micro motor handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s ; and control group where the surface was rinsed with water spray for 30 s and then air - dried . these surfaces were then bonded with clearfil se bond ( kuraray medical ) , and resin composite ( clearfil ap - x , kuraray medical ) build - up crowns were incrementally constructed on the bonded surfaces . after storage for 24 h in 37c water , the bonded teeth were sectioned into hour - glass shaped slices ( 0.7-mm thick ) perpendicular to the bonded surfaces . the specimens were then subjected to microtensile bond strength ( tbs ) testing at a crosshead speed of 1.0 mm / min . data were analyzed with one - way anova and the tukey - kramer test.resultsmaintenance spray - contaminated specimens ( oil - free and oil - containing spray groups ) showed significantly lower tbs than control specimens ( p < 0.05 ) . however , there was no significant difference between the spray - contaminated groups ( p > 0.05).conclusionmaintenance spray significantly reduces the bond strength of clearfil se bond to dentin .

PubMed_Summ6539

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: fungal diseases have markedly increased during the recent years ( 1 ) ; although more increase is observed in opportunistic mycoses . determining the mycoflora of normal people is important when the role of skin is considered as a reservoir for microorganisms . infectious diseases , mostly the ones that affect the epidermal or mucous membrane , are serious troubles all over the world because of hygiene and education deficiency . microbiome of human skin refers to complete collection of microorganisms comprising bacteria , fungi and virus . the kind and quantity of skin microbes are different from one individual to another depending on the location of the body . fungi are among the most significant groups of these skin pathogens ( 2 ) . cutaneous mycoses refer to skin infection and its appendages are involved in yeasts and filamentous fungi . they have the affinity to parasitized tissues with rich keratin and create the skin inflammatory responses and cause severe itching , burning and redness . moreover , these diseases cause cosmetic outcomes . candidiasis includes the infections that vary from superficial ; for example , oral thrush and vulvovaginitis , to visceral and potentially life - threatening diseases . superficial infections of dermal inflammation and discomfort are frequent in numerous human societies . toe webs harbor fungi more than the less occluded parts such as trunk , legs , and arms ( 2 ) . at present a normal healthy skin in adults is expected to transmit a number of representatives of the genera candida , malassezia and geotrichum as well as few anthropophilic dermatophytes as inhabitants of the normal skin . direct examination , and culture and molecular analyses are employed to recognize the skin microbial inhabitants . direct examination is based on finding the microbial elements such as unicellular yeast , mycelium and pseudohyphae . the presence of malassezia spp . in healthy human skin was identified in previous investigation in the nineteenth century . the incidence and density of colonization depended on the activity of sebaceous gland and age . the species most commonly associated with this disease are , malassezia globosa , m. furfur and m. sympodialis ( 3 - 5 ) . this disorder could be observed in temperate climates , particularly during summer in humid months . the malassezia yeast form generates dicarboxylic acids similar to azelaic acid which prohibit tyrosine kinase that consequences in hypopigmentation of skin ( 4 ) diagnosis of this disease is clinically easy and it is confirmed by microscopic examination of skin scraping on potassium hydroxide or using scotch tape . conversion from yeast form of malassezia to mycelia form was promoted with warm and humid weather . immunodeficiency , poor hygiene , diabetes and poor nutrition are other factors related to pityriasis versicolor . the seborrheic areas are chest , back , abdomen , neck , and proximal arms . the lesions possess different colors such as yellow , brown , pink , red or hypo pigmented . keratinophilic fungi are the groups which could infect the skin , hair and nail in human ( 6 , 7 ) . anthropophilic type of theses fungi can apparently live in healthy human skin which may contribute to transmission of the fungi ( 8 , 9 ) . the current study aimed to investigate the incidence of fungal flora on interdigital spaces of the human foot . samples were collected from toe webs of 865 girl students who lived in the dormitories of ahvaz jundishapur university of medical sciences in autumn 2008 . the tested web spaces did not show any signs of infection such as erythema , scaling , blistering and itching . the samples were collected into sterilized clean pockets and transferred immediately to the mycology medical laboratory . a part of the samples were digested with 20% koh and screened by a light microscope for fungal elements . another part of the samples were cultured on sabouraud glucose agar ( sga ) and sga containing 0.05 mg / ml chloramphenicol and 0.5 mg/ ml cyclohexmide . the filamentous fungi were identified after slide culturing according to their gross and morphological features . yeasts were identified on the bases of germ tube formation , morphology on the corn meal agar medium , and assay of unease activity . out of the 865 samples , 616 ( 71.2% ) were positive in direct examination or culture . the culture was positive in 349 ( 40.3% ) specimens ; and 22 ( % 2.5% ) samples were also positive for both direct examination and culture . the most common fungal isolates in direct test were yeast ( 29.4% ) , followed by conidia ( 0 . 92% ) , melanised hypha ( 0.35% ) and non - septated hypha ( 0.23% ) . skin surface is moderately dry , fairly acidic and dead cells are the prime source of nutrition . skin has an environment which inhibits the growth of numerous microorganisms , however , some have adapted to living on the skin . candida and malassezia species are two good examples that inhabit on the skin ( 3 , 4 , 10 , 11 ) . the current study performed a comprehensive and quantitative analysis of the mycoflora on the surface of interdigital skin of girl students . overall fungal structure was found on the skin of 30.9% of the students in the direct examination with koh . the rates of the total yeast counts were much higher than those of molds in samples of skin in the direct examination . the species of candida live on skin and cause the frequent skin infection named candidiasis . candida species were isolated from 1.2% of interdigital spaces of people in the current study . although skin candidiasis is not life threatening , it can affect the emotional and physical status of the patients . malassezia species is considered as an opportunistic fungus , since it stays benign until the conditions that convey it to cause infection are provided . in the current study , various fungi which can be considered as possible agents for skin diseases were isolated . in the present study , various fungi were isolated from the skin which could be considered as possible causes of skin diseases . compared to many fungal diseases , host - fungus association in dermatophytosis was significant because dermatophytes affect immunocompetent persons ; however they usually invade just superficial keratinized tissues . currently , not much has been recognized from the relevant factors which mediate adherence of these fungi to host . the capability of t. rubrum to adhere to epithelial cells is a trait to carbohydrate - specific adhesin on microconidia ( 12 ) . morphological observation detected the fibrillar projections in t. mentagrophytes through the adherence stage ( 13 , 14 ) . in the current research various saprophytic fungi actually , many of the fungal spores recovered from the skin can be found in the atmosphere . the present study demonstrated the incidence of fungal flora on interdigital spaces of human foot . the obtained results showed that fungi can survive on the surfaces of skin without showing the sign of infection . OUTPUT:

background : fungi have been extensively isolated and investigated from skin in various parts of the world . determining the mycoflora of normal people is important when the role of skin is considered as a reservoir for microorganisms.objectives:the current study aimed to investigate the incidence of fungal flora on interdigital spaces of the human foot.patients and methods : samples were collected from interdigital spaces of 865 girl students who lived in the dormitories of ahvaz jundishapur university of medical sciences . a part of the sample was digested with 20% koh and screened by a light microscope for fungal elements . another part of the sample was cultured on sabouraud glucose agar ( sga ) and sga containing 0.05 mg / ml chloramphenicol and 0.5 mg / ml cycloheximide . the fungal colonies were identified based on morphological and microscopic characteristics and biochemical tests.results:in the current study , out of the 865 samples , 616 ( 71 . 2% ) were positive in direct examination or culture . of these , 267 samples ( 30 . 9% ) were positive in direct examination . the most common fungal isolates in direct test were yeast ( 29 . 4% ) , followed by conidia ( 0 . 92% ) , melanised hypha ( 0 . 35% ) and non - septated hyphae ( 0 . 23% ) . trichophyton mentagrophytes was isolated in one of the specimens.conclusionsthe present study demonstrated the incidence of fungal flora on interdigital spaces of human foot . the current study results showed that fungi can survive on surfaces of skin without showing the sign of infection .

PubMed_Summ6540

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: implant - supported overdenture prostheses can be divided into bar overdentures and single attachment overdentures . single attachment elements for overdentures include single retentive anchors , single magnet anchors , and individually cast telescopic copings.1 among these , telescopic copings have the benefit of implant splinting found in bar overdentures and the retrievability of single attachment overdentures . however , this method is typically fabricated using gold materials , so it is not an economical treatment option . also , if an inner crown will be worn , it is difficult to maintain appropriate retentive forces . in this case report , a telescopic implant - supported overdenture prosthesis was made using a new material , polyaryletherketone ( paek ) based polymer ( pekkton ivory , cendres + mtaux sa , biel / bienne , switzerland ) . it shares benefits of typical telescopic coping , in additional to being highly economical , wear resistant , and light in weight compared to conventional implant overdenture prostheses . 1 ) presented to the department of prosthodontics at chonnam national university dental hospital . after clinical and radiographic examinations after maxillary teeth extractions and use of provisional maxillary complete denture for six months , six small diameter implant fixtures ( 3.0 10.0 mm usii , osstem implant co. ltd . , seoul , korea ) the definitive prosthesis was planned as a telescopic overdenture using paek based polymer . after a making definitive impression by polyvinylsiloxane ( honigum , dmg , hamburg , germany ) , a polymer telescopic abutment and an outer overdenture frame were fabricated with consideration of the patient 's vertical dimension ( fig . telescopic abutment and framework design were laid out by cad software ( exocad dental cad , exocad gmbh , darmstadt , germany ) . the milling machine ( s1 , vhf camfacture ag , ammerbuch , germany ) made the final framework and abutment according to the design . polymer abutment and titanium link were sandblasted by 110 um grit aluminum oxide , and bonded with primer ( sr link , ivoclar vivadent , schaan , liechtenstein ) and bonding agent ( multilink n , ivoclar vivadent , schaan , leichtenstein ) . after that , the definitive prosthesis was made by autopolymerized pour - type resin ( press lt , retec , rosbach , germany ) ( fig . 4 ) ; the design and weight of the prosthesis were adjusted to achieve acceptable esthetics and phonetics . after 6 months , there were no problems with alveolar bone around the implant fixtures and retention of the overdenture prosthesis . however , no treatment modality meets all criteria for successful treatment , and conventional overdenture material can sometimes be limited by economic , functional , and technical considerations . now , many new prosthetic materials are available to overcome these limitations , and as in this case , a new polymer can be used to make telescopic crowns and frameworks to obtain satisfactory results . paek based polymer , pekkton ivory , as used in this case , is a member of the high performance semi - crystalline thermoplastic resin group , recognized for its keto and ether group ratio . paek has good dimensional stability at high temperature , high chemical and mechanical resistance against wear , and high tensile , fatigue and flexural strength , making it an attractive material with expanded uses in medicine and dentistry.3 however , peek ( polyetheretherketone ) , a conventional paek - based polymer , can not be used as a permanent material due to its relatively weak physical properties . a new material , pekkton , is mainly composed of pekk ( polyetherketoneketone ) ; its molecular structure has an added ketone to the structure of peek with and has a wide range of uses due to its amorphous and crystalline structure . pekk reveals up to 80% greater compressive strengths than peek , so this polymer may be used in permanent prostheses according to the manufacturer.4 thus , this new polymer can be considered to have greater strength than peek and have greater esthetics titanium , higher resin bond strength than zirconia , and a lighter weight ( 1.4 g / cm ) than metal . therefore , this material is found to be mechanically suitable for fpd frameworks , milled overdenture bars , clasps , telescopic crowns , and other applications . despite the reportedly good bond strength , bonding between the titanium link and the telescopic abutment is still very sensitive , with the risk of fracture of the thin abutment wall due to connecting titanium link ; hence more studies are needed on such cases . she reported satisfaction with its strength and esthetics , and no negative symptoms . due to the lack of evidence on the long term retentive capabilities of this material , due to its functional and economic advantages , paek based polymer is a good alternative material to conventional materials and methods in the fabrication of implant overdenture . OUTPUT:

although many prosthetic materials exist for fabrication of implant - supported telescopic overdentures , available materials have not been thoroughly evaluated from a functional standpoint . this case report describes the use of polyaryletherketone ( paek ) based polymer for an implant - supported telescopic overdenture , a seldom used material in dentistry . this material is lighter than traditional materials , can accommodate changes in retentive forces , and is an easily retrievable by cad / cam fabrication . this case highlights the possibility of using new polymer materials for implant - supported telescopic overdentures .

PubMed_Summ6541

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the question of structural and mechanical alterations of the arterial wall in the case of renal transplantation has not yet been completely resolved . an insufficiency of endogenous regulators of calcium and phosphate is well known to be a significant factor affecting extraosseous calcifications.1 in dialysis patients and kidney transplant patients , volume overload and disturbances of calcium and phosphate metabolism add to the atherogenic profile , and these serve as independent risk factors for cardiovascular mortality.2 the presence of arterial calcifications was strongly and independently predictive of the outcome in end - stage renal disease ( esrd).3 on this basis , estimating the arterial stiffness ( as ) in esrd is of great interest . measuring the pulse - wave velocity ( pwv ) is a reliable means of determining the as.4,5 there are several studies of pwv in patients with renal transplantation.69 notably , 24-hour pwv analysis has not yet been conducted in adults . meanwhile , some modern devices for ambulatory blood pressure monitoring ( abpm ) allow the assessment of some as indices , and the approach to the analysis of these indices may be quite similar to that of abpm.10 accordingly , the aim of our study was to assess the feasibility of this approach in the management of patients with renal transplantation . overall , 41 patients were recruited from the kidney transplant waiting list of the privolzhsky district medical center in nizhniy novgorod , russia . the inclusion criteria were the following : age between 18 years and 55 years , esrd resulting from nondiabetic glomerulopathy ( glomerular filtration rate < 15 ml / min per 1.73 m ) , and candidate for a first kidney transplant . patients with a history of prior kidney transplant or who were candidates for a kidney - pancreas transplant were excluded from the study . the additional exclusion criteria were cardiac rhythm disturbances , body mass index higher than 35 kg / m , severe dyslipidemia , and unstable clinical presentation . our study group included 27 ( 65.8% ) men and had a mean age of 35.2 years , with a mean systolic blood pressure of 134 mmhg , mean diastolic blood pressure of 86 mmhg , and mean heart rate of 74 beats per minute . all the patients were receiving dialysis at enrollment , including 40 by hemodialysis and one by peritoneal dialysis . management of patients included the monitoring of calcium and phosphate serum levels and their correction . all measurements were performed before kidney transplantation and at 1 and 20 weeks after transplantation . approval for the study was obtained from the local research ethics committee , and written informed consent was obtained for each participant . the vasotens technology is an innovative method used for pulse - wave analysis based on oscillometric blood pressure measurements , using the bplab ( nizhniy novgorod , russia ) device for abpm.11,12 the technology was developed by the petr telegin company in nizhniy novgorod , russia . the recordings are made using a conventional blood pressure cuff for adults . during the blood pressure measurement , the pressure waveforms in the cuff are registered while performing a step - by - step deflation . the separation and timing of the forward and reflected pulse waves are determined by a special mathematical algorithm . the distance for the pwv equation used by the vasotens was measured according to the bplab user s guide requirements . the quality control method consists of a visual assessment of the curves in the vasotens clinical report screen . the pulse time index of norm ( ptin ) is calculated by the vasotens for the estimation of the 24-hour pwv . the principle of the ptin calculation is where tm is the entire period of monitoring and t1 , t2 , and tn represent the periods in which the pwv does not exceed the cut - off value of 10 m / second . essentially , all the data are shown as the mean and standard deviation ( sd ) . we used bpstat software , version 05.00.04 ( bplab ) to tabulate all the indices of every measured 24-hour waveform automatically . overall , 41 patients were recruited from the kidney transplant waiting list of the privolzhsky district medical center in nizhniy novgorod , russia . the inclusion criteria were the following : age between 18 years and 55 years , esrd resulting from nondiabetic glomerulopathy ( glomerular filtration rate < 15 ml / min per 1.73 m ) , and candidate for a first kidney transplant . patients with a history of prior kidney transplant or who were candidates for a kidney - pancreas transplant were excluded from the study . the additional exclusion criteria were cardiac rhythm disturbances , body mass index higher than 35 kg / m , severe dyslipidemia , and unstable clinical presentation . our study group included 27 ( 65.8% ) men and had a mean age of 35.2 years , with a mean systolic blood pressure of 134 mmhg , mean diastolic blood pressure of 86 mmhg , and mean heart rate of 74 beats per minute . all the patients were receiving dialysis at enrollment , including 40 by hemodialysis and one by peritoneal dialysis . management of patients included the monitoring of calcium and phosphate serum levels and their correction . all measurements were performed before kidney transplantation and at 1 and 20 weeks after transplantation . approval for the study was obtained from the local research ethics committee , and written informed consent was obtained for each participant . the vasotens technology is an innovative method used for pulse - wave analysis based on oscillometric blood pressure measurements , using the bplab ( nizhniy novgorod , russia ) device for abpm.11,12 the technology was developed by the petr telegin company in nizhniy novgorod , russia . the recordings are made using a conventional blood pressure cuff for adults . during the blood pressure measurement , the pressure waveforms in the cuff are registered while performing a step - by - step deflation . the separation and timing of the forward and reflected pulse waves are determined by a special mathematical algorithm . the distance for the pwv equation used by the vasotens was measured according to the bplab user s guide requirements . the quality control method consists of a visual assessment of the curves in the vasotens clinical report screen . the pulse time index of norm ( ptin ) is calculated by the vasotens for the estimation of the 24-hour pwv . the principle of the ptin calculation is where tm is the entire period of monitoring and t1 , t2 , and tn represent the periods in which the pwv does not exceed the cut - off value of 10 m / second . essentially , all the data are shown as the mean and standard deviation ( sd ) . we used bpstat software , version 05.00.04 ( bplab ) to tabulate all the indices of every measured 24-hour waveform automatically . the ptins in different periods before and after renal transplantation are illustrated in figure 1 . as shown in figure 1 , before kidney transplantation as our analysis showed , this value did not depend on the duration of the history of the disease or the time of the interdialysis period at which the monitoring was performed . then , a week after the renal transplantation , we observed a decrease in the ptin in most cases . the mean ptin in the whole group at this period was 27.6 ( sd , 11.1 ) . after 20 weeks , the mean ptin in the whole group increased again to 52.0 ( sd , 23.6 ) , but the detailed analysis showed that those patients who had a higher value of ptin before transplantation had a higher increase at this time . using the receiver operating characteristic curve , we determined the cutoff value of ptin that could predict the two ptin states : a state of improvement or a state of decline / without change ( figure 2 ) . the cutoff value of ptin at 45% had a sensitivity of 69% , specificity of 76% , and area under the curve of 0.65 to predict these states . for the detailed baseline characteristics of the patient groups separated according to this cut - off point , please see table 1 . as shown in table 1 , there was no significant difference between the groups for almost all characteristics except the ptin . the difference in preoperative dialysis period ( p = 0.0405 ) and the tendency toward a difference in age ( p = 0.0590 ) should be noted . the ptin at different periods before and after renal transplantation in the groups with ptin of 45% or higher or less 45% is illustrated in figure 3 . the analysis of variance showed that in the first group , the ptin changed significantly ( p < 0.05 ) , whereas in the second group , the ptin was not significantly different . the effect of renal transplantation on blood pressure ( table 2 ) was similar to the effect on the ptin . some authors have noted an improvement in the as after kidney transplantation.68 a number of studies have shown that after kidney transplantation , the disturbances in calcium and phosphate metabolism improve in general , but the media calcification , structural alterations of the arterial wall , and disturbed mechanical vessel wall properties persist.9,1315 in our study , we found that the persistence of these disturbances after kidney transplantation appears to be relatively predictable : there are clear differences in the clinical conditions of patients who develop an excess in the pwv over the cutoff value for either a small or large percentage of the monitoring period . if ptin is 45% or higher before kidney transplantation , there appears to be a good chance that the ptin will improve in the remote period after transplantation . this improvement is particularly important for the management in the initial period after implantation , when increased damage to the arterial wall , resulting in a decreased ptin in most patients , is observed . it is known that the prevalence of postoperative hypertension in patients with renal transplantation is high , and this is one reason for an aggressive therapeutic approach by physicians , reflected by administering more antihypertensive medications.16 the ptin seems to give us an opportunity to optimize this approach . regarding the influence of hemodialysis on the variability of the pwv , a study in which the measurements were performed immediately before ( pre ) and 1 hour after ( post ) the end of each dialysis session should be noted . cyclic intradialysis changes in the pwv were similar during the three dialysis sessions ; as a consequence , all postdialytic pwv values were lower with respect to the predialytic levels.17 as our analysis showed , the ptin did not depend on the time of the interdialysis period at which the monitoring was performed . in our opinion , this mismatching is a result of the smoothing effect of the nocturnal pattern of pwv in ptin , which integrates the pwv values over the course of 24 hours . thus , the analysis of the 24-hour pulse wave velocity in the management of patients with renal transplantation using ptin is feasible . OUTPUT:

the aim of our study was to assess the feasibility of using an approach to 24-hour pulse wave velocity ( pwv ) analysis similar to ambulatory blood pressure monitoring analysis in the management of patients with renal transplantation . overall , 41 patients aged between 18 and 55 years who had end - stage renal disease resulting from glomerulopathy were recruited from the kidney transplant waiting list . all the measurements were performed before kidney transplantation and at 1 and 20 weeks after transplantation . the pulse time index of norm ( ptin ) was calculated with the vasotens technology for the estimation of the 24-hour pwv , defined as the percentage of the 24-hour period during which the pwv does not exceed 10 m / second . before kidney transplantation , the mean ptin in the whole group was 56.3 ( standard deviation , 18.4 ) . then , a week after the renal transplantation , a decrease in the ptin was observed in most cases , going to 27.6 ( standard deviation , 11.1 ) . after 20 weeks , the mean ptin in the whole group increased again to 52.0 ( standard deviation , 23.6 ) . in our study , we found that the persistence of arterial stiffness disturbances after kidney transplantation appears to be relatively predictable . we determined the cutoff value of ptin that could predict the two states of ptin : a state of improvement or a state of decline / without change . the cutoff value of ptin at 45% had a sensitivity of 69% , specificity of 76% , and area under the curve of 0.65 . the analysis of variance showed that in the group with an initial ptin of 45% or higher , the ptin in the remote period after transplantation changed significantly ( p < 0.05 ) , whereas in the group with an initial ptin lower than 45% , there were no significant changes . thus , the analysis of 24-hour pulse wave velocity in the management of patients with renal transplantation using ptin is feasible .

PubMed_Summ6542

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: xanthogranulomatous pyelonephritis ( xgp ) is a rare , distinct and aggressive form of chronic infectious pyelonephritis . it accounts for lesser than 1% of chronic pyelonephritis . though common in fifth to sixth decade complications can occur in the form of psoas abscess , nephro cutaneous fistula , enterocolonic fistula , paranephric abscess and sepsis . it is essential to suspect and diagnose this condition early to prevent the morbidity and mortality . owing to its rarity and clinical curiosity a 75-year - old man presented with difficulty in micturition since 15 days , fever , abdominal and flank pain and burning micturition since 7 days . x - ray , ultrasonography ( usg ) and computed tomography ( ct ) scan abdomen findings include pyonephrosis and cortical atrophy in the right kidney . intravenous urography ( ivu ) revealed non - excretory right kidney . left kidney showed normal excretion resected specimen was yellowish lobulated renal mass measuring 13 8 6 cm with ureter [ figure 1a ] . cut section showed dilated pelvis , calyces and cortical atrophy due to extensive destruction of renal parenchyma , which were covered with thick purulent material [ figure 1b ] . histopathology revealed atrophic and dilated renal tubules showing thyroidisation and sclerosed glomeruli and interstitial fibrosis [ figure 2 ] . many areas showed histiocytes with abundant foamy cytoplasm , lymphoplasmacytic inflammatory cells with foci of polymorph nuclear leukocytes [ figure 3 and inset ] ziehl nelsen stain was negative for acid fast bacilli . ( a ) yellowish lobulated renal mass with ureter ; ( b ) dilated pelvis , calyces and cortical atrophy covered with thick purulent material atrophic and dilated renal tubules showing thyroidisation , sclerosed glomeruli and fibrosis . inset show giant cells and cholesterol clefts ( h and e , 400 ) foamy histiocytes , inflammatory cells . xgp is a severe chronic renal inflammatory condition leading to focal or diffuse kidney destruction . it may be due to defect in degradation of bacteria in the macrophages especially when associated with infection and obstruction by stones . three forms of xgp are recognised : diffuse is characterized by diffuse involvement of kidney , segmental by segmental involvement and focal - is located within the cortex . it is often misdiagnosed pre - operatively as pyelonephritis , tuberculosis , perinephric abscess and renal cell carcinoma ( rcc ) . symptoms include flank or abdominal pain , fever , palpable mass , gross hematuria , pyuria , dysuria and weight loss . in our case , symptoms were attributed to bph . other organisms include staphylococcus aureus , group b streptococcus , candida , klebsiella and bacteroides . elevation of serum creatinine and bun in our case can be attributed to impaired renal function . non - functioning , ct scan is the main stay of diagnostic imaging for xgp . xgp has been shown to be associated with transitional cell carcinoma of renal pelvis and rcc . they have even been reported in renal allograph . in diffuse or advanced stage xgp , nephrectomy is the treatment option . focal or segmental xgp if diagnosed early pre - operatively can be treated with antibiotics . pre- and post - operative broad spectrum antibiotics and symptomatic management are also key factors for successful management and better prognosis . we presented this unusual case of elderly male to stress the importance of through evaluation of renal function who gave a history of recurrent urinary tract obstruction and infection . chronic renal infection and obstruction are two common etiological factors for xgp . in all patients of prostatic enlargement , renal function must be assessed for the extent of damage . in non - functioning kidney OUTPUT:

xanthogranulomatous pyelonephritis ( xgp ) is rare and aggressive form of chronic infectious pyelonephritis . no single clinical or radiological feature is diagnostic of xgp . a 75-year - old man with prostatic enlargement presented with difficulty and burning micturition fever , abdominal and flank pain . x - ray , ultrasonography and computed tomography scan diagnosis was right kidney pyonephrosis . intravenous urography revealed non - excretory right kidney . right nephrectomy was done . histological diagnosis of xgp was made . in all patients of prostatic enlargement , renal function must be assessed for the extent of damage . surgery is the treatment choice in most cases . pre- and post - operative antibiotics are key factors for successful management and better prognosis .

PubMed_Summ6543

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: infectious complications , especially bloodstream infections ( bsis ) , are major causes of morbidity and mortality among patients who suffered from malignant hematological diseases and treated with intensive chemotherapeutic regimens [ 1 , 2 ] . in these clinical settings , bacterial cultures from blood are of great diagnostic value and the gold standard to detect bloodstream infections ; in addition to this , the results of blood cultures provide epidemiological data which are useful to determine empiric antibiotic therapy . however , the diagnosis of bsis is still challenging in this patient group , because about half of all bsi cases are culture negative mainly because of the frequently used prophylactic antibiotics . to overcome the inhibitory effect of antibiotics , special blood culture bottles containing resin have been developed ; thus , modest increase in the sensitivity of culture has been achieved . in the early 1970s , introducing empiric treatment protocols and antibiotic prophylaxis , increasing use of certain chemotherapeutic drugs associated with frequent oral mucositis , and frequent use of central venous catheters have changed the spectrum of pathogens in febrile neutropenic patients shifting it from gram - negative to gram - positive bacteria , especially viridans group streptococci and coagulase - negative staphylococci [ 36 ] . the aim of this study was to evaluate occurrence of bacterial species causing bloodstream infections due to febrile neutropenic episodes in the hematology ward of the university hospital in szeged , hungary , between 2005 and 2008 . between 2005 and 2008 , 469 patients with febrile neutropenia ( 230 females and 239 males , median age 60 years ) were observed in our department with various hematological diseases . collected data from patients documentations included demographics of patients , diagnosis , febrile episodes , source of fever and source of infection , neutrophil count , and clinical significance of the isolated organism . infectious complications were categorized into three groups : 1 fever of unknown origin ( fuo ) , 2 microbiologically documented infection ( mdi ) , and 3 clinically documented infection ( cdi ) . febrile neutropenia was defined if a single oral temperature was measured higher than 38.3 c , or temperature was 38.0 c or higher for 1 h. neutropenia was defined as absolute neutrophil count ( anc ) less than 0.5 10/l or less than 1.0 10/l and rapidly declined below 0.5 10/l . a single positive blood culture ( bc ) common skin contaminants ( cns , propionibacteria ) were considered significant only if they could be found in two consecutive bc samples or if there were concurrent skin , soft tissue , or catheter - related infections . bsi was defined as polymicrobial if more than 1 bacteria grew from bc on the same day . medical database of patients was used to collect information on the hematologic diseases , presence of febrile neutropenic episode , duration of neutropenia , and source of infection . bc samples were taken at the onset of fever . in patients having central venous catheters , bcs for collection of blood culture , the blood culture system ( bd bactec , beckton dickinson , usa ) including aerobic , anaerobic bottles , and bottles for fungi was used . after taking blood , bottles were immediately placed in an incubator , where these were incubated for 514 days depending on the type of the putative pathogens . in the case of positive signal produced by the instrument on the basis of bacterial or fungal growth , microscopic examinations ( phase contrast microscopy and examination of gram - stained preparations ) and columbia blood agar supplemented with 5% sheep blood ( biomrieux , marcy letoile , france ) , chocolate agar supplemented with poly - vitex ( biomrieux , marcy letoile , france ) , eosin methylene blue ( lab m , uk ) and sabouraud chloramphenicol ( bio - rad , france ) agars , and , for anaerobic culture , schaedler agar supplemented with 5% sheep blood ( bio - mrieux , marcy letoile , france ) were inoculated with one drop of blood . plates were incubated at 37 c for 24 h in a 5% co2 incubator or 37 c for 24 h under normal atmosphere or at 37 c for 48 h in an anaerobic cabinet ( concept 400 ; ruskinn technology ltd . , bridgend , uk ) under a gas composition of 85% n2 , 10% h2 , and 5% co2 . from pure culture , antibiotic susceptibility tests were performed on the basis of clinical laboratory standard institute recommendations [ 811 ] . at the onset of fever , after taking bc , broad spectrum antibiotics were started empirically ( piperacillin tazobactam , cefepime , and imipenem or meropenem ) . changes in empiric antibiotic therapy depended on bc results and clinical response . in afebrile and culture - negative patients with stable clinical state , empiric antibiotic treatment was continued until anc reached 500/l . vancomycin was used in patients with central venous devices , persistent fever , and hypotension . on day 45 , in patients with persistent fever suggesting fungal infection on the basis of clinical signs and computed tomography ( ct ) scans , amphotericin b was applied . between 2005 and 2008 , 469 patients with febrile neutropenia ( 230 females and 239 males , median age 60 years ) were observed in our department with various hematological diseases . collected data from patients documentations included demographics of patients , diagnosis , febrile episodes , source of fever and source of infection , neutrophil count , and clinical significance of the isolated organism . infectious complications were categorized into three groups : 1 fever of unknown origin ( fuo ) , 2 microbiologically documented infection ( mdi ) , and 3 clinically documented infection ( cdi ) . febrile neutropenia was defined if a single oral temperature was measured higher than 38.3 c , or temperature was 38.0 c or higher for 1 h. neutropenia was defined as absolute neutrophil count ( anc ) less than 0.5 10/l or less than 1.0 10/l and rapidly declined below 0.5 10/l . a single positive blood culture ( bc ) common skin contaminants ( cns , propionibacteria ) were considered significant only if they could be found in two consecutive bc samples or if there were concurrent skin , soft tissue , or catheter - related infections . bsi was defined as polymicrobial if more than 1 bacteria grew from bc on the same day . medical database of patients was used to collect information on the hematologic diseases , presence of febrile neutropenic episode , duration of neutropenia , and source of infection . bc samples were taken at the onset of fever . in patients having central venous catheters , bcs were taken from both central and peripheral veins . for collection of blood culture , the blood culture system ( bd bactec , beckton dickinson , usa ) including aerobic , anaerobic bottles , and bottles for fungi was used . after taking blood , bottles were immediately placed in an incubator , where these were incubated for 514 days depending on the type of the putative pathogens . in the case of positive signal produced by the instrument on the basis of bacterial or fungal growth , microscopic examinations ( phase contrast microscopy and examination of gram - stained preparations ) and columbia blood agar supplemented with 5% sheep blood ( biomrieux , marcy letoile , france ) , chocolate agar supplemented with poly - vitex ( biomrieux , marcy letoile , france ) , eosin methylene blue ( lab m , uk ) and sabouraud chloramphenicol ( bio - rad , france ) agars , and , for anaerobic culture , schaedler agar supplemented with 5% sheep blood ( bio - mrieux , marcy letoile , france ) were inoculated with one drop of blood . plates were incubated at 37 c for 24 h in a 5% co2 incubator or 37 c for 24 h under normal atmosphere or at 37 c for 48 h in an anaerobic cabinet ( concept 400 ; ruskinn technology ltd . , bridgend , uk ) under a gas composition of 85% n2 , 10% h2 , and 5% co2 . from pure culture , antibiotic susceptibility tests were performed on the basis of clinical laboratory standard institute recommendations [ 811 ] . at the onset of fever , after taking bc , broad spectrum antibiotics were started empirically ( piperacillin tazobactam , cefepime , and imipenem or meropenem ) . changes in empiric antibiotic therapy depended on bc results and clinical response . in afebrile and culture - negative patients with stable clinical state vancomycin was used in patients with central venous devices , persistent fever , and hypotension . on day 45 , in patients with persistent fever suggesting fungal infection on the basis of clinical signs and computed tomography ( ct ) scans , amphotericin b was applied . during the four - year study period , 1,361 patients were treated in the hematology ward because of various hematological diseases . a total of 812 febrile episodes were recorded in 469 ( 34.5% ) patients , and blood was collected for microbiological culture . of the 469 patients , 128 ( 27.3% ) had acute myeloid leukemia , 85 ( 18.1% ) non - hodgkin s lymphoma , 66 ( 14.1% ) multiple myeloma , 64 ( 13.6% ) chronic lymphocytic leukemia , 41 ( 8.7% ) acute lymphoblastic leukemia , and 85 ( 18.1% ) others ( hodgkin s lymphoma , myelodysplastic syndrome , chronic myeloprolipherative disorders etc . ) ( table 1 ) . altogether , 3,714 blood culture bottles , 6.5 bottles / patient ( ranging 212 ) , were sent to the laboratory . in 126 ( 27% ) of 469 patients , only one pair of blood culture bottles was taken by febrile episodes . clinically documented infections could be observed in 430 of 812 febrile episodes ( 52.95% ) . colitis and skin and soft tissue infections were the second and third most common infections . during the microbiological culture , 759 ( 20.4% ) of 3,714 blood culture bottles gave positive signals . from the majority of positive blood culture bottles ( 509 bottles ( 67.1% ) ) , gram - positive bacteria were cultured . among gram - positive bacteria , the most frequent isolates were coagulase - negative staphylococci ( 65% ) , staphylococcus aureus ( 10% ) , enterococcus spp . ( 6.7% ) , popionibacterium acnes ( 5.7% ) , -hemolytic streptococci ( 3.1% ) , streptococcus pneumoniae ( 2.8% ) , -hemolytic streptococci ( 2.4% ) , clostridium spp . ( 1.4% ) , and others ( 3% ) ( including listeria monocytogenes , nocardia farcinica , gemella spp . , micrococcus spp . , brevibacterium spp . , and gram - positive nonidentified bacteria ) high prevalence of escherichia coli ( 52% ) could be detected in these specimens , while 14% of samples contained pseudomonas aeruginosa , 9.6% klebsiella spp . , 8% enterobacter spp . , 3.6% citrobacter spp . , 2% stenotrophomonas maltophilia , 1.6% acinetobacter spp . , and 1.6% fusobacterium spp . only six bottles proved to be positive for fungi during the examined period ; in two cases , candida albicans and also , in two bottles , candida tropicalis could be detected , while two other bottles were positive for cryptococcus spp . among gram - positive isolates , coagulase - negative staphylococci ( cns ) were identified in 331 cases . these blood culture samples were collected from 161 febrile episodes of 149 patients . in 50 febrile neutropenic episodes , cns were relevant as a causative agent of fever because of the coexistence of skin , soft tissue , and central venous catheter - related infections . in the case of the remaining 111 cases , contamination could be the source of cns . among rarely isolated pathogens , listeria sp . was identified from one patient with acute myeloid leukemia ( aml ) due to second relapse in 2006 . the patient had clinically documented pneumonia and was treated with ampicillin . in 2006 and 2008 , blood culture sample was taken from peripheral vein . in this case , the patient was treated empirically with levofloxacin . the other patient suffered from relapsed hodgkin lymphoma and was treated according to eshap chemotherapeutic regimen ( combination of high - dose cytosine - arabinosid , methylprednisolone , cisplatin , and etoposide ) through the central venous line . two pairs of blood culture samples were taken due to febrile episode from catheter , and b. cepacea was grown from each samples . n. farcinica was isolated from a patient with large granular lymphocytic ( lgl ) leukemia . he underwent six cycles of combined chemotherapeutic treatment ( cyclophosphamide , vincristine , and prednisolone ) and later had long term steroid therapy due to coombs positive hemolytic anemia and active hemolytic events . on hospital admission , ct scan showed multiple lesions with perifocal oedema , but stereotactic core biopsy from lesions could not be performed because of the patient s severe clinical status . from one pair of blood culture , n. farcinica was isolated , but the patient died before adequate therapy could start . during the examined period , four cases of bacteremia caused by fusobacterium nucleatum two patients had acute myeloid leukemia , one patient had acute myelomonocytic leukemia , and one patient suffered from pre - b - cell lymphoblastic leukemia . two patients received chemotherapy before positive blood culture ; one of them had oral mucositis associated with the applied chemotherapy . this may have influence on the applied chemotherapy ; dose reduction or treatment delays can be observed frequently when febrile neutropenia is present , and this also has unfavorable long - term outcome in otherwise curable malignancy . bloodstream infections are among the most important bacterial infections , despite the development in the field of microbiological diagnosis and antimicrobial therapy ; these infections are responsible for the large proportion of nosocomial infections worldwide . in the early 1960s , the importance of bloodstream infection in neutropenic patients had been recognized ; thus , empirical treatment protocols were established for mainly gram - negative bacteria . later , the spectrum of pathogens associated with bsi shifted from gram - negative bacteria to gram - positive bacteria due to the increased use of antibiotic prophylaxis and indwelling catheters allowing colonizations and infections with the skin flora . nowadays , the most common pathogens isolated from blood are coagulase - negative staphylococci and various antibiotic - resistant bacteria . in the majority of cases , the source of these infections is unknown in spite of various efforts to find them . recognition of changes in the epidemiology of bsis is very important to modify the antibiotic policy because , on the basis of these findings , we can reduce the infection - related morbidity and mortality [ 15 , 16 ] . during the four - year study period , the incidence of bacteremia was 20.4% . showed that the incidence of bacteremia was 23% when they examined over two thousand patients with febrile neutropenia in cancer patients , while viscoli et al . found that bacteremia occurred in 29% of patients with febrile neutropenia [ 17 , 18 ] . our findings correlated with the abovementioned literature data because , from the majority of blood culture bottles ( 13.7% ) , gram - positive bacteria were isolated . sixty - five percent of gram - positive bacteria belonged to coagulase - negative staphylococci . however , in a study by winston et al . in north america , gram - negative bacteria ( 55.6% ) were responsible for the majority of bacteremia in febrile neutropenic patients . at the same time , other authors from italy or france showed that the most important isolates in neutropenic patients are gram - positive bacteria , including coagulase - negative staphylococci or streptococci , while gram - negative organisms including e. coli or klebsiella spp . and p. aeruginosa constitute smaller portion of the isolates [ 20 , 21 ] . in our case , the most frequently used empirical treatment in this patient group is piperacillin tazobactam or , if the patient has colitis or the possibility of abdominal infection is arisen , imipenem or meropenem is the frequently used antibiotic . thus , the increased incidence of gram - positive bacteria can be explained by the applied empirical antibiotic treatment , while the presence of coagulase - negative staphylococci could be attributed to the frequently used central venous catheters . the incidence of bacterial species in blood cultures can be influenced by the applied chemotherapy . in our case , 30% of patients with acute leukemia received high - dose ara - c chemotherapy , and 15% and 12% of patients were treated with fludarabin and ara - c plus idarubicin , respectively . on the basis of literature data , increasing prevalence of gram - positive cocci in febrile neutropenic patients could be observed after highdose cytarabine chemotherapy ; this was confirmed by our results . showed that the prevalence of staphylococci is higher than the prevalence of streptococci and enterococci in febrile neutropenic patients . similarly , our results confirmed this because , among gram - positive bacteria , the majority of the isolated strains were coagulase - negative staphylococci ; 6.7% and only 2.4% of gram - positive bacteria belonged to enterococcus spp . and -hemolytic streptococci , respectively . a total of 331 blood culture samples proved to be positive for coagulase - negative staphylococci and were collected from 161 febrile episodes of 149 patients . in 50 febrile neutropenic episodes , coagulase - negative staphylococci were relevant pathogen of fever because of the coexistence of skin , soft tissue , and central venous catheter - related infection . the remaining 111 cases were supposed to be contamination . from 32.9% of positive blood cultures bottles , gram - negative bacteria were cultured ; the majority of these proved to be positive for e. coli ( 52% ) . the second most common isolate was p. aeruginosa ( 14% ) , while the third one was klebsiella spp . in this review , the results of four articles were analyzed , and , among gram - negative organisms , the most important pathogens were also e. coli , klebsiella spp . , and p. aeruginosa . among rarely isolated bacteria , achromobacter xylosoxidans and burkholderia cepacia are usually associated with catheter - related sepsis , while s. maltophilia can cause mainly nosocomial bacteremia and the possible source of haemophilus influenzae , neisseria spp . , and gemella spp . because of the possible presence of unusual pathogens , such as anaerobic bacteria or fastidious microorganisms , the use of various blood culture bottles including anaerobic bottles should be considered . because of its rapid progression of infection in febrile neutropenic patients and difficulties in distinguishing infection from noninfected patients on the basis of clinical presentation in this patient group , the use of empirical antibiotic treatment is essential and may provide the possibility to reach better outcome . OUTPUT:

from year to year , it is important to get an overview of the occurrence of causative agents in febrile neutropenic patients to determine the empiric treatment . thus our aims were to evaluate a four - year period regarding the prevalence of bloodstream infections and the most important causative agents . during this period , 1,361 patients were treated in our hematology ward because of various hematological disorders . 812 febrile episodes were recorded in 469 patients . at that time , 3,714 blood culture ( bc ) bottles were sent for microbiological investigations , 759 of them gave positive signal . from the majority of positive blood culture bottles ( 67.1% ) , gram - positive bacteria , mainly coagulase - negative staphylococci ( cns ) , were grown . gram - negative bacteria were isolated from 32.9% of the positive blood culture bottles , in these cases the leading pathogen was escherichia coli . the high prevalence of cns was attributed to mainly contamination , while lower positivity rate for gram - negative bacteria was associated with the use of broad - spectrum empiric antibiotic treatment .

PubMed_Summ6544

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: research indicates that many sami became reindeer herders in the early 17th century , as a response to a population crisis ( 9 ) . this transition coincided with the swedish state 's increased interest in spmi , the distant regions of the north which were the sami 's traditional lands . courts were held annually , market places were built , and the first printed books in the sami language appeared ( 10 ) . further interest in the area was stirred in the late 17th century by the discovery of silver , but the mining epoch lasted for only 50 years . the sami remained very isolated , not only because of their economy and culture but also because of the great distances between households and the intense cold of the region for most of the year . at the end of the 17 century , the state also tried to encourage settlers to move to the area , offering free land , and 15 years free from taxes . this had , however , a limited impact on in - migration , a trend that did not change until the mid-18th century . during the following 100 years , the ethnic balance in spmi changed , turning the sami into a position as minority in their own lands . omran 's essay on the epidemiological transition , modeling societies change from high mortality due to infectious diseases to low mortality caused by chronic diseases , has had a great impact on the public health community and stirred research in a variety of disciplines ( 12 , 13 ) . indigenous peoples were not mentioned in his work , but few researchers would dispute that the indigenous populations of the world experienced demographic transitions much later than non - indigenous populations . however , although an indigenous demographic or health transition is generally acknowledged , due to lack of longitudinal data , it is rarely examined ( 14 , 15 ) . the main source material used for the present study is a set of data files from the demographic database ( ddb ) at ume university , one of the world 's most information - dense historical population databases . a recent addition to the ddb are 18th and 19th century parish records from spmi . the longitudinal database includes every individual in the parishes during the period when the area was colonized , largely by swedish settlers , and the sami population changed from a majority to a minority . the source material separates the sami and the settler populations and contains information on , for instance , sex , age , cause of death , migration , and fertility . each individual can be followed from the cradle to the grave allowing the reconstruction of life biographies and family composition based on ethnic categorization ( table 1 ) . working sample and missing cases individuals born in 17501895 . because data quality is poor in the earlier years , the time period has been restricted to 17501895 . only infants born within the study area and with a known birth day have been included . infant mortality is calculated by the number of deaths within the first year of life during a time period divided by the number of live births during the same period . when calculating infant mortality and making comparisons with swedish national data , 10 year intervals were used ( 16 ) . the risk of infant mortality is modeled as a cox proportional hazard model with ethnicity , sex , parity , birth season , and birth period as the explanatory covariates . 1 ) . map of sweden , including the parishes of jukkasjrvi , jokkmokk , and fllinge . sami live in four countries , speak nine different languages , and are diversified by reindeer - herding techniques , social organization , and economic resources . until the early 19th century , sami land rights were legally protected , but then a more repressive state policy replaced the sami traditional division and use of land with a national administrative system ( 17 ) . the present study includes three parishes where sami were in a great majority around 1750 . the church registers of jukkasjrvi and jokkmokk in the north sami area contained both sami and swedish settlers , whereas fllinge sami parish in the south sami area was an administrative construction exclusively for the indigenous population in the area . the magnitude and timing of colonization differed between the parishes . in the northernmost parish of jukkasjrvi , sami were in majority throughout the period 17501900 . until 1850 , there are around 400 non - sami and 1000 sami , and both groups experienced a population increase from 1880 , settlers more than the indigenous . we believe that the parish of jokkmokk is more representative of the sami parishes in general , where an ethnic majority shift occurred around 1830 , moving in a frontier wave from the south to the north . in the parish of fllinge , the ethnic majority shift came earlier : from the late 18th century , there were more non - sami than sami in the area , and the change accelerated so that at the end of the period there were almost 10 times as many swedes as sami . previous research has to a large extent exclusively counted the reindeer herding nomads in the sami group . there was , however , an ethnic complexity in the north already during the early stages of colonization , and not all sami were nomadic reindeer herders ; large groups were hunters or farmers , and during the period , many sami took up residence in settlements , becoming settlers but still sami , sometimes recorded as sami - settlers [ lappnybyggare ] in the parish registers . all these groups are included as sami in our study , resulting in a sami population larger than normally stated . this has been done to create a more in situ-oriented demography ( 18 ) . we have combined the ethnic markers in the sources using a system designed by the historian gabriella nordin in her dissertation on marriage patterns in spmi 17501900 and also presented in skld and axelsson ( 5 , 11 ) . a complementary source of information about infant mortality is the annual reports of the district physicians in the area . however , the doctors were not well acquainted with the conditions among the sami , and the reports often give laconic and judgemental descriptions of sami health . previous studies of sami mortality have revealed considerably higher rates from 1750 to1900 compared with non - sami , both in spmi and in sweden generally ( 4 , 5 , 19 ) . by contrast , the second half of the 20th century shows no ethnic mortality differences ( 3 ) . this is consistent with the occurrence of a delayed indigenous demographic and epidemiologic transition ( 20 ) , and because infant mortality is one of the early indicators of intensified change , our study aims to find evidence for declining imr among the sami before 1900 that could be interpreted as a forerunner of a general transition . long - term infant mortality trends are analyzed to compare sami and non - sami groups in the three parishes.using both northern and southern sami areas , the cultural complexity of the sami society is recognized . sex differences and seasonality are included parameters that are interpreted in terms of the varying work intensity of the reindeer nomads . parity , causes of death , and change over time are additional variables that complete the study together with an estimation of the impact of health care programs . the results are discussed from the perspective of data quality , methodological issues , and the general demographic transition in sweden . the sami have lived in spmi for thousands of years and have learned to adapt to the extreme conditions there . nevertheless , the nomadic sami lifestyle , the hazardous character of reindeer herding , and a shifting food resource resulted in a high mortality , including infant mortality . the sami were devoted parents with strong emotions and traditions attached to their children , and had developed customs for reducing risk during pregnancy , delivery , and child care . the child was believed to be endangered by evil spirits and other threats , and a newborn child was put in a skin from a newborn reindeer calf , with a piece of steel close to the infant to protect it ( 22 ) . it is universally reported by the clergy , physicians , travelers , politicians and later also expressed by the sami themselves that sami children were breast - fed for at least 2 years , and sometimes for as long as four years . during the first days after birth , before the mother produced milk , the infant was given a piece of sugar or reindeer fat in a small napkin . some sami women consumed alcohol during pregnancy but not during the last days before birth giving . however , when the infant was born , the woman was encouraged to drink quite a lot of alcohol ( 22 ) . the non - sami settlers were mostly from other parts of sweden , but sometimes from finland or norway . colonization was promoted by the state from the late 17th century , but the great explosion of in - migration occurred in the second half of the 19th century , when mining , railroads , and improved agricultural techniques offered new opportunities . from the mid-18th century , the swedish health care system tried to reduce the very high infant mortality in the country . in stockholm and other urban areas , sometimes more than half of the newborn children died within their first year of life . medical instructions were published concerning the care of infants , and district doctors were employed , even though in the 1870s it was still a rare event for someone in northern sweden to have a visit by the doctor ( 23 ) . in earlier times , the clergy were given responsibility for health care , but during the 19th century they became less and less involved . they were officially released from health duties in 1830 , and after this , their participation in medical issues in the parish was greatly reduced , although many clergy continued to assist with medical advice . from this time , midwifery services increased , although economic difficulties caused many parishes to resist official requests to employ a midwife ( 24 ) . in the early 19th century , the northern parishes had among the highest infant mortality in sweden . the imr declined over the 19th century , as a result of improved hygiene , and increased breast - feeding . in many places in sweden , instead , there was a widespread culture of artificial feeding , where undiluted and unboiled cow milk , often sour and of bad quality , replaced breast - feeding . different sorts of diarrhea were common in those areas , especially during the warm summer months . the combination of hard agricultural work that often prevented mothers from breast - feeding their infants , and the difficulties in preserving fresh milk , resulted in repeated mortality peaks from june to august . previous research has shown that high levels of artificial feeding of infants lead to higher mortality during the summer months . nevertheless , many areas in northern sweden experienced a great reduction in infant mortality during the 19th century . in some parishes , it dropped from over 50% to below 18% 50 years later ( 23 ) . swedish observers in the 18th century believed that lapland , as spmi was then known , was one of the healthiest places someone could live . it was thought that the fresh air guaranteed a long and strong life . although some clergy were afraid that the nomadic life that began soon after the birth was harmful , as were the drinking habits of the women , the sami were generally described as healthy : children were given frequent baths and infants were breast - fed for several years ( 25 ) . it was not until hellstenius in 1884 published an article on infant mortality in the counties of jmtland and hrjedalen , including the south sami area , that the extremely high infant mortality among the sami was revealed . however , hellstenius offered no explanation other than vague ideas about racial differences . later , wahlund showed a similar infant mortality among sami parishes in the northern area , twice as high as the settlers . children and adults showed no corresponding increased mortality ( 26 , 27 ) ( fig . sami infant mortality in jukkasjrvi , jokkmokk , fllinge , and sweden in 17511895 . registration before 1780 is often incomplete and the imr is unreliable . at the end of the 18th century , sami infant mortality was at the same high level as the rest of sweden , and occasionally even higher , but when the imr declined generally in sweden from 1810 , the sami in jukkasjrvi and jokkmokk stayed at high rates . the sami parish of fllinge shows considerably lower rates than the sami in the other two parishes , and until 1850 sami infants in fllinge had much lower mortality than in the rest of sweden . the trend appears to continue with only six infant deaths of 93 births during the period 18501895 . due to the low overall number of births and deaths , we have excluded 10 year averages for fllinge parish ( table 2 ) . infant mortality ( per 1000 ) in jukkasjrvi , jokkmokk , and fllinge in 17501899 source : demographic database , ume university . there is a general trend of decreasing sami infant mortality in 17501899 . in the northern parish of jukkasjrvi , sami have consistently higher imr than the rest of sweden , but the difference decreases over time . until 1850 , they also have higher rates than the non - sami in the parish , but during the second half of the century , the situation is the opposite . the non - sami in jukkasjrvi experience increased infant mortality over time . before 1850 , the non - sami in jokkmokk also have lower imr than sweden until the mid-19th century . they have an increasing imr trend over time , nevertheless their rates are lower than the sami throughout the period . in fllinge , there are insignificant imr differences between sami and non - sami , and both groups are well below the swedish average . there is an excess infant mortality for males in all three parishes , and for both sami and non - sami ( except for non - sami in fllinge ) . male and female infant mortality ( per 1000 ) in jukkasjrvi , jokkmokk , and fllinge 17501899 source : demographic database , ume university . the higher male imr is significant for both sami and non - sami in jukkasjrvi and in jokkmokk , but in fllinge only for sami . there is , however , no reason to believe that these differences have any explanatory value for the demographic transition in spmi . it was often claimed that sami families were smaller than non - sami families in the area ( 28 ) . this was often based on an assumption that a large family was an obstacle to the nomadic life of the reindeer herders ( table 4 ) . infant mortality ( per 1000 ) after parity in jukkasjrvi , jokkmokk , and fllinge 17501899 source : demographic database , ume university . in all three parishes , sami infants born as child number five or more suffered from the highest risk of dying . although we can not control for the number of older siblings that were actually alive , it seems clear that large families were less able to avoid infant mortality . the mothers who gave birth for the fifth time or more were also older than those giving birth for the first time . the health status of the mother is an important determinant of infant survival , especially during the first week . among the sami , first - born infants had the second largest risk of dying , whereas among the non - sami they experienced the greatest risk . the settlers may have lacked the well - developed traditional knowledge needed for dealing with the cold climate and other risks specific to the northern inland area . both ethnic groups in all parishes had the lowest risks for mortality for infants born as number two , three , or four in the birth order of the mother . the period of study includes great social , political , economic , demographic , and environmental changes . due to the unreliability of the data during the 18th century , the cox regression analysis is based on results from the period 18001899 ( table 5 ) . cox regression of infant mortality in jokkmokk , jukkasjrvi , and fllinge , 18001899 note : e is the relative risk , p is the p - value for each parameter in the model . the results show geographical differences between the three sami groups . in jokkmokk with an ethnic majority shift around the 1830s , this is also the only parish with the highest mortality risk among the first born infants in 18501899 . the northern parish jukkasjrvi experiences a dramatic shift from twice as high sami infant mortality in18001849 to slightly lower imr compared to the non - sami during the second half of the century . the more balanced the ethnic proportions became , the less differences occurred in infant mortality . in the southern parish of fllinge , sami were a minority from the 18th century , but nevertheless they showed higher imr over the entire period . generally , a modest male excess mortality is found and less risk for parity 24 . there are no noteworthy seasonal differences , except in fllinge where higher imr appeared among infants born during the winter months january to march . the sample from this parish is too small to include separate analyses for different periods of the 19th century . it was often claimed that sami families were smaller than non - sami families in the area ( 28 ) . this was often based on an assumption that a large family was an obstacle to the nomadic life of the reindeer herders ( table 4 ) . infant mortality ( per 1000 ) after parity in jukkasjrvi , jokkmokk , and fllinge 17501899 source : demographic database , ume university . in all three parishes , sami infants although we can not control for the number of older siblings that were actually alive , it seems clear that large families were less able to avoid infant mortality . the mothers who gave birth for the fifth time or more were also older than those giving birth for the first time . the health status of the mother is an important determinant of infant survival , especially during the first week . among the sami , first - born infants had the second largest risk of dying , whereas among the non - sami they experienced the greatest risk . the settlers may have lacked the well - developed traditional knowledge needed for dealing with the cold climate and other risks specific to the northern inland area . both ethnic groups in all parishes had the lowest risks for mortality for infants born as number two , three , or four in the birth order of the mother . the period of study includes great social , political , economic , demographic , and environmental changes . due to the unreliability of the data during the 18th century , the cox regression analysis is based on results from the period 18001899 ( table 5 ) . cox regression of infant mortality in jokkmokk , jukkasjrvi , and fllinge , 18001899 note : e is the relative risk , p is the p - value for each parameter in the model . the results show geographical differences between the three sami groups . in jokkmokk with an ethnic majority shift around the 1830s , this is also the only parish with the highest mortality risk among the first born infants in 18501899 . the northern parish jukkasjrvi experiences a dramatic shift from twice as high sami infant mortality in18001849 to slightly lower imr compared to the non - sami during the second half of the century . the more balanced the ethnic proportions became , the less differences occurred in infant mortality . in the southern parish of fllinge , sami were a minority from the 18th century , but nevertheless they showed higher imr over the entire period . generally , a modest male excess mortality is found and less risk for parity 24 . there are no noteworthy seasonal differences , except in fllinge where higher imr appeared among infants born during the winter months january to march . the sample from this parish is too small to include separate analyses for different periods of the 19th century . the sami in the northern parishes of jokkmokk and jukkasjrvi had a high imr between 1750 and 1900 , whereas the southern sami in fllinge experienced considerably lower levels . if infant mortality is used as an indicator of a positive shift in the demographic , epidemiologic , and health transitions , it can be concluded that by 1900 these transitions had not begun in the northern parts of the area . the non - sami in the area show increased imr over time , and did not follow the decreasing imr in sweden from the 1820s . the indigenous people of northern sweden experienced a delayed process , and at the end of the 19th century , their imr were still above the national average . on the other hand , the trend shows decreasing imr , and we know that the gap between the sami and the rest of sweden was closed around 1950 . other indigenous peoples of the arctic still have much higher mortality rates , and an imr below 100 was achieved only after 1950 in most countries ( 29 , 30 ) . between 1910 and 1939 , the native people in canada had an imr between 120 and 205 ( 31 ) . serning reported remaining ethnic imr differences in jukkasjrvi and jokkmokk for the period 19301948 , but they were rapidly decreasing ( 22 ) . and , from the 1960s , there are no significant mortality differences between sami and non - sami in the area ( 3 ) . therefore , the first half of the 20th century is crucial for our understanding of the imr transition in spmi , and hence for our understanding of the sami demographic , epidemiologic , and health transitions . brndstrm ( 23 ) asked if there were reasons to believe that the sami practiced birth control . contemporary observers claimed that sami women gave birth to few children , rarely more than five or six ( 31 ) , even if they married at early ages ( 11 ) . by limiting family size , they may have avoided the increased risk associated with higher order births , and by concentrating births in the seasons with lower risk , they may have improved survival . cultural responses to infectious diseases and the use of a so - called komse , a small wooden boat box where infants were kept almost constantly for 1 or even 2 years ( 32 , 33 ) helped in the care of the newborn children . the traditional nomadic life style is important for our understanding of sami infant mortality ( 25 ) , but there is no reason to believe that hard working conditions caused the sami women to stop breast - feeding their infants , as was often the case in other contexts ( 34 ) . reindeer herding was an extreme form of living , and the social organization did not offer any assistance . sami women either rejoined the continuous travel with the reindeer only a couple of days after giving birth ( 31 ) or were left alone with the child in a hut ( 22 ) . until the mid-19th century , the sami imr was considerably higher than the non - sami in the area , even though extensive breast - feeding prevented infectious diseases and nutritional deficiencies . we can note cultural differences within spmi , where the south sami joined the low imr of the district of jmtland , whereas the northern parishes remained at higher levels . however , there is no evidence that medical interventions played any significant role in the reduction in infant mortality . the sami rarely had any contact with the district physicians , and midwives were not appointed in the northern parishes until the late 19th century . kertzer and fricke ( 35 ) take a cultural approach to demographic behavior , arguing that from an anthropological perspective , the concept of agency must be given more prominence . they emphasize a cultural sphere that is interwoven with , both shaping and being shaped by , political and economic institutions as well as by kinship and other social organizational structures . the sami population has slowly increased since the 18th century and onwards , and the previous general opinion that the sami were a dying race has been proven to be mistaken . it is the sami culture , and not the sami race , that is under threat today ( 36 ) . but the path to this point has been long and winding , including great improvements in life expectancy . infant mortality was a difficult obstacle to overcome , and the final breakthrough did not occur until the 20th century . the authors have not received any funding or benefits from industry to conduct this study . OUTPUT:

the study deals with infant mortality ( imr ) that is one of the most important aspects of indigenous vulnerability.backgroundthe sami are one of very few indigenous peoples with an experience of a positive mortality transition.objectiveusing unique mortality data from the period 17501900 sami and the colonizers in northern sweden are compared in order to reveal an eventual infant mortality transition.findingsthe results show ethnic differences with the sami having higher imr , although the differences decrease over time . there were also geographical and cultural differences within the sami , with significantly lower imr among the south sami . generally , parity has high explanatory value , where an increased risk is noted for children born as number five or higher among siblings.conclusionthere is a striking trend of decreasing imr among the sami after 1860 , which , however , was not the result of professional health care . other indigenous peoples of the arctic still have higher mortality rates , and imr below 100 was achieved only after 1950 in most countries . the decrease in sami infant mortality was certainly an important factor in their unique health transition , but the most significant change occurred after 1900 .

PubMed_Summ6545

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: so far , anthropometric variables and their relation to conventional coronary risk factors in railway employees have been inadequately studied in india . to assess anthropometric variables and their relation to coronary risk factors , this cross - sectional survey was carried out in solapur division of the central railway in the year 2004 . the purpose of this study was to examine the association of obesity with cad risk factors by different anthropometric variables . this particular section of the population was selected , as it comprises all classes of employees , including both sexes , sedentary and nonsedentary job workers of various socioeconomic groups , religions , and from different parts of india . this study was designed to investigate conventional cad risk factors and their relation to anthropometric variables among the solapur division railway employees . this study was conducted among the railway employees of solapur division of the central railway . a proforma was prepared that incorporated information regarding demography ( age and sex ) , anthropometric ( height in meter , weight in kilograms , waist and hip circumferences in centimeters ) variables , occupation ( sedentary or nonsedentary ) , physical examination ( pulse , blood pressure ) , clinical data ( history of diabetes hypertension , smoking , tobacco chewing , exercise ) , and biochemical investigations [ fasting blood sugar level ( bsl ) and complete lipid profile ] . anthropometric variables were calculated by using the above measurements for body mass index ( bmi ) , waist circumference ( wc ) , waist - to - hip ratio ( whr ) , waist - to - height ratio ( whtr ) , and abdominal volume index ( avi ) . all the eligible employees of both sexes underwent physical , anthropometric examination , and biochemical investigations according to the standard guidelines used earlier . a total of 995 railway employees participated in this cross - sectional survey with age 30 and 60 years . railway employees were chosen from railway stations , divisional railway mandal office , railway police force ( rpf ) and railway hospitals . according to the nature of their job , there were 872 men of whom 484 ( 55.5% ) were of age < 45 years and 388 ( 44.5% ) were of age 45 years . a total of 123 were females , 58 ( 48% ) were of age < 45 years and 65 ( 52% ) were of age 45 years . blood pressure was measured using a standard mercury sphygmomanometer under standard conditions as mentioned in cardiovascular survey methods . biochemical investigations were performed on an automated analyzer by using the kit provided by accurex biomedical pvt . ltd . ( iso 13485 : 2003 , iso 9001 : 2008 & ce certified mumbai , india ) . was measured by cholesterol oxidase ( chod) phenol + aminophenazone ( pap ) enzymatic colorimetric technique . triglyceride ( trg ) was measured by glycerol-3-phosphate oxidase ( gpo) peroxidase ( pod ) enzymatic technique . bsl fasting was done by glucose oxidase ( god ) peroxidase ( pod ) enzymatase by autoenzyme technique . each person was examined for height , weight , wc , and hip circumference without shoes and chappals with minimal clothing as per cardiovascular survey methods . bmi was calculated by formula of weight in kg / height m. whr was calculated by wc / hc in centimeters . avi was calculated using volume formulas for cylinder ( v = rh ) and vertical cone v = ( 1/3)rh . the formula developed was avi = [ 2 cm ( waist ) + 0.7 cm ( wc hc)]/1000 , which estimates overall abdominal volume between symphysis of pubis and xiphoid appendix and theoretically includes intra - abdominal fat and adipose tissue volumes . a smoker in india consumes tobacco in the form of bidi / cigarettes and chewing tobacco . a person smoking one or more cigarettes or bidis per day at the time of study was considered as a smoker and one chewing tobacco currently , a tobacco chewer . in the present study , tobacco consumption in the form of smoking and in the form of tobacco chewing were grouped separately.physical activity according to the type of job were classified as , nonsedentary job ( moderate to heavy physical activity)sedentary job ( low physical activity ) physical activity was classified into 2 levels , moderate to high physical activity was referred as nonsedentary ( rpf , drivers , gangmen , and others)low physical activity referred ( sedentary ) to people involved in office work , research work , and so on . a smoker in india consumes tobacco in the form of bidi / cigarettes and chewing tobacco . a person smoking one or more cigarettes or bidis per day at the time of study was considered as a smoker and one chewing tobacco currently , a tobacco chewer . in the present study , tobacco consumption in the form of smoking and in the form of tobacco chewing were grouped separately . physical activity according to the type of job were classified as , nonsedentary job ( moderate to heavy physical activity ) sedentary job ( low physical activity ) physical activity was classified into 2 levels , moderate to high physical activity was referred as nonsedentary ( rpf , drivers , gangmen , and others ) low physical activity referred ( sedentary ) to people involved in office work , research work , and so on . cutoffs for high wc were > 85 cm for females and > 90 cm for males . cutoffs for high avi was calculated by receiver - operator characteristic ( roc ) curve 16.48 liter . diabetes mellitus ( dm ) : if a subject is a known diabetic on treatment with any bsl or if fasting bsl ( f - bsl ) 126 mg / dl . dyslipidemia was defined as if , t - cho 200 mg / dl , ldl , cholesterol 130 mg / dl , hdl , cholesterol 40 mg / dl , trg 150 mg / dl . hypertension was labeled if blood pressure 140 mmhg sbp and 90 mmhg dbp or known to be hypertensive on treatment with any blood pressure . the data were pooled , computerized , and analyzed by evaluation version of epi info . 6 [ ( epi info is public domain statistical software for epidemiology developed by centers for disease control and prevention ( cdc ) in atlanta , georgia ( usa ) ] . correlation of anthropometric variables and coronary risk factors in different age groups were determined using r and multiple linear regression analysis . roc curve is used to find out the cutoff point for particular value of a test as a diagnostic test . cutoff values of whtr and avi were calculated by using this curve as a tool for diagnosing central obesity . correlation ( r ) : r = 0.8 ( high correlation coefficient ) , r= 0.40.7 ( moderate correlation ) , and r= 0.3 and above ( low correlation coefficient ) . each person was examined for height , weight , wc , and hip circumference without shoes and chappals with minimal clothing as per cardiovascular survey methods . bmi was calculated by formula of weight in kg / height m. whr was calculated by wc / hc in centimeters . avi was calculated using volume formulas for cylinder ( v = rh ) and vertical cone v = ( 1/3)rh . the formula developed was avi = [ 2 cm ( waist ) + 0.7 cm ( wc hc)]/1000 , which estimates overall abdominal volume between symphysis of pubis and xiphoid appendix and theoretically includes intra - abdominal fat and adipose tissue volumes . a smoker in india consumes tobacco in the form of bidi / cigarettes and chewing tobacco . a person smoking one or more cigarettes or bidis per day at the time of study was considered as a smoker and one chewing tobacco currently , a tobacco chewer . in the present study , tobacco consumption in the form of smoking and in the form of tobacco chewing were grouped separately.physical activity according to the type of job were classified as , nonsedentary job ( moderate to heavy physical activity)sedentary job ( low physical activity ) physical activity was classified into 2 levels , moderate to high physical activity was referred as nonsedentary ( rpf , drivers , gangmen , and others)low physical activity referred ( sedentary ) to people involved in office work , research work , and so on . a smoker in india consumes tobacco in the form of bidi / cigarettes and chewing tobacco . a person smoking one or more cigarettes or bidis per day at the time of study was considered as a smoker and one chewing tobacco currently , a tobacco chewer . in the present study , tobacco consumption in the form of smoking and in the form of tobacco chewing were grouped separately . physical activity according to the type of job were classified as , nonsedentary job ( moderate to heavy physical activity ) sedentary job ( low physical activity ) physical activity was classified into 2 levels , moderate to high physical activity was referred as nonsedentary ( rpf , drivers , gangmen , and others ) low physical activity referred ( sedentary ) to people involved in office work , research work , and so on . cutoffs for high wc were > 85 cm for females and > 90 cm for males . cutoffs for high avi was calculated by receiver - operator characteristic ( roc ) curve 16.48 liter . diabetes mellitus ( dm ) : if a subject is a known diabetic on treatment with any bsl or if fasting bsl ( f - bsl ) 126 mg / dl . dyslipidemia was defined as if , t - cho 200 mg / dl , ldl , cholesterol 130 mg / dl , hdl , cholesterol 40 mg / dl , trg 150 mg / dl . hypertension was labeled if blood pressure 140 mmhg sbp and 90 mmhg dbp or known to be hypertensive on treatment with any blood pressure . the data were pooled , computerized , and analyzed by evaluation version of epi info . 6 [ ( epi info is public domain statistical software for epidemiology developed by centers for disease control and prevention ( cdc ) in atlanta , georgia ( usa ) ] . correlation of anthropometric variables and coronary risk factors in different age groups were determined using r and multiple linear regression analysis . roc curve is used to find out the cutoff point for particular value of a test as a diagnostic test . cutoff values of whtr and avi were calculated by using this curve as a tool for diagnosing central obesity . correlation ( r ) : r = 0.8 ( high correlation coefficient ) , r= 0.40.7 ( moderate correlation ) , and r= 0.3 and above ( low correlation coefficient ) . a total of 872 ( 87.63% ) were males and 123 ( 12.36% ) were females . all of them underwent physical examination , and anthropometric measurements for ht , wt , hc , and wc , but only 605 males and 95 females underwent biochemical investigations with a response rate of 69.15%in males and 77.23% in females . the subjects were 45 years of age ; 388 ( 53.35% ) males and 65 ( 52.84% ) females . high sbp was present in 290 ( 33.25% ) males and 32 ( 26.03% ) females . high dbp was present in 304 ( 34.86% ) males and 37 ( 30.08% ) females . physical inactivity was present in 767 ( 87.95% ) males and 102 ( 82.92% ) females . tobacco chewing was present in 178 ( 20.41% ) males and 12 ( 9.75% ) females . smoking was present in 151 ( 17.31 % ) males and 2 ( 1.62% ) females . high bmi was present in 172 ( 19.72% ) males and 73 ( 59.34% ) females . high wc was present in 412 ( 47.24% ) males and 98 ( 79.67% ) females . high whr was present in 504 ( 57.79% ) males and 90 ( 73.17% ) females . high whtr was present in 699 ( 80.16% ) males and 103 ( 83.73% ) females . high avi was present in 359 ( 41.16% ) males and 35 ( 28.45% ) females . dm was present in 51 ( 8.42% ) males and 2 ( 2.10% ) females . low hdl was present in 248 ( 40.99% ) males and 15 ( 15.78% ) females . high ldl was present in 117 ( 19.33% ) males and 23 ( 24.21% ) females . high t - cho was present in 151 ( 24.95% ) males and 34 ( 35.78% ) females . high trg was present in 275 ( 45.45% ) males and 19 ( 20% ) females [ table 1 ] . prevalence of coronary artery disease risk factors in both males and females , all the anthropometric variables were high . most prevalent obesity index in male population was high whtr . in female population , the most prevalent obesity index was high whtr . prevalence of overall and central obesity was comparatively more in female population for all the variables as shown in table 2 . mean age , bmi , and low hdl levels were comparatively higher in females , whereas mean sbp , dbp , trg , whr , wc , and whtr were comparatively higher in males . standard deviation values of quantitative data in male and female population are shown in table 3 . prevalence of obesity indices standard deviation values of quantitative data in male and female population total 65 females were with age 45 years and 58 with age < 45 years . in female population , high whr in age 45 years was present in 58 ( 47.15% ) . in females only high bmi was statistically significant in age 45 years with p value < 0.001 . males totalling 388 were of the age 45 years and 484 females were < 45 years of age . in male population , 45 years of age , a high whr was present in 262 ( 30.04% ) . a high bmi in age 45 years was present in 90 ( 10.32% ) . a high wc in age 45 years was present in 207 ( 23.73% ) . high avi in age 45 years was present in 279 ( 31.99% ) . in males , all anthropometric variables , such as whr , whtr , bmi , wc , and avi , were significantly raised , in the age group 45 years with p value < 0.001 . bmi had partial positive correlation ( moderate to low ) with coronary risk factors , such as age weight , sbp , dbp , f - bsl , t - cho , ldl cholesterol , trg , and other anthropometric variables . whr had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , height , weight , sbp , dbp , f - bsl , total , trg , and other anthropometric variables . whtr had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , sbp , dbp , f - bsl , ldl cholesterol , trg , and other anthropometric variables . wc had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , height , sbp , dbp , f - bsl , trg , and other anthropometric variables . avi had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , height , sbp , dbp , f - bsl , trg , and other anthropometric variables [ table 4 ] . in male population , age 45 years had odds ratio of 2.15 with whtr and 1.95 with avi . sbp had an odds ratio of 2.0 with bmi , 1.47 with wc , and 1.48 with avi . correlation of anthropometric indices with coronary artery disease risk factors in female population , age 45 years had an odds ratio of 1.673 with bmi . sedentary job had an odds ratio of 2.0 with whr , 1.86 with wc , and 1.79 with whtr . sbp had an odds ratio of 1.48 with avi and dbp had an odds ratio of 1.34 with wc . we have found that age 45 years was better correlated with high values of bmi , wc , whr , whtr , and avi . high sbp , high dbp , and sedentary job were significantly and positively correlated with high values of bmi , wc , whr , whtr and avi . high values of bmi , wc , whr , whtr , and avi were negatively associated with physical inactivity . tobacco and smoking were negatively correlated with high values of bmi , wc , whr , and whtr . dm was statistically significant and positively associated with high values of bmi , wc , whr , whtr , and avi . in dyslipidemia low hdl was correlated with high values of whr , whtr , and avi , whereas ldl cholesterol , t - cho , and trg were correlated only with high bmi and high whtr in this population [ table 4 ] . in multiple regression analysis a model was utilized that included age , bmi , whr , whtr , wc , avi , sbp , dbp , plasma t - cho , trg , and smoking . this revealed age , whtr , and whr as an independent determinant of most of the cad risk factors in both genders . multiple regression analysis for whtr and whr showed that both of them were significantly associated with most of the cad risk factors , such as age 45 years , high sbp , high dbp , dm , low hdl , high ldl , high t - cho , and high trg [ table 5 ] . relation of anthropometric variables and coronary artery disease risk factors in males and females furthermore , the whr was the single independent variable to all or most of the cad risk factors by multiple regression analysis . multiple logistic regression analysis revealed whtr and whr were significantly associated with age ( p < 0.001 ) , bmi ( p < 0.001 ) dm ( p = 0.005 ) , sbp ( p < 0.001 ) , dbp ( p < 0.001 ) , low hdl in females , and high trg in males ( p < 0.001 ) [ figure 1 ] . bmi had partial positive correlation ( moderate to low ) with coronary risk factors , such as age weight , sbp , dbp , f - bsl , t - cho , ldl cholesterol , trg , and other anthropometric variables . whr had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , height , weight , sbp , dbp , f - bsl , total , trg , and other anthropometric variables . whtr had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , sbp , dbp , f - bsl , ldl cholesterol , trg , and other anthropometric variables . wc had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , height , sbp , dbp , f - bsl , trg , and other anthropometric variables . avi had partial positive correlation ( moderate to low ) with coronary risk factors , such as age , weight , height , sbp , dbp , f - bsl , trg , and other anthropometric variables [ table 4 ] . in male population , age 45 years had odds ratio of 2.15 with whtr and 1.95 with avi . sedentary job had an odds ratio of 1.402 with bmi . sbp had an odds ratio of 2.0 with bmi , 1.47 with wc , and 1.48 with avi . correlation of anthropometric indices with coronary artery disease risk factors in female population , age 45 years had an odds ratio of 1.673 with bmi . sedentary job had an odds ratio of 2.0 with whr , 1.86 with wc , and 1.79 with whtr . sbp had an odds ratio of 1.48 with avi and dbp had an odds ratio of 1.34 with wc . we have found that age 45 years was better correlated with high values of bmi , wc , whr , whtr , and avi . high sbp , high dbp , and sedentary job were significantly and positively correlated with high values of bmi , wc , whr , whtr and avi . high values of bmi , wc , whr , whtr , and avi were negatively associated with physical inactivity . tobacco and smoking were negatively correlated with high values of bmi , wc , whr , and whtr . dm was statistically significant and positively associated with high values of bmi , wc , whr , whtr , and avi . in dyslipidemia low hdl was correlated with high values of whr , whtr , and avi , whereas ldl cholesterol , t - cho , and trg were correlated only with high bmi and high whtr in this population [ table 4 ] . in multiple regression analysis a model was utilized that included age , bmi , whr , whtr , wc , avi , sbp , dbp , plasma t - cho , trg , and smoking . this revealed age , whtr , and whr as an independent determinant of most of the cad risk factors in both genders . multiple regression analysis for whtr and whr showed that both of them were significantly associated with most of the cad risk factors , such as age 45 years , high sbp , high dbp , dm , low hdl , high ldl , high t - cho , and high trg [ table 5 ] . relation of anthropometric variables and coronary artery disease risk factors in males and females furthermore , the whr was the single independent variable to all or most of the cad risk factors by multiple regression analysis . multiple logistic regression analysis revealed whtr and whr were significantly associated with age ( p < 0.001 ) , bmi ( p < 0.001 ) dm ( p = 0.005 ) , sbp ( p < 0.001 ) , dbp ( p < 0.001 ) , low hdl in females , and high trg in males ( p < 0.001 ) [ figure 1 ] . conventional cad risk factors , such as physical inactivity , central obesity , hypertension , low hdl , age 45 years , and hypertriglyceridemia were highly prevalent in males , whereas physical inactivity , central obesity , hypertension , age 45 years , and hypercholesterolemia were highly prevalent in female population . compared to overall obesity , central obesity was better correlated with most of the cad risk factors . whtr was better predictive of cad risk factors than wc and whr in present study . cutoff value for whtr has not been calculated for the indian population , hence further studies are required for calculation in the indian context . in the present study , whtr was a powerful predictor of most of the cad risk factors , whereas whr , wc , and avi were next to it in a decreasing order . we have compared our results with various studies in which lin et al in a general population study reported that , whtr is a better indicator for predicting cvd risk factors than the other 3 indices ( bmi , wc , and whr ) in taiwan , which is comparable with our study . lin et al and hsieh et al also stated that whtr is a better predictor of most of the cad risk factors than whr , wc , and bmi . huang et al in a general population study in taiwan found that the 4 anthropometric indices ( bmi , wc , whr , and whtr ) are closely related to cardiovascular risk factors , which is comparable with our study . the results of misra et al indicated a high prevalence of diabetes , obesity , and dyslipidemia in urban slum population in northern india in middle age , particularly in females , which is comparable with our study . guerrero - romero et al in their study of 746 men and nonpregnant women randomly recruited from durango city in northern mexico , stated that avi is reliable and shown to be strongly related to igt and dm , which is comparable with our study , but they have not correlated the association with other cad risk factors , such as hypertension , dyslipidemia , and physical inactivity . in southern andhra pradesh , india , a study of randomly selected urban and rural population by venkatramana et al suggested that bmi and wc are better indicators of cad risk factors , which is partially comparable with our study as other anthropometric variables have not been used in their study . reeder et al in 5 canadian provinces ( alberta , manitoba , ontario , quebec , and saskatchewan ) general population study , found that wc was the measure of abdominal obesity most highly correlated with cardiovascular disease risk factors , which is partially comparable with our study . in omani population al - riyami and afifi , in their study among male adults aged 20 years and above in a community - based survey as a part of the national health survey , reported that current smokers were of low bmi compared with nonsmokers and exsmokers and currently light smokers were also of low bmi compared with exsmokers , which is comparable with our study . ledoux et al , in a canadian general population study stated that the wc and bmi correlate most closely with blood pressure and plasma lipids , which is comparable with the present study . onat et al , in a random sample of turkish general adult population , observed that the wc and whr were strongly associated with bmi and dbp and plasma trg in turkish women , which is similar to and comparable with our results . hsieh et al , in a study found that , the whtr and whr increased with age in both the genders , which is comparable with our results . rosmond et al , in a selected population study , reported that obesity ( bmi ) and centralization of body fat stores ( whr ) are differently associated with occupational factors as well as leisure time activities . hu et al reported that television watching and other sedentary behaviors are related to risk of obesity and type 2 dm in women . both these studies are comparable with the current study . slattery et al in a study of the us railroad population quoted that occupationally and leisure time physically inactive employees are at a higher risk of developing cad risk factors and cardiovascular death , which is consistent with the current study . several studies showed that smokers have , on an average , lower bmi than nonsmokers and that smoking cessation is often associated with weight gain . in the present study , whtr has been found to be significantly and positively associated with most of the cad risk factors , hence whtr can be used routinely as an anthropometric tool for prediction of cad risk factors in epidemiologic studies.[2529 ] the other parameters of coronary artery risk [ c - reactive protein ( crp ) , homocysteine , and others ] have not been done in the present study because of limitations of study to conventional cad risk factors and resource limitations . other cad risk factors , such as hyperhomocysteinemia , have not shown a robust utility in chd risk stratification , and there are no clinical trial data showing that intervention to lower homocysteine levels reduces chd events . measurement of homocysteine levels should be reserved for individuals with atherosclerosis at a young age or out of proportion to established risk factors . elevations in acute - phase reactants , such as fibrinogen or crp , may reflect overall atherosclerotic burden or extravascular inflammation that could potentiate atherosclerosis or its complications . crp measured by high - sensitivity assay , adds predictive information to that derived from established coronary artery risk factors , such as cholesterol . elevated levels of the acute - phase reactant crp and fibrinogen may merely reflect ongoing inflammation rather than a direct etiologic role for crp in cad . in the present study , the prevalence of metabolic syndrome ( using atp iii criteria modified for indians ) was 25.17% in males and 27.35% in females . among all the components of metabolic syndrome , high wc was most prevalent in females and systolic hypertension in males . in the current study , the most common cad risk factor was truncal obesity in the solapur division railway employees . generalized obesity , overweight , and central obesity problem was more prevalent in subjects with age 45 years , sedentary job , physical inactivity , and female gender . there was a significant lack of physical activity and exercise among sedentary job workers , leading to overweight and obesity . generalized obesity , overweight , and central obesity were significantly correlated with cad risk factors , such as age 45 years , dyslipidemia , hypertension , dm , and physical inactivity . central obesity measured by whtr was strongly correlated with majority of cad risk factors than whr , wc , and avi . these observations serve to underline the central role of overweight / obesity and the additive deleterious effects of abdominal obesity in the pathogenesis of lipid and carbohydrate metabolism , leading to chd and type 2 dm , and hypertension . the present study shows a disturbing burden of coronary risk factors mainly truncal obesity , physical inactivity , hypertension in a sample population of railway employees . there is an urgent need to undertake population - based measures to reverse the trend . out of all the anthropometric variables , whtr was significantly and positively associated with most of the cad risk factors , hence whtr can be used routinely as an anthropometric tool for prediction of cad risk factors in epidemiologic studies . by preventing obesity and overweight , a substantial part of chd mortality may be prevented because a majority of the cad risk factors are strongly correlated with anthropometric indices . we concluded that weight control should be an integral part of the prevention of cardiovascular disease . turn in obesity express highway probably lies in lifestyle modifications , going back to a traditional lifestyle with a judicious use of modern technology . OUTPUT:

background and objectives : anthropometric variables and their relation to conventional coronary artery disease ( cad ) risk factors in railway employees have been inadequately studied in india . this cross - sectional survey was carried out in the solapur division of the central railway in the year 2004 , to assess the anthropometric variables in railway employees and their relation to conventional cad risk factors.materials and methods : a total of 995 railway employees , with 872 males and 123 females participated in this cross - sectional study . all subjects underwent anthropometric measurements , fasting lipid profile , and blood sugar level . various anthropometric indices were calculated for body mass index ( bmi ) , waist circumference ( wc ) , waist - to - hip ratio ( whr ) , waist - to - height ratio ( whtr ) , and abdominal volume index ( avi ) . statistical analysis was done by epi info 6 statistical software.results:compared to all other obesity indices , whtr was most prevalent in both genders . high whtr was present in 699 ( 80.16% ) males and 103 ( 83.73% ) females . age 45 years , high systolic bp , high diastolic bp , low hdl , high triglyceride , and diabetes mellitus were positively correlated with high bmi , high wc , high whr , high whtr , and high avi . high bmi , high wc , high whr , high whtr , and high avi were negatively associated with physical inactivity.conclusions:over all , anthropometric variables in both genders were significantly deranged in subjects with coronary risk factors . compared to all other anthropometric variables , whtr was statistically significantly associated with a majority of coronary artery risk factors . hence we recommend inclusion of whtr as a parameter of obesity to predict coronary artery disease risk factor along with wc , whr , and bmi in epidemiologic studies .

PubMed_Summ6546

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: polymerase chain reaction ( pcr ) is a commonly used laboratory procedure nowadays for a variety of tasks , such as dna cloning , sequence determination and snp detection . consequently , numerous primers need to be designed for dna amplification in order to produce enough dna . for dna sequencing , to design primers for the promoter and exon regions of a gene , one needs to retrieve the required sequence information for each single exon and promoter , including their corresponding flanking sequences , convert them to the correct format , switch to a primer design application like primer 3 ( 1 ) , import the sequence information and adjust parameter settings if necessary before submitting the request . while this is tolerable for primer design for a gene that has a single exon , a human , mouse or rat gene can easily have more than 10 exons , and each of the above steps may thus need to be repeated 10 times or more . furthermore , if an exon is too long to sequence properly in one run , several primers have to be designed to map overlapping sections of the exon . the whole process requires many manual steps for repeated window opening , browsing , application switching , copying and pasting , typing and so on , which can be tedious , time - consuming and error prone . in fact , for a gene with 10 exons , the process can easily exceed 300 steps . to improve the situation , we have developed primerz to replace almost all of these manual steps so that users can easily complete a primer design task using just a few clicks for a gene or batched human snps . more than 2000 primers have been designed with primerz at our institute since 2004 and the success rate is over 70% . there are a multitude of user - definable options available including product size , maximum exon length , excluded regions of the query sequence , gc - content and maximum allowable local alignment score . simply by submitting a candidate gene name , a snp i d or up to 100 batched snp ids , in most cases all the primer sequences should be returned in a minute or two . the generated information , including gene transcript graph , primer data from primer3 , and direct links to ucsc in - silico pcr ( 3,4 ) for pcr product prediction , to ncbi blast and to ensembl source data , is integrated and displayed on a single page for convenient viewing . additionally , all the primer data can be exported in csv format for further processing . primerz takes advantage of the well - developed public - domain database ensembl , through its api ( application programming interface ) . when a gene query is received , primerz will access the ensembl database through ensj api ( 5 ) to retrieve promoter and exon information . by default but with an adjustable setting , primerz retrieves one region of 1440 bp upstream from the start of 5-utr which it treats as the promoter region . the promoter region is thereafter divided into four 360 bp non - overlapping segments plus their respective flanking sequences . all exons are directly flanked with 240 bp sequences , except when an exon of the gene is > 360 bp , when the sequence will be split into segments of 360 bp for a better quality sequencing result . for example , an exon of 1000 bp will produce two 360 bp segments and one 280 bp segment . the above sequence information , plus parametric settings packaged by primerz are then fed into primer3 for primer design . all returned primer results , together with a transcript graph , are integrated into a one - page report for final output . the self - explanatory workflow of the whole primerz system is shown in figure 1 . the software development environment included the following software : java , jdk : j2sdk1.4.2_06 , server vmstruts framework 1.2red hat enterprise linux academic editionmysql 4.1tomcat 5.0 web serverensembl java api java , jdk : j2sdk1.4.2_06 , server vm red hat enterprise linux academic edition tomcat 5.0 web server the api provided by ensembl is used for gene information retrieval . java language is used to pipeline gene data into primer 3 and merge the returned results . primerz is an easy - to - use tool to design primers for genes and snps , using only a few simple steps to design the wanted primers . it currently provides gene primer design for all ensembl species while snp primer design is currently only available for human snps . for gene primer design , there are some essential parameters required for optimal design of primers , such as maximum exon length , exon flanking region , product size range and excluded region . the excluded region value allows the program to bypass regions with low sequence quality or containing repetitive elements such as alus or lines for primer design . for snp primer design , a snp rsid or an affy_probid(6 ) as well as a batch file containing mixed i d types can be accepted as input , where the maximum number of snps per batch is limited to 100 . the result page comprises three major parts : initial input data and parameters , the gene transcript diagram ( only available for gene primer design ) and designed primer information . the first part lists all the input data and parameters plus ensembl database version , for ease of reference . the second part shows each promoter fragment and exon of a transcript diagram , and links to their accompanying original primer3 output . finally , the third section presents tabulated primer information and incorporates executable links to ncbi blast and ucsc in - silico pcr to check specificity and product prediction . ensembl link button offers the ensembl exon report of the transcript so that a user can trace all primers to their original sequence information . a csv format text file of the results can be downloaded at this results page . in a manual operation benchmarking test , it took a person very familiar with all processes about 1260 s and 380 discrete steps to design the primers of hadhsc ( l-3-hydroxyacyl - coenzyme a dehydrogenase , short chain ) , our benchmark gene with 10 exons . with automated primerz , the same operation took only 16 s and three steps . this comparison clearly demonstrates the superior efficiency and ease - of - use of primerz for gene primer design . a benchmark test on batched snps showed a similar dramatic reduction in workload from 90 discrete steps to two steps , from 840 to 49 s , and from 40 result pages to a single page . primerz has been designed to obtain reliable primers for pcr experiments and to allow standardized , automated primer design for batch operation . users can access the ucsc in - silico pcr directly from the result page to verify their primers to achieve higher accuracy and lower cost . primerz also allows users to modify the conditions of primer design , including the maximum exon size , the flanking region of the target sequence , the exclusion region and the maximum allowed polya and ca - repeats in the pcr products . in addition , primerz will offer primer design from ncbi transcripts in the near future , which should be of great interest to those users who use ncbi data to design primers . the results from ncbi and ensembl will be shown in the same page . following the release of primer3 web interface in november 2006 , we are installing and testing a local copy of primer3 web to alleviate the burden on the original primer3 website and the restriction on the number of snps allowed . primer z is a simple - to - use program that greatly facilitates and enhances the traditionally time - consuming task of accurate primer design for pcr , and should be an excellent additional tool for the modern molecular biologist . OUTPUT:

primerz ( http://genepipe.ngc.sinica.edu.tw/primerz/ ) is a web application dedicated primarily to primer design for genes and human snps . primerz accepts genes by gene name or ensembl accession code , and snps by dbsnp rs or affy_probe ids . the promoter and exon sequence information of all gene transcripts fetched from the ensembl database ( http://www.ensembl.org ) are processed before being passed on to primer3 ( http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi ) for individual primer design . all results returned from primer 3 are organized and integrated in a specially designed web page for easy browsing . besides the web page presentation , csv text file export is also provided for enhanced user convenience.primerz automates highly standard but tedious gene primer design to improve the success rate of pcr experiments . more than 2000 primers have been designed with primerz at our institute since 2004 and the success rate is over 70% . the addition of several new features has made primerz even more useful to the research community in facilitating primer design for promoters , exons and snps .

PubMed_Summ6547

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the prevalence rates of t2 dm increase with age , and older people are a growing population that account for a high proportion of cases among adults . older patients are more likely to present cardiovascular complications and comorbid conditions , which entail specific goals to control the disease . however , elderly patients are systematically excluded from clinical trials , and there is also a lack of reliable data on the response to pharmacological treatments in this age group . in a primary care reallife setting , t2 dm patients in the older age subgroup ( > 65 years ) had a better control of glycaemic targets and cardiovascular risk factors than younger patients in spite of having a higher prevalence of chronic complications . moreover , this age subgroup was less intensively treated with glucoselowering and lipidlowering drugs than younger patients . t2 dm in elderly people should be clinically managed taking into account the observed differential agerelated pattern of the disease . type 2 diabetes mellitus ( t2 dm ) has become one of the most serious and challenging public health issues of our time , and the human , social and economic burden associated with the disease has dramatically increased over the past few decades . according to the international diabetes federation 382 million people worldwide have diabetes , and 316 million are at high risk of developing t2 dm 1 . in spain , a recent epidemiological survey estimated that the prevalence rate of t2 dm is around 13.8% , and that about 6% of the spanish population is unaware of their disease 2 . moreover , the study showed that diabetes is more frequent in men and prevalence rates increase with age 2 . the global prevalence of diabetes in people 6079 years of age has been estimated to be 18.6% 1 ; the prevalence of diagnosed diabetes in the united states in subjects 75 years was 20% in 2012 , which is more than eightfold the rate reported among adults aged 1844 years ( 2.4% ) 3 . similar prevalence rates have been found in spain , with 40% of the population aged 75 years and over having known diabetes ( 41.3% of women and 37.4% of men ) 2 . the strong link between age and diabetes is of concern if we take into account the progressive increase in life expectancy , which is likely to result in a substantial increase in the number of older people with diabetes , and a concomitant increase in the costs for the health system in the near future . there is compelling evidence that older onsetdiabetes has differential characteristics compared with onset in middleaged or earlier populations 4 . on the one hand , the disease starts insidiously in people 65 years and over , and remains frequently undiagnosed until a routine analysis is performed or after the subject is admitted to a hospital for any other reason . on the other hand , older people are more likely to present cardiovascular complications , have higher rates of comorbid conditions , mortality , and prevalence of geriatric syndromes ( e.g. cognitive dysfunction , functional impairment , frailty , falls and fractures , polypharmacy , depression , vision and hear impairment , persistent pain , urinary incontinence ) than older people without diabetes 5 . finally , some studies report that older adults have a worse glycaemic control than other age groups with diabetes 6 , and have the highest rates of hyperglycaemic crises and also of hypoglycaemia episodes requiring emergency department visits 5 . although recommendations in clinical guidelines may vary per country , decisionmaking should not be in general based on the age of the patient but on a combination of factors including general health status and functional and cognitive ability , among others 4 , 5 , 7 , 8 . thus , in elderly individuals with preserved cognitive and functional abilities and a good life expectancy , the recommendation is a glycated haemoglobin goal similar to that recommended for younger adults . conversely , the goal for glycaemic control in frail elderly subjects not meeting the above criteria or with greater hypoglycaemia vulnerability should be more relaxed , as the short life expectancy precludes the medium and longterm benefits resulting from very tight control goals 4 , 9 . indeed , the benefits associated with glycaemic control require 510 years to reduce the incidence of microvascular complications 4 , 10 , and it is not yet certain whether it has an actual impact in the incidence of cardiovascular disease ( cvd ) in these patients . the objective of the present populationbased crosssectional study was to retrospectively assess and compare the clinical characteristics , degree of glycaemic and cardiovascular risk factors control , treatments , and diabetesrelated complications between older t2 dm patients and younger adults in a primary care population database in catalonia , spain . secondarily , we aimed to compare these same variables stratifying by gender and different age subgroups . descriptive , populationbased , crosssectional study at the primary care setting in catalonia , spain . data were extracted from sidiap ( information system for the development of research in primary care ) 11 , which is a computerised database containing anonymised patient 's records for the 5.8 million people attended by general practitioners in the catalan health institute . sidiap includes data on demographic variables , diagnoses , clinical variables , prescriptions , specialist referrals , laboratory test results , and medications withdrawn from pharmacist offices , obtained from the catsalut general database . data were obtained for patients 30 years diagnosed with t2 dm by 31 december 2011 and attended a primary care centre during 2011 . patients with type 1 diabetes mellitus or gestational diabetes were excluded . for the objective of the study , we extracted demographic data , including age ( further categorised into age subgroups : 65 , 6675 , 7685 , and > 85 years ) and sex ; clinical variables included diabetes duration ; smoking status ; body mass index ( bmi ) ; blood pressure ( bp ) ( systolic and diastolic ) ; standardised glycated haemoglobin ( hba1c ) values ; lipid levels including total cholesterol ( tc ) , lowdensity lipoproteins or ldl cholesterol ( ldlc ) , highdensity lipoproteins or hdl cholesterol ( hdlc ) , nonhdl cholesterol , and triglycerides ( tg ) , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula and urine albumintocreatinine ratio ( acr ) . values of clinical variables corresponded to the most recent registered value in the last 15 months except for bmi , which was the most recent value in the last 24 months , and smoking status , which corresponded to the most recent information recorded in the medical history . as for comorbidities , the diagnose of hypertension and/or dyslipidaemia was considered if mentioned in an active record up to the cutoff date , and we also extracted information on the presence of diabetesrelated chronic complications , namely ischaemic heart disease , heart failure , stroke , peripheral artery disease , diabetic retinopathy and chronic kidney disease ( defined according to egfrmdrd4 and acr values ) . control of cv risk factors were defined as follows : no current smoking ; bmi < 30 kg / m ; bp < 140/90 mmhg ; hba1c 7% ( 53.0 mmol / mol ) ; tc 250 mg / dl ; ldlc < 130 mg / dl for patients without cvd and < 100 mg / dl for those with cvd ; hdlc > 50 mg / dl for women and > 40 mg / dl for men ; and tg 150 mg / dl . a descriptive analysis was performed stratified by gender and age subgroup . for qualitative variables , proportions and means were compared by pearson 's chisquared test and analysis of variance ( anova ) , respectively . all hypothesis contrasts were bidirectional and the statistical significance level was set at 0.05 . moreover , the prevalence of diabetesrelated complications and the degree of glycaemic control was studied stratifying by t2 dm duration ( 5 , 510 , 1020 and > 20 years ) . all analyses were performed with stata / se version 13 for windows ( stata corp . , college station , tx , usa ) and r software version 3.0.1 ( the r foundation for statistical computing , vienna , austria ) . descriptive , populationbased , crosssectional study at the primary care setting in catalonia , spain . data were extracted from sidiap ( information system for the development of research in primary care ) 11 , which is a computerised database containing anonymised patient 's records for the 5.8 million people attended by general practitioners in the catalan health institute . sidiap includes data on demographic variables , diagnoses , clinical variables , prescriptions , specialist referrals , laboratory test results , and medications withdrawn from pharmacist offices , obtained from the catsalut general database . data were obtained for patients 30 years diagnosed with t2 dm by 31 december 2011 and attended a primary care centre during 2011 . patients with type 1 diabetes mellitus or gestational diabetes were excluded . for the objective of the study , we extracted demographic data , including age ( further categorised into age subgroups : 65 , 6675 , 7685 , and > 85 years ) and sex ; clinical variables included diabetes duration ; smoking status ; body mass index ( bmi ) ; blood pressure ( bp ) ( systolic and diastolic ) ; standardised glycated haemoglobin ( hba1c ) values ; lipid levels including total cholesterol ( tc ) , lowdensity lipoproteins or ldl cholesterol ( ldlc ) , highdensity lipoproteins or hdl cholesterol ( hdlc ) , nonhdl cholesterol , and triglycerides ( tg ) , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula and urine albumintocreatinine ratio ( acr ) . values of clinical variables corresponded to the most recent registered value in the last 15 months except for bmi , which was the most recent value in the last 24 months , and smoking status , which corresponded to the most recent information recorded in the medical history . as for comorbidities , the diagnose of hypertension and/or dyslipidaemia was considered if mentioned in an active record up to the cutoff date , and we also extracted information on the presence of diabetesrelated chronic complications , namely ischaemic heart disease , heart failure , stroke , peripheral artery disease , diabetic retinopathy and chronic kidney disease ( defined according to egfrmdrd4 and acr values ) . control of cv risk factors were defined as follows : no current smoking ; bmi < 30 kg / m ; bp < 140/90 mmhg ; hba1c 7% ( 53.0 mmol / mol ) ; tc 250 mg / dl ; ldlc < 130 mg / dl for patients without cvd and < 100 mg / dl for those with cvd ; hdlc > 50 mg / dl for women and > 40 mg / dl for men ; and tg 150 mg / dl . a descriptive analysis was performed stratified by gender and age subgroup . for qualitative variables , proportions and means were compared by pearson 's chisquared test and analysis of variance ( anova ) , respectively . all hypothesis contrasts were bidirectional and the statistical significance level was set at 0.05 . moreover , the prevalence of diabetesrelated complications and the degree of glycaemic control was studied stratifying by t2 dm duration ( 5 , 510 , 1020 and > 20 years ) . all analyses were performed with stata / se version 13 for windows ( stata corp . , college station , tx , usa ) and r software version 3.0.1 ( the r foundation for statistical computing , vienna , austria ) . a total of 318,020 subjects with a diagnosis of t2 dm were included in the study ; 53.8% of them were males ( n = 171,219 ; table 1 ) . mean age of the overall population was 68.8 years ( sd = 11.9 ) ; the mean age at diagnosis was 61.6 years ( sd = 11.7 ) , and the median disease duration was 6.7 years [ interquartile range ( iqr ) = 6.2 years ) . according to prespecified age categories , 38.0% of subjects were 65 ( 62.9% males ) ; 29.4% were 6675 ( 54.3% males ) ; 25.8% were 7685 ( 45% males ) ; and 6.8% were > 85 years ( 33.4% males ) . demographic and clinical characteristics of the study population by gender and age group the number of patients with available data varied depending on each studied variable . acr , albumintocreatinine ratio ; bmi , body mass index ; bp , blood pressure ; egfrmdrd , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula ; hba1c , standardised glycated haemoglobin ; hdlc , highdensity lipoproteins hdl cholesterol ; ldlc , lowdensity lipoproteins ldl cholesterol ; tc , total cholesterol . there was a progressive improvement in glycaemic control values ( hba1c ) with age in both genders ( p < 0.001 ) despite longer diabetes duration in older age groups . in the total sample , kg / m vs. 31.0 kg / m , respectively ) , and declined with age for both genders ( p < 0.001 ) . of note , in both genders the mean values of diastolic bp , tc , ldlc and tg were significantly lower in the older age groups ( p < 0.001 ) . the average values of egfrmdrd also decreased gradually with age in both genders ; thus , the percentage of patients with renal failure ( egfr < 60 ml / min ) and urine acr increased gradually with age in both genders ( p < 0.001 ) . the degree of control of main cardiovascular risk factors for t2 dm and pharmacological treatments is shown in table 2 . the percentage of subjects with fair glycaemic control ( hba1c 7% ) was significantly higher among older age groups ( p < 0.001 ) ; moreover , a lower proportion of patients in the older age groups were not well controlled ( hba1c > 10% ) in spite of having more comorbid conditions . overall , a 22% of patients in both genders were not taking any glucoselowering drugs . its use was progressively reduced with increasing age , with a total of 71.5% of men and 68.4% of women older than 85 years taking any glucoselowering agent . however , there was also a parallel increase in the use of insulin with age , particularly in monotherapy . there were no substantial differences in the control of blood pressure ( bp 140/90 mmhg ) with age , although the control was slightly better among patients 65 years , particularly in women ( 67.3% vs. 71% of men ) , while 65.5% of men and 62.9% of women older than 65 years had their bp under control . as for the pharmacological treatment of hypertension , there was a greater proportion of older subjects being pharmacologically treated compared with younger adults , and more frequently treated with a combination of different drugs . degree of control of main cardiovascular risk factors for t2 dm and pharmacological treatment by gender and age group hba1c 7% = 53 mmol / mol ; hba1c 7.5% = 58.5 mmol / mol ; hba1c 8.5% = 69.4 mmol / mol ; hba1c 10% = 85.8 mmol / mol . bmi , body mass index ; bp , blood pressure ; hba1c , standardised glycated haemoglobin ; ldlc , lowdensity lipoproteins ldl cholesterol . in both genders , the control of dyslipidaemia , both in patients without cvd and with cvd ( ldlc levels < 130 mg / dl and < 100 mg / dl , respectively ) was better among patients 6685 years than in patients 65 years , while in the age group > 85 years the highest values across all age groups was observed . additionally , lipidlowering drugs were used less frequently by both women and men in the older age groups ( p < 0.001 ) . as for the use of antiplatelet agents , their use was progressively higher with increasing age ( p < 0.001 ) , being used by 53.9% of men and 46.2% of women older than 85 years . finally , the percentage of patients currently smokers decreased with age ( p < 0.001 ) , and in all age groups there was a much lower proportion of women smokers . as for the combined control of different cardiovascular risk factors ( namely hba1c 7% , bp 140/90 mmhg , ldlc < 130 mg / dl or 100 mg / dl , and no smoking ) , it was achieved in 22.6% of men and 24.9% of women 65 years , while these percentages were significantly higher among patients > 65 years , ranging between 29.7% and 35.2% in men , and 29% and 32% in women across older age groups ( p < 0.001 ) . the prevalence of chronic micro and macrovascular complications associated with t2 dm by gender and age subgroup is shown in table 3 . there was a sharp increase in the frequency of heart failure and all macrovascular complications ( ischaemic heart disease , stroke and peripheral artery disease ) with increasing age ( p < 0.001 in all complications ) . the global prevalence of ischaemic heart disease was 8.6% in women vs. 15.9% in men ; the prevalence of stroke was 6.4% in men vs. 5.3% in women ; the prevalence of peripheral artery disease was 5.7% in men vs. 2.0% in women ; and the prevalence of heart failure was 4.7% in men vs. 6.6% in women . prevalence of diabetesrelated complications by gender and age subgroup acr , albumintocreatinine ratio ; cvd , cardiovascular disease ; egfrmdrd , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula . as for microvascular complications , diabetic retinopathy was more frequent among patients > 65 years ( p < 0.001 ) , although taking into account the diabetes duration , there was a progressive decrease in frequency with increasing age , particularly in men ( figure 1 ) . the assessment of kidney disease by egfrmdrd showed a progressive increase in renal failure cases ( egfrmdrd < 60 ml / minute ) with age , which was also the case for acr values , and both complications together were observed up to a 20% of men and 19.3% of women older than 85 years compared with a 2.2% of men and 1.9% of women furthermore , albuminuria ( acr > 30 mg / mmol ) increased with age and was more frequent in men than in women in all age groups ( p < 0.001 ) . impact of t2 dm duration , age and gender on the prevalence of diabetic retinopathy ( dr ) we further studied whether diabetes duration ( 5 years , 510 years , 1020 years and > 20 years ) was related to the degree of glycaemic control and presence of diabetesrelated complications . the older the patients were the higher the percentage achieving a glycaemic goal of hba1c values 7% , and this was true in all age subgroups regardless the duration of t2 dm . moreover , patients in older age subgroups were more likely to achieve target glycaemic values irrespective of having a cvd or heart failure . for instance , the proportion of patients with a disease duration 15 years and no cvd who achieved target hba1c values 7% was 49% among those aged 65 years , and 54% among those aged 6575 years ; in patients with a disease duration > 15 years and cvd , 56% aged 65 years and 83% aged 6575 years achieved target hba1c values 7% and 8.5% , respectively . as for individual diabetesrelated complications , there was a higher prevalence among subjects with a longer duration of t2 dm and increasing age , particularly in those with a disease lasting for more than 20 years . this was true for heart failure ( 5.4% if t2 dm lasting between 0 and 20 years vs. 10.1% after 20 years of diabetes across age groups , p < 0.001 ) , coronary artery disease ( 12.3% vs. 21.3% after 20 years of diabetes , p < 0.001 ) , stroke ( 5.8% , but 10.8% after 20 years of diabetes , p < 0.001 ) and peripheral artery disease ( 3.9% vs. 8.6% after 20 years of diabetes , p < 0.001 ) . in the case of diabetic retinopathy , patients with a longer duration had also a higher prevalence of diabetic retinopathy ( 6.7% vs. 26% after 20 years of diabetes , p < 0.001 ) a total of 318,020 subjects with a diagnosis of t2 dm were included in the study ; 53.8% of them were males ( n = 171,219 ; table 1 ) . mean age of the overall population was 68.8 years ( sd = 11.9 ) ; the mean age at diagnosis was 61.6 years ( sd = 11.7 ) , and the median disease duration was 6.7 years [ interquartile range ( iqr ) = 6.2 years ) . according to prespecified age categories , 38.0% of subjects were 65 ( 62.9% males ) ; 29.4% were 6675 ( 54.3% males ) ; 25.8% were 7685 ( 45% males ) ; and 6.8% were > 85 years ( 33.4% males ) . demographic and clinical characteristics of the study population by gender and age group the number of patients with available data varied depending on each studied variable . acr , albumintocreatinine ratio ; bmi , body mass index ; bp , blood pressure ; egfrmdrd , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula ; hba1c , standardised glycated haemoglobin ; hdlc , highdensity lipoproteins hdl cholesterol ; ldlc , lowdensity lipoproteins ldl cholesterol ; tc , total cholesterol . there was a progressive improvement in glycaemic control values ( hba1c ) with age in both genders ( p < 0.001 ) despite longer diabetes duration in older age groups . in the total sample , kg / m vs. 31.0 kg / m , respectively ) , and declined with age for both genders ( p < 0.001 ) . of note , in both genders the mean values of diastolic bp , tc , ldlc and tg were significantly lower in the older age groups ( p < 0.001 ) . the average values of egfrmdrd also decreased gradually with age in both genders ; thus , the percentage of patients with renal failure ( egfr < 60 ml / min ) and urine acr increased gradually with age in both genders ( p < 0.001 ) . the degree of control of main cardiovascular risk factors for t2 dm and pharmacological treatments is shown in table 2 . the percentage of subjects with fair glycaemic control ( hba1c 7% ) was significantly higher among older age groups ( p < 0.001 ) ; moreover , a lower proportion of patients in the older age groups were not well controlled ( hba1c > 10% ) in spite of having more comorbid conditions . overall , a 22% of patients in both genders were not taking any glucoselowering drugs . its use was progressively reduced with increasing age , with a total of 71.5% of men and 68.4% of women older than 85 years taking any glucoselowering agent . however , there was also a parallel increase in the use of insulin with age , particularly in monotherapy . there were no substantial differences in the control of blood pressure ( bp 140/90 mmhg ) with age , although the control was slightly better among patients 65 years , particularly in women ( 67.3% vs. 71% of men ) , while 65.5% of men and 62.9% of women older than 65 years had their bp under control . as for the pharmacological treatment of hypertension , there was a greater proportion of older subjects being pharmacologically treated compared with younger adults , and more frequently treated with a combination of different drugs . degree of control of main cardiovascular risk factors for t2 dm and pharmacological treatment by gender and age group hba1c 7% = 53 mmol / mol ; hba1c 7.5% = 58.5 mmol / mol ; hba1c 8.5% = 69.4 mmol / mol ; hba1c bmi , body mass index ; bp , blood pressure ; hba1c , standardised glycated haemoglobin ; ldlc , lowdensity lipoproteins ldl cholesterol . in both genders , the control of dyslipidaemia , both in patients without cvd and with cvd ( ldlc levels < 130 mg / dl and < 100 mg / dl , respectively ) was better among patients 6685 years than in patients 65 years , while in the age group > 85 years the highest values across all age groups was observed . additionally , lipidlowering drugs were used less frequently by both women and men in the older age groups ( p < 0.001 ) . as for the use of antiplatelet agents , their use was progressively higher with increasing age ( p < 0.001 ) , being used by 53.9% of men and 46.2% of women older than 85 years . finally , the percentage of patients currently smokers decreased with age ( p < 0.001 ) , and in all age groups there was a much lower proportion of women smokers . as for the combined control of different cardiovascular risk factors ( namely hba1c 7% , bp 140/90 mmhg , ldlc < 130 mg / dl or 100 mg / dl , and no smoking ) , it was achieved in 22.6% of men and 24.9% of women 65 years , while these percentages were significantly higher among patients > 65 years , ranging between 29.7% and 35.2% in men , and 29% and 32% in women across older age groups ( p < 0.001 ) . the prevalence of chronic micro and macrovascular complications associated with t2 dm by gender and age subgroup is shown in table 3 . there was a sharp increase in the frequency of heart failure and all macrovascular complications ( ischaemic heart disease , stroke and peripheral artery disease ) with increasing age ( p < 0.001 in all complications ) . the global prevalence of ischaemic heart disease was 8.6% in women vs. 15.9% in men ; the prevalence of stroke was 6.4% in men vs. 5.3% in women ; the prevalence of peripheral artery disease was 5.7% in men vs. 2.0% in women ; and the prevalence of heart failure was 4.7% in men vs. 6.6% in women . prevalence of diabetesrelated complications by gender and age subgroup acr , albumintocreatinine ratio ; cvd , cardiovascular disease ; egfrmdrd , estimated glomerular filtration rate ( egfr ) using the modified diet in renal disease ( mdrd4 ) formula . as for microvascular complications , diabetic retinopathy was more frequent among patients > 65 years ( p < 0.001 ) , although taking into account the diabetes duration , there was a progressive decrease in frequency with increasing age , particularly in men ( figure 1 ) . the assessment of kidney disease by egfrmdrd showed a progressive increase in renal failure cases ( egfrmdrd < 60 ml / minute ) with age , which was also the case for acr values , and both complications together were observed up to a 20% of men and 19.3% of women older than 85 years compared with a 2.2% of men and 1.9% of women furthermore , albuminuria ( acr > 30 mg / mmol ) increased with age and was more frequent in men than in women in all age groups ( p < 0.001 ) . impact of t2 dm duration , age and gender on the prevalence of diabetic retinopathy ( dr ) we further studied whether diabetes duration ( 5 years , 510 years , 1020 years and > 20 years ) was related to the degree of glycaemic control and presence of diabetesrelated complications . the older the patients were the higher the percentage achieving a glycaemic goal of hba1c values 7% , and this was true in all age subgroups regardless the duration of t2 dm . moreover , patients in older age subgroups were more likely to achieve target glycaemic values irrespective of having a cvd or heart failure . for instance , the proportion of patients with a disease duration 15 years and no cvd who achieved target hba1c values 7% was 49% among those aged 65 years , and 54% among those aged 6575 years ; in patients with a disease duration > 15 years and cvd , 56% aged 65 years and 83% aged 6575 years achieved target hba1c values 7% and 8.5% , respectively . as for individual diabetesrelated complications , there was a higher prevalence among subjects with a longer duration of t2 dm and increasing age , particularly in those with a disease lasting for more than 20 years . dm lasting between 0 and 20 years vs. 10.1% after 20 years of diabetes across age groups , p < 0.001 ) , coronary artery disease ( 12.3% vs. 21.3% after 20 years of diabetes , p < 0.001 ) , stroke ( 5.8% , but 10.8% after 20 years of diabetes , p < 0.001 ) and peripheral artery disease ( 3.9% vs. 8.6% after 20 years of diabetes , p < 0.001 ) . in the case of diabetic retinopathy , patients with a longer duration had also a higher prevalence of diabetic retinopathy ( 6.7% vs. 26% after 20 years of diabetes , p < 0.001 ) older people are a growing population with t2 dm that account for approximately 50% of all cases of diabetes in adults and have differential characteristics , requiring tailored management approaches 1 , 5 , 8 . the present descriptive study assessed the clinical and characteristics , the degree of glycaemic control , the presence of chronic diabetesrelated complications and the use of pharmacological treatments in a population of 318,020 adults with t2 dm treated in a reallife clinical setting . the results evidenced the existence of different profiles between age groups : except for the control of bp , diabetic patients older than 65 years had a better glycaemic control and a better control of dyslipidaemia , obesity and tobacco smoking than patients 65 years ; they were less frequently treated with glucoselowering and lipidlowering drugs , but more frequently with antiplatelet agents . they also had a better control of glycaemic targets and cardiovascular risk factors in spite of a progressive increase in the prevalence of chronic complications with increasing age . we observed a better glycaemic control among elderly patients that was independent of t2 dm duration and the degree of obesity , as it has been previously reported in another crosssectional study 12 . moreover , glycaemic goals were more often achieved by patients in the older subgroups regardless the presence of a cvd , in accordance with the results from clinical trials and observational studies suggesting that a global control of cardiovascular risk factors in older patients provides a greater benefit regarding morbidity and mortality than an intensive glycaemic control 13 , 14 , 15 , 16 , 17 . antihypertensive treatment , for instance , has benefits even in very old patients 18 , 19 , 20 , 21 , and there are also compelling evidences of the benefit of statins and antiplatelet agents in older adults in secondary prevention of cvd , while its use in primary prevention is controversial , and individual characteristics and the risk of related adverse events should be taken into account 5 , 7 , 22 , 23 , 24 , 25 . there is a lack of data regarding the benefits of the pharmacological treatment of t2 dm among elderly people , mainly because they are systematically excluded from clinical trials , and evidences have been inferred from studies in middleaged adults 5 . from our results , both men and women 65 years used less glucoselowering drugs , albeit with a progressive increase in insulin use with increasing age , which is consistent with the evidence that elderly patients eventually require insulin as a result of the natural progression of the disease but also because of the high prevalence of renal failure that contraindicates other antidiabetic drugs 26 , 27 . moreover , as bp increases with age , older patients used more hypertensive agents than younger patients reaching a similar control of bp . in relation to lipidlowering drugs , they used less , which would be in agreement with the observed better control of dyslipidaemia , although the particular subgroup 85 years had the worse level of control across all age groups . this is probably because of the fact that they were using less lipidlowering drugs because general practitioners do not prescribe them based on the scarce evidences on the benefits of statins in very old people . as expected , increasing age was associated with a parallel increase in the prevalence of micro and macrovascular complications except for retinopathy , which decreased after 85 years , and they were more frequent in men . this pattern was dependent on the diabetes duration and also on the degree of obesity in the case of heart failure , which suggests that control and prevention of cvds must be an important goal based not only on the age of the patient but also on disease 's duration . the main strength is that this is the largest crosssectional study conducted in spain to study t2 dm in older population through the use of a large primary care database with high quality records previously validated in other studies 28 , 29 , and that is closer to the reallife clinical practice than randomised clinical trials , which usually exclude elderly patients . however , no causal associations between risk factors and presence of diabetesrelated complications can be drawn because of the crosssectional design , and we estimated the strength of these associations stratifying by other variables . moreover , the retrospective records for diabetic neuropathy were also scarce , probably because it is difficult to diagnose and there is a lack of uniform diagnostic criteria . in addition , and inherent to all crosssectional studies conducted in elderly populations , there is a survival bias because patients with diabetesrelated complications , poor control and/or severe forms of t2 dm usually die at a younger age than patients with a late onset and/or well controlled disease . it is possible that those who survive have different metabolic characteristics and also a slower decline of beta cell function in the natural history of t2 dm than those who do not survive . avoidance of this bias could only be addressed through the design of prospective controlled longterm followup studies . finally , mortality could have also impacted the prevalence of particular factors and complications , as populations at high risk have greater mortality rates and therefore survivors in older age groups have a lesser prevalence than actually expected . patients with t2 dm older than 65 years have a better glycaemic control and a better global control of cardiovascular risk factors than younger adults . however , older age groups were also more likely to achieve glycaemic targets irrespective of having cvd and longer diabetes duration . finally , the use of agents to control hyperglycaemia and dyslipidaemia was lower in older ages . this differential age and genderrelated pattern stresses the need to individually adapt the therapeutic and care approaches of t2 dm in elderly people to allow the best benefit and the lowest risk at all stages of the disease . further research is warranted to investigate through prospective and interventional studies the observed differences in the clinical behaviour and treatment of t2 dm in elderly people . jbdlp , mmc and jfn wrote the manuscript and contributed to the discussion ; xmt , ac and jmfrl contributed to the discussion ; jfn , mmc and dm designed and conducted the study , reviewed / edited the manuscript and contributed to the discussion . mmc had full access to all data in the study and takes responsibility for the integrity of data and the accuracy of the data analysis . OUTPUT:

summarybackgroundolder subjects with type 2 diabetes mellitus ( t2 dm ) have differential characteristics compared with middleaged or younger populations , and require tailored management of the disease.aimsto evaluate how clinical characteristics , degree of control of glycaemia and cardiovascular risk factors , presence of chronic complications and treatments differ between older t2 dm patients and younger adults.methodscrosssectional study using data from a populationbased electronic database . we retrieved data from 318,020 patients 30 years diagnosed with t2 dm , attended during 2011 in primary care centres in catalonia , spain . we performed descriptive and comparative analyses stratified by gender and age subgroups : 65 , 6675 , 7685 and > 85 years.resultsboth men and women across older age subgroups ( > 65 years ) had longer diabetes duration than younger adults ( 8.0 vs. 5.6 in men and 8.4 vs. 6.9 years in women ; p < 0.001 ) , but better glycaemic control ( mean glycated haemoglobin 7.1 vs. 7.7 in men and 7.1 vs. 7.4 in women ; p < 0.001 ) , and better combined control of different cardiovascular risk factors ( p < 0.001 ) . moreover , older patients were more likely to achieve glycaemic targets irrespective of having cardiovascular disease . the use of oral antidiabetics decreased with increasing age , and insulin in monotherapy was more frequently prescribed among patients in the older age subgroups . diabetesrelated complications were more frequent in men of all group ages . in the older age subgroups , patients of both sexes had a longer duration of t2 dm but better glycaemic control . in this context , the prevalence of diabetic retinopathy decreased unexpectedly with increasing age.conclusioncontrol of glycaemia and cardiovascular risk factors was better among older t2 dm patients . there is a need for prospective studies to quantify the weight of risk factors in each complication to adapt the therapeutic and care approaches in elderly people .

PubMed_Summ6548

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the perception of the sensory consequences of one s own actions is inherently different to the perception of other sensory events . for example , people tend to perceive the sensory consequences of their actions as attenuated ( blakemore et al . 1998 ; shergill et al . 2003 ) , which is proposed to facilitate the distinction between self- and externally generated actions ( blakemore et al . another well - described perceptual distortion with voluntary actions is the temporal attraction between a self - generated action and its sensory outcome : a willed action is perceived to occur later in time , whereas its sensory consequence ( e.g. , a tone ) is perceived to occur earlier in time . this attraction is absent for involuntary actions , suggesting it is the intentionality that leads to the temporal binding of the action and its effect . the term 2002 ) , it has been suggested to be a quantitative index of awareness of action or agency , that is , the sense that one controls one s own actions . as an objective and replicable behavioral measure , it has considerable advantages over verbal self - reports in the study of volition . the intentional binding paradigm has therefore been applied to study agency in healthy individuals ( e.g. , moore et al . 2011 ) and in clinical populations , such as individuals with parkinson s disease ( moore et al . 2010b ) or schizophrenia ( haggard et al . 2003 ) . in many of these studies , the magnitudes of action binding ( the temporal attraction of action toward its outcome tone ) and tone binding ( the attraction of consequent tone toward action ) are summed up to obtain an for example , the drug ketamine , which can induce a reversible psychosis in healthy individuals , enhances overall binding , similarly to that observed in schizophrenia , and has been suggested to increase agency ( moore et al . 2011 ) . despite the growing use of binding as a measure of agency , the underlying mechanisms of action and tone binding remain largely unclear . moore and haggard ( 2008 ) have shown that action binding depends on both a predictive process ( modulated by the probability of the tone following the action ) and an inferential process ( as action binding is apparent even in low effect probability as long as the tone occurs ) . both of these processes are significantly supported by the contingency or causality relation between the action and tone ( moore et al . 2009 ) , suggesting a critical role for learning an action tone binding on the other hand is related to a more general association process , as it does not depend on establishing a specific action a predictive process has also been suggested to account for tone binding , in which predicted sensory outcomes reach perceptual threshold more rapidly ( waszak et al . for example , repetitive transcranial magnetic stimulation over the pre - supplementary motor area can specifically alter tone binding with no effect on action binding ( moore et al . these studies suggest that action and tone binding may be driven by distinct mechanisms . despite this body of evidence , there are few studies which examine the mechanisms of both action and tone binding . the present study aims to satisfy this experimental challenge by considering the role of cue integration in both action and tone binding . in many sensorimotor tasks , these experimentally tractable models have also been suggested to contribute to the sense of agency , and the intentional binding in particular ( moore and fletcher 2012 ; moore and haggard 2008 ) . according to this framework , the sensorimotor system optimally combines information from different sources , such as multiple sensory modalities ( ernst and banks 2002 ; hillis et al . 2002 ) and prior expectations ( krding and wolpert 2004 ) , in order to reduce variability in performance ( e.g. , ernst and banks 2002 ) . in binding , the action event and the sensory outcome event ( tone ) provide two separate cues for estimating their time . the time estimates are then a weighted average of the action and tone events , where the weight of each cue corresponds to its reliability ( or in other words the precision of estimates , expressed as the inverse of the variance ) relative to the reliability of the other cue . if both action and tone binding are supported by action effect cue integration , this framework could explain the temporal attraction between action and tone events in binding . in this study , we investigated the contribution of cue integration to action and tone binding . to this end , we manipulated the reliability of the tone event by modulating its intensity relative to a background white noise . based on each subject s individual auditory detection threshold , we generated three tones with increasing intensities , which in the presence of noise provided high , intermediate and low levels of uncertainty in the perception of tone onset . we tested three main predictions of the cue integration hypothesis under different conditions of tone reliability . first , if cue integration underlies both action and tone binding measures , action binding will be weakest under high tone uncertainty , whereas tone binding will be strongest . these changes should be mainly driven by differential weighting of the action and tone cues according to uncertainty , in the conditions where both cues are provided . second , if such cue integration mechanism is in fact common to both action and tone binding , the extent of changes in these measures as a result of modifying uncertainty will be related . finally , in conditions where both action and tone cues are provided , the variability of time estimates should be lower ( i.e. , time estimates should be more precise ) than in conditions where only one cue is provided , reflecting the key behavioral advantage of cue integration for perceptual precision . twenty right - handed volunteers ( ten females ) aged 1836 ( mean : 26 , sd : 6 ) took part in the study and were compensated 14.5 for their participation . all subjects reported no history of neuropsychiatric disorders and had normal or corrected - to - normal vision . subjects were tested with a modified version of the intentional binding task ( haggard et al . white noise ( 1,000 hz frequency ) was played continuously , while pure tones ( 1,000 hz ; 100-ms duration ) were played at intervals of 16 s. tones were generated by multiplying the amplitude of a sinusoidal waveform by factors between 0.01 and 0.1 ( fixed 0.01 interval between them ) . overall level of noise was 80-db spl , and tones were between 63 and 83-db spl ( intervals of 13-db spl between each tone ) . subjects task was to press a key to indicate when they were able to hear a tone . for each tone intensity ( 10 in total ) , six trials were played pseudorandomly , making up a total of 60 trials . clock on a computer screen marked with numbers from five to sixty in intervals of five ( fig . 1 ) . a single hand rotated clockwise ( period of 2,560 ms ) , providing a time stamp for reporting the perceived time of events . on each trial , subjects used a keyboard to report the time of self - paced button presses or tones ( 1,000 hz ; 100 ms ) . in the baseline tone condition , a tone was played at random without a prior action between 2.5 and 6 s after trial onset . in the baseline action condition in the two operant conditions , a tone followed the button press by 250 ms , and subjects were asked to report either the time of their button press or the tone . subjects were discouraged from pre - planning the time at which they press the button.fig . they were asked to press a button at their own pace , which triggered a tone ( 250-ms delay ) . the tone had low , intermediate or high intensity ( interleaved in a pseudorandomized order ) . subjects reported either the time of the button press or the time of the tone ( conditions blocked ) using the position of the rotating clock hand . binding is measured as the difference between the means of estimation errors for action or tone events , and those in the corresponding baseline conditions , when the action and tone occur separately illustration of the modified intentional binding task . subjects attended to a they were asked to press a button at their own pace , which triggered a tone ( 250-ms delay ) . the tone had low , intermediate or high intensity ( interleaved in a pseudorandomized order ) . subjects reported either the time of the button press or the time of the tone ( conditions blocked ) using the position of the rotating clock hand . binding is measured as the difference between the means of estimation errors for action or tone events , and those in the corresponding baseline conditions , when the action and tone occur separately in contrast to previous intentional binding studies , a background white noise was played throughout the trials in order to increase the uncertainty about the time of tone onset . the tones had one of three amplitudes , generated as a function of each subject s detection threshold ( see analyses ) . these three amplitudes were used to produce three levels of uncertainty with regard to estimating the time of tone onset . the three levels of uncertainty were pseudorandomly interleaved in the three task conditions in which tones were played . in the experimental blocks , each of the four block types consisted of 30 trials and was repeated four times . in total , 120 trials were performed for each condition , 40 trials per level of uncertainty . the preliminary tone detection performance was fitted with a psychometric ( weibull ) function , using a maximum - likelihood procedure ( wichmann and hill 2001 ) . each subject s amplitude of detection threshold was calculated at 50 % threshold in the psychometric function . in addition to the threshold amplitude , two more amplitudes were calculated , by multiplying that of the detection threshold by 2 and 5 . this generated low ( detection threshold ) , intermediate and high intensities for the tones used in the binding task . across subjects , low tones had a mean intensity of 78-db spl ; intermediate tones , 84-db spl ; and high , 92-db spl ; the noise was fixed at overall level of 80-db spl . low , intermediate and high tone intensities were used to provide high , intermediate and low levels of uncertainty about the tone onset , respectively . mean estimation errors ( i.e. , the difference between actual and estimated time of event ) were calculated separately for each level of uncertainty for action and tone in the baseline and operant conditions . trials with outlier estimation errors ( 2.5 sd from mean ) were removed from each subject s dataset ( on average approximately three trials per subject ) . one subject was excluded from the study , as the standard deviation ( sd ) of his baseline action values was greater than two times the group mean sd . for each level of uncertainty , the mean estimation errors in baseline action and tone conditions were subtracted from their corresponding operant conditions to obtain action and tone binding measures , respectively . to explore the effect of uncertainty on binding , we performed repeated - measures anovas with uncertainty ( high , intermediate and low ) as a within - subject factor on the following datasets : ( 1 ) sds of estimation errors in baseline tone condition ; ( 2 ) action and tone binding values ; and ( 3 ) mean estimation errors in baseline and operant tone conditions . anovas were followed by two - tailed paired t tests , except for the comparisons of binding across uncertainties , in which the direction was hypothesized according to the cue integration prediction . two additional analyses were performed : ( 1 ) correlating the ratios between action binding in low and high uncertainty and the corresponding ratios in tone binding , using spearman s ranked correlation , and ( 2 ) pairwise comparisons of sds in baseline versus operant action and tone conditions for each level of uncertainty . twenty right - handed volunteers ( ten females ) aged 1836 ( mean : 26 , sd : 6 ) took part in the study and were compensated 14.5 for their participation . all subjects reported no history of neuropsychiatric disorders and had normal or corrected - to - normal vision . subjects were tested with a modified version of the intentional binding task ( haggard et al . auditory stimuli were presented by sennheiser hd250 linear ii headphones throughout the testing session . an auditory detection task was first performed to identify each subject s detection threshold . white noise ( 1,000 hz frequency ) was played continuously , while pure tones ( 1,000 hz ; 100-ms duration ) were played at intervals of 16 s. tones were generated by multiplying the amplitude of a sinusoidal waveform by factors between 0.01 and 0.1 ( fixed 0.01 interval between them ) . overall level of noise was 80-db spl , and tones were between 63 and 83-db spl ( intervals of 13-db spl between each tone ) . subjects task was to press a key to indicate when they were able to hear a tone . for each tone intensity ( 10 in total ) , six trials were played pseudorandomly , making up a total of 60 trials . clock on a computer screen marked with numbers from five to sixty in intervals of five ( fig . 1 ) . a single hand rotated clockwise ( period of 2,560 ms ) , providing a time stamp for reporting the perceived time of events . on each trial , subjects used a keyboard to report the time of self - paced button presses or tones ( 1,000 hz ; 100 ms ) . in the baseline tone condition , a tone was played at random without a prior action between 2.5 and 6 s after trial onset . in the baseline action condition in the two operant conditions , a tone followed the button press by 250 ms , and subjects were asked to report either the time of their button press or the tone . subjects were discouraged from pre - planning the time at which they press the button.fig . they were asked to press a button at their own pace , which triggered a tone ( 250-ms delay ) . the tone had low , intermediate or high intensity ( interleaved in a pseudorandomized order ) . subjects reported either the time of the button press or the time of the tone ( conditions blocked ) using the position of the rotating clock hand . binding is measured as the difference between the means of estimation errors for action or tone events , and those in the corresponding baseline conditions , when the action and tone occur separately illustration of the modified intentional binding task . they were asked to press a button at their own pace , which triggered a tone ( 250-ms delay ) . the tone had low , intermediate or high intensity ( interleaved in a pseudorandomized order ) . subjects reported either the time of the button press or the time of the tone ( conditions blocked ) using the position of the rotating clock hand . binding is measured as the difference between the means of estimation errors for action or tone events , and those in the corresponding baseline conditions , when the action and tone occur separately in contrast to previous intentional binding studies , a background white noise was played throughout the trials in order to increase the uncertainty about the time of tone onset . the tones had one of three amplitudes , generated as a function of each subject s detection threshold ( see analyses ) . these three amplitudes were used to produce three levels of uncertainty with regard to estimating the time of tone onset . the three levels of uncertainty were pseudorandomly interleaved in the three task conditions in which tones were played . each of the four block types consisted of 30 trials and was repeated four times . in total , 120 trials were performed for each condition , 40 trials per level of uncertainty . the preliminary tone detection performance was fitted with a psychometric ( weibull ) function , using a maximum - likelihood procedure ( wichmann and hill 2001 ) . each subject s amplitude of detection threshold was calculated at 50 % threshold in the psychometric function . in addition to the threshold amplitude , two more amplitudes were calculated , by multiplying that of the detection threshold by 2 and 5 . this generated low ( detection threshold ) , intermediate and high intensities for the tones used in the binding task . across subjects , low tones had a mean intensity of 78-db spl ; intermediate tones , 84-db spl ; and high , 92-db spl ; the noise was fixed at overall level of 80-db spl . low , intermediate and high tone intensities were used to provide high , intermediate and low levels of uncertainty about the tone onset , respectively . mean estimation errors ( i.e. , the difference between actual and estimated time of event ) were calculated separately for each level of uncertainty for action and tone in the baseline and operant conditions . trials with outlier estimation errors ( 2.5 sd from mean ) were removed from each subject s dataset ( on average approximately three trials per subject ) . one subject was excluded from the study , as the standard deviation ( sd ) of his baseline action values was greater than two times the group mean sd . for each level of uncertainty , the mean estimation errors in baseline action and tone conditions were subtracted from their corresponding operant conditions to obtain action and tone binding measures , respectively . to explore the effect of uncertainty on binding , we performed repeated - measures anovas with uncertainty ( high , intermediate and low ) as a within - subject factor on the following datasets : ( 1 ) sds of estimation errors in baseline tone condition ; ( 2 ) action and tone binding values ; and ( 3 ) mean estimation errors in baseline and operant tone conditions . anovas were followed by two - tailed paired t tests , except for the comparisons of binding across uncertainties , in which the direction was hypothesized according to the cue integration prediction . two additional analyses were performed : ( 1 ) correlating the ratios between action binding in low and high uncertainty and the corresponding ratios in tone binding , using spearman s ranked correlation , and ( 2 ) pairwise comparisons of sds in baseline versus operant action and tone conditions for each level of uncertainty . table 1 summarizes the estimation errors and their sds for all experimental conditions across subjects . we first sought to verify the assumption that reducing tone intensities against the background noise would increase uncertainty with regard to estimates of tone event onset . baseline tone condition , that is , where tones were played at random , and not associated with a button press or action ( fig . 2 ) . repeated - measures anova showed a main effect of intensity ( f(1.29 , 24.43 ) = 23.8 , p < 0.001 ) on estimation error sd . post hoc two - tailed ( bonferroni corrected ) comparisons confirmed an increase in the sd of estimation errors for low - intensity tones , relative to both intermediate ( t19 = 4.38 , p < 0.001 ) and high ( t19 = 5.94 , p < 0.001 ) intensities , and a weak trend toward increased sd in intermediate- compared to high - intensity tones ( t19 = 1.69 , p = 0.11 ) . high- , intermediate- and low - intensity tones were thus able to provide low , intermediate and high levels of temporal uncertainty , respectively.table 1mean estimation errors and mean standard deviation ( sd ) of estimation errors across subjects ( mean standard error in parentheses ) . values are shown for the estimated time of action and tone in the baseline and operant conditions for the three levels of uncertaintylevel of uncertaintyconditioneventmean ( se ) estimation error ( ms)mean ( se ) sd of estimation error ( ms)lowbaselineaction8 ( 11)75 ( 6)tone35 ( 11)61 ( 3)operantaction31 ( 11)79 ( 5)tone16 ( 22)76 ( 4)intermediatebaselineaction8 ( 11)75 ( 6)tone46 ( 11)66 ( 3)operantaction23 ( 10)70 ( 5)tone19 ( 21)80 ( 5)highbaselineaction8 ( 11)75 ( 6)tone95 ( 11)90 ( 5)operantaction24 ( 10)71 ( 6)tone10 ( 23)77 ( 4)fig . 2the standard deviation ( sd ) of estimation errors for the different tone intensities in baseline tone condition , wherein a tone was played at random without a prior action . sds were increased in trials with low tone intensity relative to both intermediate and high intensities ( * * * p < 0.001 ) . high , intermediate and low tone intensities thus provided low , intermediate and high levels of sensory uncertainty in estimating the time of tone onset . error bars indicate mean standard errors for the study group mean estimation errors and mean standard deviation ( sd ) of estimation errors across subjects ( mean standard error in parentheses ) . values are shown for the estimated time of action and tone in the baseline and operant conditions for the three levels of uncertainty the standard deviation ( sd ) of estimation errors for the different tone intensities in baseline tone condition , wherein a tone was played at random without a prior action . sds were increased in trials with low tone intensity relative to both intermediate and high intensities ( * * * p < 0.001 ) . high , intermediate and low tone intensities thus provided low , intermediate and high levels of sensory uncertainty in estimating the time of tone onset . error bars indicate mean standard errors for the study group the cue integration hypothesis predicts that as uncertainty about the timing of the tone increases ( i.e. , reliability is reduced ) , action binding will be reduced , whereas tone binding will be enhanced . to test this , we first calculated action and tone binding separately for each level of uncertainty , by subtracting estimation errors in the baseline conditions from their corresponding operant conditions , in which the action was associated with a tone ( fig . 3 ) . to examine the effect of cue integration on action and tone binding independently , we entered these measures to two separate repeated - measures anovas , with uncertainty ( low , intermediate and high ) as a within - subject factor.fig . shapes represent the event ( rectangle action , oval tone ) , and their shade denotes the condition ( white baseline , gray operant ) . numbers indicate the mean action and tone binding across subjects ( mean standard error in parentheses ) . significance level in pairwise comparisons is indicated by * * * p < 0.001 and * p 0.05 action and tone binding for the three levels of tone uncertainty . shapes represent the event ( rectangle action , oval tone ) , and their shade denotes the condition ( white baseline , gray operant ) . numbers indicate the mean action and tone binding across subjects ( mean standard error in parentheses ) . significance level in pairwise comparisons is indicated by * * * p < 0.001 and * p 0.05 a main effect of uncertainty on action binding was found ( f(1.34 , 25.37 ) = 4.22 , p = 0.04 ) . one - tailed ( bonferroni corrected ) post hoc t tests indicated a reduction in action binding in the high relative to low uncertainty ( t19 = 4.465 , p < 0.001 ) , and a just significantly reduced action binding in the intermediate relative to low uncertainty ( t19 = 2.261 , p = 0.05 ) . a main effect of uncertainty was also found for tone binding measures ( f(1.64 , 31.2 ) = 28.69 , p < 0.001 ) . post hoc pairwise comparisons confirmed an increase in tone binding ( i.e. , an earlier estimate of the tone event ) in the high uncertainty condition , relative to both intermediate ( t19 = 5.546 , p < 0.001 ) and low ( t19 = 6.109 , p < 0.001 ) levels of uncertainty . in addition , higher tone binding was observed in the intermediate compared to low uncertainty ( t19 = 2.4 , p = 0.04 ) . differences in action binding could only result from changes in estimation errors in the operant condition , as there were no different levels of uncertainty in baseline action condition . by contrast , the differences in tone binding could arise from changes in either baseline or operant conditions , as estimation errors were calculated separately for each level of tone uncertainty in both of these conditions . to explore where differences in tone binding originated from , we examined the estimation errors in the baseline and operant tone conditions in two separate anovas . a main effect of uncertainty on baseline tone estimation errors was found ( f(1.56 , 29.7 ) = 69.81 , p < 0.001 ) , with significant post hoc ( bonferroni corrected ) pairwise comparisons between the three levels of uncertainty ( high intermediate : t19 = 8.97 , p < 0.001 ; high low : t19 = 9.23 , p < 0.001 ; intermediate low : t19 = 2.88 , p = 0.03 ) . by contrast , there was no effect of uncertainty on operant tone estimation errors ( f(1.7 , 32.31 ) = 1.88 , p = 0.174 ) . taken together , these results indicate that the differences observed in tone binding across the three levels of uncertainty were driven by changes in estimation errors in the baseline condition , in which only the tone cue was provided . on the other hand , in action binding these differences could only arise from changes in the operant condition , indicating a contribution of cue integration . we next examined the relation between changes in tone binding and changes in action binding across uncertainties . if the extent of change in action binding , arising from cue integration , is correlated with the extent of change in tone binding , this would support a common effect of cue integration on tone binding as well . specifically , we looked at action and tone binding measures in the low and high uncertainty conditions ( the conditions which showed a highly significant difference , above ) . we correlated the ratio between action binding in the low and high uncertainty conditions and the corresponding ratio in tone binding . there was no significant correlation between the change in action and tone binding as a result of uncertainty across subjects ( spearman s rho = 0.038 , p = 0.876 ) , indicating there was no consistent relation between these changes in action and tone binding . a critical assumption of the cue integration account is that the integration of multiple cues reduces variability in performance . therefore , if cue integration contributes to tone binding , sd in the operant condition should be lower than the sd in the corresponding baseline condition . however , two - tailed ( bonferroni corrected ) comparisons revealed a significant increase in sd in operant relative to baseline tone conditions in both intermediate ( t19 = 3.92 , p = 0.003 ) and low ( t19 = 3.77 , p = 0.004 ) levels of uncertainty . for action binding , the mean sd in operant action condition was lower than sd in baseline action condition for low and intermediate uncertainties , although not statistically significant ( t19 = 1.66 , p = 0.3 ; and t19 = 1.67 , p = 0.3 ) . taken together , the results suggest that in contrast to action binding , tone binding is unlikely to be driven by action we studied the contribution of action effect cue integration to the perception of action and its sensory outcome in intentional binding . according to the cue integration hypothesis , the compression in the perceived temporal interval between a voluntary action and its sensory consequence results from using both events as temporally informative cues . the time estimates are based on a weighted average of the two events , in which the weight of each cue is determined by its relative reliability . as predicted by cue integration , our data show that reducing the reliability of the sensory outcome results in a smaller shift in the perceived time of action toward its outcome ( reduced action binding ) . the cue integration hypothesis also predicted an increase in the shift of the perception of the sensory outcome toward the action with increasing uncertainty ( i.e. , increased tone binding ) . however , the results of additional analyses point to a separate mechanism involved in tone binding . action binding has been described in terms of a postdictive or inferential process , as it occurs even when the action is not strongly predictive of a tone , as long as the tone event occurs ( moore and haggard 2008 ) . our results suggest that this postdictive process could be mediated by a cue integration mechanism . on the other hand , a predictive process has also been proposed to support action binding , as when the action is highly predictive of a tone , action binding occurs even in trials in which tones are absent ( moore and haggard 2008 ) . consistent with this notion , even in our high uncertainty condition , in which tones were at each individual subject s perceptual threshold , action binding measures were significantly above zero ( data not shown ) . the association between the action and its outcome has been suggested to explain the predictive component of action binding ( moore et al . our finding that action binding is supported by cue integration is consistent with a previous study , suggesting that the estimation of time of movement depends on cue integration ( lau et al . this integration combines information about the time of action with other sources , as in the sensory outcome of an action . information about the time of one s own voluntary action could draw upon proprioceptive as well as internal volitional signals , such as an efference copy of motor commands ( von holst 1954 ) or components of the readiness potential ( lau et al . 2007 ) . when sensory uncertainty is high or in the absence of sensory feedback , the perception of action relies more on these internal representations , thereby reducing action binding . the cue integration framework has been successfully used to explain many perceptual phenomena in the sensorimotor system ( e.g. , ernst and banks 2002 ) and has been suggested to support the sense of agency ( moore and fletcher 2012 ) . particularly , the integration of internal , volitional signals with external sensory cues can help dealing with uncertainty in the attribution of agency . therefore , alongside the well - described action effect association mechanism ( see above ) , this integration could be another mechanism that links agency and intentional binding and reflects the volitional components that are captured in binding . for example , abnormal agency in disease states or under experimental interventions could arise from impairments in the internal volitional signals that normally contribute to the experience of agency . in turn , these impaired signals can lead to distinct changes in intentional binding , resulting from abnormal weighting of the action and outcome events . future studies can thus apply the cue integration approach to explain abnormalities in action binding in terms of volitional deficits . if cue integration can account for action binding effects , can it also explain tone binding ? tone binding was enhanced with increasing tone uncertainty , which at first glance is consistent with cue integration . however , this effect is attributable to increasing perceptual shifts in the baseline condition ( tone only ) as a function of tone intensity , rather than changes in the operant conditions , in which both action and tone events occurred together . moreover , the changes in action and tone binding that resulted from sensory uncertainty were not correlated , suggesting different underlying mechanisms . crucially , the prediction that integrating cues reduces performance variability was not satisfied for tone binding : variability in estimation errors was significantly increased when two cues were provided in the operant tone condition , compared to baseline tone condition . these results show that the perceptual changes we observed in tone binding are likely to be driven by an alternative mechanism . according to this account , the neural representation of a predicted sensory event , such as a sensory outcome following a voluntary action , is activated prior to its occurrence . because of this ramped predictive activity , when the predicted sensory outcome occurs , it reaches perceptual threshold faster than when it is not predicted . consequently , estimation errors are smaller in the operant tone condition than they are in the baseline tone condition , leading to tone binding . our results suggest that this pre - activation mechanism can better account for the changes in tone binding under different levels of uncertainty . we found increased tone binding under high uncertainty , resulting from increased estimation errors in baseline tone condition . as tone intensity was reduced against a background noise for increasing sensory uncertainty , more time would be required for the tones to reach the perceptual threshold for detection . this additional time would be reflected in the increased estimation errors in the baseline condition . by contrast , in the operant condition , the learned action effect association could diminish these differences in perceptual latencies . in other words , for pre - activated tone representations , the differences in intensities could be negligible , resulting in the lack of differences in estimation errors that was observed in the operant condition across uncertainties . our results thus support the hypothesis that tone binding results from changes in perceptual latencies , driven by a predictive pre - activation mechanism ( waszak et al . these results add to the growing evidence that different mechanisms underlie action and tone binding ( waszak et al . effect association is required for action binding ( e.g. , moore and haggard 2008 ) , a more general association is sufficient for tone binding to occur ( desantis et al . such interventions include transcranial magnetic stimulation of the pre - supplementary motor area ( moore et al . effect cue integration is the most plausible explanation for the effect of uncertainty on action binding , differences in tone binding could be better accounted for by changes in perceptual latencies . effect association can contribute to action binding through a prediction mechanism ( moore and haggard 2008 ) . similarly , a prediction mechanism could be implemented for the tone to reach the perceptual threshold more rapidly and thereby lead to tone binding ( waszak et al . 2010a ) have motivated the study of volitional disorders in patients with neurological and psychiatric illnesses , as well as healthy adults ( e.g. , moore et al . 2010b , 2011 ) . often , action and tone binding measures have been added together ( i.e. , action binding plus the negative of tone binding ) to generate an this measure has been used as a single metric of agency for comparing groups or measuring the effects of experimental interventions . however , if , as our data suggest , action and tone binding have different underlying contributory mechanisms , then disease states or interventions may have differential effects on these two forms of binding . not only that our data indicate these two measures can be partially independent , but we also show that under some circumstances action and tone binding can be inversely related : recall that high sensory uncertainty led to a reduction in action binding , while tone binding was increased . we therefore suggest that future studies should consider action and tone binding separately , rather than summing up these measures for studying volition . first , our study draws upon the principles of cue integration , but does not apply computational techniques to model the data . formal modeling of individual subject data would require many more trials for each condition per subject , which were not obtained here . moreover , statistically optimal cue integration has been classically described for integrating multiple sources of information about one sensory event or object . although action and tone events are synthesized in binding , it is possible that some of the principles of cue integration may not apply for the binding task , such as the statistical optimality . second , we did not use a continuous variation of uncertainty , which would allow us to examine the psychometric properties of sensory uncertainty as a continuous effect . such continuous variation was opted instead for the greater power conferred by the ordinal uncertainties . third , our study only varies uncertainty in perception of action outcome tone and does not alter uncertainty in perception of time of action for fully covering the contribution of action effect cue integration to binding . one solution could be to study clinical populations , such as patients with movement disorders , in which there is uncertainty over actions . in conclusion , our results suggest that cue integration between action and effect contributes to the intentional binding effect for actions . by contrast , cue integration did not account for the observed changes in tone binding . this supports the notion that action and tone binding are driven by distinct underlying mechanisms . our data support the use of intentional binding in the investigation of the mechanisms of volition , but suggest that action and tone binding should be considered separately in future studies . OUTPUT:

intentional binding describes the perceived temporal attraction between a voluntary action and its sensory consequence . binding has been used in health and disease as an indirect measure of awareness of action or agency , that is , the sense that one controls one s own actions . it has been proposed that binding results from cue integration , in which a voluntary action provides information about the timing of its consequences or vice versa . the perception of the timing of either event is then a weighted average , determined according to the reliability of each of these two cues . here we tested the contribution of cue integration to the perception of action and its sensory effect in binding , that is , action and tone binding , by manipulating the sensory reliability of the outcome tone . as predicted , when tone reliability was reduced , action binding was diminished and tone binding was increased . however , further analyses showed that cue integration accounted for changes in action binding , but not tone binding . these findings establish a role for cue integration in action binding and support the growing evidence suggesting that action and tone binding are , at least in part , driven by distinct mechanisms .

PubMed_Summ6549

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: synovial chondromatosis is a disease with unknown etiology , originating from synovia and characterized by the presence of metaplastic cartilaginous nodules in the synovial cavities , bursa or tendon sheaths . the disease is commonly seen in men and between the 3rd and 5th decades of life . although the exact etiology is not known the knee , hip and elbow joints are frequently reported to be involved by the condition . however , shoulder and ankle joints are involved extremely rarely . the disease is classified in 3 stages and evaluated according to following criteria : the early stage with intrasynovial differentiation without loose bodies , the transitional stage by intrasynovial cartilaginous nodules with loose bodies and late stage with multiple loose bodies . the treatment decision is made according to the patient 's age , symptoms and the disease stage . the main advantages of the arthroscopic approaches are decreased morbidity , synchronous visualization and treatment feature for intra and extra articular pathologies . the hypertrophic synovia and multiple loose bodies are typical arthroscopic findings . in this case report , we presented an arthroscopically managed adult patient with anteriorly localized right ankle chondromatosis and discussed the potential benefits of arthroscopic surgery . a twenty - eight year old male patient was admitted to our hospital with decreased range of motion , swelling and increased pain during movement in the right ankle joint . he had no history of trauma , systemic inflammatory disease or family history of bone or joint diseases . the physical examination revealed that he had mild tenderness around the anterior ankle joint on palpation with palpable loose bodies . multiple nodules 39 mm in diameter with calcifications were located at the anterior aspect of the right ankle on the plain anteroposterior and lateral x - ray images ( fig . 1 ) . magnetic resonance imaging ( mri ) revealed multiple calcified well - circumscribed loose bodies at the same location and synovitis in the ankle joint ( fig . the laboratory tests were within the normal limits and the patient was scheduled for arthroscopic surgery with the diagnosis of anterior impingement syndrome due to right ankle synovial chondromatosis . the ankle joint was entered via anteromedial and anterolateral arthroscopic portals during spinal anesthesia and tourniquet application . multiple loose bodies and hypertrophic synovia around the anterior ankle joint were seen ( fig . 3 ) . arthroscopic partial synovectomy and excision of loose bodies were performed ( fig . the drain was removed in the 1st postoperative day and the active and passive range of motion exercises was started . the patient was allowed partial weight bearing with crutches and at the 2nd week he was mobilized with full weight . there were multiple cartilaginous loose bodies , with the biggest and smallest dimensions of 0.9 cm 0.7 cm 0.5 cm and 0.4 cm 0.3 cm 0.2 cm in the permanent pathology report respectively ( fig . the patient 's dorsiflexion and plantar flexion degrees were 25 and 30 , respectively , at the end of the 11th postoperative month . no complications were diagnosed in the follow - up period with no recurrence on the plain x - ray images and mri . trauma , degenerating joint diseases , osteochondritis dissecans , rhomatoid arthritis and tuberculosis arthritis are examples of the secondary form . our case was evaluated in the primary synovial osteochondromatosis group due to the absence of previous trauma or inflammatory pathologies . complaints of pain , swelling of the joint ( especially after physical activity ) with or without accompanying pain , decreased range of motion , palpable mass , locking paresthesias and joint clicking are main symptoms and signs in patients with synovial chondromatosis . the suspected diagnosis was confirmed by the appropriate radiologic investigations and pathologic examination after history taking and physical evaluation . the calcified form synovial osteochondromatosis could be seen in the anteroposterior and lateral plain x - ray images . mri investigation enabled the diagnosis of the disease in the early stage , the exact localization of the disease and intrinsic property of chondroid tissue . the tenosynovial giant cell tumor , calcifying aponeurotic fibroma , periosteal chondroma , osteocartilaginous loose bodies and soft tissue chondrosarcoma must be kept in mind in the differential diagnosis . the disease is slowly progressive and is considered to be a self - limiting condition . in the early stages of the disease and in asymptomatic patients , treatment can be planned conservatively with frequent follow - up visits . degenerative changes could occur in the later stages of the disease in patients without appropriate therapy . although the classical treatment approach for ankle joint chondromatosis is open surgery , arthroscopic surgery is rarely encountered in the literature . some important advantages of arthroscopic surgery are wide visualization areas , easy access to difficult to reach areas , lower morbidity , no need for casting and immobilization , early rehabilitation and quick recovery period . however , there is the possibility of limited synovectomy and residual loose bodies . arthroscopic surgery enables wide regional visualization , lowers morbidity , promotes early rehabilitation , shortens the recovery period and decreases the immobilization period . written informed consent was obtained from the patient for publication of this case report and accompanying images . a copy of the written consent is available for review by the editor - in - chief of this journal upon request . nevres hurriyet aydogan , ahmet ozmeric , onur kocadal , murad pepe , talip kara took part in surgical procedure , literature search , preparation of the paper and review . serap gozel took part in pathological investigation.key learning pointssynovial chondromatosis is a disease originating from synovia and characterized by the presence of metaplastic cartilaginous nodules.pain , swelling of the joint especially after physical activity and decreased range of motion are main symptoms.treatment is arranged according to the patient 's complaints , age and disease stage.there are many advantages of arthroscopic surgery in selected patients . synovial chondromatosis is a disease originating from synovia and characterized by the presence of metaplastic cartilaginous nodules.pain , swelling of the joint especially after physical activity and decreased range of motion are main symptoms.treatment is arranged according to the patient 's complaints , age and disease stage.there are many advantages of arthroscopic surgery in selected patients . synovial chondromatosis is a disease originating from synovia and characterized by the presence of metaplastic cartilaginous nodules . pain , swelling of the joint especially after physical activity and decreased range of motion are main symptoms . OUTPUT:

introductionsynovial chondromatosis is characterized by the presence of metaplastic cartilage nodules originating from the synovia , bursa and tendon sheaths . although it is extremely rare in the ankle joint , malignant transformation is possible . the choice of treatment is usually open surgery for excision of loose bodies and synovectomy . limited data is available concerning arthroscopic approaches.presentation of casea 28-year - old male patient was evaluated for pain and swelling of the right ankle joint . based on the findings of physical examination and radiographic investigations , arthroscopic surgery was performed due to ankle impingement syndrome . a diagnosis of synovial osteochondromatosis was made following the pathological survey.discussionsynovial chondromatosis is slowly progressive and is considered to be a self - limiting situation . treatment strategies are decided on according to the patient 's complaints , age and disease stage . open or arthroscopic surgery . can be performed . some advantages of arthroscopic surgery are wide visualization areas , easy access to areas difficult to reach , lower morbidity , no necessity for casting and immobilization , early rehabilitation and quick recovery period.conclusionin conclusion , arthroscopic management can be successful in selected patients with synovial osteochondromatosis localized to the ankle joint .

PubMed_Summ6550

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the norfolk component of the european prospective investigation into cancer and nutrition ( epic - norfolk ) study recruited 25,639 men and women aged 4079 years at baseline in 19931997 . the epic - norfolk study was initiated to investigate the relationship between diet and cancer but has since broadened its scope to include a range of chronic diseases , including t2d . the recruitment procedures , collection of questionnaire data , and anthropometric and dietary measures have been described in detail elsewhere ( 10,11 ) . in brief , participants residing in norfolk , england , were recruited from age - sex registers of general practices and attended a baseline health check . follow - up of participants constituted a postal questionnaire at 18 months , a second health check in 19982000 , and a further postal questionnaire in 20022004 . from the 25,639 participants in epic - norfolk at baseline , we ascertained incident cases of t2d ( n = 892 ) and selected a random subcohort of 4,000 participants . this subcohort was representative of the entire epic - norfolk cohort in terms of age , bmi , education level , physical activity level , smoking status , and total energy intake ( data not shown ) . among the subcohort of the 4,749 participants , we excluded those with unknown diabetes status ( n = 1 ) or prevalent diabetes at baseline ( n = 121 ) , those with fewer than 7 days of diary data ( n = 435 ) or who did not return a diary ( n = 15 ) , or those with missing information on potential confounding variables ( n = 73 ) . participants with prevalent myocardial infarction , stroke , or cancer were also excluded ( n = 400 ) . the final sample for analysis consisted of 653 incident t2d cases and a subcohort of 3,166 individuals ( including 115 incident t2d cases ) . all volunteers gave written informed consent , and the study was approved by the norwich district ethics committee . we ascertained incident t2d cases by self - report of doctor - diagnosed diabetes from three follow - up health and lifestyle questionnaires , i.e. , answering to has a doctor ever told you that you have diabetes ? or diabetes medication that was self - reported or brought to the second health check . in addition , external sources of information through record linkage included listing of any epic - norfolk participant in the general practice diabetes register , local hospital diabetes register , hospital admissions data with screening for any diabetes - related admissions among study participants , and office of national statistics mortality data with coding for diabetes . participants who gave a self - report of history of diabetes that could not be confirmed against any other sources of ascertainment were not considered as a confirmed case of t2d . follow - up was censored at the date of diagnosis of t2d , 31 july 2006 , or the date of death , whichever came first . at the baseline medical examination , participants were instructed by trained interviewers on how to complete the 7-day food diary ( 11,12 ) . the food diary consisted of 45 color pages containing food portion photographs and detailed instructions on how to record and describe preparation methods and quantities of foods eaten at main meals , snacks , and between meals . completed diaries were returned by post to the coordinating center at the university of cambridge . the food diary has been validated with weighed food records , 24-h urine collections , and blood biomarkers ( 13 ) . intake of f&v ( including tinned and dried ) was calculated from food diary data to give average daily quantity of intake for each participant . in order to precisely quantify the actual intake of five - a - day public health guidelines ) ( 14 ) , all recorded foods and dishes were disaggregated into their component parts . composite dishes containing fruits and/or vegetables included homemade and shop - bought desserts , vegetable bakes , stews , pies , and soups , for example . the f&v quantity and type was derived for the composite dishes by using recipes from mccance and widdowson as previously described ( 12 ) and by using ingredients listed on the packages of products and ready - made meals . potatoes were not included as a vegetable because they differ from vegetables regarding energy and carbohydrate content and are frequently used as a substitute for cereals ( 15 ) . f&v juices were also not included because they differ from their source of origin in terms of food matrix and fiber content , and as such may be dissimilarly associated with diabetes ( 16 ) . variety of fruit , vegetables , and combined f&v intake was derived by calculating the total number of different items consumed at least once in a 1-week period , irrespective of quantity of intake . the groupings of items included 58 different fruit items ( range 058 ) , 59 different vegetable items ( range 059 ) , and hence a total of 117 different f&v items consumed over a 1-week period , as recorded in the 7-day food diary . at recruitment , participants completed a detailed health and lifestyle questionnaire . participants self - reported their education level ( low , o level , a level , or degree ) , occupational social class ( manual or nonmanual ) , smoking status ( current , former , or never ) , and baseline history of myocardial infarction , stroke , and cancer ( yes or no ) . area deprivation was assessed from residential postal codes using the townsend deprivation index , which provides a material measure of deprivation and disadvantage based on unemployment , car ownership , home ownership and household overcrowding . a validated , four - point physical activity index was derived , incorporating occupational and leisure - time components of physical activity ( 18 ) . trained nurses measured height , weight , and waist circumference according to standardized protocols ( 10 ) . ( hba1c ) was measured halfway through the baseline health check ( 19951997 ) and was available in approximately half of the epic - norfolk cohort . hba1c was measured using high - performance liquid chromatography on a bio - rad diamat ( bio - rad , richmond , ca ) , on a sample of edta - anticoagulated blood . baseline characteristics were summarized by tertiles of combined f&v quantity and variety among the subcohort participants , using means with sds , medians with interquartile ranges ( iqrs ) , or frequencies ( where appropriate ) . multivariable , prentice - weighted cox regression ( 19 ) was used to estimate the associations between quantity and variety of fruit , vegetables , and combined f&v intake and hazard of diabetes , with intake defined as tertiles ( with the lowest tertile as the reference category ) . to check the proportional hazards assumption of the models , interactions between quantity and variety of fruit , vegetables , and combined f&v intake and current age ( i.e. , the underlying timescale ) were tested . the proportional hazards assumption was not violated for quantity and variety of fruit , vegetables , or combined f&v intake ( all p values 0.32 ) . hazard ratios ( hrs ) and 95% cis were estimated using the following modeling strategy . we additionally adjusted for bmi ( continuous ) , waist circumference ( continuous ) , education level ( low , o level , a level , or degree ) , townsend deprivation index ( continuous ) , occupational social class ( manual or nonmanual ) , physical activity level ( inactive , moderately inactive , moderately active , or active ) , smoking status ( current , former , or never ) , family history of diabetes ( yes or no ) , total energy intake ( continuous ) , and season of diary completion ( december , january , february = winter ; march , april , may = spring ; june , july , august = summer ; and september , october , november = autumn ) . in model 3 , in order to estimate the association between quantity of f&v consumption and hazard of diabetes independent of the effect of variety , we additionally adjusted for variety of f&v intake and vice versa for the analysis of variety in intake . we examined multicolinearity in model 3 using the variance inflation factor . in sensitivity analyses , the association between f&v quantity and variety and the hazard of diabetes was also investigated by including other potentially confounding variables in model 3 , including hypertension ( yes or no ) , dairy intake ( continuous ) , total fiber intake ( continuous ) , red and processed meat intake ( continuous ) , and percentage energy from carbohydrate ( continuous ) , protein ( continuous ) , fat ( continuous ) , and alcohol intake ( continuous ) . analyses were also repeated after additionally excluding participants who 1 ) developed diabetes within the first 2 years of follow - up ( n = 26 ) , 2 ) had a baseline hba1c level 6.5% ( n = 15 ) in the subsample with hba1c data available ( n = 1,333 ) , and 3 ) were in the top and bottom 1% of the ratio of energy intake to energy expenditure . multiplicative interaction terms were added to model 3 for quantity and variety of combined f&v intake to examine effect modification by sex , age ( < 60 or 60 years ) , bmi ( normal weight < 25 kg / m , overweight / obese 25 kg / m ) , and smoking status ( never smoker or ever smoker ) by using the wald test . additionally , spline regression was used to demonstrate the continuous association between quantity and variety of combined f&v intake and the hr ( 95% ci ) of diabetes with knots placed at quartiles of the distribution ( 20 ) . all statistical analyses were performed using stata / se 11.1 ( stata - corp , college station , tx ) . the norfolk component of the european prospective investigation into cancer and nutrition ( epic - norfolk ) study recruited 25,639 men and women aged 4079 years at baseline in 19931997 . the epic - norfolk study was initiated to investigate the relationship between diet and cancer but has since broadened its scope to include a range of chronic diseases , including t2d . the recruitment procedures , collection of questionnaire data , and anthropometric and dietary measures have been described in detail elsewhere ( 10,11 ) . in brief , participants residing in norfolk , england , were recruited from age - sex registers of general practices and attended a baseline health check . follow - up of participants constituted a postal questionnaire at 18 months , a second health check in 19982000 , and a further postal questionnaire in 20022004 . from the 25,639 participants in epic - norfolk at baseline , we ascertained incident cases of t2d ( n = 892 ) and selected a random subcohort of 4,000 participants . this subcohort was representative of the entire epic - norfolk cohort in terms of age , bmi , education level , physical activity level , smoking status , and total energy intake ( data not shown ) . among the subcohort of the 4,749 participants , we excluded those with unknown diabetes status ( n = 1 ) or prevalent diabetes at baseline ( n = 121 ) , those with fewer than 7 days of diary data ( n = 435 ) or who did not return a diary ( n = 15 ) , or those with missing information on potential confounding variables ( n = 73 ) . participants with prevalent myocardial infarction , stroke , or cancer were also excluded ( n = 400 ) . the final sample for analysis consisted of 653 incident t2d cases and a subcohort of 3,166 individuals ( including 115 incident t2d cases ) . all volunteers gave written informed consent , and the study was approved by the norwich district ethics committee . we ascertained incident t2d cases by self - report of doctor - diagnosed diabetes from three follow - up health and lifestyle questionnaires , i.e. , answering yes to has a doctor ever told you that you have diabetes ? or diabetes medication that was self - reported or brought to the second health check . in addition , external sources of information through record linkage included listing of any epic - norfolk participant in the general practice diabetes register , local hospital diabetes register , hospital admissions data with screening for any diabetes - related admissions among study participants , and office of national statistics mortality data with coding for diabetes . participants who gave a self - report of history of diabetes that could not be confirmed against any other sources of ascertainment were not considered as a confirmed case of t2d . follow - up was censored at the date of diagnosis of t2d , 31 july 2006 , or the date of death , whichever came first . at the baseline medical examination , participants were instructed by trained interviewers on how to complete the 7-day food diary ( 11,12 ) . the food diary consisted of 45 color pages containing food portion photographs and detailed instructions on how to record and describe preparation methods and quantities of foods eaten at main meals , snacks , and between meals . completed diaries were returned by post to the coordinating center at the university of cambridge . the food diary has been validated with weighed food records , 24-h urine collections , and blood biomarkers ( 13 ) . intake of f&v ( including tinned and dried ) was calculated from food diary data to give average daily quantity of intake for each participant . in order to precisely quantify the actual intake of five - a - day public health guidelines ) ( 14 ) , all recorded foods and dishes were disaggregated into their component parts . composite dishes containing fruits and/or vegetables included homemade and shop - bought desserts , vegetable bakes , stews , pies , and soups , for example . the f&v quantity and type was derived for the composite dishes by using recipes from mccance and widdowson as previously described ( 12 ) and by using ingredients listed on the packages of products and ready - made meals . potatoes were not included as a vegetable because they differ from vegetables regarding energy and carbohydrate content and are frequently used as a substitute for cereals ( 15 ) . f&v juices were also not included because they differ from their source of origin in terms of food matrix and fiber content , and as such may be dissimilarly associated with diabetes ( 16 ) . variety of fruit , vegetables , and combined f&v intake was derived by calculating the total number of different items consumed at least once in a 1-week period , irrespective of quantity of intake . the groupings of items included 58 different fruit items ( range 058 ) , 59 different vegetable items ( range 059 ) , and hence a total of 117 different f&v items consumed over a 1-week period , as recorded in the 7-day food diary . at recruitment participants self - reported their education level ( low , o level , a level , or degree ) , occupational social class ( manual or nonmanual ) , smoking status ( current , former , or never ) , and baseline history of myocardial infarction , stroke , and cancer ( yes or no ) . area deprivation was assessed from residential postal codes using the townsend deprivation index , which provides a material measure of deprivation and disadvantage based on unemployment , car ownership , home ownership and household overcrowding . , four - point physical activity index was derived , incorporating occupational and leisure - time components of physical activity ( 18 ) . trained nurses measured height , weight , and waist circumference according to standardized protocols ( 10 ) . venous blood samples were taken by trained study nurses . hemoglobin a1c ( hba1c ) was measured halfway through the baseline health check ( 19951997 ) and was available in approximately half of the epic - norfolk cohort . hba1c was measured using high - performance liquid chromatography on a bio - rad diamat ( bio - rad , richmond , ca ) , on a sample of edta - anticoagulated blood . baseline characteristics were summarized by tertiles of combined f&v quantity and variety among the subcohort participants , using means with sds , medians with interquartile ranges ( iqrs ) , or frequencies ( where appropriate ) . multivariable , prentice - weighted cox regression ( 19 ) was used to estimate the associations between quantity and variety of fruit , vegetables , and combined f&v intake and hazard of diabetes , with intake defined as tertiles ( with the lowest tertile as the reference category ) . to check the proportional hazards assumption of the models , interactions between quantity and variety of fruit , vegetables , and combined f&v intake and current age ( i.e. , the underlying timescale ) were tested . the proportional hazards assumption was not violated for quantity and variety of fruit , vegetables , or combined f&v intake ( all p values 0.32 ) . hazard ratios ( hrs ) and 95% cis were estimated using the following modeling strategy . model 1 was adjusted for sex . in model 2 , we additionally adjusted for bmi ( continuous ) , waist circumference ( continuous ) , education level ( low , o level , a level , or degree ) , townsend deprivation index ( continuous ) , occupational social class ( manual or nonmanual ) , physical activity level ( inactive , moderately inactive , moderately active , or active ) , smoking status ( current , former , or never ) , family history of diabetes ( yes or no ) , total energy intake ( continuous ) , and season of diary completion ( december , january , february = winter ; march , april , may = spring ; june , july , august = summer ; and september , october , november = autumn ) . in model 3 , in order to estimate the association between quantity of f&v consumption and hazard of diabetes independent of the effect of variety , we additionally adjusted for variety of f&v intake and vice versa for the analysis of variety in intake . we examined multicolinearity in model 3 using the variance inflation factor . in sensitivity analyses , the association between f&v quantity and variety and the hazard of diabetes was also investigated by including other potentially confounding variables in model 3 , including hypertension ( yes or no ) , dairy intake ( continuous ) , total fiber intake ( continuous ) , red and processed meat intake ( continuous ) , and percentage energy from carbohydrate ( continuous ) , protein ( continuous ) , fat ( continuous ) , and alcohol intake ( continuous ) . analyses were also repeated after additionally excluding participants who 1 ) developed diabetes within the first 2 years of follow - up ( n = 26 ) , 2 ) had a baseline hba1c level 6.5% ( n = 15 ) in the subsample with hba1c data available ( n = 1,333 ) , and 3 ) were in the top and bottom 1% of the ratio of energy intake to energy expenditure . multiplicative interaction terms were added to model 3 for quantity and variety of combined f&v intake to examine effect modification by sex , age ( < 60 or 60 years ) , bmi ( normal weight < 25 kg / m , overweight / obese 25 kg / m ) , and smoking status ( never smoker or ever smoker ) by using the wald test . additionally , spline regression was used to demonstrate the continuous association between quantity and variety of combined f&v intake and the hr ( 95% ci ) of diabetes with knots placed at quartiles of the distribution ( 20 ) . all statistical analyses were performed using stata / se 11.1 ( stata - corp , college station , tx ) . statistical significance was set at p < 0.05 . the median ( iqr ) duration of follow - up was 10.9 ( 9.811.8 ) years . the median quantity of combined f&v intake was 3.7 ( 2.55.0 ) portions per day and the mean ( sd ) variety of combined f&v intake was 11.7 ( 3.9 ) items / week . fewer than 26% of study participants reported consuming at least five portions of f&v per day . there was nearly a threefold difference in quantity and in excess of a twofold difference in variety of combined f&v consumption between the highest versus lowest tertiles of f&v intake ( table 1 ) . participants who consumed higher quantities and a greater variety of combined f&v had more favorable lifestyle , anthropometric , and dietary profiles . baseline characteristics by tertiles of quantity and variety of fruit and vegetable intake separately showed similar results ( data not shown ) . the pearson correlation coefficient between quantity of fruit and quantity of vegetable intake was 0.29 , and between variety of fruit and variety of vegetable intake was 0.30 . quantity of combined f&v intake was strongly positively correlated with variety of combined f&v intake ( 0.60 ) . descriptive characteristics at baseline by combined f&v quantity and variety tertiles in 3,166 subcohort participants in the epic - norfolk study as shown in table 2 , quantity of fruit , vegetables , and combined f&v intake were all inversely associated with incident t2d ( model 1 ) . further adjustment did not appreciably alter the hrs ( model 2 ) . after additionally adjusting for the effects of variety of intake , an inverse association with quantity of vegetable intake remained , but the associations for quantity of fruit and quantity of combined f&v intake with t2d were attenuated , such that fruit was no longer associated and f&v intake was borderline inversely associated with t2d . further adjustment for hypertension , dairy intake , total fiber intake , percentage energy from carbohydrate , protein , fat , and alcohol intake , and red and processed meat intake did not change our results ( data not shown ) . those meeting the recommendation to consume at least five portions of f&v per day did not differ from those not meeting this recommendation in hazard of t2d , excluding and including variety of intake ( hr 0.85 [ 95% ci 0.701.02 ] and 0.98 [ 0.801.21 ] , respectively ) . as shown in table 3 , greater variety in fruit , vegetables , and combined f&v intake was inversely associated with incident t2d in adjusted analyses and also when accounting for quantity of intake . the relative reduction in the hazard of t2d with every additional two - item increase in f&v variety per week was 8% ( 0.92 [ 0.870.97 ] ) . the mean estimated variance inflation factor was < 1.9 ( < 1.6 for both f&v quantity and f&v variety ) , indicating that colinearity of the variables included in model 3 was low . hrs ( 95% cis ) of incident diabetes for quantity of fruit , vegetables , and combined f&v intake in the epic - norfolk study hrs ( 95% cis ) of incident diabetes for variety of fruit , vegetables , and combined f&v intake in the epic - norfolk study figure 1 shows the continuous association between quantity and variety of combined f&v intake and t2d . as shown , the hr for t2d decreased between an intake of 3.57.0 portions per day ( fig . 1a ) , and this association was largely unchanged after accounting for the effects of variety of f&v ( fig . 1b ) . for variety , consuming 12 different f&v items per week was associated with a decreased hr of t2d ( fig . 1c ) , and this association was largely unaffected after accounting for the effects of quantity of f&v intake ( fig . the percentage of participants achieving a quantity of > 3.5 portions per day was 53.2% , and the percentage achieving a variety of > 12 different f&v items per week was 40.3% . the upper percentile of the first tertile for quantity and variety of f&v intake was used as the reference category . a : the association between quantity of f&v intake and hr ( 95% ci ) of diabetes adjusted for sex , bmi , waist circumference , education level , townsend deprivation index , occupational social class , physical activity level , smoking status , family history of diabetes , total energy intake , and season . c : the association between variety of f&v intake and hr ( 95% ci ) of diabetes adjusted for sex , bmi , waist circumference , education level , townsend deprivation index , occupational social class , physical activity level , smoking status , family history of diabetes , total energy intake , and season . results were unaffected in sensitivity analyses after excluding participants who 1 ) developed t2d within the first 2 years of follow - up , 2 ) had a baseline hba1c level of 6.5% in the subsample with hba1c data , and 3 ) were in the top and bottom 1% of energy intake to energy expenditure ( data not shown ) . we found no evidence of interaction between either quantity or variety in f&v intake with sex , age , bmi , or smoking status and incident diabetes ( p > 0.10 ) . in this prospective study of nearly 4,000 men and women with dietary information from prospective 7-day food diaries , we observed that a greater quantity of vegetable intake and a greater variety of fruit , vegetables , and combined f&v intake may independently be beneficial for reducing the risk of t2d . after accounting for potential confounding factors and the effects of quantity of intake , each different additional two item per week increase in variety of f&v intake was associated with an 8% reduction in the incidence of t2d . previous epidemiological studies have reported inconsistent findings for an association between quantity of f&v intake and risk of t2d . two separate meta - analyses have reported no overall association between fruit , vegetables , and combined f&v intake and diabetes risk , although there was significant heterogeneity of association between the included studies ( 21,22 ) . ( 21 ) did however find a significant inverse association between green leafy vegetable intake and risk of t2d ( hr for highest vs. lowest intake group 0.86 [ 95% ci 0.770.97 ] ) . although low heterogeneity in f&v consumption may be one explanation for the null findings in some study populations , our current results suggest that it may also be due to differences in the assessment methods used for measuring f&v intake . although ffqs can be used to rank individuals according to their relative intake ( 8) , they are less suitable for the assessment of absolute intake ( 11,23 ) , which they tend to overestimate . for example , in the epic - norfolk study , mean consumption of f&v was much higher when assessed by ffq ( 6.5 portions per day ) than by a food diary ( 3.8 portions per day ) ( 11 ) . for this reason , ffqs are not ideal for examining adherence to , or for informing , public health guidelines . furthermore , ffqs are based on perceptions of habitual intake , whereas food diaries are based on self - report of foods and amounts actually consumed in real time ( 8) . additionally , because ffqs contain only a limited list of precoded food items , which tend to be grouped together , unlike the food diary , which is open ended , they may not be as suitable as food diaries for assessing variety of food intake . despite the fact that variety in f&v intake has been advocated by many national and international bodies ( 57 ) , no studies that we are aware of have explored associations between variety in intake and risk of t2d . our current findings suggest that quantity ( at least 3.5 portions of f&v per day ) and variety ( at least 12 different f&v items per week ) in f&v intake are both inversely and independently associated with t2d . however , only 50% and 40% of the participants reported meeting these thresholds for quantity and variety of intake , respectively . there are several unique strengths of our study , including the large sample size , prospective study design , use of a 7-day prospective food diary with disaggregated f&v data , thorough assessment of new cases of t2d with self - report information supplemented by external sources , and comprehensive information on covariates , thus minimizing sources of bias and confounding . another strength of our study was that we had hba1c data available on a subsample of participants and were thus able to demonstrate that our findings were unlikely to have been influenced by the presence of previously undiagnosed cases of t2d at baseline . however , several potential limitations of our study merit discussion . first , because of the observational nature of the study , we can not exclude the possibility of residual confounding or confounding by unmeasured factors . second , we used baseline dietary consumption data to characterize individuals and did not take into account possible misclassification with respect to changes in consumption patterns over time . however , as this type of misclassification is likely to be nondifferential , the effect would be to attenuate the observed hrs toward the null , suggesting that the true associations between quantity and variety in f&v intake may be stronger than reported in the current study . we were also not able to adjust for lifestyle factors ( e.g. , smoking and physical activity ) that may have changed during follow - up . finally , our population is predominantly of european - caucasian origin ( 99.1% ) and middle aged . thus , the generalizability of our findings to other populations may be limited . nevertheless , in comparison with the general population of england , epic - norfolk participants are comparable with respect to characteristics including anthropometry , blood pressure , and lipids ( 10 ) . the biological mechanisms for the inverse associations of f&v intake and diabetes risk are not clear . our findings suggest that f&v may be inversely associated with diabetes through two distinct but complementary pathways . a plausible biological mechanism to explain the beneficial effect of quantity of f&v intake on t2d is via the low energy and high fiber content of f&v , and as such their ability to reduce the overall energy content of the diet . it has previously been demonstrated that those who consume the highest quantity of f&v , in comparison with low consumers , have a lower risk of weight gain ( 24,25 ) , a major risk factor for diabetes ( 26 ) . a decreased risk of t2d with increasing quantities of vegetable intake in particular may be explained by the fact that vegetables are generally consumed with other foods as part of a meal and therefore may displace or buffer the harmful effects of deleterious foods from the diet , such as energy - dense foods or foods that increase the risk of t2d . alternatively , higher consumption of specific vegetables , particularly green leafy vegetables , might reduce the risk of t2d due to the presence of relatively high concentrations of potentially beneficial bioactive compounds ( 21 ) . the biological mechanisms for the inverse associations of variety of f&v intake with t2d are not clear but may be attributable to individual or combined effects of the many different bioactive phytochemicals contained in f&v ( e.g. , vitamin c and carotenoids ) ( 27,28 ) . thus , consumption of a wide variety of f&v will increase the likelihood of consuming these phytochemicals . as the current study was not designed to examine mechanisms of association , future studies will be required to investigate this further . in conclusion , using the prospective 7-day food diary to assess f&v intake , we found that a greater variety of fruit , vegetables , and combined f&v intake is associated with a reduced risk of t2d , whereas for quantity , only greater vegetable , but not fruit intake , was associated with a reduced risk . these findings support current public health recommendations encouraging consumption of f&v as part of a balanced diet and place particular emphasis on the important and independent role that both quantity and variety in f&v intake may play in helping to prevent the development of t2d . OUTPUT:

objectivethe association between quantity of fruit and vegetable ( f&v ) intake and risk of type 2 diabetes ( t2d ) is not clear , and the relationship with variety of intake is unknown . the current study examined the association of both quantity and variety of f&v intake and risk of t2d.research design and methodswe examined the 11-year incidence of t2d in relation to quantity and variety of fruit , vegetables , and combined f&v intake in a case - cohort study of 3,704 participants ( n = 653 diabetes cases ) nested within the european prospective investigation into cancer and nutrition - norfolk study , who completed 7-day prospective food diaries . variety of intake was derived from the total number of different items consumed in a 1-week period . multivariable , prentice - weighted cox regression was used to estimate hazard ratios ( hrs ) and 95% cis.resultsa greater quantity of combined f&v intake was associated with 21% lower hazard of t2d ( hr 0.79 [ 95% ci 0.621.00 ] ) comparing extreme tertiles , in adjusted analyses including variety . separately , quantity of vegetable intake ( 0.76 [ 0.600.97 ] ) , but not fruit , was inversely associated with t2d in adjusted analysis . greater variety in fruit ( 0.70 [ 0.530.91 ] ) , vegetable ( 0.77 [ 0.610.98 ] ) , and combined f&v ( 0.61 [ 0.480.78 ] ) intake was associated with a lower hazard of t2d , independent of known confounders and quantity of intake comparing extreme tertiles.conclusionsthese findings suggest that a diet characterized by a greater quantity of vegetables and a greater variety of both f&v intake is associated with a reduced risk of t2d .

PubMed_Summ6551

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the rh1 alloimmunization responsible for the hemolytic disease of the newborn occurs when the rh1-negative mother s blood comes into contact with the foetus s rh1 positive red blood cells . after the passing of foetal red blood cells into the maternal circulation , the rh1 antigens on foetal red blood cells , which are foreign antigens to the maternal immune system , trigger the immunological processes producing anti - rh1 allo - antibodies of the immunoglobulin class igg . these antibodies cross the placenta , attack foetal red blood cells and lead to a foetal hemolytic anemia . the immunoprophylaxis by anti - rh1 immunoglobulins has been established since the 1970s , but this disease remains the leading cause of fetal anemia . the severe forms of hemolytic disease are observed in 10% of fetuses or newborn affected by this disease . it exposes to fetal complications such as hydrops , hypoxic brain damage and fetal death . we report a case of dramatic outcome of an observation of severe hemolytic anaemia in a newborn due to rh1 incompatibility , which led to death . a male newborn presenting the antecedents of consanguinity was admitted 30 minutes of life to the pediatric department of mohammed v military teaching hospital for the issue of hydrops fetalis on rhesus incompatibility ; the birth weight was 1800 g and his blood group was a rh1 . after birth , the baby was intubated and placed on mechanical ventilation due to respiratory distress and hypoxia . the blood group of his mother , aged 31 , was ab rh1-negative and that of his father aged 37 was a rh1 . the mother had a history of 4 term deliveries , 3 abortions , and 1 living child . , she was sent to gynecology department of mohammed v military teaching hospital after the discovery of fetal ascites . preterm birth was induced at 30 weeks of gestation by cesarean section under spinal anaesthesia and she was transferred to the medical intensive care unit and the newborn was transferred to the paediatric department . the laboratory tests of the newborn on the first day of life showed hyperbilirubinaemia ( total serum bilirubin level = 30 mg / l ) , hyperuremia ( 1.03 g / l ) , hyperkalaemia ( 7.2 mmol / l ) and hyponatremia ( 134 the blood count showed bicytopenia with macrocytic regenerative anemia ( hemoglobin = 4g / dl , mean corpuscular volume = 183 fl , reticulocyte count = 176600/l ) associated with thrombocytopenia at 120 000/l . the blood smear showed erythroblastosis ( 1256 erythroblasts per 100 leukocytes ) , howell jolly bodies , anisocytosis and many macrocytes ( figure 1 ) . after drainage of the ascites fluid , the newborn was transfused with red blood cell concentrates and was also treated with conventional phototherapy . the evolution was unfavorable with a steady increase of total serum bilirubin level ( 71 mg / l ) , hemoglobin ( 9.4 g / dl ) , reticulocytes ( 187203/l ) and circulating erythroblasts ( 1386 erythroblasts per 100 leukocytes ) and a decrease in platelet count ( 72 000/l ) on the second day ( table i ) and died three days after the death of his mother , who died from pulmonary embolism in the intensive care unit . our case report shows that there is rh1 incompatibility between the ab rh1-negative mother and the a rh1 newborn . the feto - maternal blood incompatibility constitutes the major cause of autoimmune hemolytic anaemia among newborns and must be evoked first before a neonatal anemia with early onset jaundice . the allo - antibodies of the most common obstetrical interest are anti - rh1 , anti - rh4 and anti - kel1 , representing respectively 35% , 37% and 13% of identified allo - antibodies ; they are responsible for 88% , 8% and 2% respectively for severe fetomaternal incompatibilities . our patient presented anemia associated with erythroblastosis , howell jolly bodies , many macrocytes and high reticulocytosis showing a very active erythropoiesis , to compensate for the hemolysis . biological signs of autoimmune hemolytic anemia are regenerative anemia which can be macrocytic or normochromic normocytic anemia , a decrease in haptoglobin , an increase in lactate dehydrogenase related to the importance of hemolysis ; a hemoglobinemia with hemoglobinuria in the case of intravascular hemolysis and sometimes an increase in unconjugated bilirubin and a decrease in the glycated hemoglobin and the direct antiglobulin test is positive in 95% of cases . the direct antiglobulin test is based on the detection of erythrocytic autoantibodies either in serum , or when they are attached on red blood cells . in this pathology , it is necessary to exclude physiologic jaundice due to newborn s immature liver . however , the physiologic jaundice of the newborn is never present at birth and appears from the 36th hour to reach a maximum on the 3rd-4th day and disappears before the 10th day . it is also necessary to eliminate abo incompatibility which is exclusively found in newborns with a or b blood type and whose mothers are o blood type and neonatal jaundice associated with hyperhemolysis due to common congenital hemolytic anemia : red blood cell membrane disorders ( hereditary spherocytosis , hereditary elliptocytosis , and hereditary pyropoikilocytosis ) , red blood cell enzyme defects ( glucose 6 phosphate dehydrogenase deficiency , pyruvate kinase deficiency and other red blood cells enzymopathies ) and neonatal hemolysis due to hemoglobinopathies(-thalassaemia major and -globin and -globin chain structural abnormalities ) . the cases of polycythemia vera and certain infectious syndromes can also be accompanied by jaundice . in case of prolonged jaundice the irregular agglutinin test is an important test for pregnancy monitoring as part of the prevention of anti - rh1 alloimmunization and management of feto - maternal incompatibilities . it aims at detecting and identifying red cell alloantibodies directed against erythrocyte antigens other than a or b of unexpressed abo system on the surface of its own red blood cells capable of inducing , by feto - maternal incompatibility , hemolytic disease in the fetus and/or newborn . the irregular agglutinin test is done 2 times ( 1st and 6th or 7th prenatal examinations ) in rh1 pregnant women without transfusion history and 4 times ( 1 , 4 , 6 and 7th prenatal examinations ) in rh1 women with a history of transfusion or pregnancy and in the rh1 negative women . this test is also practiced at childbirth in rh1 negative women before the anti - d immunoglobulin injection . postnatal management of hemolytic disease of the newborn due to rh1 incompatibility aims at preventing postnatal death from anemia complications and neonatal kernicterus and may include : intensive phototherapy which is the most commonly used treatment and its effectiveness is evaluated by regular monitoring of the concentration of total serum bilirubin , exchange transfusion which is the last resort in the treatment of hyperbilirubinaemia and its adverse effects are numerous : hypocalcaemia and thrombocytopenia , convulsions , necrotizing enterocolitis , apnea , bradycardia , hyperkalemia and hypoglycemia . the treatment of hyperbilirubinaemia can also be done using intravenous immunoglobulin ( ivig ) ( 0.51 g / kg ) . a few small randomized controlled trials showed that the use of ivig reduced the need for exchange transfusion , the duration of intensive phototherapy and length of hospitalization , but a randomized controlled trial conducted in the netherlands did not confirm these results . other drugs which have been proposed in the treatment of neonatal jaundice are : d - penicillamine and metalloporphyrins which inhibit hemeoxygenase and reduce the production of bilirubin , albumin which increases bilirubin transport capacity in the blood and reduces the blood concentration of unconjugated bilirubin , and phenobarbital which increases bilirubin uptake , conjugation and excretion . blood transfusions may also be needed to correct severe anemia . despite blood transfusion and treatment by intensive phototherapy , our patient died four days after his birth with hemolysis , kidney failure , jaundice and hypoxia . the best treatment is to prevent causal anti - d immunization with intravenous ( iv ) anti - rh1 immunoglobulin in rh1 negative pregnant women to neutralize the foetal red blood cells in the maternal vascular compartment . when the newborn is rh1 negative , the rhesus is confirmed on the second sample . if negativity is confirmed , anti - d immunization in mothers is unnecessary . if the newborn is rh1 , the prophylaxis of alloimmunization to rh1 antigen is based on the iv injection of anti - rh1immunoglobulins . it is necessary first of all to perform the double determination of abo group and the phenotype of rh - kell of the newborn , a direct antiglobulin test on the red blood cells of the newborn , the irregular agglutinin test on maternal serum at childbirth and kleihauer test on maternal blood collected at least one hour after delivery . the iv injection of anti - rh1 immunoglobulins is carried out within 72 hours at the latest following delivery . the monitoring of these high - risk pregnancies requires specialized centres and collaboration between the gynecologist and the blood transfusion centre biologist . hemolytic disease of the newborn related to rh1 incompatibility is rare but serious . in order to avoid this drama , it is necessary to strengthen the prevention and clinico - biological monitoring in patients with a history of feto - maternal rhesus alloimmunization by sensitizing and advising all rh1 negative unimmunized women that rh1 prophylaxis should be applied after all birthing of rh1 child and must also always be carried out after any miscarriage . OUTPUT:

we report a case of dramatic outcome of severe hemolytic disease in a newborn due to rh1 incompatibility . a newborn with a rh1 blood group was admitted in the mohammed v military teaching hospital for the problem of hydrops fetalis associated with rh1 incompatibility . the blood group of his mother , aged 31 , was ab rh1-negative and that of his 37 year old father was a rh1 . the mother had a history of 4 term deliveries , 3 abortions , and 1 living child . there was no prevention by anti - d immunoglobulin postpartum . the mother s irregular agglutinin test was positive and the pregnancy was poorly monitored . the laboratory tests of the newborn showed a high total serum bilirubin level ( 30 mg / l ) and macrocytic regenerative anemia ( hemoglobin=4 g / dl , mean corpuscular volume = 183 fl , reticulocytes count = 176600/m3 ) . the blood smear showed 1256 erythroblasts per 100 leukocytes , howell jolly bodies and many macrocytes . the direct antiglobulin test was positive . he was transfused with red blood cell concentrates and treated with conventional phototherapy . the evolution was unfavourable ; he died three days after the death of his mother . the monitoring of these high - risk pregnancies requires specialized centers and a close collaboration between the gynaecologist and the blood transfusion specialist to strengthen the prevention , as well as clinico - biological monitoring in patients with a history of rh1 fetomaternal alloimunization .

PubMed_Summ6552

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: tourette syndrome ( ts ) is a childhood neuropsychiatric disorder characterized by motor and phonic tics . ts is often complicated by behavioral disorders such as attention - deficit hyperactivity disorder ( adhd ) , obsessive - compulsive disorder ( ocd ) , and anxiety and emotional disorders . approximately one - third of ts patients engage in self - injurious behaviors . as a self - limited disease , while ts symptoms are often controlled effectively via behavioral and drug therapies , conventional therapy does not work for a small number of patients . since 1995 , researchers have been working toward the use of stereotactic surgery in the treatment of ts . in 1999 , bilateral subthalamic deep brain stimulation ( dbs ) was first applied in the treatment of ts with substantial efficacy . subsequently , researchers have attempted the use of dbs for the treatment of ts with various targets . this study was conducted at the department of functional neurosurgery at xuanwu hospital , capital medical university . we performed globus pallidus internus ( gpi ) dbs on 25 patients with drug - resistant ts and conducted follow - up assessments of 24 of the patients for over 1 year . twenty - five patients with refractory ts were admitted to our hospital for treatment between september 2007 and august 2014 . following the electrode placement surgery , specifically , he experienced severe anxiety when the dbs stimulator was turned on . because of this side effect and the observation that dbs produced no remarkable improvement in ts symptoms , the patient requested that the stimulator to be switched off . as this patient refused to undergo a procedure to adjust the electrode position , we excluded him from our research sample . thus , the study population included 24 patients : 22 male and two female individuals aged 1841 years ( mean age : 25.3 6.4 years ) with an average medical history of ts of 14.7 years ( 821 years ) . most of the patients had comorbid disorders , including ocd ( 18 cases ) , adhd ( 16 cases ) , emotional disorder ( 15 cases ) , and self - injury behavior ( three cases ) . all patients met the diagnostic criteria for ts as per the diagnostic and statistical manual of mental disorders , 4 edition , text revision ( dsm - iv - tr ) and exhibited complex motor tics complicated with phonic tics . the diagnostic confidence index ( dci ) scores for the participant group ranged from 58 to 96 ( 77.71 12.12 ) [ table 1 ] . surgical procedures were performed according to the declaration of helsinki and were approved by the institutional review board at xuanwu hospital . baseline clinical characteristics and dbs complications of the 24 patients with tourette syndrome one patient experienced a mild sexual dysfunction , subcutaneous fluid accumulation , and infection in the ipg site . diplopia , flashing , fatigue , dizziness , and limb convulsions were observed as transient complications and disappeared following adjustment the stimulation parameters and electrode settings . dbs : deep brain stimulation ; dci : diagnostic confidence index ; ygtss : yale global tic severity scale ; adhd : attention deficit hyperactivity disorders ; ed : emotional disorder ; ocd : obsessive - compulsive disorder ; sib : selfinjury behavior ; ipg : implantable pulse generator . the surgical inclusion criteria were as follows : ( 1 ) ts diagnosis according to diagnostic and statistical manual of mental disorders , 4 edition , text revision criteria and the dci , ( 2 ) chronic and severe tic disorder with severe functional impairment , ( 3 ) the patient had not responded to adequate doses of three classes of drugs administered for at least 12 weeks each or could not tolerate medications because of side effects , and ( 4 ) the patient was over 18 years of age . our exclusion criteria barred patients whose tic disorder was attributable to another medical , psychiatric , or neurological disease , those with severe cardiovascular , pulmonary , or hematological disorders , and those with cerebral structural abnormalities from participation . we first performed magnetic resonance scanning ( 1.5 tesla , siemens , germany ) and identified the three - dimensional coordinates of the posterior ventral globus pallidus according to the schaltenbrand after placing the patient under local anesthesia with mild sedation , we created a 2.5 cm long incision in the scalp , starting 2.5 cm from the coronal suture and running parallel to the midline . after drilling a hole in the skull , we ensured that the dura mater had been coagulated before opening it via a cruciate incision . using a high - impedance microelectrode with a tip diameter of 12 m , we recorded extracellular discharges 10 mm above the target and confirmed the tissue characteristics . a dbs device ( model 3387 , medtronic , minneapolis , mn we then incised the retroauricular and subclavian regions and implanted the connecting wire and implantable pulse generator ( ipg , kinetra 7428 or soletra 7426 ) . we conducted bilateral gpi stimulation in twenty patients and unilateral gpi stimulation in four other patients who could not afford bilateral stimulation device or whose symptoms affected only one side . the dbs devices were switched on 1 week after surgery in a unipolar stimulation mode . the stimulation parameters included a pulse width of 90120 s , frequency of 65185 hz , and amplitude of 2.53.7 v. the stimulation parameters were individually adjusted according to the extent of symptomatic improvement and degree of side effects with the goal of obtaining an optimal treatment with minimal side effects . patients continued the use of any medications they had been treated with before the surgery . the follow - up data were compiled by an assessment group that was independent from the surgical group . the severity scores for motor tics , phonic tics , overall damage , and global tics were assessed based on the yale global tic severity scale ( ygtss ) . the assessments were performed 1 week before the surgery and 3 , 6 , and 12 months after the surgery . the symptoms of ocd were assessed using the yale - brown obsessive - compulsive scale ( y - bocs ) . surgical safety was evaluated by means of the wechsler adult intelligence scale - revised in china ( wais - rc ) . the postoperative improvement rate of symptoms was calculated as follows : improvement rate = ( preoperative ygtss score postoperative ygtss score)/preoperative ygtss score 100% . all statistical analyses were performed using the statistical software package spss version 17.0 ( ibm statistics , chicago , il , usa ) . statistical differences were assessed through a one - way analysis of variance ( anova ) using the student newman keuls test for post hoc comparisons after assessing the normality of data distribution . a criterion of p < 0.05 was used for statistical significance . twenty - five patients with refractory ts were admitted to our hospital for treatment between september 2007 and august 2014 . following the electrode placement surgery , specifically , he experienced severe anxiety when the dbs stimulator was turned on . because of this side effect and the observation that dbs produced no remarkable improvement in ts symptoms , the patient requested that the stimulator to be switched off . as this patient refused to undergo a procedure to adjust the electrode position , we excluded him from our research sample . thus , the study population included 24 patients : 22 male and two female individuals aged 1841 years ( mean age : 25.3 6.4 years ) with an average medical history of ts of 14.7 years ( 821 years ) . most of the patients had comorbid disorders , including ocd ( 18 cases ) , adhd ( 16 cases ) , emotional disorder ( 15 cases ) , and self - injury behavior ( three cases ) . all patients met the diagnostic criteria for ts as per the diagnostic and statistical manual of mental disorders , 4 edition , text revision ( dsm - iv - tr ) and exhibited complex motor tics complicated with phonic tics . the diagnostic confidence index ( dci ) scores for the participant group ranged from 58 to 96 ( 77.71 12.12 ) [ table 1 ] . surgical procedures were performed according to the declaration of helsinki and were approved by the institutional review board at xuanwu hospital . baseline clinical characteristics and dbs complications of the 24 patients with tourette syndrome one patient experienced a mild sexual dysfunction , subcutaneous fluid accumulation , and infection in the ipg site . diplopia , flashing , fatigue , dizziness , and limb convulsions were observed as transient complications and disappeared following adjustment the stimulation parameters and electrode settings . dbs : deep brain stimulation ; dci : diagnostic confidence index ; ygtss : yale global tic severity scale ; adhd : attention deficit hyperactivity disorders ; ed : emotional disorder ; ocd : obsessive - compulsive disorder ; sib : selfinjury behavior ; ipg : implantable pulse generator . the surgical inclusion criteria were as follows : ( 1 ) ts diagnosis according to diagnostic and statistical manual of mental disorders , 4 edition , text revision criteria and the dci , ( 2 ) chronic and severe tic disorder with severe functional impairment , ( 3 ) the patient had not responded to adequate doses of three classes of drugs administered for at least 12 weeks each or could not tolerate medications because of side effects , and ( 4 ) the patient was over 18 years of age . our exclusion criteria barred patients whose tic disorder was attributable to another medical , psychiatric , or neurological disease , those with severe cardiovascular , pulmonary , or hematological disorders , and those with cerebral structural abnormalities from participation . we used a crw human stereotactic instrument ( radionics inc . , usa ) for location orientating . we first performed magnetic resonance scanning ( 1.5 tesla , siemens , germany ) and identified the three - dimensional coordinates of the posterior ventral globus pallidus according to the schaltenbrand , we created a 2.5 cm long incision in the scalp , starting 2.5 cm from the coronal suture and running parallel to the midline . after drilling a hole in the skull , we ensured that the dura mater had been coagulated before opening it via a cruciate incision . using a high - impedance microelectrode with a tip diameter of 12 m , we recorded extracellular discharges 10 mm above the target and confirmed the tissue characteristics . a dbs device ( model 3387 , medtronic , minneapolis , mn , usa ) was implanted intracranially and fixed in place . we then incised the retroauricular and subclavian regions and implanted the connecting wire and implantable pulse generator ( ipg , kinetra 7428 or soletra 7426 ) . we conducted bilateral gpi stimulation in twenty patients and unilateral gpi stimulation in four other patients who could not afford bilateral stimulation device or whose symptoms affected only one side . the dbs devices were switched on 1 week after surgery in a unipolar stimulation mode . the stimulation parameters included a pulse width of 90120 s , frequency of 65185 hz , and amplitude of 2.53.7 v. the stimulation parameters were individually adjusted according to the extent of symptomatic improvement and degree of side effects with the goal of obtaining an optimal treatment with minimal side effects . patients continued the use of any medications they had been treated with before the surgery . the follow - up data were compiled by an assessment group that was independent from the surgical group . the severity scores for motor tics , phonic tics , overall damage , and global tics were assessed based on the yale global tic severity scale ( ygtss ) . the assessments were performed 1 week before the surgery and 3 , 6 , and 12 months after the surgery . the symptoms of ocd were assessed using the yale - brown obsessive - compulsive scale ( y - bocs ) . surgical safety was evaluated by means of the wechsler adult intelligence scale - revised in china ( wais - rc ) . the postoperative improvement rate of symptoms was calculated as follows : improvement rate = ( preoperative ygtss score postoperative ygtss score)/preoperative ygtss score 100% . all statistical analyses were performed using the statistical software package spss version 17.0 ( ibm statistics , chicago , il , usa ) . statistical differences were assessed through a one - way analysis of variance ( anova ) using the student newman keuls test for post hoc comparisons after assessing the normality of data distribution . a criterion of p < 0.05 was used for statistical significance . among 24 cases , 18 patients experienced a lesion - like effect after the dbs surgery and exhibited varying symptomatic improvement ranging from 10% to 80% ( self - assessment ) . when the lesion - like effect disappeared 37 days later , such that the symptoms had completely reappeared , we switched the dbs on . the follow - up data were obtained over a period of more than 12 months ( ranging from 12 to 99 months ) after the operation [ table 2 ] . at the 3-month follow - up assessment , six of the patients reported that they had received no benefit from the stimulation while the remaining 18 cases exhibited varying degrees of symptom amelioration . , we found a significant improvement in four types of ygtss scores from 3 months onward . the final follow - up data ( > 12 months ) are not presented in table 2 . ygtss : yale global tic severity scale ; sd : standard deviation . at the 6-month follow - up assessment , all patients had significantly improved symptoms and 56% of patients had a significant decrease in ygtss scores compared with the baseline ( p < 0.01 ) . at the 12-month follow - up , symptom improvements tended to be stable ( ygtss scores had improved by 57.8% from baseline , p < 0.01 ) . the average improvement of motor tics , phonic tics , social impairment , and global scores were 53.7% , 48.1% , 64.8% , and 57.8% , respectively . particularly , the mean score of global impairment was reduced to 14.2 points , which suggested that the social function of the patients was significantly improved . at the 12-month follow - up assessment , self - evaluations indicated that symptoms had improved by 50%80% after the dbs surgery , with an average improvement of approximately 70% . the improvement reflected by the self - assessment was higher than that of the ygtss score . this might be because the patients felt that their active control over tics had greatly increased after operations , such that the associated symptoms , such as emotional disorders and ocd , decreased as well . the y - bocs reflected a decrease in obsessive - compulsive tendencies at the 3 and 6-month follow - up assessments . we found a statistical difference between baseline score and scores at 3 , 6 , and 12 months . at the 12-month follow - up , y - bocs scores had stabilized such that they were similar to those at 6 months , with an average improvement of 38.59% compared with baseline [ figure 1 ] . y - bocs scores before and after gpi - dbs in ts patients . compared with baseline values , y - bocs scores were statistically lower at 3 , 6 , and 12-month follow - up assessments . * p < 0.01 versus baseline . y - bocs : yale - brown obsessive - compulsive scale ; gpi : globus pallidus internus ; dbs : deep brain stimulation ; ts : tourette syndrome . the mean preoperative scores from the wais - rc were as follows : the verbal intelligence quotient ( viq ) was 98.04 7.87 , the performance - iq ( piq ) was 99.21 7.26 , and the full - iq ( fiq ) was 98.30 6.74 . at the 12-month follow - up assessment , the mean viq , piq , and fiq scores were 100.08 7.71 , 99.29 7.32 , and 99.88 7.21 , respectively . there were no significant changes before versus after the surgery in any of the patients [ figure 2 ] . we found no significant difference between viq , piq , and fiq scores at baseline , 3 , 6 , and 12-month assessments . wais - rc : wechsler adult intelligence scale - revised in china ; gpi : globus pallidus internus ; dbs : deep brain stimulation ; ts : tourette syndrome ; viq : verbal intelligence quotient ; piq : performance - iq ; fiq : full - iq . at the early stage of dbs - on ( immediately after the stimulator had been turned on ) , temporary complications included diplopia , flashing , fatigue , dizziness , and limb convulsions . by adjusting the stimulation parameters and electrode settings , we found that these transient complications could be eliminated . one patient reported mild sexual dysfunction 3 months after the dbs had been switched on , and his dbs device was removed because of infection in the ipg site happening at 23 months after the operation . another patient also experienced postoperative subcutaneous fluid accumulation in the ipg pocket , which , although improved by puncture and aspiration at 12 months , finally resulted in infection 22 months postoperation and subsequent removal of the implanted device . a similar incident occurred in a third patient 26 months after the surgery whose tics began to mildly deteriorate following the removal of his ipg and electrode . among 24 cases , 18 patients experienced a lesion - like effect after the dbs surgery and exhibited varying symptomatic improvement ranging from 10% to 80% ( self - assessment ) . when the lesion - like effect disappeared 37 days later , such that the symptoms had completely reappeared , we switched the dbs on . the follow - up data were obtained over a period of more than 12 months ( ranging from 12 to 99 months ) after the operation [ table 2 ] . at the 3-month follow - up assessment , six of the patients reported that they had received no benefit from the stimulation while the remaining 18 cases exhibited varying degrees of symptom amelioration . , we found a significant improvement in four types of ygtss scores from 3 months onward . the final follow - up data ( > 12 months ) are not presented in table 2 . ygtss : yale global tic severity scale ; sd : standard deviation . at the 6-month follow - up assessment , all patients had significantly improved symptoms and 56% of patients had a significant decrease in ygtss scores compared with the baseline ( p < 0.01 ) . at the 12-month follow - up , symptom improvements tended to be stable ( ygtss scores had improved by 57.8% from baseline , p < 0.01 ) . the average improvement of motor tics , phonic tics , social impairment , and global scores were 53.7% , 48.1% , 64.8% , and 57.8% , respectively . particularly , the mean score of global impairment was reduced to 14.2 points , which suggested that the social function of the patients was significantly improved . at the 12-month follow - up assessment , self - evaluations indicated that symptoms had improved by 50%80% after the dbs surgery , with an average improvement of approximately 70% . the improvement reflected by the self - assessment was higher than that of the ygtss score . this might be because the patients felt that their active control over tics had greatly increased after operations , such that the associated symptoms , such as emotional disorders and ocd , decreased as well . the y - bocs reflected a decrease in obsessive - compulsive tendencies at the 3 and 6-month follow - up assessments . we found a statistical difference between baseline score and scores at 3 , 6 , and 12 months . at the 12-month follow - up , y - bocs scores had stabilized such that they were similar to those at 6 months , with an average improvement of 38.59% compared with baseline [ figure 1 ] . y - bocs scores before and after gpi - dbs in ts patients . compared with baseline values , y - bocs scores were statistically lower at 3 , 6 , and 12-month follow - up assessments . * p < 0.01 versus baseline . y - bocs : yale - brown obsessive - compulsive scale ; gpi : globus pallidus internus ; dbs : deep brain stimulation ; ts : tourette syndrome . the mean preoperative scores from the wais - rc were as follows : the verbal intelligence quotient ( viq ) was 98.04 7.87 , the performance - iq ( piq ) was 99.21 7.26 , and the full - iq ( fiq ) was 98.30 6.74 . at the 12-month follow - up assessment , the mean viq , piq , and fiq scores were 100.08 7.71 , 99.29 7.32 , and 99.88 7.21 , respectively . there were no significant changes before versus after the surgery in any of the patients [ figure 2 ] . we found no significant difference between viq , piq , and fiq scores at baseline , 3 , 6 , and 12-month assessments . wais - rc : wechsler adult intelligence scale - revised in china ; gpi : globus pallidus internus ; dbs : deep brain stimulation ; ts : tourette syndrome ; viq : verbal intelligence quotient ; piq : performance - iq ; fiq : full - iq . at the early stage of dbs - on ( immediately after the stimulator had been turned on ) , temporary complications included diplopia , flashing , fatigue , dizziness , and limb convulsions . by adjusting the stimulation parameters and electrode settings , we found that these transient complications could be eliminated . one patient reported mild sexual dysfunction 3 months after the dbs had been switched on , and his dbs device was removed because of infection in the ipg site happening at 23 months after the operation . another patient also experienced postoperative subcutaneous fluid accumulation in the ipg pocket , which , although improved by puncture and aspiration at 12 months , finally resulted in infection 22 months postoperation and subsequent removal of the implanted device . a similar incident occurred in a third patient 26 months after the surgery whose tics began to mildly deteriorate following the removal of his ipg and electrode . approximately 30%40% of ts patients experience complete remission after puberty whereas another 30% experience further deterioration with aging . some ts patients do not respond to treatment with systematic drugs or behavioral therapy and , thus , search for alternative treatments . indeed , some symptoms might last into adulthood , making ts a life - long disease . the management of patients with malignant ts can be very challenging , to the extent that some individuals might opt for surgical treatments . since then , a variety of surgical methods have been tested , leading to a large body of literature concerning possible ts mechanisms and treatments . in 1999 , vandewalle et al . described the first use of dbs for the treatment of ts . according to the literature , the thalamus and globus pallidus were selected as stimulation targets in the vast majority of patients . the average amount of tic improvement following dbs is generally 60%70% while a few studies have reported rates as high as 90%100% . there does not appear to be a significant therapeutic difference between stimulation of the thalamus or globus pallidus although stimulation of the anterior limb of the internal capsule and nucleus accumbens seems to be less effective ( 25%50% ) for treating ts . however , these sites might impact emotion ( stimulating different regions can cause feelings of depression or anxiety ) . thus , these regions might be useful targets in the treatment of severe affective disorders . a large number of studies have suggested that the basal ganglia play an important role in the pathophysiology of ts . according to the basal ganglia - thalamus - cortex loop theory described by mink , dysfunction of this loop leads to ts symptoms . therefore , dbs stimulation of the globus pallidus or thalamus , which are positioned in this loop , could bidirectionally regulate abnormal impulses in the striatum and thalamus . dysfunctions in the limbic striatal loop and orbitofrontal cortex - medial thalamic nuclei loop are associated with the onset of ts and ocd . as projections from the frontal thalamus and frontal striatum pass through the anterior limb of the internal capsule , dbs of this region might have therapeutic benefit . in this study , we treated 24 ts patients with gpi - dbs and conducted follow - up assessments for over 12 months . before the surgery , our patients responded poorly to conventional medication and psychological - behavioral treatment . at the 12-month follow - up assessment , we found that the motor and phonic tics had significantly improved in all 24 patients . specifically , gpi - dbs was effective for rapid and transient motor tics ( clonic tics ) , phonic tics , and slow and sustained movements ( dystonic tics ) . the impulse to move ( sensory tics or premonitory urge ) was also significantly alleviated by the surgery in this patient group . social impairment scores were reduced by 64.8% , indicating restored social function in the patient population . in addition , we found varying degrees of improvement in comorbid disorders , such as ocd , self - injury behavior , and emotional disorders ( testiness and irritability ) , after the surgery . a study investigating quality of life in ts patients after gpi - dbs obtained similar findings and concluded that symptomatic improvement might lead to unexpected major psychosocial changes . in our study , we observed an improvement in both tic and ocd symptoms in our patient population . the improvement in ocd symptoms that we found is similar to the outcome reported for the use of ventral capsule / ventral striatum as dbs targets for treatment of ocd . since it can be difficult to completely distinguish ocd symptoms from tics in ts patients with comorbid ocd , it might be difficult to discern the mechanisms underlying the observed improvement . therefore , it still needs more evidence for concluding that gpi is an appropriate target for ocd treatment based on this study . overall , our data indicate that bilateral gpi - dbs can be used to effectively regulate abnormal nerve impulses in the basal ganglia - related loop , thereby ameliorating tics and various accompanying symptoms in patients with ts , and improve patients quality of life with no significant changes in their intelligence or personality . the incidence of complications associated with dbs generally exceeds 25% , and 4%6% of these complications are permanent . in our study , a total of three patients encountered long - term postoperative surgical complications , which correspond to 12.5% of the participant group . the case of mild sexual dysfunction ( reduced sexual drive ) in one patient requires further investigation . two patients demonstrated skin erosion and subsequent infection at the ipg site who both engaged in robust athletic exercise after the operation . it is possible that the long - term and high - intensity friction from physical activity led to broken skin and infection in this area . compared with the disabling symptoms and refractory nature of ts , milder complications such as fatigue , a mild decrease in sex drive , and focal dystonia might be seen as acceptable . therefore , the application of dbs to the treatment of ts seems appropriate and efficacious . the application of dbs in the treatment of refractory ts has gained increasing attention in the academic community . in addition to the anterior limb of the internal capsule and the nucleus accumbens , all further surgery targets have been found to have good efficacy . recently , a double - blind , randomized , crossover trial provided additional evidence that dbs in the gpi can significantly improve tics . however , the study had a small number of patients , a short follow - up period , and inconsistent assessment criteria , making it difficult to ascertain the optimal therapeutic approach . indeed , the use of standard treatment criteria and assessment measures , as well as complete follow - up data , is essential for identifying new targets and improving surgical efficacy . in addition , since dbs is a reversible ( i.e. , patients return to the preoperative state a few hours after switching off the stimulator ) procedure , the combination of dbs with modern imaging techniques such as functional magnetic resonance imaging , positron emission computed tomography , and single photon emission computed tomography might greatly contribute to investigations of the pathophysiological basis of ts ( such as dopamine metabolism in the cortex - striatum - thalamus - cortex loop in the basal nucleus and dopamine receptor abnormality ) . first , this study as an open research project lacks randomized , double - blind , safety / efficacy study design and thus can not exclude the possibility of placebo effect . second , the follow - up study lasted for only 1 year , and longer - term effect was not available . in addition , this study is limited by the lack of a comparison target of stimulation , and it is insufficient to conclude that gpi serves as the optimal stimulation target . postoperative neuroimaging study would be helpful in future research to further delineate the relationship between actual stimulation area and treatment effect . this project was supported by a grant from national natural science foundation of china ( no . first , this study as an open research project lacks randomized , double - blind , safety / efficacy study design and thus can not exclude the possibility of placebo effect . second , the follow - up study lasted for only 1 year , and longer - term effect was not available . in addition , this study is limited by the lack of a comparison target of stimulation , and it is insufficient to conclude that gpi serves as the optimal stimulation target . postoperative neuroimaging study would be helpful in future research to further delineate the relationship between actual stimulation area and treatment effect . this project was supported by a grant from national natural science foundation of china ( no . OUTPUT:

background : deep brain stimulation ( dbs ) has been a promising treatment for patients with refractory tourette syndrome ( ts ) for more than a decade . despite successful dbs treatment of ts in more than 100 patients worldwide , studies with a large patient sample and long - term follow - up assessments are still scarce . accordingly , we investigated the clinical efficacy and safety of globus pallidus internus ( gpi ) dbs in the treatment of intractable ts in 24 patients with a 1-year follow - up assessment.methods:bilateral/unilateral gpi - dbs was performed in 24 patients with ts . we evaluated symptoms of tics and obsessive - compulsive disorder ( ocd ) through the yale global tic severity scale ( ygtss ) and yale - brown obsessive - compulsive scale ( y - bocs ) . we used the wechsler adult intelligence scale - revised in china ( wais - rc ) to evaluate the safety of the treatment . we conducted follow - up assessments of all patients for at least 12 months ( 1299 months).results : symptoms of tics and ocd were significantly relieved at a 12-month follow - up assessment . the mean ygtss score was 74.04 11.52 , 49.83 10.91 , 32.58 7.97 , and 31.21 8.87 at baseline , 3 , 6 , and 12 months , respectively . the mean ygtss scores obtained at the follow - up assessments were significantly different from the baseline ( p < 0.05 ) . the improvement in motor tics was superior to that in phonic tics . the mean y - bocs scores were 21.61 4.97 , 18 4.58 , 14.39 3.99 , and 13.78 4.56 at baseline , 3 , 6 , and 12 months , respectively ( p < 0.05 ) . we observed a remarkable improvement in psychiatric comorbidities , such as ocd and attention - deficit hyperactivity disorder , after the procedure . wais - rc scores were comparable before and after the operation . there were no severe postoperative complications.conclusion:gpi-dbs appears to comprehensively alleviate tic symptoms and psychiatric comorbidities in patients with ts , thus significantly improving patients quality of life .

PubMed_Summ6553

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: rheumatoid arthritis ( ra ) is a chronic , systemic , autoimmune disease , and the most common form of chronic joint inflammation , affecting 0.51% of the uk population . ra is most prevalent in individuals aged 40 years or older with the risk of developing ra being up to 5 times higher in women . as a consequence of their disease ra patients typically suffer severe joint pain , reduced muscle strength , and impaired physical function . although outcomes of the disease have improved with modern approaches to drug treatment , using agents such as methotrexate and biologics , the disease is still a progressive one with long - term joint damage and disability the expectation rather than the rule . a major feature of the disease is severe inflammation of the synovium where there is a 3100 times elevation of proinflammatory cytokines such as tumour necrosis factor alpha ( tnf- ) , interleukin-6 ( il-6 ) , interleukin-1 ( il-1 ) , and c - reactive protein ( crp ) . the course of ra is typically one of exacerbations and remissions but , even during inactive phases of the disease , systemic levels of cytokines remain dysregulated when compared to those without rheumatoid arthritis . ra also results in downregulation of anabolic factors for muscle , for example , muscle levels of insulin - like growth factor i ( igf-1 ) . the circulating levels of cytokines reflect disease activity and level of inflammation present and also may play a significant role in the systemic effects of the disease , such as vascular disease and rheumatoid cachexia . in addition to the articular features of the disease , ra is associated with increased morbidity and mortality from cardiovascular disease ( cvd ) [ 7 , 8 ] . the relative risk of myocardial infarction is estimated to be double in women with ra relative to those without , and cvd events typically occur a decade earlier and to a greater extent in patients with ra relative to healthy controls ; sometimes even before the fulfilment of all criteria of ra . a recent meta - analysis of 24 studies , comprising 111,758 patients with 22,927 cardiovascular events , reported a 50% increased risk of cvd deaths in patients with ra compared with the general population . this increase in cvd in ra patients appears to be independent of traditional cardiovascular risk factors . given that chronic low - grade inflammation is thought to play an important role in the underlying cause of cvd , atherosclerosis , it seems reasonable to hypothesize that systemic inflammation contributes to elevated cvd in persons with ra . most ra patients also suffer from an accelerated loss of muscle mass , a condition known as rheumatoid cachexia . this loss contributes to disability and has a significant impact on an individuals ' quality of life . rheumatoid cachexia has been reported in two thirds of all ra patients , including patients with stable ra [ 5 , 14 ] . roubenoff and colleagues proposed that rheumatoid cachexia is caused by the cytokine - driven ( principally tnf- ) hypermetabolism and protein degradation . however , poor nutrition and low physical activity levels are also believed to contribute . it has been demonstrated that ra patients do less exercise than their healthy counterparts ; more than 80% of ra patients are physically inactive in some countries , whilst in the uk it is believed that approximately 68% of ra patients are physically inactive . the extreme physical inactivity of ra patients ' becomes a vicious circle in terms of health and disease progression . thus it has become apparent that encouraging physical activity is an important and essential part of the overall treatment of ra . the purpose of this paper is to highlight the importance of exercise in patients with ra and to demonstrate the multitude of beneficial effects that a properly designed exercise intervention has in this population . in order to present this aim firstly , a brief explanation of the background of ra and the benefits of exercise in the general population is presented . secondly , the benefits of exercise in ra are highlighted , focusing on the areas of cardiovascular disease , musculoskeletal and joint health , and overall function . thirdly , the perceptions of ra patients regarding exercise are discussed and finally exercise prescription for ra is reviewed . this expert review has been derived from a combination of systematic reviews and other research papers focusing on randomised controlled trials , published guidelines , the recent literature , and also making use of our own specialised experience . it is not within the scope of this review to discuss the benefits of standard low - intensity physiotherapy techniques such as range of motion , stretching , and/or specific joint strengthening . the review , however , does encompass a range of physical activity and physical exercise . we broadly define physical activity as any bodily movement produced by skeletal muscles resulting in energy expenditure above resting levels and physical exercise ( exercise or exercise training ) to be a subset of leisure time physical activity that pertains to planned , structured , and repetitive bodily movements , aimed at improving or maintaining fitness , physical performance , or health . we have based our definition of functional ability from the disablement process in ra as described by escalante and del rincon ( 2002 ) of pathology , impairment , functional limitation , and disability . overview of the benefits of exercise in the general population : older adultsit is widely acknowledged that regular exercise / physical activity provides multiple health benefits for the general population and patients with chronic diseases . this includes improvements in cardiovascular health and reducing the risk of coronary artery disease , stroke , and type 2 diabetes by attenuating hypertension and dyslipidemia , improving insulin sensitivity and reducing adiposity ; reducing the risk of colon and breast cancers ; increasing muscle strength and mechanical properties and bone mineral density [ 22 , 23 ] ; improving balance and reducing the incidence of falls ; facilitating psychological well - being . by engaging in recommended exercises older adults can help reduce the risk of chronic disease ( e.g. , of developing cvd by about 30%50% ) , premature mortality , functional limitation , and disability .basic recommendations from the american college of sports medicine ( acsm ) suggest for health benefit that every adult should accumulate at least 30 minutes of moderate - intensity physical activity on most days of the week . acsm have issued a separate set of guidelines for older adults , that is , men and women aged 65 years and above and adults aged 5064 years with clinically significant chronic conditions such as ra . these guidelines are similar with additional importance stressed on muscle strengthening exercises and exercises to improve balance and flexibility . it is widely acknowledged that regular exercise / physical activity provides multiple health benefits for the general population and patients with chronic diseases . this includes improvements in cardiovascular health and reducing the risk of coronary artery disease , stroke , and type 2 diabetes by attenuating hypertension and dyslipidemia , improving insulin sensitivity and reducing adiposity ; reducing the risk of colon and breast cancers ; increasing muscle strength and mechanical properties and bone mineral density [ 22 , 23 ] ; improving balance and reducing the incidence of falls ; facilitating psychological well - being . by engaging in recommended exercises older adults can help reduce the risk of chronic disease ( e.g. , of developing cvd by about 30%50% ) , premature mortality , functional limitation , and disability . basic recommendations from the american college of sports medicine ( acsm ) suggest for health benefit that every adult should accumulate at least 30 minutes of moderate - intensity physical activity on most days of the week . acsm have issued a separate set of guidelines for older adults , that is , men and women aged 65 years and above and adults aged 5064 years with clinically significant chronic conditions such as ra . these guidelines are similar with additional importance stressed on muscle strengthening exercises and exercises to improve balance and flexibility . apart from the general effects of exercise previously mentioned in the general population , exercise has been shown to have specific health benefits in people with ra . in fact , as evident from past research , including findings from randomised controlled trials [ 5 , 2841 ] , exercise is considered to be fundamentally beneficial for ra patients . the reported benefits of properly designed physical exercise programs include improved cardiorespiratory fitness and cardiovascular health , increased muscle mass , reduced adiposity ( including attenuated trunk fat ) , improved strength , and physical functioning , all achieved without exacerbation of disease activity or joint damage . furthermore , when comparing the effectiveness of high and low intensity exercise training in stable ra , it is found that the former was more effective in increasing aerobic capacity , muscle strength , joint mobility , and physical function with no detrimental effect on disease activity in patients with controlled [ 5 , 36 ] and active ra . a goal for any ra treatment regime should be to reduce cardiovascular comorbidity , in line with the overall aim of prolonging and improving quality of life . the benefits of physical activity , exercise training , and cardiorespiratory fitness in primary and secondary cardiovascular disease prevention are well established [ 42 , 43 ] . low aerobic fitness is strongly associated with all - cause and cardiovascular disease mortality in apparently healthy men and women , those with comorbid conditions ( obesity , hypertension , and type 2 diabetes mellitus ) and those with known coronary artery disease . in general , patients with ra are less physically active and have aerobic capacities , the measure of cardiorespiratory fitness , 20 to 30% lower than age - matched healthy controls [ 45 , 46 ] . furthermore , in a cross - sectional study of 65 ra patients ( 43 females ) , metsios et al . observed that physically inactive ra patients had a significantly worse cardiovascular risk factor profile ( higher systolic blood pressure and elevated total cholesterol , and low - density lipoprotein levels ) when compared with physically active ra patients . meta - analyses of exercise - based cardiac rehabilitation estimate a reduction in mortality of around 20 to 30% . given that the main cause of reduced life expectancy in persons with ra is cvd related , the probable cardioprotective benefit of exercise training and regular physical activity to ra patients can not be ignored . to date , however , most studies of the beneficial effects of exercise training in ra have focused on improvements in functional ability and other ra - related disease outcomes . in a recent cochrane review , moderate evidence for a positive effect of short - term dynamic exercise on aerobic capacity in ra patients was found . it is worth noting , however , that none of the 8 studies reviewed reported any other cardiovascular risk factors . a wider review of 40 studies of exercise in ra observed that none investigated exercise interventions in relation to cvd in ra . clearly , future studies are required to specifically investigate the effect of exercise training and cardiorespiratory fitness on cvd risk in ra . summary of cv health and ra(i ) ra patients have an increased cv risk factor profile ; ( ii ) ra patients have been shown to be less active and have poor aerobic fitness ; ( iii ) the relationships between physical activity , aerobic fitness , and cv risk in ra patients requires more research ; ( iv ) reducing cv risk through exercise could have an enormous impact in patients with ra . ( i ) ra patients have an increased cv risk factor profile ; ( ii ) ra patients have been shown to be less active and have poor aerobic fitness ; ( iii ) the relationships between physical activity , aerobic fitness , and cv risk in ra patients requires more research ; ( iv ) reducing cv risk through exercise could have an enormous impact in patients with ra . as mentioned previously , approximately two thirds of ra patients suffer from cachexia ( i.e. , significant muscle wasting ) [ 5 , 14 ] . rheumatoid cachexia is defined as a loss of body cell mass which predominates in skeletal muscle . unlike the cachexia associated with conditions such as hiv - aids , cancers , copd , and frail old age , rheumatoid cachexia is usually characterised by stable bodyweight as the decrease in muscle mass is masked by a concomitant increase in fat mass . these detrimental changes in body composition not only causes muscle weakness and increased disability , but also contribute to fatigue and augmented risk of diabetes and cvd [ 5 , 6 , 47 ] . it has been proposed that cachexia occurs in ra due to the excess production of proinflammatory cytokines , principally tnf- , which is catabolic and thought to alter the balance between protein degradation and protein synthesis in ra . however , it is unlikely that this is the only cause as specifically blocking tnf- has proved unsuccessful in reversing muscle loss in previously untreated ra patients . thus the precise mechanism by which rheumatoid cachexia occurs is not known but reduced insulin action , muscle igf - i levels , testosterone , and low habitual physical activity are likely to be contributing mediators [ 5 , 53 , 54 ] . furthermore , the use of high - dose steroid therapy to control disease activity can exacerbate muscle atrophy in ra . in addition , the symptoms of the disease , for example , pain and fatigue , also result in ra patients being less physically active ; decreasing physical activity then becomes part of the viscous circle of further decreasing muscle mass and has detrimental effects on other aspects of skeletal muscle health . loss of strength , of up to 70% , is a common finding in ra patients in comparison to healthy counterparts . loss of muscle mass is the main contributor to loss of muscle strength ; however , it is not the only factor responsible [ 23 , 58 ] . with ra , the loss of muscle mass , decreased physical activity , and immunologic factors may combine with alterations in skeletal muscle properties that could result in decreased muscle strength . a summary of these pertinent factors and how they are interlinked with other ra disease - related factors that result in functional limitation are shown in figure 1 . although there was a suggestion that ra patients have a lower activation capacity , recent studies have shown that in stable ra quadriceps muscle recruitment , strength , and other skeletal muscle properties are not compromised [ 60 , 61 ] . however , a case study in active ra indicates that these parameters might be negatively affected during increased disease activity and especially in the presence of an effusion , which adversely affects mechanical joint and muscle function . quadriceps wasting , as well as a dramatic loss of force production , which was not due to pain or impaired muscle quality , was observed . if muscle physiological properties are impaired during times of disease flare , it is likely that this would impact on the length of recovery time needed after flare . this would thereby further emphasise the importance of early and persistent exercise training in these patients and early treatment of joint effusions to avoid possible reflex inhibition and altered joint geometry caused by the effusion that may interfere with exercise training . the impaired physical function that is characteristic of ra is strongly correlated with the diminished muscle mass , but to date there is no standard treatment for rheumatoid cachexia . high intensity resistance exercise has been shown to safely reverse cachexia in patients with ra and , as a consequence of this restoration of muscle mass , to substantially improve physical function and reduce disability in ra patients [ 5 , 28 , 63 , 64 ] . for example , a 24-week high - intensity progressive resistance training ( prt ) program produced significant increases in lean body mass , reduced fat mass ( notably trunk adiposity ) , and substantial improvements in muscle strength and physical function in ra patients . it is notable that the low - intensity range of movement exercises performed by an age- , sex- and disease - matched group of patients as the control condition elicited no changes in body composition or physical function . this investigation also revealed increases in previously diminished muscle levels of igf - i- and igf - binding protein-3 following prt suggesting a probable contributing mechanism for rheumatoid cachexia . other exercise training programs have also been suggested to induce an anti - inflammatory effect , specifically relating to tnf- production . however , immune function ( including tnf- and il-6 ) was unaltered following 12 weeks of high - intensity prt . in terms of the magnitude of hypertrophic and strengthening effects of prt observed in ra patients [ 5 , 63 , 64 ] these are similar to those reported for healthy middle - aged or older subjects ( e.g. , [ 23 , 57 , 6668 ] ) . the study by hakkinen and colleagues in fact provides a direct comparison of training response . they identified almost identical body composition changes ( increased thigh muscle cross - section and reduced thigh fat thickness ) and comparable strength increases in female ra patients and age - matched healthy women following completion of the same resistance exercise program . furthermore , a range of skeletal muscle parameters ( force , muscle architecture , coactivation of antagonist muscles , contractile properties , etc . ) were observed to be no different between well - controlled ra and their healthy counterparts , resulting in similar muscle quality ( muscle force per size ) between the groups , even in cachetic ra patients [ 60 , 61 ] . consequently it is now clear that patients with ra are not resistant to the anabolic effects of exercise as previously suggested . these findings are important to health professionals and those involved in prescribing exercise for people with ra as rheumatoid muscle should respond to exercise training in a similar way to that of muscle in healthy individuals . in fact now much research is promoting the fact that there are more detrimental effects if exercise is not undertaken . as high - intensity prt performed by ra patients , with both newly diagnosed and long - standing disease , has proved to be efficacious in increasing muscle mass , strength , and improving physical function , whilst being well tolerated and safe , it is advocated that such programs are included in disease management to counteract the effects rheumatoid cachexia [ 5 , 56 , 57 , 71 , 72 ] . prt can also benefit other health aspects , for example , improving coordination and balance which ra can detrimentally affect . it is also important to maintain normal muscle strength in order to stabilise the knee joint , preventing joint angulation , and later osteoarthritis . summary of rheumatoid cachexia and musculoskeletal health and exercise types for treatment(i ) at least 50% ra patients suffer loss of lean mass ; ( ii ) intensive progressive resistance training can increase lean mass , reduce fat mass , increase strength and improve function ; ( iii ) prt is the most effective exercise to improve skeletal muscle size and strength ; ( iv ) prt , even performed at high intensity , is safe in ra . ( i ) at least 50% ra patients suffer loss of lean mass ; ( ii ) intensive progressive resistance training can increase lean mass , reduce fat mass , increase strength and improve function ; ( iii ) prt is the most effective exercise to improve skeletal muscle size and strength ; ( iv ) prt , even performed at high intensity , is safe in ra . in people with ra , not only does the typically sedentary lifestyle put them at greater risk of lower bone mineral density ( bmd ) , but the disease itself ( systemic inflammatory activity and high - dose oral steroid medication when used as part of ra treatment ) results in radiological changes including bone loss ( especially peripherally ) [ 74 , 75 ] . lower bmd has been shown to occur at the femoral neck , distal forearm , and hip , but not the spine , in ra when compared with controls [ 74 , 76 ] . lower bmd in ra is found in patients on glucocorticoid treatment , and those with lower strength ( handgrip and quadriceps ) and physical capacity [ 74 , 77 , 78 ] . thus highlighting how physical activity that involves muscle strengthening may assist in mitigating the bone loss in people with ra . loss of bmd with age is difficult to mitigate and requires long - term weight loading on bone ( either by repetitive weight - bearing and/or strengthening exercises ) . several studies have reported no change in bmd with exercise training programmes in people with ra . however most of these investigations have either been too short in duration to detect changes , have featured low participant numbers , or did not include sufficient weight loading stimulus [ 56 , 79 ] . the rheumatoid arthritis patients in training program ( rapit ) study observed a reduced rate of bmd loss in the hip , but not the spine , during 2 years of high - intensity weight - bearing exercise training . this mitigation of bmd loss was associated with increases in both muscle strength and aerobic fitness . the authors concluded that there is an essential role for the combination of high - intensity , weight- and impact - bearing exercises in improving bone mineral density in ra patients . summary of exercise types for bone health(i ) load - bearing exercise , prt and/or weight bearing , is required to increase bmd ; ( ii ) combination of prt and weight / impact - bearing exercises may be required to improve bmd . ( i ) load - bearing exercise , prt and/or weight bearing , is required to increase bmd ; ( ii ) combination of prt and weight / impact - bearing exercises may be required to improve bmd . the role of exercise in promoting the joint health of a person with ra is of great importance , especially as this is the most pronounced and invariant element of the ra disease pathology . tendons are extensible structures that transmit forces from muscle to bone and reversibly deform under mechanical loads , with stiffer tendons providing more efficient force production . sheaths , leading to synovial hypertrophy and sometimes infiltration of synovial tissue within the tendon . the raised circulating inflammatory cytokines also affect collagen , leading to damage and disorganisation of the tendon structure . in addition , tendons gradually lose their elasticity and stiffness as they age and in persons who do not engage regularly in physical activities or following disuse [ 23 , 81 , 82 ] . only recently have tendon properties been investigated in ra , with tendon stiffness in stable established ra being lower than that of matched healthy controls ( manuscript in preparation ) . in the case study example described above , lower patella tendon stiffness that was observed only in the effused knee during the acute phase was found in both knees 1 year later , despite maintenance of regular physical activity . local effects of the joint effusion are likely to be responsible for the acute decrease in tendon stiffness whilst the systemic inflammatory processes of ra could be responsible for the long - term effects . tendon stiffness can be increased , however , following strength training in older people and with endurance training . potential beneficial exercise training effects in tendons of ra patients are to date unknown and warrant further investigation . the ligament forms another essential component of the joint , with the main function being to passively stabilise and guide the joint through its normal range of motion . similar to the research surrounding tendons and the effects of exercise , it is known that exercise strengthens ligaments and that even relatively short periods of immobilisation weakens them [ 85 , 86 ] . thus , it may be suggested that regular physical activity for the ra patient is essential in order to maintain normal ligament and , consequently , overall joint health and function . the primary function of cartilage within the synovial joint is to protect the bone from damage by helping to minimise friction between adjacent bones during movement . it is known that periods of compression and decompression , which can be achieved through the mechanical forces and regular cyclic loading of an exercise bout , are required to prevent cartilage tissue from becoming fragile and dysfunctional [ 8890 ] . furthermore , it is known that cartilage responds in a site - specific way to this loading . for many years , intensive dynamic and weight - bearing exercises were considered inappropriate for people with ra due to concerns that such activities may exacerbate disease . furthermore , research has revealed that patients are concerned about whether such exercise can cause damage to the structure of the joint . research by de jong and colleagues [ 28 , 77 , 92 , 93 ] has shed light on this area of concern . they investigated the effects of a high - intensity exercise program in the rapit study . this involved biweekly participation in a 1.25-hour exercise session including aerobic , muscle strengthening , joint mobility , and an impact - delivering sport or game it was concluded that exercise did not cause an increase in the rate of damage to either large or the small joints of the hands and feet . although initially there was a suspicion that those large joints which were badly damaged prior to the start of the study deteriorated more rapidly in the exercise group than controls , results from a follow - up study led the authors to retract this conclusion . at 18 months following the cessation of the exercise program , there was no significant difference in the rate of damage of the large joints between those patients available at follow - up who were still exercising and those who had discontinued exercise . another finding from the rapit study indicates that there was no significant change in cartilage oligomeric matrix protein ( comp ) level , a measure of cartilage damage , in patients after 3 months of exercising . range of movement and flexibility are also improved as a result of exercise , reducing movement limitation . for example , van den ende et al . found that joint mobility increased as a result of a short - term intensive exercise programme in ra patients with active disease . joint proprioception has also been reported to improve after physical activity and deteriorate after immobilisation or joint disease [ 96 , 97 ] . whilst yet to be determined in the ra population , elderly people who regularly practiced tai chi showed better proprioception at the ankle and knee joints than sedentary controls . it may also be that joint lubrication is enhanced as a result of physical activity , further acting to promote the health of the ra joint . more specifically , after resting for long periods , synovial fluid is squeezed out from between the two surfaces of joint , resulting in contact between the areas of cartilage . when movement is resumed , the mechanism of fluid film lubrication is reactivated . a study by lynberg et al . is typical of findings that prt does not exacerbate joint inflammation ( synovitis , joint swelling , joint tenderness , periarticular tenderness , and range of motion were all clinically assessed ) . furthermore , in patients with moderate disease activity a reduction in the number of clinically active joints after vigorous exercise has sometimes been observed [ 36 , 101 ] . ra is also characterised by an increase in blood flow ( synovial hyperaemia ) and vascularisation of the synovium [ 102 , 103 ] . whilst the links between this process and joint destruction are poorly understood , it is thought that proliferation of the joint synovium and the action of cytokines such il-1 and tnf- act to break down the superficial layers of joint cartilage . however , some evidence suggests that intermittent cycles of raised intra - articular pressure during dynamic exercise might increase synovial blood flow , suggesting a beneficial effect of dynamic exercises in joint inflammation . using a quantitative method , ultrasonography , recent research has suggested no acute effect of handgrip exercise on synovial hyperaemia of the wrist joint in ra patients . in summary , adequate strength and endurance of the muscles alongside tone and elasticity of the connective tissues promotes optimal joint stability , alignment and attenuation of impact and compressive forces [ 89 , 108 ] . summary of exercise types for joint health(i ) resistance training increases tendon stiffness and strengthens connective tissue ; ( ii ) cyclic loading ( e.g. , walking , cycling , strength endurance exercises ) enhances cartilage integrity and joint lubrication ; ( iii ) mobility exercises increase range of motion . ( i ) resistance training increases tendon stiffness and strengthens connective tissue ; ( ii ) cyclic loading ( e.g. , walking , cycling , strength endurance exercises ) enhances cartilage integrity and joint lubrication ; ( iii ) mobility exercises increase range of motion . patients with rheumatoid arthritis usually suffer from disability , severe pain , joint stiffness , and fatigue which impair physical function . even after controlling for the disease with development of powerful disease - modifying antirheumatic drugs ( dmards ) , patients still suffer from functional limitation , often leading to work disability . however , exercise has been shown to significantly improve some or all of these symptoms , especially function as well as psychological well - being [ 5 , 56 , 63 , 111 , 112 ] . for example , a two - year strength training program resulted in improvements in subjective patient assessments of disability by the health assessment questionnaire ( haq ) . similarly , marcora and colleagues found a significant inverse correlation between increases in leg lean mass following 12 weeks prt and the perceived difficulty in performing activities of daily living ( adls ) . for example , an intensive prt program failed to improve modified haq scores in a group of ra patients despite significant improvements in muscle mass and strength . it was concluded that patients involved in this program had relatively low disability and that the modified haq was not sensitive to change in a low disability group . however , an internationally accepted definition of fatigue in ra currently does not exist , and its aetiology still remains a mystery . fatigue can be described as a subjective experience , a feeling of extreme , persistent tiredness , weakness or exhaustion which can be both mental and physical . identifying ways to reduce fatigue and improving overall quality of life are very important . so far few methods have shown to be effective , however , recent research suggests that fatigue can be reduced by performing exercise . a systematic review which explored the effectiveness of nonpharmacological interventions for fatigue also concluded that both aerobic and resistance exercise interventions reduce ra fatigue . summary : it is important to note the following(i ) exercise can reduce pain , morning stiffness , and even reduce fatigue in ra ; ( ii ) exercise can improve functional ability and psychological well - being ; ( iii ) exercise has not been shown to exacerbate disease activity . ( i ) exercise can reduce pain , morning stiffness , and even reduce fatigue in ra ; ( ii ) exercise can improve functional ability and psychological well - being ; ( iii ) exercise has not been shown to exacerbate disease activity . whilst there are numerous reasons why exercise is considered to be of fundamental benefit , it is apparent that the ra population is less physically active than the general population . therefore , it is important for those involved in the care of ra patients to be aware of factors that may positively and negatively affect the uptake of and compliance to an exercise prescription . the perceptions of people with ra may provide reasoning for the lower physical activity levels of ra patients when compared to the general population . thus , understanding the perceptions of ra patients regarding exercise is salient to the role of the health professional . the obstacles to action study ( new zealand ) investigated factors influencing exercise participation for individuals with self - reported arthritis who were defined as their qualitative analysis of focus group discussions revealed that active people with arthritis believed more strongly in the benefits of physical activity , reported significantly higher levels of encouragement from others , and had greater overall levels of self - efficacy when compared with the less active participants . arthritis , fatigue , and discomfort were ranked by both groups as the top three barriers . however , the active participants reported significantly lower impact scores for these barriers than the inactive group , and these findings persisted after adjusting for occupational status , body mass index , and comorbidities . other barriers suggested to affect the successful uptake of exercise recommendations in arthritis patients have also been revealed . physical barriers have included pain , fatigue , and physical capabilities , alongside the additional complications of further comorbidities . psychological aspects such as a lack of enjoyment , motivation , and confidence have been identified as negative influences . however , receiving assistance from instructors and the opportunity for social interaction have been highlighted as factors encouraging patients to exercise . especially prevalent in those on a limited income , environmental barriers such as cost and a lack of adequate insurance have also been revealed as barriers among nonexercisers . it has also become clear that a lack of transportation can be a major hindrance . time constraints brought about by lifestyle and other commitments is a factor common to both the general and patient population , often further compounded by the distance necessary to travel to an exercise facility [ 40 , 91 , 117120 ] . it is also important to consider patient perceptions and potential barriers when promoting the maintenance of an exercise program . for example , working towards strengthening patient beliefs that they are able to continue exercise outside of the healthcare environment may be valuable . as previously identified in oa patients , worry that exercise may have detrimental effects on joint health was also present in ra patients . additionally , these patients had specific apprehensions regarding the effects of impact and repetitive exercises . joint pain has also been highlighted as a definitive barrier and has also been perceived as a prominent factor in determining the patients ' exercise behaviour [ 120 , 123 ] . in contrast , however , qualitative research suggests that patients feel that their joints benefit from exercise , with quotes indicating that joints are however , evidence suggests that whilst patients with arthritis believe exercise to be an important factor in treatment , uncertainty about which exercises to do , and how to do them without causing harm , deters many patient from exercising at all . within the obstacles to action study insufficient advice from a healthcare provider was a theme for the insufficiently active individuals , with queries relating to the type , frequency , and intensity of appropriate exercise . due to their condition ra patients are in frequent contact with their health professionals and this contact influences their perceptions about the role of exercise as part of their treatment . moreover , because patients are constantly making decisions about treatment due to the fluctuating nature of ra , it is important for patients to understand how to modify their exercise according to their symptoms [ 126 , 127 ] . the perceptions and behaviour of the rheumatologist is an important consideration when working towards a successful exercise prescription . research by iversen et al . found that discussions about exercise were four times more likely to occur when the rheumatologist initiated exercise discussion , with discussions strongly impacting on the likelihood that a patient received an exercise prescription . furthermore , although high - intensity exercise is now considered to provide the greatest benefit , the outcome expectations of patients , rheumatologists , and physiotherapists for high intensity exercise have been found to be significantly less positive than those for a conventional exercise program , with rheumatologists reporting their most negative attitudes towards aerobic exercise . it is also interesting to note that , when examining the predictors of exercise behaviour in ra patients 6 months following a visit with their rheumatologist , iversen et al . found that if a patient 's rheumatologist was currently performing aerobic exercise , the patient was more likely to be engaged in exercise . a further issue relating to the health professional is their own assertion and certainty when prescribing exercise to those with ra . in the study by iversen et al . , only 51% of rheumatologists reported they felt confident that they knew when exercises were appropriate for their patients with ra . correspondingly , recent research has revealed that patients perceive uncertainties within the health profession regarding the impact of exercise on pain and joint health . in particular , this was in relation to whether the sensation of exercise discomfort or pain equated to actual joint damage and the effects of different types of exercise on the health of their joints . these concerns pose a further challenge to ra patients [ 38 , 45 , 93 , 129 , 130 ] . despite these reservations , patients have demonstrated an awareness of the advantages of exercise in terms of improving strength , mobility , and function and reducing pain . however , due to the effects of ra and considering the aforementioned issues , if the perception of exercise as a positive feature of ra treatment is to supersede the apparent negative connotations , continual emphasis of the benefits of exercise in this population is of great importance [ 40 , 77 , 131 ] . this also means that clear exercise guidelines and prescription is necessary to attend to the fact that ra patients are currently faced with ambiguous and incomplete information . in addition to the pivotal role of the rheumatologist in influencing exercise prescription [ 126 , 127 ] , these recommendations are also relevant to the other health professionals involved in the treatment and care of ra patients ( i.e. , nurse specialists , physiotherapists , and occupational therapists ) and significant others such as the patient 's family and friends . key recommendations for health professionals and significant others in the improvement of patient perceptions regarding exercise(i ) impart better advice regarding the effects and benefits of exercise ; ( ii ) clarify specific exercise recommendations ; ( iii ) consider methods of overcoming individual barriers to exercise . ( i ) impart better advice regarding the effects and benefits of exercise ; ( ii ) clarify specific exercise recommendations ; ( iii ) consider methods of overcoming individual barriers to exercise . the benefits of dynamic exercise in improving outcomes for patients with ra were highlighted following a systematic review by van den ende et al . however , this early meta - analysis was limited to six studies . in the intervening decade , numerous studies of varying quality have investigated the effects of aerobic and/or muscle strengthening exercise training programs for ra patients . this growing body of evidence , which is the subject of a number of systematic reviews [ 49 , 50 , 132135 ] , strongly suggests that exercise is effective in management of patients with ra , and does not induce adverse effects . current guidelines now advise that exercise is beneficial for most individuals with ra ( e.g. , nice guidelines , 2009 ) . however , whilst the exercise benefits for ra patients are widely recognized , further studies are required to investigate the most effective exercise prescription ( intensity , frequency , duration , and mode ) , the optimum modes of exercise delivery , and how adherence to training can be facilitated . a summary of exercise types and recommendations for individuals with ra based on current evidence is depicted in table 1 . typically exercise interventions have focused on effects of aerobic training , strength training and a combination of aerobic training and strength training . the aerobic activities most often included in exercise interventions are walking , running , cycling , exercise in water , and aerobic dance . walking is a good mode of exercise as it is inexpensive , requires no special skills , is safe , and can be performed both indoors and outdoors . regular brisk walking , even in short bouts , improves aerobic fitness and reduces aspects of cvd risk in healthy adults . cycling is also an excellent mode of aerobic activity that works the large muscle groups of the lower extremity . cycling , in line with the guidelines in table 1 , improves aerobic capacity , muscle strength , and joint mobility ( e.g. , by 17% , 17% , and 16% , resp . hydrotherapy ( the use of water ) has been shown to be very effective for ra sufferers . as little as two 30-minute sessions for 4 weeks have been shown to significantly reduce joint tenderness , improve knee range of movement , and improve emotional and psychological well - being . dancing is another form of aerobic exercise which has reported improvements in aerobic power and resulted in positive changes in depression , anxiety , and fatigue , with no deterioration in disease activity in ra patients . see table 1 for aerobic exercise types and recommendations for individuals with ra . with a loss in muscle mass , and subsequent functional limitation and burgeoning disability a characteristic of the disease , ra several studies have demonstrated the beneficial effects for ra patients of performing muscle strengthening exercises , in particular prt . these improvements include increases in muscle mass , reduction in fat mass , and substantial improvements in physical function [ 5 , 63 , 64 ] . exercises that involve the large muscle groups of the upper and lower extremities as well as hand strengthening exercises have been shown to be effective [ 5 , 63 , 111 ] . the effects of a two - year dynamic strength training program in early ra patients found significant improvements in muscle strength ( 1959% ) along with reductions in systemic inflammation , pain , morning stiffness , and disease activity . these findings suggest that long - term dynamic strength training can significantly improve the physical well - being of ra patients without exacerbating disease activity . muscle strength gains from prt programmes can also be maintained over several years of continued training at sufficient intensity [ 56 , 92 ] . these examples have assisted in recommendations for strength training being developed , a summary of which is presented in table 1 . the optimum exercise program for ra patients would include both aerobic and resistance training . with poor cardiovascular health being the main cause of death in ra and with ra patients tending to have poor cardiorespiratory fitness , the requirement of aerobic exercise as part of treatment is crucial . whilst the addition of strengthening exercises helps to mitigate rheumatoid cachexia and other musculoskeletal and joint health issues , and induces substantial improvements in physical function and the ability to perform adls . exercise programs for ra patients should be initially supervised by an experienced exercise professional so that the program can be tailored to individual aspirations and adapted to the disease activity , joint defects , and symptoms of patients . following on from moderate to high intensity prt or combined programs , ra patients have been shown to have high adherence rates to exercise in real life although , continuation of both high - intensity and high - frequency sessions may be required for maintenance of training gains in aerobic fitness , muscle strength , and functional ability , but evidence is still required regarding the minimum maintenance regimen . home - based exercise programs have also been investigated and have been shown to improve quality of life and functional status . however , due to the difficulties in ensuring that exercise of sufficient intensity is performed these exercises often fail to elicit significant increases in muscle strength or aerobic fitness . although the minimal exercise dose for functional improvements and health maintenance is unknown , even regular training performed once weekly has been shown to improve function assessed subjectively by haq scores and health status . as many ra patients have below average physical capacity , exercise training should be initiated at a lower intensity . evidence of exercise prescription in ra patients with severe disability ( functional classes iii and iv ) is still lacking [ 57 , 93 ] . exercise programs , even over long periods and at high intensities , have been found to be safe as well as effective . however , little is known as to whether exercise , particularly strength training , should be continued through inflammatory flares and further research should be conducted on the effects of exercise on joints that are already severely damaged . for continued training adaptation ( i.e. , increased fitness ) a progression of the exercise dose ( i.e. , duration and/or intensity ) unfortunately , studies have also shown that most of the beneficial muscle adaptations are also lost after cessation of the exercise training . thus , as with healthy individuals , the beneficial effects of exercise ( prt , aerobic , mobility ) are lost if training is discontinued . the importance for the inclusion of exercise training in the treatment of ra is now clear and proven . exercise in general seems to improve overall function in ra without any proven detrimental effects to disease activity . thus all ra patients should be encouraged to include some form of aerobic and resistance exercise training as part of their routine care . more research is still required on the optimal dose and types of exercises , especially when combining types , as well as how best to incorporate exercise into the lives of ra patients across the variable course of the disease . OUTPUT:

this paper aims to highlight the importance of exercise in patients with rheumatoid arthritis ( ra ) and to demonstrate the multitude of beneficial effects that properly designed exercise training has in this population . ra is a chronic , systemic , autoimmune disease characterised by decrements to joint health including joint pain and inflammation , fatigue , increased incidence and progression of cardiovascular disease , and accelerated loss of muscle mass , that is , rheumatoid cachexia . these factors contribute to functional limitation , disability , comorbidities , and reduced quality of life . exercise training for ra patients has been shown to be efficacious in reversing cachexia and substantially improving function without exacerbating disease activity and is likely to reduce cardiovascular risk . thus , all ra patients should be encouraged to include aerobic and resistance exercise training as part of routine care . understanding the perceptions of ra patients and health professionals to exercise is key to patients initiating and adhering to effective exercise training .

PubMed_Summ6554

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: portal obstruction is the single most common etiology of portal hypertension in children , representing roughly 50% of all cases in the majority of series . the causes of portal vein obstruction fall into one of following categories : perinatal events ( umbilical catheterization , omphalitis , and dehydration ) , congenital malformations outside the portal vein ( abernethy malformation ) , thrombophilic states ( deficiency of protein - c , s or antithrombin - iii , etc . ) , tumors , abdominal infections , and a category where the etiology is unknown [ 1 , 2 ] . portal obstruction in children is usually detected early in the first decade , because of splenomegaly , gastrointestinal bleeding , or both . development of esophageal varices is almost universal , and the actuarial risk of bleeding reaches 76% at 24 years of age . probability of bleeding is directly correlated with the size of varices as seen on endoscopy , from the absence of bleeding episode in children without varices or with grade i varices , to 85% prevalence of bleeding in patients with grade ii or iiii varices , as reported by lykavieris et al . . of note , this study showed that varices tended to increase in size over the years instead of disappearing , defying the classical concept of spontaneous improvement as children grow - up . variceal bleeding is generally well tolerated , owing to normal function of the liver ; however , the main concern in the management is to reduce the recurrence of episodes . endoscopic therapy works by physical obliteration of esophageal varices and has shown excellent results , with a 90% rate of success in the long - term control of bleeding . it usually represents the first approach due to its relative simplicity , low frequency of immediate complications , and widespread availability . the high rate of success has led to ample use of this technique ; however , an increase of long - term complications is usually observed , as bleeding from ectopic varices , low - grade encephalopathy , hepatopulmonary syndromes , further development of hypersplenism , and cholestasis secondary to portal cholangiopathy . particularly challenging is the management of cholestasis ; this syndrome has been described in 6% of patients with portal vein obstruction , especially after long - term followup [ 6 , 7 ] , and it is the consequence of dilated peribiliary venous plexus ( cavernoma ) in the wall of biliary ducts ( figure 1 ) . affected patients exhibit high levels of ggt and bilirubin , with dilated bile ducts ( mainly intrahepatic ) as seen on the abdominal ultrasound . biopsy samples show different degrees of fibrosis and even biliary type of cirrhosis , with a pattern indistinguishably from primary sclerosing cholangitis in some cases . complete resolution can be achieved with surgical decompression of the portal system by means of a portosystemic or a meso - rex shunts . in rare cases congenital hepatic fibrosis ( chf ) is part of a spectrum of fibropolycystic diseases , in which the pathological hallmark is the presence of ductal plate malformation . it combines biliary dysplasia , perilobular fibrosis , and renal polycystic disease in different patterns , giving rise to a wide diversity of clinical manifestations observed throughout the years . two different forms have been described in association with renal disease : autosomic recessive ( arpkd ) and dominant ( adpkd ) polycystic kidney diseases . in arpkd , clinical signs of renal disease can be observed during the first years , appear later , or remain subclinical . findings of portal hypertension become evident , generally in the first years of life , usually in the form of variceal bleeding and hypersplenism . it has been estimated that 25% of affected individuals develop clinically significant portal hypertension , with a trend toward increased frequency with increasing age . interestingly , children with portal hypertension were younger than the mean age of the whole cohort , suggesting that a particular subset of patients is at risk of developing this complication , probably related to specific still unknown genetic or environmental factors . adpkd patients , in contrast with arpkd , tend to present later in life with progressive renal disease and less liver involvement . however , because variceal bleeding can occur as early as age 4 , screening relatives of the index case ( most commonly an adult with multiple renal cysts ) by regular ultrasounds have been recently advocated . chf has also been reported as part of other rare syndromes , such as nephronopthisis ( with end - stage renal disease within 5 to 10 years ) , jeune syndrome ( lung and thoracic hypoplasia ) , meckel - gruber syndrome ( encephalocele and polydactily ) , ivemark syndrome ( interstitial fibrosis leading to renal failure ) , chronic diarrhea related to enterocolitis cystic superficialis and intestinal lymphangiectasia , and others . in all cases , accompanying liver findings include ductal plate malformation , fibrosis , and biliary cysts in different combinations . patients with congenital hepatic fibrosis characteristically have well - preserved liver function ; they behave as those with portal vein obstruction , with regard to the risk and tolerance to bleeding . moreover , cavernomatous transformation of the portal vein and abnormal intrahepatic branching have been described in chf patients , suggesting that anomalies in the development of portal veins are part of the spectrum of liver disease in this condition [ 13 , 14 ] . given the relatively benign liver disease , management recommendations for children with chf - related portal hypertension are based on endoscopic eradication of varices . however , the frequent need for kidney transplantation in children with arpkd leads to perform a surgical portosystemic shunt before the transplant surgery . successful shunt facilitates abdominal surgery and avoids varices bleeding that could represent a risk for the transplanted organ . for the rare patients with repeated acute or chronic cholangitis , who develop cirrhosis , or for those with pulmonary complications , liver transplantation is a potential therapeutic option . decision about when ( and if ) to combine it with kidney transplantation should be considered on a case - by - case evaluation . this disease affects 1 in 15000 to 1 in 20000 newborns and constitutes the main indication for liver transplantation in children . current treatment strategy includes the kasai portoenterostomy operation , followed by liver transplantation in cases of its failure or later complications from cirrhosis . children with biliary atresia tend to develop varices very early , with an estimated risk of bleeding of 15% before the age of two . when associated with high bilirubin levels , it portends a poor prognosis , and constitutes an indication to proceed to transplantation as soon as possible , owing to the more than tenfold rise in the risk of death when conjugated bilirubin levels are over 10 mg% . even in anicteric patients , there is a considerable risk of bleeding , highlighting their tendency to suffer from severe portal hypertension , probably related to the intense fibrosis as is observed at the time of portoenterostomy , and the diffuse compromise of intrahepatic portal vein described in some . cholangitis , a frequent complication after portoenterostomy , can be responsible for thrombophlebitis of the portal system , accelerating the development of portal hypertension . bleeding can be predicted in patients with large varices , associated red signs , presence of gastric varices , and portal hypertensive gastropathy ( figure 2 ) . recent data supports the implementation of prophylactic sclerotherapy or banding to prevent the first hemorrhage . sclerotherapy would be preferred over rubber band ligation owing to size constraints faced in little children . approximately 5% of cystic fibrosis patients develop liver cirrhosis before adolescence . like other cholestatic type of cirrhosis , it is characterized by a high degree of portal hypertension , with preserved synthetic function for many years [ 22 , 23 ] . as the management of lung disease continues to improve , liver disease is becoming a major determinant of the outcome , being the third most common cause of death . it has been estimated that nearly 60% of cirrhotic patients experimented an episode of variceal bleeding before the second decade of life , contributing to the 10 to 20% of deaths in the cystic fibrosis group as a whole . data coming from recent cohort studies show that liver disease in cystic fibrosis patients poses a special threat to their wellbeing and survival . this is not only related to the complications of cirrhosis itself ; affected children tend to have higher shwachman scores and worse pulmonary function suggesting a synergistic effect between liver and lung disease [ 22 , 25 ] . in fact , improvement in the severity of respiratory disease is well documented after liver transplantation in many of those patients [ 24 , 26 ] . altogether , approaching a child suffering from variceal bleeding in the context of cystic fibrosis should be tailored to each specific case . endoscopic treatment should be offered to all , being especially useful in the context of acute hemorrhage . however , concern remains over the long - term endoscopic treatment due to the need for multiple anesthetics procedures , and the possible development of pulmonary complications from portal hypertension itself . in patients with relatively well - preserved liver and lung functions , a selective portocaval shunt ( or a tips , when feasible ) could offer many years of benefit without compromising the outcome [ 23 , 27 ] . patients with advanced liver disease , or severe and refractory bleeding , with good pulmonary function are probably best managed with liver transplantation [ 24 , 26 , 28 ] . results of combined liver - lung transplantation are currently not encouraging ; hence waiting for advanced lung disease before deciding to go for liver transplantation does not seem to be advisable . this presinusoidal type of portal hypertension is produced by intimal thickening of small intrahepatic portal vein radicles . the clinical picture resembles that of prehepatic portal vein obstruction but with a patent ( an even , dilated ) portal vein on ultrasound . well - tolerated variceal bleeding and hypersplenism have been reported in this syndrome mainly described in asian patients . recent reports coming from western - country children surviving from acute leukemia treated with 6-thioguanin highlights the alleged toxin exposure as one of the possible causes of the endothelial damage . chronic hepatitis associated to hbv or hcv infection can rarely present in the first two decades of life with a picture of portal hypertension secondary to cirrhosis . children exhibit better responses rates to antiviral treatment ; thereby there is better control of complications , including those of cirrhosis [ 3234 ] . appropriate treatment with immunosuppressive drugs usually results in control and regression of fibrosis in most patients . a small percentage , however , progresses to decompensated cirrhosis and hemorrhagic complications ; these should be managed in a staggered manner according to the medium - term prognosis of the disease , from endoscopic treatment to liver transplantation in end - stage patients . it is the most common indication for liver transplantation from metabolic diseases in the western hemisphere . although some improvement of liver function tests has been reported with the use of ursodeoxycholic acid , at the present , there is no effective treatment for this condition , and management of affected patients is restricted to the complications of ongoing cirrhosis , using the same principles described for other etiologies . budd - chiari syndrome encompasses a series of different causes producing obstruction to the hepatic venous outflow . these patients tend to present with hepatomegaly and ascitis rather than with variceal hemorrhage , but those developing secondary cirrhosis can experiment bleeding from esophageal varices . management is very complex , strongly influenced by the clinical picture ( acute versus chronic ) , etiology , and extent of the liver damage . in contrast with portal vein obstruction , most budd - chiari patients have an associated thrombophilic state that has to be accurately investigated and treated . avoiding the morbidity and mortality associated with the first bleed from esophageal varices is the rationale behind primary prophylaxis . clear recommendations exist for the adult population , but unfortunately this is not the case for pediatric patients . application of such strategy should comply with two premises : correct identification of the population at risk and availability of an effective treatment . in spite of many efforts , achieving the first goal has been elusive , owing to the heterogeneity of the population with portal hypertension in pediatric ages . stratifying patients at risk according to specific etiologies could be the best way to manage this problem . regarding the second goal , the absence of controlled randomized trials in primary prophylaxis of esophageal varices bleeding in children makes any recommendation problematic and debatable . low number of patients and difficulties in recruitment are major obstacles to the realization of such studies , as seen with the use of propranolol in children , which is in strong contrast to the adult population . a group of expert analyzed possibilities on primary prophylaxis of variceal hemorrhage in children , concluding that future research should focus on the natural history , diagnosis of varices , prediction of variceal bleeding , and explore therapeutic efficacy of different protocols . currently , it remains intuitive to offer endoscopic obliteration to patients with high - risk varices who had never bled , preferably by band ligation . endoscopic examination should be only offered to patients when decision to proceed with sclerotherapy or banding has already been taken in advance [ 5 , 20 ] . data in children with cirrhosis secondary to biliary atresia showed that esophageal varices developed very early in life in 70% of them . in addition , endoscopic signs indicating a high risk of mediate bleeding were found in 30% of those with esophageal varices . another recent study , on a similar population , showed that grade ii - iii varices developed with similar frequency after failed and successful portoenterostomy , but , following failed portoenterostomy , esophageal varices were encountered significantly earlier . the authors recommended that after failed portoenterostomy surveillance should start early , for example , at six months of age . there are different approaches in the care of children at risk for esophageal varices bleeding among pediatric gastroenterologists , most of them based on personal preferences and local expertise rather than strong evidence . in addition , attitudes from parents could be different from those of physicians ; a high percentage of them would accept an endoscopy to be carried out in their children if a prophylactic treatment can avoid bleeding or even to establish the current risk of bleeding in the absence of treatment . acute bleeding is the most feared complication of portal hypertension , with an associated mortality up to 20% , mainly in patients with affected liver function . as a consequence , focus on treatment has been directed to the control of hemorrhagic episodes , reaching a rate of success higher than 90% in recent years . volume resuscitation initiated without delay , should restore hemoglobin levels to around 8 g% , and insure good perfusion of vital organs with plasma expanders . overzealous use of volume / plasma expanders should be avoided , however , because of the theoretical risk of rebound portal hypertension and rebleeding . antibiotics directed at the intestinal flora should be part of the treatment from the beginning , as well as vasoactive drugs , preferably by the intravenous route . among many drugs tested in adult patients , octreotide has been the most widely used in children , at a dose of 1 - 2 ug / kg by bolus over 20 minutes , followed by continuous infusion at 2 ug / kg / h , maintained for 2 to 5 days . its use in this setting has been advocated to promote easier and safer endoscopic procedures . once stabilized , patients should be treated by direct approach of the varices , either with band ligation or sclerosant injection . both treatments are highly effective in controlling the acute episode , and the choice of one particular method depends on the local expertise and other technical issues . in a general sense , endoscopic variceal ligation is preferred in most cases , owing to its simplicity and lower rate of complications , but sclerotherapy is probably easier to implement during active bleeding , and is the best option in small children [ 45 , 46 ] . ideally , the operator should master both techniques and have all appropriate tools available during the procedure . despite the high rate of success achieved with these approaches : in 5 to 10% of cases bleeding can not be controlled , and rescue therapy is needed , usually after the failure of a second attempt by endoscopy . this rescue therapy involves a surgical option , or a radiological approach ( tips ) , when feasible . once again , both procedures are equally effective , but when used in an emergency scenario their results are less satisfactory . tips has the advantage of avoiding a laparotomy , but its availability is limited to specialized services and is not suitable for small children , especially in cases of portal vein obstruction or biliary atresia , which are the main causes of variceal hemorrhage among pediatric patients . the choice of the surgical technique , on the other hand , depends on the medium - term prognosis of the disease . shunting procedures are preferred in patients with relatively well - preserved liver function , like those with portal vein obstruction , congenital hepatic fibrosis , or compensated cirrhosis . once the first bleeding has occurred , there is a substantial risk for rebleeding in the next years ; consequently , eradication of esophageal varices becomes a logical goal . endoscopic variceal ligation and sclerotherapy have been reported to be equally successful in achieving this . variceal ligation is usually preferred because of its reported simplicity , lesser number of sessions needed , and a safer profile when compared to sclerotherapy [ 45 , 46 ] . both techniques are complementary and have been used even in primary prophylaxis with good results [ 5 , 20 ] . an observational study in children with portal hypertension , of several different etiologies , showed a benefit of secondary prophylaxis in avoiding esophageal varices bleeding . in this study , in contrast , a large study including mainly adolescents did not find differences between propranolol and endoscopic ligation in the recurrence of bleeding . longer followup of endoscopic treatments is available , showing recurrence of esophageal varices in 40% of the patients , with a tendency to worsening of gastric varices , portal hypertensive gastropathy , and rising incidence of ectopic varices , all of them representing a more difficult problem to solve . progression of the spleen size and late incidence of complications like portal cholangiopathy in patients with portal obstruction , formerly considered a rare entity , affect children quality of life . moreover , for these complications endoscopic treatments are clearly unsuitable . in those cases , or when hemorrhagic episodes are refractory to other treatments , surgery becomes the only option . total portosystemic shunts are those more than 10 mm in diameter , constructed between the main veins of the portal system and the inferior vena cava . they provide excellent control of hemorrhages and ascitis , but at the high cost of encephalopathy , and are rarely used in children . partial shunts comprises portocaval or mesocaval anastomoses of 8 mm in diameter or less , allowing part of the portal flow to reach the liver sinusoids , and thus reducing the risk of systemic complications without losing efficacy for the prevention of further bleeding . this type of shunts has been widely used in children employing the internal jugular vein as a graft , with excellent results [ 53 , 54 ] . selective shunts are constructed by the anastomoses of the splenic vein to the left renal vein , thereby decompressing gastroesophageal varices through the short gastric veins ( distal splenorenal shunt ) , and maintaining portal perfusion to the liver . surgical shunts have gained renewed interest in the management of portal hypertension in children with good liver function , in view of better results obtained with the refinement of surgical techniques driven by the development of liver transplantation programs , and the emergence of nonhemorrhagic complications after successful eradication of esophageal varices . the mesenteric - left portal vein bypass ( rex shunt ) is constructed between the superior mesenteric vein and the recessus of rex at the level of intrahepatic left branch of portal vein . originally developed to treat patients who have portal vein thrombosis after liver transplantation , it was extended immediately to the treatment of children with extrahepatic portal vein obstruction , allowing them for the first time to reach a real cure for their disease . in fact , when successful , it can restore the normal flow to the liver with normalization of hematological tests . availability of this technique is promoting a change of paradigm in the treatment of portal vein obstruction , towards an early indication of surgery , before progressive fibrosis of the main portal vein branches precludes the feasibility of such anastomoses . the percentage of children with portal obstruction who can benefit for a meso - rex shunt is still unknown . recent data coming from pediatric series , albeit small in number of patients , have reproduced the rates of success obtained in adult patients , making tips a good option even in small children and expanding indications to postransplant portal hypertension , and children with portal vein obstruction with a favorable anatomy . future studies will clarify the role of this therapy in the management of pediatric portal hypertension . treatment of hemorrhagic complications from portal hypertension in children has its own specificities because of the different etiologies involved , and the natural history of these disorders compared to adults ( table 1 ) . , considerable progress has been achieved in the last years , mainly derived from better control of bleeding from esophageal varices . longer followup , however , uncovers new complications for which endoscopic treatment is inappropriate , promoting a renewed interest on surgical approaches . as a general principle , management of portal hypertension in children rests on two main characteristics : the etiology of the portal hypertension and the age of the patient . OUTPUT:

portal hypertension in children represents a particular diagnostic and management challenge for several reasons : ( 1 ) treatment outcomes should be evaluated in relationship with a long - life expectancy , ( 2 ) pediatric patients with portal hypertension constitute an heterogeneous population , both in terms of individual characteristics and diversity of liver diseases ; making comparison between treatment outcomes very difficult , ( 3 ) application of techniques and procedures developed in adult patients ( v.gr . tips ) face size limitations in small children , and ( 4 ) absence of data from well - controlled trials in children forces pediatric specialists to adapt results obtained from adult cohorts suffering from diseases such as hcv and alcoholic cirrhosis . despite those limitations , substantial progress in the treatment of children with portal hypertension has been achieved in recent years , with better outcomes and survival . two main factors influence our therapeutic decision : age of the patient and etiology of the liver disease . therefore , diagnosis and treatment of complications of portal hypertension in children need to be described taking such factors into consideration . this paper summarizes current knowledge and expert opinion .

PubMed_Summ6555

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: catheter - based radiofrequency ablation ( rfa ) delivered during endoscopic retrograde cholangiopancreatography ( ercp ) has recently emerged as a possible therapeutic option within the bile duct 1 2 3 4 . intrabiliary extension of neoplasm remains an important challenge in the endoscopic eradication of complex ampullary lesions 5 6 , and rfa may represent a viable treatment adjunct for this problem . recently , the use of rfa at the ampulla and within the distal bile duct has been described 7 8 . herein we present 4 cases assessing the technical feasibility , safety , and treatment outcomes of rfa employed at the time of ercp to treat ampullary lesions with intraductal extension . the study was conducted at the medical university of south carolina ( musc ) from july 1 , 2014 through october 1 , 2015 . after institutional review board approval , we retrospectively identified eligible adult subjects through the musc endoscopy report database ( endoworks , olympus america , center valley , pa ) by searching for reports that contained the keywords radiofrequency ablation ( rfa ) and endoscopic retrograde cholangiopancreatography ( ercp ) . we excluded patients who underwent rfa of a stricture not associated with an ampullary lesion . all procedures were performed by an experienced pancreaticobiliary endoscopist under general anesthesia using a side - viewing duodenoscope . ampullary resection was performed either en bloc or in piecemeal fashion by delivering electrosurgical current through a snare with or without prior submucosal lift . intraductal extension of the lesion was assessed cholangiographically ( fig . 1 ) and/or visually ( fig . 2 ) . in some cases , a biliary sphincterotomy extension and papillary balloon dilation was performed to expose the inside of the terminal bile duct for assessment and therapy . ablative therapy was delivered using a standard argon plasma coagulation ( apc ) probe ( erbe usa inc . , mariette , ga ) at a flow rate of 1.0 l / min to 1.2 l / min and 30 to 40 maximum watts ( w ) and/or the habib endohpb rfa bipolar cautery probe ( emcision united kingdom , london , united kingdom ) at 10 w for 60 to 90 seconds , extrapolating from manufacturer s recommendations of 7 to 10 w 120 seconds 9 . given the proximity to the pancreatic orifice and the benign nature of the target lesions , a shorter duration of treatment was chosen . in general , apc was reserved for treating exposed target tissue in the duodenum or very distal duct , whereas rfa was reserved for treating hidden or difficult to access tissue within the duct . all patients undergoing rfa received a temporary pancreatic stent ( 5 fr , 2 5 cm ) and rectal indomethacin to reduce the risk of post - ercp pancreatitis ( pep ) , as well as a plastic endobiliary prostheses to prevent biliary obstruction and cholangitis . cholangiogram showing a filling defect in the distal bile duct ( arrow ) representing bulky intraductal extension of an ampullary adenoma . endoscopic view of the papilla after ampullectomy demonstrating intraductal extension of the adenoma ( arrow ) . technical success was defined as the ability to successfully position the rfa probe across the biliary orifice and deliver thermal energy to the region of the papilla and terminal bile duct , resulting in coagulation of the visualized target areas . clinical success was defined as endoscopic absence of polypoid or adenomatous - appearing tissue at the treatment site and histologic absence of neoplasm based on extensive follow - up biopsies from the papilla , pancreaticobiliary septum , biliary orifice , and distal bile duct . when the distal bile duct was not fully exposed by prior sphincterotomy , a pediatric biopsy forceps was introduced into the distal duct to acquire tissue . patient demographics , procedure indications , and treatment outcomes are listed in table 1 . four eligible patients were identified , all of whom were men with a mean age of 63 years ( range 54 84 ) . three patients ( 75 % ) had a history of familial adenomatous polyposis ( fap ) . three patients were treated for ampullary adenoma and 1 for ampullary adenoma with a focus of adenocarcinoma ( he declined surgical evaluation ) . fap , familial adenomatous polyposis ; lgd , low - grade dysplasia ; hgd , high - grade dysplasia ; imc , intramucosal cancer ; apc , argon plasma coagulation ; rfa , radiofrequency ablation ; pep , post - endoscopic retrograde cholangiopancreatography pancreatitis ; eus , endoscopic ultrasound video 1 presents a synopsis of 2 representative cases . all rfa procedures were technically successful , resulting in a perceptible tissue effect ( fig . 3 ) . rfa was performed immediately following endoscopic resection in 1 case and during a subsequent session in the remaining cases . the mean number of rfa sessions per patient was 1.5 ( range 1 3 ) . all patients were discharged uneventfully after the procedure without any immediate adverse events ( aes ) . one patient developed obstructive jaundice due to a fibro - inflammatory bile duct stricture at the level of prior rfa that manifested 3 days after biliary stent removal ( approximately 6 weeks after the rfa ) and has required ongoing endobiliary stent therapy in excess of 3 months . 3 patients had visual and histologic evidence of complete eradication ; the patient with a focus of adenocarcinoma who declined surgery developed overt invasive ampullary cancer . video 1 this footage consists of 2 video clips demonstrating catheter - based rfa of intraductal ampullary adenoma although endoscopic ampullectomy is the preferred treatment for noninvasive ampullary lesions with a success rate reported as high as 92 % 10 , biliary extension of neoplasm represents a significant obstacle to endoscopic eradication . exposure and eversion of the adenoma through a biliary sphincterotomy to allow resection or ablation has been described in amenable cases 5 11 12 . however , broad adenomatous involvement of the distal bile is associated with limited treatment success ( < 50 % ) and has been considered an indication for surgical resection 5 . based on its ease of use and the ability to precisely position the probe within the distal duct , radiofrequency ablation may represent the first viable treatment adjunct for this challenging scenario . to date , only single case reports of rfa for benign ampullary lesions have been described ; we aimed to expand our understanding of this technology by presenting our experience in 5 patients . catheter - based rfa was technically successful in all cases , and based on short - term follow up in a small sample , may be safe and clinically effective . however , because rfa induces thermal injury and subsequent necrosis of the bile duct wall and beyond , several safety concerns exist . first , while rfa has been associated with a favorable safety profile when applied to malignant biliary strictures 1 2 3 4 , it remains unclear whether rfa in the intra - pancreatic portion of the bile duct without the protective buffer of a surrounding tumor especially in the vicinity of the pancreatic orifice will be associated with an increased risk of pancreatitis . until additional data on the risk of post - ercp pancreatitis in this context if the pancreatic and biliary orifices are in close proximity , especially if adenoma appears to involve the pancreaticobiliary septum , it may be best to perform the rfa adjacent to a guidewire which has already been placed in the pancreatic duct ( subsequently guaranteeing pancreatic access for stent placement ) rather than adjacent to a plastic pancreatic stent which may be damaged or even fractured during rfa . another safety concern is the development of clinically important post - rfa biliary strictures that occurred in 1 of our patients , akin to what has been observed in the esophagus after rfa of barrett s epithelium 13 . this concern is particularly relevant in the context of benign ampullary disease in which patients do not typically undergo long - term stent placement , as is the case when rfa is performed for palliation of malignant strictures . along these lines , until additional data are available , we have attempted to minimize rfa across the cystic duct takeoff to avoid thermal injury - related obstruction of the cystic duct , which has intentionally been induced by electrohydraulic lithotripsy to treat refractory bile leak 14 . in our series , rfa appears to have provided effective adjunctive therapy in all 4 cases of benign pathology but was ineffective in the setting of early adenocarcinoma , underscoring the concept that surgical resection remains first - line therapy for ampullary cancer ( our patient declined surgery and chemoradiation ) . despite the apparent effectiveness for benign lesions , it is important to consider that intrabiliary extension is often nodular in nature , leading to heterogeneous contact between the rfa probe and the target tissue ; this may lead to incomplete therapy and/or an increased risk of buried neoplasm as is the concern when rfa is used to treat nodular barrett s esophagus . moreover , it can be technically challenging to ensure circumferential contact of the probe and the target tissue within a dilated bile duct , even when luminal air is suctioned to induce collapse of the duct around the probe . in these cases , a balloon - based rfa device that flattens nodular tissue and maximizes treatment contact may be of value . an additional consideration is that the proximal extent of neoplasm is often difficult to assess cholangiographically and the role of cholangioscopy to guide probe placement should be further explored . prospective studies are necessary to evaluate these issues and determine the long - term effectiveness of this modality . in summary , catheter - based rfa after endoscopic resection of ampullary lesions that extend up the bile duct is technically feasible . concerns regarding injury to the pancreas and bile duct as well as incomplete treatment of nodular target tissue exist and will be addressed by additional clinical experience and research . OUTPUT:

background and study aims : catheter - based radiofrequency ablation ( rfa ) delivered during endoscopic retrograde cholangiopancreatography ( ercp ) may represent a viable treatment option for intraductal extension of ampullary neoplasms , however , clinical experience with this modality is limited . after ampullary resection , 4 patients with intraductal extension underwent adjunctive rfa of the distal bile duct . all patients received a temporary pancreatic stent to reduce the risk of pancreatitis , as well as a plastic biliary stent to prevent biliary obstruction . three patients were treated for adenoma and 1 for adenoma with a focus of adenocarcinoma . during a short follow - up period , 3 patients experienced complete eradication of the target lesion , whereas the patient with a focus of adenocarcinoma had progression to overt invasive cancer . there were no immediate adverse events . one patient developed a post - rfa bile duct stricture , which has required additional endoscopic therapy . catheter - based rfa of ampullary lesions that extend up the bile duct is technically feasible . additional research is necessary to understand the risks and long - term benefits of this technique .

PubMed_Summ6556

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: reproductive tract infections ( rtis ) , including both sexually transmitted infections ( stis ) and non - sexually transmitted infections ( non - stis ) of the reproductive tract are responsible for major ill - health throughout the world.(1 ) world health organization estimates that each year there are over 340 million new cases of sexually transmitted infections in which 7585% occur in developing countries . in india alone , 40 million new cases emerge each year.(2 ) a majority of women continue to suffer from rtis leading to complications like pelvic inflammatory disease ( pid ) , infertility , cervical cancer , postabortal , and puerperal sepsis , chronic pelvic pain , and ectopic pregnancy . rtis in many cases are asymptomatic among women , making their detection and diagnosis difficult.(3 ) an effort has been made in this regard to detect rti cases among the women in the field practice area of urban health training centre ( uhtc ) , hubli , karnataka . the objective of the study was to know the prevalence of rtis among the reproductive age group women and the socio - demographic factors influencing the occurrence of the disease . this study was undertaken in the field practice area of uhtc , hubli , and reproductive age group women of 1545 years were identified for the study purpose . it is a cross - sectional time bound study , conducted from september 2003 to august 2004 . the sample size 656 was calculated by taking into consideration 19% of women under 1545 years in urban community , at 95% confidence interval and 3% permissible error covering 1.96 under normal curve . all houses in the field practice area were numbered by using a random numbering table . houses were selected on the basis of a simple random sampling technique until 656 women of the reproductive age group were covered in 520 families . a pretested structured pro forma was used to interview the women about their socio - demographic , reproductive history , current , and past rti symptoms . the syndromes related to rti as recommended by government of india , ministry of health and family welfare , for management of rtis / stds were considered . all 656 women were given referral slips and encouraged after counseling to attend for clinical examination and laboratory tests in uhtc . in the center , per speculum examination was done , and vaginal and endocervical swabs were taken . in unmarried women , women with menstrual bleeding and women in their postpuerperal period at the time of clinical examination were asked to come for gynecological examination after cessation of menstrual bleeding or lochia . blood sample for a serological test to diagnose syphilis was taken from every respondent after written consent and counseling . wet mount microscopy of vaginal secretions was done to detect trichomonas vaginalis . immediately after per speculum examination , the vaginal and endocervical swabs were sent to microbiology department , karnataka institute of medical sciences ( kims ) , in a cold box , gram stained , and inoculated in suitable media like chocolate agar and thayer martin medium for gonorrhea and sabouraud dextrose agar ( sda ) media for candidiasis . for diagnosis of bacterial vaginosis ( bv ) any three out of four criteria were taken as positive:(4 ) watery vaginal discharge.vaginal ph more than 4.5 using ph indicator paper.amine odour test positive ( odour described as fishy after addition of 10% koh).clue cells in gram 's stained vaginal smear under microscopy amine odour test positive ( odour described as fishy after addition of 10% koh ) . statistical tests like proportions , z - test , and chi - square test were used . data were tabulated on microsoft excel sheets and analyzed using software epi info version 6 . statistical tests like proportions , z - test , and chi - square test were used . data were tabulated on microsoft excel sheets and analyzed using software epi info version 6 . the present study revealed that 265 women were found to be suffering from rti based on their symptoms , giving a prevalence of 40.4% [ table 1 ] . distribution of women according to rti symptoms table 1 shows that a majority of women , 215 ( 32.7% ) , complained of abnormal vaginal discharge followed by lower backache in 206 ( 31.4% ) and lower abdominal pain in 154 ( 23.5% ) women ( n=656 ) . table 2 shows on clinical examination that 245 ( 37.35% ) women had significant clinical findings suggestive of rti in which 242 ( 36.9% ) women had vaginitis , followed by pid in 205 ( 31.25% ) women ( n=656 ) . distribution of women according to the clinical findings of rti out of 656 women taken for the sample study , 265 women had symptoms of rti and 391 women had no symptoms of rti . among symptomatics , 192 ( 72.4% ) women ( n=265 ) had positive clinical signs and among asymptomatics , 53 women ( 13.5% ) ( n=391 ) had signs of rti on clinical examination with majority of women having vaginitis , cervicitis , and tenderness in the fornix . based on laboratory findings , 225 women were positive for rti giving a prevalence of 34.3% in which a majority of women were positive for candidiasis 105 ( 16.01% ) followed by bacterial vaginosis 82 ( 12.5% ) , trichomoniasis 28 ( 4.27% ) , syphilis 10 ( 1.52% ) , and gonorrhea 0% [ table 3 ] . distribution of women according to laboratory investigations of rti a total of 4.12% women had mixed infections with candidiasis , bacterial vaginosis , and gram - negative organisms ( n=656 ) [ table 3 ] . out of 265 symptomatic women , 192 women had positive clinical signs in which 178 women ( 92.7% ) ( n=192 ) had positive laboratory tests , with majority having candidiasis . out of 391 asymptomatic women , 53 women had positive clinical signs and 338 women with no clinical signs of rti , in which 22 women ( 6.5% ) ( n=338 ) had a positive laboratory test with 18 women being positive for candidiasis by culture , and 4 women being positive for the venereal disease research laboratory ( vdrl ) test for syphilis . table 4 shows the trend of clinical findings of rti in relation to age with maximum prevalence between 20 and 29 years age group . sd ( 7.61 years ) . socio - demographic profile of the women in the reproductive age group of 15 - 45 years with rti signs it was found that the number of women 50% among muslims had rti compared to other religion ( p<0.001 ) [ table 4 ] . married women ( 43% ) had more rti compared to unmarried and divorced / separated women ( p<0.001 ) ; similarly the prevalence of rti increased with relation to married life from < 1 year ( 30.4% ) to > 5 years ( 51.75% ) [ table 4 ] . the prevalence of rti was common among illiterate women ( 46.5% ) and showed a decreased trend with an increase in level of education ( p<0.001 ) [ table 4 ] . it was found that 38% of women who were home makers had rti against 26% of employed women and 15% of students [ table 4 ] . the rti prevalence showed an increasing trend with the decrease in socioeconomic class where 82% of women belonging to the class v or lower socioeconomic group had rti ( p<0.001 ) [ table 4 ] . it was found that 38% of women who used clothes during menstruation had rti against 15% of those who used sanitary pads [ table 4 ] . the prevalence of rti was 33% in women having children more than one and it increased with increase in parity ( p<0.001 ) [ table 4 ] . only 34% of women were using family planning methods and among them , the occurrence of rti was 84% in the women using intra uterine contraceptive device ( iucd ) ( p<0.001 ) [ table 4 ] . it was found that the prevalence of rti among pregnant women was 51% ( p<0.05 ) [ table 4 ] . from this study , the prevalence of rti was 34.3% based on the laboratory findings against 40.4% based on only the symptoms . it was observed that a majority of women , 215 ( 32.77% ) , complained of abnormal excessive vaginal discharge followed by lower backache 206 ( 31.4% ) and lower abdominal pain 154 ( 23.48% ) . where a majority of women , 53.4% , complained of abnormal vaginal discharge.(5 ) our study showed that a majority of women , 242 ( 36.9% ) , had vaginitis on examination followed by pid in 205 women ( 31.25% ) which is in accordance with the observation of garg et al . and singh et al . where a majority of women on clinical examination had vaginitis of 94.6% and 52.1% , respectively.(67 ) this study is in accordance with the observations made by parikh et al . and ranchan et al . , where the prevalence of rti on laboratory findings was 17% and 26.3% , respectively , with majority of women having candidiasis.(89 ) this study is also in accordance with prasad et al . where prevalence of syphilis was 1.5% and to garg et al . , where the prevalence of trichomonas vaginalis was 4.3%.(106 ) in this study maximum prevalence of rti was found in the reproductive age group women of 2029 years , which differs from the study of rathore et al . , where mean age of women with rti was 33.59 years.(11 ) it was found in the study that marital status and rti are related to each other , as married women who are leading active sexual life are having more chance of getting rti.(12 ) also with increased duration of married life , the risk of occurrence of rti is more , due to enhanced sexual activity.(10 ) the trend of increased rti with decreased educational status of women shows that illiterate women were more ignorant about the occurrence of rti with poor genital and menstrual hygiene and their health seeking behavior is also low.(11 ) in our study , the rti occurrence in unmarried women and students was mainly due to poor genital and menstrual hygiene . similarly , poor socioeconomic class contributes to increased occurrence of rti due to ignorance and economic backwardness.(13 ) women who used clothes during the menstrual period had increased risk of rti due to lack of genital and menstrual hygiene which facilitated growth of endogenous infections.(78 ) it was found in the study that there is association between parity of women and occurrence of rti which is statistically significant . women with more number of children are exposed to increased number of deliveries , contraceptive device , and gynecological surgeries which contributes to occurrence of rti in women.(12 ) this study is in accordance with rathore et al . , where 2.4% among nulliparous women had rti compared to 13% among primigravida and 28.5% among multigravida.(11 ) it was observed that 84% of women among iucd users had rti . iucd users are at more risk of acquiring rti as they are exposed to iatrogenic and exogenous infections.(10 ) it was found that 51% among pregnant women had rti . it is due to hormonal change , they are prone for endogenous infections like candidiasis and mixed infections.(14 ) this is in accordance with maitra et al . , where 1 out of 4 pregnant women had rti , with abnormal vaginal discharge being common symptom followed by pain during urination.(13 ) hence the study highlights the need for community - based studies requiring laboratory investigations with feasible tests to know the exact prevalence of the disease , as the self - reported morbidity alone can not measure the burden of any disease in the community to necessitate proper prevention and control measures . this study will serve as a reference for researchers interested in the field of rti / sti epidemiology , who may in future take up similar studies to compare and highlight the performance of reproductive and child health programme ( rch ) over the years in combating this disease . OUTPUT:

background : reproductive tract infections ( rtis ) is a global health problem including both sexually transmitted infections ( stis ) and non - sexually transmitted infections ( non - stis ) of the reproductive tract . rti / sti is an important concern , as it possess risk for human immunodeficiency virus transmission . hence a community study was done in hubli , in terms of active search of the cases based on the symptoms , clinical examination , and feasible laboratory tests along with providing treatment , counseling , and follow-up.objectives:the objective was to know the prevalence of rtis among the reproductive age group women and the socio - demographic factors influencing the occurrence of the disease.materials and methods : a cross - sectional study was done using a simple random sampling technique to select households . a pretested structured pro forma was used to collect data on rtis from 656 women of 1545 years , residing in the field practice area . this was followed by clinical examination and collection of samples for laboratory tests in urban health training centre , attached to karnataka institute of medical sciences , hubli.results:the prevalence of rtis among the reproductive age group women was 40.4% based on their symptoms , with majority having abnormal vaginal discharge . the prevalence of rtis based on clinical finding was 37.4% with majority having vaginitis . the laboratory test revealed a prevalence of 34.3% with majority having candidiasis . the influence of socio - demographic factors like increased parity , poor socio - economic conditions , poor menstrual hygiene , illiteracy has its direct effect on occurrence of rti in the community.conclusion:this depicts that whereever possible , clinical and laboratory findings should support self - reported morbidity to know the exact prevalence of any disease in the community .

PubMed_Summ6557

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the incidence of bladder forming a part of an inguinal hernia is 14% . with correct knowledge of anatomy and careful dissection , injuries to the bladder during hernia repair we hereby report a case where the patient first presented with a scrotal abscess and vesicocutaneous fistula after surgical repair of sliding hernia . a 65-year - old morbidly obese man underwent mesh hernioplasty for large right inguinal hernia . after removing the urethral catheter , he developed gradually increasing right scrotal swelling with fever . thereafter , he developed continuous urine leakage from the site of incision and drainage , figure 1 . we carried out a cystogram via the urethral catheter that revealed a fistulous communication between bladder and scrotal skin , figure 1 . , cystoscopy revealed normal anterior and posterior urethra , non - obstructing prostatic lobes and a defect in the anterior bladder wall with no evidence of mesh erosion . almost the whole of the bladder was lying in the right scrotum and densely adherent to the right testis and cord structures and mesh . there was a fistulous opening at the dome of the bladder wall well away from the mesh . our main concerns were inguinal hernia repair and creation of extraperitoneal space to reposition the bladder in the normal position , which was not possible without performing right high inguinal orchiectomy . hence , we performed right high inguinal orchiectomy and removal of mesh and extraperitoneal space was made to reposition the urinary bladder to its normal position . fistula opening was repaired in two layers and the bladder was put on continuous drainage via 20 french urethral catheter , figure 2 . post - operatively at 2 weeks , there was no urinary leak on cystogram and the urethral catheter was removed and normal voiding was restored . scars of previous surgery with vesicocutaneous fistula and cystogram showing contrast in the left hemiscrotum the entire urinary bladder lying in the scrotum , with the bladder re - positioned into the normal position levine coined the term scrotal cystocoele in 1951 for inguinoscrotal herniation of the bladder . urinary bladder herniations are usually diagnosed at the time of inguinal herniorraphy and are commonly repaired through the same incision . they are sometimes found incidentally during the evaluation of a patient with lower urinary tract symptoms and associated inguinal hernias . two - stage micturition is the classical symptom , with the second stage facilitated by some form of external pressure on the bladder . the para - peritoneal type is the most common type and the extra - peritoneal type is the least common . because imaging all patients with large hernias may not be cost - effective , imaging studies are performed only when bladder herniation is suspected . the diagnostic triad of lateral displacement of the distal one - third of the ureter , small asymmetric bladder and incomplete visualization of the bladder base on an intravenous urogram has been described by reardon and lowman . iatrogenic injury to the bladder during hernia repair can be due to multiple factors , such as an inexperienced surgeon in the early part of the learning curve or an obese patient with large hernial sac with unrecognized bladder component . in our patient , there could have been an injury to the bladder that was not recognized at the time of hernia repair , which led to subsequent scrotal abscess formation resulting in a vesicocutaneous fistula . if unrecognized , these usually present immediately after catheter removal , but presentation can sometimes be delayed in case the fistula is very small and there is no infravesical obstruction . management includes immediate repair in case it is recognized intraoperatively . in case of unrecognized injury and with delayed presentation , the first step is to put a wide caliber per urethral catheter followed by thorough evaluation with urine culture examination and cystogram . a small fistula can be healed with only continuous bladder drainage with per urethral catheter or preferably suprapubic cystostomy , provided lower tract infravesical obstruction has been ruled out . a larger fistula needs open surgical management . careful dissection is needed in the extraperitoneal space while separating the sac from cord structures as the bladder forms a part of the posterior wall of the sac . after completing bladder dissection , the fistula is repaired in two to three layers and an adequate space is created in the extraperitoneal plane to reposition the bladder . sometimes , large hernias could be treated by resection of the herniated bladder as described by thomas and gomella . in our case , the whole bladder was lying in the scrotum and extensive adhesions were present between the cord structures and the bladder . high inguinal orchiectomy was performed to create space for the bladder and for proper closure of the inguinal canal . urinary bladder rarely forms a part of an inguinal hernia and , with the correct knowledge of anatomy and careful dissection injuries to the bladder during hernia repair , surgery can be prevented . surgically creation of an extraperitoneal space for bladder repositioning is of paramount importance , sometimes needing inguinal orchiectomy in the elderly . OUTPUT:

sliding inguinal hernias are usually direct inguinal hernias containing various abdominal viscera . the incidence of bladder forming a part of an inguinal hernia , called as scrotal cystocele , is 14% . the risk of bladder injury is as high as 12% when repairing this type of hernia . this case report emphasizes this aspect in a 65-year - old man who presented with urinary leak through the scrotal wound following right inguinal hernia repair .

PubMed_Summ6558

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: unlike tears and ganglion cysts of the anterior cruciate ligament ( acl ) , mucoid degeneration is a less - understood entity . the injury or loss of functional synovial lining protecting the acl is the primary lesion causing mucoid degeneration of acl though there was no significant preceding trauma that patients can relate to current symptoms.1 but the symptomatology , mri findings , and arthroscopy appearance are consistent.2 the excision of the degenerated acl has been the treatment of the choice , the authors believe that if the taut and hypertrophied acl were to be debulked and notchplasty done , full extension could be achieved without having to excise the entire acl . the purpose of this study was to describe the clinical characteristics and diagnosis of mucoid degeneration of the acl and to assess the outcomes of arthroscopic treatment in a series of 20 patients . the mean age was 42.2 years ( range 28 - 52 years ) in males and 39.4 years ( range 30 - 54 years ) in females . all the patients had clinical symptoms of central knee pain behind patella without any prior trauma ( 18 patients on terminal extension and 2 patients on terminal flexion ) . in four patients , there was mean flexion deformity of 6. the type of activity performed was : physically active like running , sports , and army training ( n=6 , 30% ) ; moderately active doing routine work ( n=12 , 60% ) ; and sedentary ( n=2 , 10% ) . the symptoms started insidiously , had a mean duration of 21 months ( range 1247 months ) without preceding significant trauma . eighteen patients had extension deficit and two patients had limited flexion.34 there was medial joint pain in two patients . anterior lachman and anterior drawer test showed firm endpoint in all patients , with + 1 laxity in three patients . all patients were treated with nonsteroidal anti - inflammatory drugs and physiotherapy for a minimum of 2 months before contemplating magnetic resonance imaging ( mri ) and treatment . plain roentgenograph of both the knees was done with anteroposterior weight bearing , lateral and skyline views . radiographic diagnosis was made only when all three key criteria56 were met : ( 1 ) abnormally thickened and ill - defined acl , ( 2 ) maintenance of normal orientation and continuity , and ( 3 ) increased intraligamentous signals ( intermediate signal intensity on t1-weighted images and high signal intensity on t2-weighted and proton density weighted images [ figure 1 ] . proton density show increasing intraligamentous signal intensity of the anterior cruciate ligament over the left knee arthroscopy was performed by use of a 30 lens through standard anterolateral and anteromedial portals . all compartments were explored to evaluate the state of menisci , ligaments , and cartilage . the chondral lesion of each patient was described according to the outerbridge classification.7 the locations of the lesions on the articular surfaces of the patella , trochlea , medial femoral condyle , lateral femoral condyle , medial tibial plateau , and lateral tibial plateau were recorded . bulk specific to anteromedial ( am)posterolateral ( pl ) bundles of acl , its color , and its tautness hooked with probe were recorded . impingement of acl fibers to lateral wall of intercondylar notch , and lateral compartment during flexion extension maneuver were recorded [ figure 2 ] . arthroscopic examination of a left knee , showing impingement ( arrow ) of hypertrophied posterolateral portion of acl to lateral wall and roof of intercondylar notch during extension the aim of surgery was to remove as much of the degenerative mass as possible without having to sacrifice the entire acl . thus , the remaining acl consisted of some intact anteromedial or posterolateral portion of the acl interspersed with degenerate acl tissue . care was taken to see that this remaining acl had intact attachment to the femoral condyle and did not impinge on the roof or lateral wall of the notch [ figure 3 ] . by use of basket forceps , the materials were stained with h and e and then with mucoid tissue - specific alcian blue [ figure 4 ] . in knees without notch narrowing , debridement of the hypertrophied acl was performed first beginning with the removal of small osteocartilaginous fragments from the upper portion of the lateral wall and roof by use of a 6.4-mm curved osteotome . this allowed easier inspection of the inner space between the acl and the lateral wall , and accurate removal of impinging structures . we decompressed the lateral wall and roof from anterior to posterior while performing a flexion extension maneuver with a 4.5-mm motorized bur and curette . care was taken to remove all visible impinging structures in the posterior portion of the notch . copious debridement of mucoid hypertrophied lesions of the acl was performed by use of basket forceps as well as a 4.2-mm motorized shaver . some of the mass was removed by first teasing between the anterior fibers of the acl using a probe and then removing it with an arthroscopy grabber . the major posterior portion of the mass was removed using the basket punch ( acufex ) introduced through the anteromedial portal , with the arthroscope through the anterolateral portal . the probe was used to assess the tension and the clearance of the remaining acl and the notch . arthroscopic examination of a left knee , showing impingement of hypertrophied posterolateral portion of acl to lateral wall and roof of intercondylar notch during extension photomicrograph showing distorted collagen fibers with scanty myxomatous degeneration ( h and e stain , 40 ) during the followup , no immobilizer or brace was used except in one patient who had undergone acl reconstruction . all other patients were encouraged to perform daily active range of motion exercises with quadriceps strengthening and allowed to carry full weight bearing loads immediately . preoperative central knee pain on terminal extension was moderate in 10 knees and severe in 8 knees . postoperatively , 12 knees showed complete pain relief and 7 showed pain improvement by at least 3 visual analogue scale ( vas ) grades , for a total of 16 had well to excellent results regarding pain on terminal extension . preoperative average international knee documentation committee ( ikdc ) score8 was 33.6 which improved postoperatively to the average 73.2 . the flexion deformity was found in four patients , with a mean angle of 6. postoperatively , it improved significantly with no deformity . mris of all 20 patients showed an acl that appeared bulky , occupying almost the entire intercondylar notch , with a marked increased signal , particularly in the t2-weighted images , and with a mass - like configuration intertwined with its fibers with celery stalk sign.910 on mri , 6 patients had medial compartment arthritis , 4 patients had torn medial meniscus grade iii , and 1 patient had grade ii tear in posterior horn of lateral meniscus . arthroscopy showed osteoarthritic changes in 9 knees and concomitant degenerative pathologies in 4 knees ; these included meniscal tears and synovitis . six ( 30% ) degenerative lesions of the medial meniscus and 1 ( 0.5% ) degenerative lesion of lateral meniscus were noted . three femoropatellar cartilaginous lesions ( 15% ) , 4 ( 20% ) medial femorotibial lesions ( two grade 1 , one grade 2 , one grade 3 ) , and 1 ( 0.5% ) lateral femorotibial lesion grade 1 were observed . it filled the entire intercondylar notch and was unusually taut , toward 90 of flexion in 2 patients with hypertrophied am bundle of acl , and taut in extension in rest of the patients with hypertrophied pl bundle of acl . the posterolateral portion of the acl bulged into the lateral compartment in extension impinging in the notch . by flexion when each knee was brought into full extension , impingement of the hypertrophied acl to the lateral wall and roof of the intercondylar notch was observed.1112 impingement was particularly apparent in knees with a severely hypertrophied acl or narrowed notch , as well as limited knee joint extension . arthroscopic treatment consisted of debridement of the afflicted portion of the acl in all cases . in six knees with evident notch narrowing , notchplasty was performed first . because yellowish degenerative hypertrophied lesions were entangled around the posterolateral acl fibers , the anteromedial portion was retained in 18 patients . in 2 patients , posterolateral portion of acl was retained because of hypertrophied degenerated am bundle of acl . although in one patient after debridement , the remaining portion of the acl was not enough to stabilize the knee , so we had to reconstruct the acl with hamstring graft which is comparable with the study by lintz et al.(7%).1 at an average followup time of 24 months ( range 12 - 36 months ) , all except two patients had a full range of painless motion . it was 1 grade higher as compared with the opposite knee in 14 knees and the same as the opposite knee in 6 knees . all patients had a firm endpoint on lachman test without any symptoms of instability , inferring some intact portion of the acl between the tibia and the femur . two patients had pivot shift positive + 1 with glide and 18 patients had negative pivot shift . a soft endpoint on anterior translation would imply no intact acl tissue in the intercondylar area . the histopathologic appearance and reports of the biopsy specimens were consistent with mucoid degeneration of the acl . regression of the size and bulkiness of the treated acl was seen , with the t2-weighted images showing decreased signal with some intact acl fibers between the tibia and femur . the mucoid hypertrophy of the acl is a rare condition found in middle - aged individuals . mucoid degeneration of anterior cruciate ligament is not an uncommon pathology , but is often unknown . according to bergin et al.6 and salvati et al.,13 reported its occurrence as 2 and 5% , respectively , of knee where mri was done . our findings were incidental in initial 4 cases where clinical and radiological findings were not correlated as radiologist reported partial rupture of acl only . in practice and in the literature , it is often confused with a diagnosis of partial acl rupture . it becomes apparent in two subpopulations of patients . the first group is younger , active , athletic , in whom we can assume an acl mechanism affected by real trauma or repeated microtraumas causing an early lesion.14 the second group is older and presents with progressive degenerative acl lesions , with frequent concomitant degenerative meniscal lesions . the pathogenesis of mucoid degeneration is unclear , but injury , ganglion cysts , and degenerative process leading to loss of synovial lining have been implicated as the most likely etiologic factors in the production of this change . in younger group the possible cause of repetitive minor trauma is impingement of the acl to the lateral wall and roof of the narrow notch , which has been reported to be more common in female patients.15 in second group there is subtle alterations in joint kinematics due to osteoarthritis , meniscal tears , and other degenerative changes , leading to stretching of cruciate ligaments . fealy et al.16 suggested that knee pain on flexion might be caused by tensioning of the diseased am bundle of the acl . for kumar et al.18 the pain is attributable to the effect of the acl mass in the posterior notch . hsu et al.19 and kim et al.11 attribute it to incarceration of the pathological acl in the posterior femoro - tibial compartment . however , we found that the hypertrophied acl bulged into the lateral compartment , impinged on the lateral tibiofemoral joint , and caused an extension or flexion block , depending on the position of the impingement in the lateral tibiofemoral joint . we believe the most important source of pain is mechanical impingement , associated with unique function of the acl in providing nociceptive sensory signals . it is mentioned elsewhere only by mcintyre et al.2 who reported one case of atraumatic acl rupture at 1 postoperative year after partial resection . our results indicate that postoperative laxity , largely asymptomatic , can increase anterior laxity over time and evoke instability . mucoid hypertrophy of the acl should be clinically suspected in elderly person presenting with persistent knee pain on terminal extension without preceding trauma , especially when associated with extension deficit , which is more common in elderly individual with degenerated knee . arthroscopic debridement of mucoid hypertrophy of the acl in conjunction with notchplasty can effectively provide symptomatic improvement without instability . OUTPUT:

background : mucoid degeneration of the anterior cruciate ligament ( acl ) is a less understood entity . the purpose of this study was to diagnose mucoid degeneration of anterior cruciate ligament and to assess the effectiveness of arthroscopic treatment in these patients.materials and methods : between december 2007 and november 2011 , 20 patients were diagnosed to be suffering from mucoid degeneration of anterior cruciate ligament ( acl ) on the basis of magnetic resonance imaging ( mri ) , histopathology , and arthroscopy findings . 12 patients were males and 8 patients were females , with mean age of 42.2 years for males ( range 28 - 52 years ) and 39.4 years for females ( range 3054 years ) . they presented with pain on terminal extension ( n=10 ) and on terminal flexion ( n=2 ) without history of significant preceding trauma . mri showed an increased signal in the substance of the acl both in the t1- and t2-weighted images , with a mass - like configuration that was reported as a partial or complete tear of the acl by the radiologist . at arthroscopy , the acl was homogenous , bulbous , hypertrophied , and taut , occupying the entire intercondylar notch . a debulking of the acl was performed by a judicious excision of the degenerated mucoid tissue , taking care to leave behind as much of the intact acl as possible . releasing it and performing a notchplasty treated impingement of the acl to the roof and lateral wall . in one patient , we had to replace acl due to insufficient tissue left behind to support the knee.results:good to excellent pain relief on terminal flexion extension was obtained in 19 of 20 knees . the extension deficit was normalized in all knees . lachman and anterior drawer test showed a firm endpoint in all , and 85% ( n=17 ) showed good to excellent subjective satisfaction.conclusions:mucoid hypertrophy of the acl should be suspected in elderly persons presenting pain on terminal extension or flexion without preceding trauma , especially when there is no associated meniscal lesion or ligamentous insufficiency . they respond well to a judicious arthroscopic release of the acl with notchplasty .

PubMed_Summ6559

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: prostate cancer ( pca ) is the fifth - most - common cancer among men in singapore , with an age - standardized rate of 17.4 cases per 100,000/y , and the incidence has been increasing steadily over the past 35 years . the average annual rate of increase between 1968 and 2002 was 5.6% , with the past 10 years showing a somewhat steeper increase . pca could become a major public health issue with the aging of our country 's population . during the past decade , a considerable number of modifications have been made to improve the technique of pca biopsy . total prostate volume is also an important factor , and higher pca detection rates have been reported in men with smaller prostates . the current concept regarding prostate biopsy is that systematic sextant biopsies , even when directed laterally , do not provide adequate prostate sampling . several extended biopsy techniques have been introduced to improve the pca detection rate compared with that of systematic sextant biopsy . these techniques vary in the number of cores taken and the location from which samples are obtained , but none have taken into consideration the age of the patient or the volume of the prostate gland . life expectancy is based on patient age and has a pivotal role in diagnosis and treatment . over - diagnosis of clinically insignificant pca is considered a major potential drawback of prostate - specific antigen ( psa ) screening , especially in older patients . pca volumes to be detected can be larger in older patients , and thus fewer cores are needed , which reduces over - diagnosis of tumors ( insignificant pca ) at biopsy . on the basis of the above information and using data from the european prostate cancer detection study , the use of the vienna nomogram ( vn ) prostate biopsy model was developed . this model indicates the optimal number of cores based on patient age and total prostate volume . thus , the use of the vn should result in higher pca detection rates , especially in younger patients and those with larger prostates , and , at the same time , should avoid the detection of insignificant cancers , especially in older patients . , we used the vn to determine the efficacy of this model in the detection of pca in our local population . we also assessed the incidence of complications due to the use of such a template . with approval from our institutional review board , 120 men were enrolled prospectively between january 2006 and june 2007 . the study population consisted of consecutive referrals for evaluation of elevated psa scores ( > 4 ng / ml ) and/or abnormal digital rectal examination ( dre ) findings . all patients underwent transrectal ultrasound ( trus ) examination of the prostate , which was followed by prostatic biopsies . patients were excluded from the study if they had a history of pca , acute or chronic prostatitis , histologic evidence of prostatic intraepithelial neoplasia of any grade , urinary retention , indwelling urinary catheter , or confirmed urinary tract infection . before the procedure , patients were observed for a minimum of 4 hours after the procedure for immediate complications and were given advice to return to hospital if they had delayed complications . in each of the 120 patients , 6 to 18 cores were taken from the peripheral zone for trus - guided biopsy , as indicated by the vn ( table 1 ) . each biopsy core was labeled according to location on the prostate and was sent separately for histologic review . biopsy tissue was considered positive if adenocarcinoma was diagnosed , and the number of positive cores , the gleason score , and the grade were reported . all other findings ( high - grade prostatic intraepithelial neoplasia , atypia , and dysplasia ) were considered negative . in this study , trus - guided biopsy performed according to the vn protocol was restricted to the first biopsy . further management was dependent on individual urologists , and complication rates were subsequently updated by chart reviews . chicago , il , usa ) and stratified for age , psa , and trus findings . the patients ' mean age was 62.68.3 years ( range , 40 - 86 years ) . the mean psa score was 13.42 ng / ml , and the mean number of cores obtained was 9.683.1 . according to the vn , 27 out of a total of 120 patients had pca , for a detection rate of 22.5% . in the group of patients with psa scores < 10 ng / ml , the detection rate was 14.9% ( 14 of 94 patients ) . the group of patients with psa scores > 10 ng / ml had a detection rate of 50% ( 13 of 26 ) . histopathologic features presented on prostate biopsy in 27 pca patients whose gleason scores were 3 + 3 , 3 + 4 , 4 + 3 , 4 + 4 , and 4 + 5 in 11.1% ( 3 patients ) , 37.0% ( 10 ) , 29.6% ( 8) , 18.5% ( 5 ) , and 3.7% ( 1 ) respectively ( fig . two of these cases were diagnosed on repeat trus biopsy , and two were discovered on transurethral prostatectomy , for a false - negative rate of 3.3% . four patients ( 3.3% ) had bleeding per rectum : one of them required adrenaline injection , another required hemostasis under spinal anaesthesia , and the other two had rectal bleeding that resolved spontaneously without further intervention . detection rates of pca have varied , and review of the literature from several asian countries found that the detection rate of pca in patients with raised psa scores is in the range of 14.6% to 26.5% . the austrian study that used the vn had a detection rate of 36.7% ( table 2 ) . data from other countries in asia uniformly reported a low cancer detection rate in connection with psa scores ranging from 4 to 10 ng / ml . in comparison , the detection rate of pca with psa scores ranging from 4 to 10 ng / ml has always been about 25% in western countries . the low positive predictive value of elevated psa scores in asian countries may be due to the low incidence of pca in this geographic area , but it also may be partly due to inadequate sampling . recent reports in the literature have queried the adequacy of sextant biopsy for the detection of small nonpalpable pca . in our study , we used the vn , and the positive predictive value was 22.5% , a value that is comparable to other published data from asian countries . the key to higher pca detection rates with the use of the vn is varying the number of cores according to prostate volume . because larger prostate glands can result in more sampling errors during biopsy the studies by remzi et al . and ung et al . stressed the importance of prostate volume in pca detection and showed that detection rates are , in fact , dependent on prostate volume . . also found that the most important factor in a failure to diagnose pca at the primary screening was a large prostate volume . evaluating the variation of pca detection in relation to prostate size through random systematic sextant biopsies , uzzo et al . found that 23% of the patients had pca in a large prostate ( > 50 ml ) , whereas 38% of patients with smaller prostates had pca ( p<0.01 ) . although a study by lecuona and heyns found that the detection rates for the vn and an eight - core prostate biopsy were similar , the detection rate in the vn group was higher for patients with larger prostate volume ( > 50 ml ) . thus , the vn could be useful in patients with larger prostates in which potential undersampling could occur . the rationales for using age as one of the parameters to determine the number of biopsy cores taken are twofold : first , younger men have a longer life expectancy , which makes even smaller cancers clinically significant , and , thus , more cores are needed ; and , second , older men may require fewer biopsy cores to avoid oversampling and overtreatment . if the time to critical pca volume is less than life expectancy , there might be no need for pca detection , as these pcas will be clinically insignificant . standard sextant biopsies have reported high false - negative rates of 15% to 28% . by combining systematic and target sampling , the advantages of using a vn are , first , higher pca detection rates , especially in younger patients and larger prostates ; second , at the same time , the avoidance of detection of insignificant cancers , especially in older patients ; and , third , the fact that it provides urologists with a clear and fixed number of biopsy cores on the basis of patient age and prostate volume . in our study , the complication rate was low ( 7.5% ) . this rate was comparable to the rates in large - scale studies looking at morbidities of trus prostatic biopsy . moreover , our complication rate was low despite our having performed more biopsies on each patient ( than we would have with the sextant biopsy ) . with the use of the vn , our pca detection rate of 22.5% is comparable to published data for asian patients . the nomogram offers an easy tool with which to select the optimal number of prostate biopsy cores on the basis of patient age and total prostate volume . with this biopsy strategy OUTPUT:

purposethe purpose of this study was to determine the efficacy of the vienna nomogram prostate biopsy model in the detection of prostate cancer in our local population . we also assessed the incidence of complications from using such a template.materials and methodsfrom january 2006 to june 2007 , 120 men with either elevated prostate - specific antigen ( psa ) scores ( > 4 ng / ml ) and/or abnormal digital rectal examination were enrolled prospectively to undergo extraction of 6 to 18 cores for transrectal ultrasound - guided prostate biopsy , as indicated by the vienna nomogram.resultsthe mean age was 62.68.3 years ( range , 40 - 86 years ) . the mean psa score was 13.42 ng / ml . the mean number of cores obtained was 9.683.1 . according to the vienna nomogram , 27 out of a total of 120 patients had prostate cancer , for a detection rate of 22.5% . in the group of patients with psa scores < 10 ng / ml , the detection rate was 14.9% ( 14 of 94 patients ) . the group of patients with psa scores > 10 ng / ml had a detection rate of 50% ( 13 of 26 ) . the complication rate in our study was 7.5%.conclusionswith the use of the vienna nomogram , our prostate cancer detection rate is comparable to previously published data for asian patients . this nomogram offers an easy tool with which to select the optimal number of prostate biopsy cores to be taken on the basis of patient age and total prostate volume . with this biopsy strategy , we also have found that the complication rate from prostate biopsy is low .

PubMed_Summ6560

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: selective laser trabeculoplasty ( slt ) is a new and promising treatment that uses the 532-nm frequency - doubled q - switched neodymium : yytrium aluminum garnet laser . slt was developed to selectively target pigmented trabecular meshwork ( tm ) cells without causing thermal or collateral damage to the nonpigmented cells or structures of the tm.1 clinical trials of slt have been encouraging , with reasonable response rates , effective intraocular pressure ( iop ) reduction and minimal side effects.25 comparable studies have shown slt to be as effective as argon laser trabeculoplasty ( alt),6 while histological investigations have demonstrated less damage to the ultrastructure of the tm.78 as a result of these studies , slt has been advocated as a treatment for the management of open - angle glaucoma ( oag ) with a role as a possible primary treatment.3 in the current study , we assess the iop lowering effect and the complications of slt in egyptian patients with primary open - angle glaucoma ( poag ) . sixty - five patients ( 106 eyes ) were enrolled in this prospective study from june 2007 to january 2009 . patients with a diagnosis of oag were considered eligible for this study if they were newly discovered on no previous medication ( primary group of 41 eyes [ group 1 ] ) , or had confirmed glaucoma poorly controlled on medications , or requesting a decrease number of medications ( adjunctive group of 65 eyes [ group 2 ] ) . patients were excluded from the study if they had evidence of glaucoma other than oag ( angle closure , inflammatory , or neovascular ) in the study eye , were younger than 18 years , had any ocular condition in the study eye that hindered adequate visualization and treatment of the tm , ( 4 ) had prior glaucoma surgery in the study eye . preoperative assessment included ophthalmic examination snellen visual acuity , iop measurement by goldmann applanation tonometry , slit - lamp examination and gonioscopy , and funduscopy with evaluation of cup : disc ratio and pallor . at least two preoperative iop readings were taken within 2 weeks before the laser treatment was performed . a drop of miotic ( pilocarpine nitrate 2% ) and brimonidine tartrate 0.2% ( alphagan ; allergan inc . , irvine , ca ) were installed in the eye before laser treatment to assist in visualization of tm and to prevent iop spikes . the procedure was performed with topical benoxinate hydrochloride 0.4% for anesthesia . with the patient seated at the laser slit - lamp system , a goldmann three - mirror goniolens or latina lens was placed on the eye with methylcellulose 1% . patients were treated with the ellex , solo slt laser ( ellex medical pty . ltd , adelaide , australia ) a frequency - doubled q - switched nd : yag laser emitting at 532 nm with a pulse duration of 3 nsec and a spot size of 400 m , coupled to a slit - lamp delivery system . a low - power helium neon laser served as an aiming beam to provide easy targeting of the treatment area . if cavitation bubbles appeared the laser energy was reduced by 0.1 mj until only a few bubbles formed and treatment was continued at this energy level . if no cavitation bubble was observed , the pulse energy was increased by 0.1 mj until bubble formation and then decreased as described above . approximately 100 adjacent , but nonoverlapping , laser spots were placed over 360 of the tm . immediately after the laser treatment , prednisolone acetate ( 1% ) drops were administered once in the treated eye then three times daily for 3 days . the same preoperative antiglaucoma medication regimen was continued until the second postoperative visit ( 1 week ) . patients were evaluated at 1 day , 1 week , 2 weeks , 3 weeks , 4 weeks , and at 3 , 6 , 12 and 18 months . at each visit , the visual acuity and iop were measured , and slit - lamp examination of the anterior segment was performed . gradual reduction of antiglaucoma medications was initiated 1 week following the procedure , after ensuring an adequate pressure drop . combined therapy was considered two medications and each medication was decreased separately . medically necessary medication changes were made at the physician 's discretion . data are described are range , mean standard deviation , frequencies ( number of cases ) and relative frequencies ( percentages ) as appropriate . comparison of iop over the study period was performed with one - way analysis of variance ( anova ) with multiple comparisons post hoc for the two groups . comparison of the number medications was performed with the kruskal - wallis analysis of variance ( anova ) test with multiple comparisons post hoc for the two groups . a probability value ( p - value ) less than 0.05 was considered statistically significant . all statistical calculations were performed with microsoft excel version 7 ( microsoft corporation , redmond , wa ) and spss ( statistical package for the social science ; spss inc . , chicago , il ) version 13 for microsoft windows , arcus quickstat ( biomedical ) ( research solutions , cambridge , uk ) . the procedure was performed with topical benoxinate hydrochloride 0.4% for anesthesia . with the patient seated at the laser slit - lamp system , a goldmann three - mirror goniolens or latina lens was placed on the eye with methylcellulose 1% . patients were treated with the ellex , solo slt laser ( ellex medical pty . ltd , adelaide , australia ) a frequency - doubled q - switched nd : yag laser emitting at 532 nm with a pulse duration of 3 nsec and a spot size of 400 m , coupled to a slit - lamp delivery system . a low - power helium neon laser served as an aiming beam to provide easy targeting of the treatment area . if cavitation bubbles appeared the laser energy was reduced by 0.1 mj until only a few bubbles formed and treatment was continued at this energy level . if no cavitation bubble was observed , the pulse energy was increased by 0.1 mj until bubble formation and then decreased as described above . approximately 100 adjacent , but nonoverlapping , laser spots were placed over 360 of the tm . immediately after the laser treatment , prednisolone acetate ( 1% ) drops were administered once in the treated eye then three times daily for 3 days . the same preoperative antiglaucoma medication regimen was continued until the second postoperative visit ( 1 week ) . patients were evaluated at 1 day , 1 week , 2 weeks , 3 weeks , 4 weeks , and at 3 , 6 , 12 and 18 months . at each visit , the visual acuity and iop were measured , and slit - lamp examination of the anterior segment was performed . all ophthalmic medications were recorded before surgery and at each subsequent visit . gradual reduction of antiglaucoma medications was initiated 1 week following the procedure , after ensuring an adequate pressure drop . data are described are range , mean standard deviation , frequencies ( number of cases ) and relative frequencies ( percentages ) as appropriate . comparison of iop over the study period was performed with one - way analysis of variance ( anova ) with multiple comparisons post hoc for the two groups . comparison of the number medications was performed with the kruskal - wallis analysis of variance ( anova ) test with multiple comparisons post hoc for the two groups . a probability value ( p - value ) all statistical calculations were performed with microsoft excel version 7 ( microsoft corporation , redmond , wa ) and spss ( statistical package for the social science ; spss inc . , chicago , il ) version 13 for microsoft windows , arcus quickstat ( biomedical ) ( research solutions , cambridge , uk ) . one hundred and six eyes with oag were enrolled in the study and received 360 laser treatment of tm . females comprised 53% of the cohort and the mean age of the cohort was 53.2 years ( range , 18 - 78 years ) . mean preoperative iop was 19.55 4.8 mmhg which dropped significantly after 24 hours post - slt to 12.03 2.7 mmhg . iop was 14.32 3.0 mmhg , 14.72 2.1 mmhg , 15.16 3.6 mmhg and 16.03 2.8 mmhg at 1 , 6 , 12 , and 18 months of follow - up , respectively . the decrease in mean iop was statistically significant throughout follow - up ( p < 0.001 ) . there was a tendency towards increased iop with follow - up , yet the mean final iop at the end of the study was statistically significantly lower than the pretreatment mean iop ( p<0.05 ) . figure 1 shows the mean iop and standard deviation ( sd ) of all patients throughout the study period . mean ( sd ) intraocular pressure ( mmhg ) of all patients throughout the study the greatest drop in iop occurred 24 hours after slt ( 7.52 mmhg ) which was equivalent to a 38% drop from the baseline iop . there was a tendency toward and increase in iop during follow - up , with a mean iop reduction of 3.52 mmhg ( 18% from baseline ) at 18 months ( p= 0.001 ) . the intraocular pressure reduction expressed as mean and percentage drop from baseline we further compared the mean iop for each group individually . group i ( primary treatment with no preoperative medications ) had a preoperative mean iop of 21.54 mmhg that decreased significantly to 17.4 mmhg ( p<0.001 ) . iop decreased significantly in group ii ( adjunctive treatment where patients had been using antiglaucoma medications ) from 18.29 mmhg preoperatively to 14.89 mmhg by the end of the study ( p=0.001 ) . mean intraocular pressure changes ( mmhg ) in both primary and adjunctive groups over the study period success was defined as iop < 21 mmhg with at least a twenty percent drop of iop from baseline and no secondary surgeries . at 1-month follow - up , success remained similar at 18 months postoperatively with 74 eyes attaining the desired drop ( 70% of cases ) . hence despite a mean drop of iop of 18% at the end of follow - up , 70% of the patients met the success criteria . by the end of follow - up , six patients required laser retreatment and none needed any other surgical intervention to lower the iop . number of patients with any intervention in each group among patients using preoperative medications ( group ii ) , the mean number of medications used dropped statistically significantly throughout the study from 2.25 0.97 before the procedure to 1.0 ( 1.3 ) at the end of 18 months follow - up ( p= 0.004 ) . mean number of medications used in the adjunctive group throughout the study during the first 24 hours following the procedure , mild flare and cells were noted in the anterior chamber . this resolved spontaneously without treatment except in one case , which was successfully treated with topical steroids and resolved in 1 week . we had five cases ( 4.7% ) of increased iop 1 week following the procedure , the increase in iop ranged from 2 to 10 mmhg , only three eyes had an iop spike of 5 mmhg or more . one hundred and six eyes with oag were enrolled in the study and received 360 laser treatment of tm . females comprised 53% of the cohort and the mean age of the cohort was 53.2 years ( range , 18 - 78 years ) . mean preoperative iop was 19.55 4.8 mmhg which dropped significantly after 24 hours post - slt to 12.03 2.7 mmhg . iop was 14.32 3.0 mmhg , 14.72 2.1 mmhg , 15.16 3.6 mmhg and 16.03 2.8 mmhg at 1 , 6 , 12 , and 18 months of follow - up , respectively . the decrease in mean iop was statistically significant throughout follow - up ( p < 0.001 ) . there was a tendency towards increased iop with follow - up , yet the mean final iop at the end of the study was statistically significantly lower than the pretreatment mean iop ( p<0.05 ) . figure 1 shows the mean iop and standard deviation ( sd ) of all patients throughout the study period . the greatest drop in iop occurred 24 hours after slt ( 7.52 mmhg ) which was equivalent to a 38% drop from the baseline iop . there was a tendency toward and increase in iop during follow - up , with a mean iop reduction of 3.52 mmhg ( 18% from baseline ) at 18 months ( p= 0.001 ) . the intraocular pressure reduction expressed as mean and percentage drop from baseline we further compared the mean iop for each group individually . group i ( primary treatment with no preoperative medications ) had a preoperative mean iop of 21.54 mmhg that decreased significantly to 17.4 mmhg ( p<0.001 ) . iop decreased significantly in group ii ( adjunctive treatment where patients had been using antiglaucoma medications ) from 18.29 mmhg preoperatively to 14.89 mmhg by the end of the study ( p=0.001 ) . mean intraocular pressure changes ( mmhg ) in both primary and adjunctive groups over the study period success was defined as iop < 21 mmhg with at least a twenty percent drop of iop from baseline and no secondary surgeries . at 1-month follow - up , success remained similar at 18 months postoperatively with 74 eyes attaining the desired drop ( 70% of cases ) . hence despite a mean drop of iop of 18% at the end of follow - up , 70% of the patients met the success criteria . by the end of follow - up , six patients required laser retreatment and none needed any other surgical intervention to lower the iop . among patients using preoperative medications ( group ii ) , the mean number of medications used dropped statistically significantly throughout the study from 2.25 0.97 before the procedure to 1.0 ( 1.3 ) at the end of 18 months follow - up ( p= 0.004 ) . mean number of medications used in the adjunctive group throughout the study during the first 24 hours following the procedure , mild flare and cells were noted in the anterior chamber . this resolved spontaneously without treatment except in one case , which was successfully treated with topical steroids and resolved in 1 week . we had five cases ( 4.7% ) of increased iop 1 week following the procedure , the increase in iop ranged from 2 to 10 mmhg , only three eyes had an iop spike of 5 mmhg or more . selective photothermolysis takes place when thermal damage is confined to the target , melanin , by using a specific laser wavelength with a laser exposure time ( 3 ns ) equal to or shorter than the thermal relaxation time of melanin . thus , pulsed lasers with low threshold radiant exposures can selectively target pigmented tm cells and avoid collateral thermal damage to adjacent non - pigmented cells.9 histologically , slt has not been reported to cause coagulative damage to the tm.78 the literature has reported variable rates of the short and long - term efficacy of slt , with mean reductions in iop ranging from 2 to 14 mmhg at 1 month postoperatively , 36 mmhg at 3 months postoperatively , and 57 mmhg at 6 months postoperatively.3461011 to our knowledge this is the first study to address the effect of this technique on egyptian patients whether it was used alone or as an adjunct to medical therapy for glaucoma . our study shows slt to be an effective procedure with continued average iop lowering over 18 months consistent with the previous studies . latina et al . , studied 101 patients ( 45 patients on maximum antiglaucoma medication and 56 patients who had a previous failed alt ) treated by slt.1 they1 found a 70% success rate based on a 3-mmhg ( 20% ) or more reduction in iop and no additional medication at 6 months after treatment . this outcome is very similar to our results of 69 - 70% of patients achieving 20% or more reduction in iop . latina et al.,1 reported the greatest reduction in iop occurred on the first postoperative day ( 30.2% ) and by 26 weeks , the average iop reduction ( in percent ) from baseline for the entire cohort was 18.7% ( 4.6 mmhg ) . nagar et al.,2 achieved a 20% reduction of iop in 82% of their patients with 360 slt and mc ilraith et al.,12 achieved similar results . these outcomes are comparable to our results of 38% at day one , 25% by 6 months and 18% at 18 months follow - up . slt proved effective for the primary treatment of poag and ocular hypertention , with a mean drop of iop of 30 % from baseline at 18 months postoperatively in melamed et al.,3 study . prasad et al.,13 achieved a 35% drop of iop after 2 years of follow - up of primary cases of glaucoma treated with 360 slt . these results are comparable to our findings in the primary treatment group which showed a mean drop of 19.2% at 18 months . saito et al.,14 found a significant drop in iop in japanese patients undergoing slt as adjunctive treatment for poag which tended to decrease with 1 year follow - up . in a different study on chinese patients with maximally tolerated medical therapy for poag , adjunctive slt achieved iop drop of 15% at 18-months follow - up.15 our adjunctive group showed a comparable mean drop of 18.6% at 18 months . as with other studies , treatment failure occurred during the first month of follow - up and it remained the same throughout follow - up . the outcomes of our study do not indicate an advantage for slt in one group over the other . the number of medication used by patients dropped significantly in our study from 2.25 0.97 before laser treatment to 1.00 1.3 at the end of follow - up , these results are comparable to francis et al . 's report,16 showing a decrease in the number of medications after slt from 2.8 1.1 to 1.5 0.9 at 12 months , postoperatively . adverse effects included ocular discomfort in 21 patients ( 19.8% ) , when the shots were closer to the ciliary body . the same observation was reported by latina et al.,1 where pain and discomfort was reported in 15% of patients and redness in 9% . nagar et al.,2 also reported transient pain and discomfort in 39% of patients undergoing 360 slt . we did not encounter cases of iritis which could be explained by our routine use of pre- and postoperative steroids . iop spikes more than 5 mmhg were recorded in three patients ( 2.8% ) in the current study . reports of iop spikes in the literature range widely from 0 to 27%,129 this can be explained by the use of different a preoperative regimen . latina et al.,1 and nagar et al.,2 did not premedicate with antiglaucoma drops and both reported iop spike of 24% and 27% , respectively . however , johnson et al.,9 ( similar to us ) used pre- and postoperative -agonists to control iop spikes reporting no iop spikes in 136 eyes . slt was also effective in reducing the number of medications used by patients which is an economic advantage in developing countries . there is a tendency of the iop lowering effect to wane over time hence , regular follow - up is required . OUTPUT:

purpose : to assess the change in intraocular pressure ( iop ) in egyptian patients after selective laser trabeculoplasty ( slt ) as a primary or adjunctive treatment for primary open - angle glaucoma ( poag).materials and methods : one hundred and six eyes with poag were enrolled in this prospective study . patients were divided into two groups : recently diagnosed cases with no preoperative medications ( group 1 ) and ; patients with confirmed glaucoma on medical therapy ( group 2 ) . all patients underwent 360 slt . patients were evaluated to 18 months postoperatively . data were analyzed on postoperative changes in iop , number of medications and complications . a p - value less than 0.05 was statistically significant.results:a statistically significant drop in iop occurred , from 19.55 4.8 mmhg preoperatively , to16.03 2.8 mmhg postoperatively ( p < 0.001 ) . each group had a statistically significant drop in iop ( p < 0.001 ) . there was a statistically significant decrease in the number of medications in group 2 from 2.25 0.97 medications preoperatively to 1.0 1.3 medications postoperatively ( p=0.004 ) . no serious complications occurred for the duration of the study.conclusion:slt can be safely and effectively used as primary or adjunctive therapy for the treatment of poag .

PubMed_Summ6561

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: it is not easy to define a good health care system and good health care services . in these definitions , there is a complexity of elements or components , which contribute separately , but influence in a harmonized manner the perceptions towards a given health care system ( 1 , 2 ) . the health care system in albania has undergone several periods in which the health care concept has evolved significantly ( 3,4 ) . currently , the health care system in albania consists of three main pillars : primary , secondary and tertiary health care services ( 3 ) . the quality of health care is the consequence of strong links between service providers and users of the health care services at all levels ( 5 ) . perceived quality is one of the principal determinants of utilization and non - utilization of health care services ( 6 , 7 ) , a major issue in developing and transitional countries including albania , a former communist country in the western balkans which has undergone tremendous political and socioeconomic changes in the past two decades associated with significant health consequences ( 8 , 9 ) . in addition , the rapid process of transition in albania over the past two decades has been associated with an intensive process of internal migration ( from rural areas to urban areas of the country , especially in tirana , the albanian capital city ) and external migration ( mainly to the neighboring countries including greece and italy ) ( 9 ) . migration is linked to an increased aging which , in turn , enhances the general and already existing aging effect on healthcare utilization ( that is the relative care needs of the albanian population ) . to date , however , the available information regarding the quality of primary health care services in albania is scarce . in this framework , the aim of our study was to assess the quality of the primary health care services in albania with a main focus on family physicians perceptions towards the quality of health care services provided to the general population . a cross - sectional study was conducted in january - march 2013 including a representative sample of 132 physicians providing primary health care services in several polyclinics ( health centers ) of tirana . initially , a simple random sample of 150 physicians operating at primary health care level in tirana was targeted for recruitment . of these , 18 physicians could not be contacted ( n=7 ) , or refused to participate ( n=11 ) . the final study population consisted of 132 physicians ( 59 men aged 41.36.9 years and 73 women aged 43.74.8 years ; overall response rate : 132/150=88% ) . a structured self - administered and anonymous questionnaire was applied to all male and female primary health care physicians who agreed to participate in this survey . the questionnaire consisted of self - assessment of the following key dimensions / components of primary health care services : physical conditions at the workplace ( measurement scale : good [ score : 2 ] , average [ score : 1 ] , bad [ score : 0 ] ) ; availability and quality of working devices and equipment for proper diagnostic and treatment services ( measurement scale : not available [ score : 0 ] , available but not good [ score ; 1 ] , available and good [ score : 2 ] ) ; sources of scientific information available at the workplace ( not available [ score : 0 ] , available but outdated [ score : 1 ] , available and updated [ score ; 2 ] ) ; level of autonomy in decision - making ( no autonomy [ score : 0 ] , partial autonomy [ score : 1 ] , sufficient autonomy [ score : 2 ] ) . a summary score ( ranging from 0 to 8) was calculated for each physician based on these four dimensions of the quality of health care services which was dichotomized into inadequate quality ( overall score : 0 - 4 ) vs. adequate quality of health care services ( summary score : 5 - 8 ) . in addition , demographic data ( age and sex of physicians ) , information on working experience , number of population served , working place ( polyclinic , or health center ) , type of specialization received and involvement in teaching / training activities were collected for all physicians included in the study . median values ( and their respective interquartile ranges ) were used to describe the distribution of age , duration of work experience and the number of population served by the physicians included in this cross - sectional study . conversely , frequency distributions ( absolute numbers and their respective percentages ) were used to describe the distribution of sex , working place , specialization , involvement in teaching and training activities of the primary health care physicians . similarly , absolute numbers and their respective percentages were used to describe the distribution of the key dimensions / components of primary health care services according to physicians perceptions ( physical conditions at the workplace , devices and equipment , sources of information and level of autonomy ) . binary logistic regression was used to assess the association between the self - assessed overall quality of primary health care services ( adequate vs. inadequate ) with baseline characteristics of primary health care physicians . odds ratios ( ors ) , 95% confidence intervals ( 95%ci ) and their respective p - values were calculated . spss ( statistical package for social sciences , version 15.0 ) , was used for all the statistical analyses . demographic characteristics , working experience , specialization received , teaching involvement and population coverage of primary health care physicians included in this survey are presented in table 1 . median age of study participants was 44 years ( interquartile range : 38 - 51 years ) . median working experience was 14 years ( interquartile range : 4.5 - 23.5 years ) . median number of population served was 2500 inhabitants ( interquartile range : 2000 - 4000 ) . about 37% of the physicians were specialized in family medicine , 42% were general practitioners , whereas 21% had received other types of specializations including cardiology , pediatrics , rheumatology , or allergology . only 29.5% of primary health care physicians included in this study were involved in teaching and training activities ( table 1 ) . baseline characteristics of a representative sample of primary health care physicians in tirana in 2013 ( n=132 ) . * median values and interquartile ranges ( in parentheses ) . numbers and column percentages ( in parentheses ) . table 2 presents the distribution of selected key dimensions / components of primary health care services according to physicians perceptions . overall , 31% of the physicians considered good the physical conditions at their workplace , whereas 24% deemed them about 24% of the physicians perceived that there were no devices and equipment for a proper diagnosis and treatment of their patients , as opposed to 40% of the physicians who considered the equipment and devices available and appropriate . about 48% of the physicians stated that there were no sources of scientific information available at their workplace , compared with 20% of physicians who reported availability of updated sources of scientific information at their workplace . about 67% of the physicians perceived a complete lack of autonomy in decision - making , whereas 10% of physicians perceived sufficient autonomy in decision - making in their current ( routine ) health care practice ( table 2 ) . distribution of selected key dimensions of primary health care services according to physicians perceptions table 3 presents the association of the self - assessed quality of services with characteristics of primary health care physicians included in this survey . age of physicians was positively related to the self - perceived level of quality of health care services . hence , younger physicians reported a lower quality of health care services compared with their older counterparts , a finding which was borderline statistically significant ( or=0.79 , 95%ci=0.61 - 1.04 ) . the odds of perception of adequate health care services were lower in men compared to women , a finding which was statistically significant ( or=0.68 , 95%ci=0.42 - 0.91 ) . physicians with less than ten years of working experience had significantly lower odds of perceiving the services as adequate ( or=0.77 , 95%ci=0.51 - 0.94 ) . the number of population served was a borderline predictor of the quality of primary health care services ( p=0.09 ) . physicians specialized in family medicine had significantly higher odds of perception of services as adequate compared with the rest of physicians who were not trained in family medicine ( or=1.56 , 95%ci=1.13 - 1.97 ) . on the other hand , involvement in teaching or training activities was not significantly related to the self - perceived quality of primary health care services ( table 3 ) . association of quality of services with characteristics of primary health care physicians ; odds ratios ( adequate vs. inadequate quality ) from binary logistic regression main findings of this survey relate to a positive association of an adequate quality of primary health care services with female gender , older age , working experience and training in family medicine of physicians operating at primary health care level in tirana , the albanian capital . these are generally in line with previous reports from the international literature ( 5 - 7 ) . albanian doctors working at the primary health care sector face many difficulties in their professional practice . hence , albanian physicians are currently expected to provide not only high - quality services , but they should also apply competencies related to leadership , management , and community support at large . from this point of view , our findings suggest that older doctors and those with more years of working experience tend to report a higher quality of primary health care services reflecting a more favorable attitude which may be presumably linked to a higher level of professional skills and competencies . the population coverage was only a borderline predictor of the self - reported quality of services in the sample of primary health care physicians included in this study . this is an intuitive finding , in line with the expected direction , as the level of physicians competencies is related to the experience gained in the course of their health care practice ( 6 ) . our study was based on doctors perceptions about their working conditions and working environment and this can imply a subjective evaluation that can bear the possibility of information biases in the assessment of the current situation in terms of the quality of primary health care services in albania . therefore , health authorities in albania should develop and implement suitable instruments to measure the quality of health care services at all levels . furthermore , there is also a need to place in the public domain tool kits that can be used by physicians , administrators , and patient groups to assess and improve the quality of care . similar to many countries , albania should develop a national quality report , based on standardized comprehensive and scientifically valid measures , which should describe the country s progress in improving quality of care ( 10,11 ) . measurement and ranking of the quality of health care services should also involve patients perspective , in line with experiences and practices from other countries ( 10,11 ) . the current survey was an attempt to provide evidence about the perceptions of primary health care physicians regarding different aspects of their profession . our findings indicate that albanian doctors face several difficulties in performing their everyday tasks and , therefore , health authorities must undertake measures to improve their performance through provision of better working environment , availability and improvement of the instruments and diagnostic devices for diagnostic and treatment services . our findings provide useful evidence on the self - perceived quality of health care services from primary health care physicians perspective in transitional albania . OUTPUT:

aim : to date , the available information regarding the quality of primary health care services in albania is scarce . the aim of our study was to assess the quality of primary health care services in albania based on physicians perceptions towards the quality of the services provided to the general population.methods:a cross - sectional study was conducted in january - march 2013 including a representative sample of 132 physicians ( 59 men aged 41.36.9 years and 73 women aged 43.74.8 years ; overall response rate : 132/150=88% ) providing primary health care services in several polyclinics ( health centers ) of tirana , the albanian capital city . a structured self - administered and anonymous questionnaire was applied including physicians perceptions regarding different dimensions of the quality of primary health care . binary logistic regression was used to assess the association of self - perceived quality of health care services with baseline characteristics of physicians.results:self-perceived adequate quality of health care services was positively related to the age of physicians , their working experience , female gender , a lower population served , and specialization in family medicine.conclusion:our findings provide useful evidence on the self - perceived quality of health services from primary health care physicians perspective in transitional albania . health authorities in albania should implement suitable instruments to measure the quality of health care services at all levels .

PubMed_Summ6562

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: coenurosis , also known as gid or sturdy , is a larval helminth infection of herbivorous animals . adult tapeworm of t. multiceps inhabits small intestine of some domestic and wild carnivores , e.g. dogs , jackals , foxes and coyotes . eggs excreted in the environment by the definitive hosts are ingested by herbivorous intermediate hosts including sheep , goat , horse , cattle , camel , deer and pig . as a result the oncosphere passes through the intestinal wall and via bloodstream primarily localizes in the cns . this causes neurological symptoms and even death in young animals ( 1 - 3).furthermore , coenurosis is a zoonotic disease in which human may be accidentally infected and subsequently be suffered from - serious neurological problems . a few human cases has been reported from different countries including italy , egypt and the united states ( 4 , 5 ) . the infection rate of c. cerebralis , varied from 0.32 - 18.7% in sheep , goat , and wild sheep . ovine cenurosis has been reported in 18.7% ( 6 ) , 9.8% ( 7 ) , 3.8% ( 8) and0.3% ( 9 ) of animals . investigations on de - finitive hosts in different endemic regions of iran indicated rather high rates between 3 and 40% ( 10 - 13 ) in dogs , 7.5% in jackals,18.2% in foxes and 40% in wolves ( 10 , 13 ) . in other parts of the world similar prevalence rates of ovine cenuriasis have been recorded e.g. 3% in jordan ( 1 ) , 1.336.8% in turkey ( 14 , 15 ) , and 2.5% in bangladesh ( 16 ) . recorded prevalence rate ranging from 2.3 to 4.5% of sheep in kenya ( 2 ) . significant economic losses due to livestock morbidity and mortality caused by t. multiceps have been documented in several investigati - onsi - n ende - mic countries ( 17 , 18 ) . in iran the financial damage resulting from the condemnation of meat and viscera of sheep due to coenurosis one accepted method for distinguishing taeniid tapeworms at intra- and inter - specific levels has been the use of larval rostellar hook dimensions particularly total length of large and small hooks ( 19 - 24 ) . due to their keratin - like contents , hook measurement is not a complexprocedure and this makes hook morphometry a suitable tool for identification of different species of tapeworms . hook size is believed to be influenced by a combination of genetic and host factors . using enzyme electrophoresis on six loci in the taeniid tapeworm , echinococcus granulosus , lymbery ( 1998 ) showed that the total larval hook lengths particularly the total length of small hooks was the most affected hook character in the isolatesfrom different intermediate hosts ( 25 ) . for example , in bacteria a sound genetic basis is documented for the flagellar morphology in salmonella and shigella ( 26 ) . in passerine birds microsatellite and mtdna variations have been significantly associated with phenotypic traits like bill length ( 27 ) . however no study has been undertaken to investigate possible association of variability within different genes and the larval rostellar hook length in taeniid cestodes . this study was conducted to investigate the rostellar hook morphometry and the influence of mitochondrial gene variations on the hook length in sheep isolates of t. multiceps . a total of 4500 sheep heads were examined for the presence of t. multiceps metacestodes in the period of october 2010 to may 2011 in three major food processing companies in tehran , alborz and qom provinces of iran.after opening the skulls , coenuri were detached from the brain and were transferred to the helminthology lab in the school of medicine , kerman university of medical sciences . the metacestodes were then rinsed three times in normal saline and the specimens were stored at -20c until used . the fluid - filled coenuri were contained several scoleces surrounded by a thin , transparent membrane . all the scoleces within each coenure were counted and biometric characters based on the larval rostellar hook size were measured . for each metacestode five scoleces were randomly selected . total lengths of each of three large and three small hooks per scolex were measured by a calibrated eyepiece micrometer under medium power magnification ( fig . all measurements were taken by a single person ( s.r).representative mitoch - ondrial co1 and 12s rrna gene sequences of all the isolates were obtained from ncbi genbank to find out possible association between mitochondrial gene variability and hook morphometry . the large and small hook length data as well as the corresponding co1 and 12s rrna haplotypes were managed in the statistical package for the social sciences ( spss , v. 21 ) . cluster analysis was applied to classify the subjects into homogeneous subgroups using interclass correlation coefficient ( icc ) . random effects model was applied to estimate how much of variation in thehook length was attributable to the genetic differences between the subjects . dendrogram and scatter plot were generated based on the large and small hook length using hierarchical cluster analysis . a total of 4500 sheep heads were examined for the presence of t. multiceps metacestodes in the period of october 2010 to may 2011 in three major food processing companies in tehran , alborz and qom provinces of iran.after opening the skulls , coenuri were detached from the brain and were transferred to the helminthology lab in the school of medicine , kerman university of medical sciences . the metacestodes were then rinsed three times in normal saline and the specimens were stored at -20c until used . the fluid - filled coenuri were contained several scoleces surrounded by a thin , transparent membrane . all the scoleces within each coenure were counted and biometric characters based on the larval rostellar hook size were measured . for each metacestode five scoleces were randomly selected . total lengths of each of three large and three small hooks per scolex were measured by a calibrated eyepiece micrometer under medium power magnification ( fig . all measurements were taken by a single person ( s.r).representative mitoch - ondrial co1 and 12s rrna gene sequences of all the isolates were obtained from ncbi genbank to find out possible association between mitochondrial gene variability and hook morphometry . the large and small hook length data as well as the corresponding co1 and 12s rrna haplotypes were managed in the statistical package for the social sciences ( spss , v. 21 ) . cluster analysis was applied to classify the subjects into homogeneous subgroups using interclass correlation coefficient ( icc ) . random effects model was applied to estimate how much of variation in thehook length was attributable to the genetic differences between the subjects . dendrogram and scatter plot were generated based on the large and small hook length using hierarchical cluster analysis . inspection of 4500 sheep brains revealed that 114 ( 2.5% ) heads were infected by t. multiceps metacestodes . the average total length of thelarge and small hooks was 158.9 m ( range : 110 - 195 ) and 112.1 m ( range : 63 - 132 ) , respectively . significant icc s were obtained from random effects models showing that the large and small hook lengths are significantly different among t. multiceps isolates ( p<0.001 , table 1 ) . the results indicated that respectively 57.0% and 22.6% of variation in large and small hook lengths are attributable to different individuals in t. multiceps isolates . this means that based on large and small hook length , statistically significant clusters are distinguishable within the isolates.the results of hierarchical analysis are presented as a dendrogram in fig . the dendrogram contained two main clades one of which comprised 97.1% of the isolates.subclades a , b and c contained the majority of the isolates i.e.44 isolates ( 43.1% ) in the subclade a , 25 isolates ( 24.5% ) in the subclade b and 18 isolates ( 17.6% ) in the subclade c.no associations were found between hook length and co1 gene variability , however 12s rrna variability was significantly associated with theboth large and small hook length ( table 1 ) . coenurus cerebralis is a serious disease of herbivores with a worldwide distribution caused by the larval form of the cestode t. multiceps . different prevalence rates for coenurosis have been reported depending on various geographical , climatic and socio - economic conditions as well as environmental factors and livestock husbandry systems(28 ) . coenurosis is more prevalent in developing countries of africa and asia(2 ) . apparently , estimating precise prevalence of coenurosis is difficult because animal brains are not usually inspected during routine veterinary examinations . according to the present study the prevalence of ovine coenurosis was 2.5%.previous studies in iran indicated a range of relative frequency between 0.3 and 18.7% . the present prevalence is higher than those obtained by yuossefi ( 0.3% ) in iran , abedl - maogood ( 2005 ) in egypt ( 1.5% ) and scala et al . ( 2007 ) in italy ( 0.35%)(9 , 29 , 30).other studies indicated higher prevalences in urmia ( 18.7% ) , tabriz(3.8% ) and shiraz(9.8% ) ( 6 - 8).in the neighboring turkey similar prevalence rates were recorded as 1.3 - 36.8%(14 , 15 ) . in bangaladesh and ethiopia the prevalence of t. multiceps metacestode was obtained as 2.5% and 2.7% respectively ( 2 , 16 ) . regarding the relatively high prevalence of ovine cenuriasis in iran and the resulting economic losses due to the disease ( 7 ) , implementation of control and prevention programs in the endemic regions are recommended . the present study revealed that the average number of scoleces in the metacestode is 85 with a range of 40 - 550 scoleces per coenure . our finding is almost similar to the findings of other studies in which the highest number of scoleces per cyst reached 550 ranging from 10 to 370 scoleces per cyst ( 2 , 31 - 33 ) . presence of different numbers of scoleces may be related to the differences in the age of the coenuri . table 2 compares the rostellar hook morphometric characters of t. multiceps derived from existing data in the literature.the results of morphometric study showed that the mean sd total length of the large and small hooks were 158.99.3 m and 112.19.4 m respectively . the range of large hook length was 110.3 - 195.3 m , and 63.0 - 132.3 m for the small hooks . as it is illustrated in the scatter plot ( fig . 3 ) hook lengths of the majority of the isolates were found to be 150 - 165 m and 105 - 120 m for the large and small hooks respectively . the classical work of verster indicates the average large and small hook lengths as 166.7 and 125.0 respectively ( 23 ) . our results are in agreement with those of verster as well as the other published morphometric studies on t. multiceps hooks ( table 2 ) . based on the small and large hook values for each individual isolate , two main clusters were identified in the dendrogram ( fig . most of the isolates were located in the three main sub clades a , b and c. however , morphologically defined variants have not been described in t. multiceps so far . varcasia et al . described genetic diversity within sardinian populations of t. multiceps , however morphometric analysis was not carried out on that population ( 34 ) . obviously more comprehensive morphological studies in other regions are required to clarify possible morphometric diversity within t. multiceps populations from different intermediate hosts . mixed model analysis in the present study established a significant association between 12s rrna variability and larval rostellar hook lengths . according to the results of the present study 38% and 8% of the large and small hook length variations rostellar hooks are known to be made of keratin - like proteins ( 35 , 36 ) , however further genomic studies on keratin - related genes are required to improve our understanding on the genetic basis of larval hook development . hook length analysis revealed statistically significant difference among individual isolates , indicating intraspecific variation within t. multiceps in iran . morphometric analyses in the present study showed an association between the rostellar hook length and sequence variability in the mitochondrial 12s rrna . OUTPUT:

backgroundthe purposes of the present study were morphometric characterization of rostellar hooks of taenia multiceps and to investigate the association of hook length variation and the variability within two mitochondrial genes of sheep isolates of the parasite.methodsup to 4500 sheep brains were examined for the presence of c. cerebralis . biometric characters based on the larval rostellar hook size were measured for each individual isolate . representative mitochondrial co1 and 12s rrna gene sequences for each of the isolates were obtained from ncbi genbank . morphometric and genetic data were analyzed using cluster analysis , interclass correlation coefficient ( icc ) and random effects model.resultsone hundred and fourteen sheep ( 2.5% ) were found infected with the coenuri . the minimum and maximum number of scoleces per cyst was 40 and 550 respectively . each scolex contained 2227 hooks arranged in two rows of large and small hooks . the average total length of the large and small hooks was 158.9 and 112.1 m , respectively . using icc , statistically significant clusters of different hook sizes were identified within the isolates . the length of the large and small hooks was significantly associated with the variability in mitochondrial 12s rrna gene.conclusiontaenia multiceps , is a relatively important zoonotic infection in iranian sheep with the prevalence rate of 2.5% . hook length analysis revealed statistically significant difference among individual isolates . associations between the rostellar hook length and variability in the mitochondrial 12s rrna was documented .

PubMed_Summ6563

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: light upconversion is the generation of high - energy photons from low - energy photons , for example , the conversion of red light to blue light . generating upconverted light can be achieved using different systems such as two - photon absorption dyes , rare earth - doped materials or nanoparticles , and triplet triplet annihilation ( tta - uc ) . among these systems , tta - uc offers many advantages : it works at low excitation power ( down to 1 mw cm ) , it uses sensitizers having high molar absorptivity , and the obtained upconversion quantum yields are high , typically 15% in aqueous solution . since its popularization more than a decade ago , tta - uc has been used in many applications such as photocatalysis , solar energy harvesting , drug delivery and activation , and luminescence bioimaging . tta - uc is based on the photophysical interplay of photosensitizer and annihilator chromophores ( see figure s1 ) . the photosensitizer absorbs low energy light , after which intersystem crossing leads to a long - lived triplet state . the energy of this triplet state is transferred to the annihilator upon diffusional collision by means of triplet triplet energy transfer ( ttet ) ; a succession of ttet leads to a concentration buildup of long - lived triplet - state annihilators . triplet annihilation upconversion , in which one of them departs with the energy of both triplet states , to reach a high - energy singlet state . finally , this singlet excited state returns to the ground state by emission of a high - energy photon , thus realizing light upconversion . tta - uc has been demonstrated in an extensive assortment of organic , inorganic , and/or supramolecular materials , as well as in nano- or microsized particles . among the various applications of tta - uc , some of them require to operate above room temperature , such as bioimaging and phototherapy . because ttet and tta occur via molecular collisions , these processes are highly dependent on molecular diffusion ; the efficiency of tta - uc was reported as being greatly influenced by the fluidity of the matrix containing the dyes , and hence by the temperature . for many materials , a higher temperature leads to a higher fluidity , and therefore to higher tta - uc efficiency . for example , green - to - blue tta - uc in a rubbery polymer matrix was only visible above the glass transition temperature of the material , where the matrix becomes more fluid . however , diffusion is not the only important factor . first of all , temperature - dependent chemical phenomena such as dye aggregation may affect upconversion as well : counterintuitively , it was recently shown that at lower temperatures , mixed aggregation of sensitizer and annihilator molecules in diluted conditions resulted in higher tta - uc efficiency . it has also been shown that upconversion in gel matrices decreased at higher temperatures due to temperature - dependent disassembly of the host material . overall , understanding the temperature dependence of all chemical and physical properties of a given matrix is necessary for optimizing upconversion . our group recently demonstrated that green - to - blue and red - to - blue tta - uc can be realized in the phospholipid membrane of neutral pegylated liposomes composed of 1,2-dimyristoyl - sn - glycero-3-phosphocholine ( dmpc ) . this knowledge was later used for the activation of photoactivatable chemotherapeutic agents in the photodynamic window . in our initial studies it was reported that the upconversion intensity was reversibly affected by changes in temperature . upon heating the sample from 15 to 25 c the upconversion intensity increased significantly , which we interpreted as a consequence of the gel - to - liquid crystalline phase transition temperature ( tm ) of the dmpc lipid bilayer . upon raising the temperature above tm the molecular diffusion of the dyes in the membrane is expected to increase greatly , which should lead to higher ttet and tta rates , and thus higher tta - uc efficiencies . in this work , we systematically investigated the temperature dependency of tta - uc in neutral pegylated liposomes made of different lipids with different transition temperatures tm , to optimize the lipid composition of red - to - blue tta - uc drug - delivery systems functioning at human body temperature . palladium tetraphenyltetrabenzoporphyrin ( 1 ) was purchased from bio - connect ( huissen , the netherlands ) . perylene ( 2 ) was purchased from sigma - aldrich chemie bv ( zwijndrecht , the netherlands ) . all lipids were purchased from either lipoid gmbh ( ludwigshafen , germany ) or avanti polar lipids ( alabaster , al , usa ) and stored at 18 c . phosphate buffered saline ( dpbs ) was purchased from sigma - aldrich and had a formulation of 8 gl nacl , 0.2 gl kcl , 0.2 gl kh2po4 , and 1.15 gl k2hpo4 with a ph of 7.17.5 . all liposome formulations were prepared by the classical hydration - extrusion method . as an example , the preparation of liposome sample o12 is described here . aliquots of chloroform stock solutions containing the liposome constituents were added together in a flask to obtain a solution with 5.0 mol dopc , 0.20 mol dspe - mpeg-2000 , 2.5 nmol compound 1 , and 25 nmol compound 2 . the organic solvent was removed by rotary evaporation and subsequently under high vacuum for at least 30 min to create a lipid film . 1.0 ml dpbs buffer , with or without 0.3 m sodium sulfite , was added and the lipid film was hydrated by 4 cycles of freezing the flask in liquid nitrogen and thawing in warm water ( 60 c ) . the resulting dispersion was extruded through a whatman nuclepore 0.2 m polycarbonate filter at least 10 c above the main phase transition temperature of the lipid for at least 11 times using a mini - extruder from avanti polar lipids , inc . ( alabaster , alabama , usa ) , fitted with two 1001rn gastight syringes from hamilton ( bonaduz , switzerland ) . warning : heating the gastight syringes to 5070 c will cause the teflon plunger to leak at room temperature it is advised to use one set of syringes for hot extrusion only ! the number of extrusions was always odd to prevent any unextruded material ending up in the final liposome sample . the extrusion filter remained practically colorless after extrusion , suggesting near - complete inclusion of the dyes in the lipid bilayer . liposomes were stored in the dark at 4 c and used within 7 days . the average liposome size and polydispersity index were measured with a malvern instruments zetasizer nano - s machine , operating with a wavelength of 632 nm . differential scanning calorimetry ( dsc ) was performed on a ta instruments ( de , usa ) nano - dsc iii instrument in the range of 5 to 50 c with a scanning rate of 1 c min at 3 atm . the capillary cell ( v = 300 l ) was filled with the liposome solution ( lipid bulk concentration of 5 mm ) , and the reference cell was filled with pbs buffer solution . the liposome dispersions were degassed for 1015 min prior to measurement on a nalgene degassing station . for each sample , at least two cycles of heating and cooling were performed with 10 min of thermal equilibration between the ramps . the machine was cleaned beforehand with 50% formic acid and rinsed thoroughly with milli - q water . absorption and emission spectroscopy was conducted in a custom - built setup ( figure s2 ) . all optical parts were connected with fc - uvxxx-2 ( xxx = 200 , 400 , 600 ) optical fibers from avantes ( apeldoorn , the netherlands ) , with a diameter of 200600 m , respectively , and that were suitable for the uv vis range ( 200800 nm ) . typically , 2.25 ml of sample was placed in a 111-os macro fluorescence cuvette from hellma in a cuv - uv / vis - tc temperature - controlled cuvette holder with stirring from avantes . deoxygenated toluene samples were prepared in a glovebox in a sealed fluorescence cuvette . the cuvette holder temperature was controlled with a tc-125 controller and t - app computer software from quantum northwest ( liberty lake , wa , usa ) , while the sample temperature was measured with an omega rdxl4sd thermometer with a k - type probe submerged in the sample . the sample was excited with a 10 mw collimated 630 nm laser light beam ( 4 mm beam diameter , 80 mw cm ) from a diomed 630 nm pdt laser . the 630 nm light was filtered through a 630 nm band - pass filter ( fb63010 from thorlabs , dachau / munich , germany ) put between the laser and the sample . the excitation power was controlled using the laser control in combination with a ndl-25c-4 variable neutral density filter ( thorlabs ) , and measured using a s310c thermal sensor connected to a pm100usb power meter ( thorlabs ) . vis absorption spectra were measured using an avalight - dhc halogen - deuterium lamp ( avantes ) as light source and a 2048l starline spectrometer ( avantes ) as detector , both connected to the cuvette holder at a 180 angle and both at a 90 angle with respect to the red laser irradiation direction . the filter holder between cuvette holder and detector was in a position without a filter ( figure s2 , item 8) . luminescence emission spectra were measured using the same detector but with the uv vis light source switched off . to visualize the spectrum from 450 to 950 nm , while blocking the red excitation light , a thorlabs nf-633 notch filter was used in the variable filter holder . all spectra were recorded with avasoft software from avantes and further processed with microsoft office excel 2010 and origin pro 9.1 software . temperature dependent luminescence experiments were done with continuous irradiation and temperature ramping , except for phosphorescence measurements of compound 1 to prevent bleaching during the experiment . instead , spectra were taken every 5 c with 10 min thermal equilibration between temperature points . the absolute quantum yield of upconversion was determined by means of an integrating sphere setup . neutral pegylated liposome dispersions were prepared in phosphate buffered saline ( pbs ) by hydration and extrusion of lipid films containing six different neutral phosphatidylcholines , i.e. , 1,2-dioleyl - sn - glycero-3-phosphocholine ( dopc ) , 1,2-dilaureyl - sn - glycero-3-phosphocholine ( dlpc ) , 1,2-dimyristoyl - sn - glycero-3-phosphocholine ( dmpc ) , 1,2-dipentadecanoyl - sn - glycero-3-phosphocholine ( dpdpc ) , 1,2-dipalmitoyl - sn - glycero-3-phosphocholine ( dppc ) , and 1,2-distearoyl - sn - glycero-3-phosphocholine ( dspc ) and in the presence of 4 mol % of sodium n-(carbonyl - methoxypolyethylene glycol-2000)-1,2-distearoyl - sn - glycero-3-phosphoethanolamine ( dspe - mpeg-2000 , see figure 1 ) . addition of dspe - mpeg-2000 is a well - known strategy to prevent liposome aggregation and fusion , and moreover increases the hydrophobic dye loading capacity of phospholipid membranes . the lipid composition of liposome samples o , l , m , pd , p , and s is shown in table 1 . a well - investigated red - to - blue tta - uc dye couple consisting of palladium tetraphenyltetrabenzoporphyrin ( 1 ) and perylene ( 2 , see figure 1 ) was selected for incorporation in the lipid bilayer of the liposomes . samples containing these dyes , i.e. , o12 , l12 , m12 , pd12 , p12 , and s12 ( defined in table 1 ) , were prepared following an identical procedure . the hydrodynamic diameters ( z - ave = 137 6 nm ) and polydispersity indices ( pdi = 0.09 0.02 ) , as measured by dynamic light scattering ( dls ) , were found to be very similar regardless of the lipid type or dye concentration . chemical structures of dopc , dlpc , dmpc , dpdpc , dppc , dspc , dspe - mpeg-2000 , palladium tetraphenyltetrabenzoporphyrin ( 1 ) , and perylene ( 2 ) . dsc measurements were performed with a scanning rate of 1 c min at 3 atm pressure . all liposomes were prepared with 5.0 mm lipid and 0.20 mm dspe - mpeg-2000 in pbs ( without sulfite ) . compound 2 was incorporated at 0.5 mol % with respect to the phospholipid ; higher dye contents could not be reproducibly obtained with our liposome preparation method . tm is defined as the main transition temperature of the bilayer , and h as the molar enthalpy change of the phase transition ( the enthalpy change of the pretransition is included , in case there is one ) . it is well - known that phase changes of phospholipid membranes greatly influence the two - dimensional translational molecular diffusion coefficient ( dt in m s ) of membrane solutes . therefore , the gel - to - liquid phase transition temperature ( tm ) and the total enthalpy change of the phase transition ( h ) were measured for samples based on dmpc , dpdpc , dppc , and dspc using differential scanning calorimetry ( dsc , see table 1 , figure 2b , and figure s3 ) . tm and h for dye - free pegylated liposomes m , pd , p , and s were found to be very close to literature values for peg - free liposomes , i.e. , the peg groups did not significantly influence the phase transition at these concentrations . upon functionalization of the pegylated liposomes with compounds 1 and 2 , a small decrease in the main transition peak height was observed , but the main features of the thermogram remained . these results indicate that for liposome samples m12 , pd12 , p12 , and s12 compounds 1 and 2 were indeed buried in the lipid bilayer , and that their presence only minimally perturbed the physical properties of the membranes . no transitions were found between 5 and 50 c for samples o , o12 , l , and l12 , because tm for pure dopc and dlpc are reported to be below the freezing point of water . ( a ) typical absorption ( solid , left axis ) and emission spectrum ( dashed , right axis , exc = 630 nm , intensity 80 mw cm ) of l12 liposomes ( [ dlpc ] = 1.0 mm , = 0.5 m , = 5 m ) at 20 c in 0.3 m sodium sulfite pbs under air . ( b ) differential scanning calorimetry thermograms between 5 and 50 c of liposomes with tta - uc dyes ( o12 , l12 , m12 , pd12 , p12 , and s12 , solid ) or without ( o , l , m , pd , p , and s , dashed ) . the thermograms for liposomes s and s12 were recorded between 35 and 65 c ( figure s3 ) . measurements were performed in heating mode with a scanning rate of 1 c min at 3 atm pressure . ( c , d ) temperature evolution of the upconversion quantum yield ( uc , c ) and of the residual sensitizer phosphorescence quantum yield ( p , d ) of o12 , l12 , m12 , pd12 , p12 , and s12 . samples were heated from 5 to 50 c at a rate of 1 c min while continuously irradiated with 80 mw cm 630 nm light , at 1.0 mm lipid and = 0.5 m and = 5 m . next , uv vis absorption and emission spectroscopy was performed on samples o12 , l12 , m12 , pd12 , p12 , and s12 at 20 c in the presence of 0.3 m sodium sulfite ( figure 2 ) . in these samples , earlier work showed that despite the large increase in buffer ionic strength , na2so3 does not affect the formation of dopc and dmpc upconverting liposomes and allows stable tta - uc to occur in air . moreover , preliminary studies indicated that a 1:10 dye ratio ( 1:2 = 0.05:0.50 mol % with respect to the lipid ) resulted in optimized upconversion in m12 , while higher dye - loading was severely limited by the solubility of 2 in the membrane . the absorption spectra of these samples showed the superposition of the characteristic bands of 1 at 440 and 630 nm and the vibronically structured band of 2 from 350450 nm . upon irradiation with 630 nm laser light ( 10 mw , 80 mw cm ) , phosphorescence of 1 at 800 nm and upconversion emission of 2 at 474 nm were observed for each sample . the emission stability at 20 c was tested for each formulation by continuously irradiating for 1 h and collecting emission spectra . all samples exhibited good emission stability during this period ( figure s4 ) . the absolute quantum yield of upconversion ( uc , 420610 nm ) and residual sensitizer phosphorescence ( p , 725950 nm ) , defined by the number of emitted photons divided by the number of absorbed photons ( supporting information ) , was determined by means of an integrating sphere setup at room temperature ( 21.3 c ) . uc had values of 3.6% , 2.8% , 2.0% , 0.7% , 0.6% , and 0.3% for o12 , l12 , m12 , pd12 , p12 , and s12 , respectively . who show that the upconversion intensity of green - to - blue tta - uc in liposomes decreases strongly when going from dopc to dmpc , while no upconversion was observed at all in dspc . thus , the fact that we observe tta - uc in the long - chained saturated phospholipids ( i.e. , dpdpc , dppc , dspc ) at room temperature is interesting in itself . this may be explained by the longer triplet lifetimes ( t ) of sensitizer 1 ( t = 250 s in dmf ) compared to the green - absorbing sensitizer platinum octaethylporphyrin ( ptoep , t = 50 s in toluene ) , which increases the possibility for tta - uc . to investigate the temperature dependency of tta - uc in o12 , l12 , m12 , pd12 , p12 , and s12 , these samples were heated from 5 to 50 c at a rate of 1 c.min while stirring , and upconversion spectra were continuously recorded . the same samples were used as for the quantum yield determination these measurements were conducted within 24 h of each other . figure 2 shows the evolution of uc and p vs temperature for each liposome formulation . these curves were obtained by recording the intensity of phosphorescence ( ip ) and upconversion ( iuc ) vs temperature and scaling these to the measured absolute quantum yields at 21.3 c ( vide supra ) . for o12 and l12 , both uc and p gradually decreased with increasing temperature . for m12 , pd12 , and p12 , uc increased up to 25 , 33 , and 42 c , respectively , and then decreased gradually , whereas p decreased steeply up to 25 , 34 , and 42 c , respectively , and then continued to decrease , but less steeply . for s12 , uc increased and p decreased with increasing temperature . when the samples were brought back from 50 to 5 c , the initial emission spectra at 5 c were obtained again in all cases ( figure s5 ) and the uv vis absorption spectra were identical to those obtained at the beginning of these experiments ( figure s6 ) ; both findings showing that bleaching did not occur and that the thermophotophysical evolution is reversible . the shape of the observed temperature behavior was nearly identical at 5 lower concentration for m12 , showing that the influence of liposome scatter is negligible ( figure s7 ) . also , in a control experiment in which dspe - mpeg-2000 was omitted from sample m12 , the shape of the observed temperature behavior was very similar , which indicates that pegylation did not have significant influence on the observed thermophotophysical behavior ( figure s8 ) . interestingly , for m12 , pd12 , and p12 , the temperature values at which uc maximizes and p kinks are very close to the phase transition temperature of the bilayer ( tm ) recorded with dsc . the increase of uc when approaching tm is easily explained : heating the liposomes below tm greatly increases the membrane fluidity and thus increases the lateral diffusion coefficient ( dt ) of membrane dyes , which in turn causes an increase in tta - uc efficiency . for instance , the dt for fluorescent probes in dmpc lipid bilayers has been reported to increase from 0.01 m s at 15 c to 6 m it is worth mentioning that for such dmpc bilayers , the foremost change in dt ( a three - order increase in magnitude ) was found between 20 and 25 c , and so the most considerable transition in tta - uc efficiency was expected to occur in this temperature domain . this is indeed in accordance with our data for m12 . in the absence of accurate literature data of dt in dpdpc and dppc across the full temperature range , we assume that the same explanation holds for the results obtained with pd12 and p12 . however , this rationale is clearly no longer valid above tm : although dt continues to increase ( vide supra ) , uc decreased . furthermore , for o12 and l12 , in absence of a phase transition between 5 and 50 c , uc and p both decrease across the entire temperature range . it is thus clear that other photophysical phenomena must play a role in the temperature dependence of tta - uc in lipid bilayers . therefore , the thermophotophysical behavior of the isolated dyes was considered in dopc , dmpc , and toluene ( figure 3 ) . first , the fluorescence intensity of compound 2 ( exc = 420 nm , em = 474 nm ) was found to decrease by 10% in both dopc liposomes and toluene when heated from 5 to 50 c . this is most likely explained by a slightly increased thermal deactivation . in dmpc , the fluorescence intensity increased by 25% when heated from 5 to 30 c , with the most sharp increase around 25 c , and then decreased slightly again up to 50 c . in all three systems , no significant spectral fluorescence differences are observed between 5 and 50 c ( figure s9 ) . this observation is in agreement with the work of khan et al . , who reported that perylene tends to form staggered nonfluorescent aggregates in the tightly packed gel membrane below tm , which break apart in the more loosely packed liquid - crystalline state above tm . since the fluorescence intensity is lower in the presence of such aggregates , the tta - uc efficiency is lower below tm . overall , dissociation of perylene aggregates gives an additional explanation for the increase of upconversion intensity up to tm . temperature - dependent emission spectroscopy of compounds 2 or 1 in toluene , dmpc liposomes , or dopc liposomes . ( a ) normalized fluorescence intensity at 474 nm of compound 2 in toluene ( dashed , 20 m ) , m2 liposomes ( purple , [ dmpc ] = 1 mm ) , or o2 liposomes ( black , [ dopc ] = 1 mm ) as a function of temperature . ( b ) temperature variation of the normalized phosphorescence intensity at 800 nm in 5 c intervals for compound 1 in toluene under argon ( open circles ) and for liposomes o1 ( black triangles , [ dopc ] = 1 mm ) or m1 ( purple squares , [ dmpc ] = 1 mm ) prepared in pbs with 0.3 m sodium sulfite . second , the phosphorescence intensity of 1 ( exc = 630 nm , em = 800 nm ) was investigated under deoxygenated conditions . in toluene solution , roughly 50% of the phosphorescence intensity is lost upon going from 5 to 50 c due to increased thermal deactivation . when the dye was inserted into dopc or dmpc liposomes ( o1 and m1 , respectively ) about 70% phosphorescence intensity was lost upon going from 5 to 50 c ; the additional 20% loss of phosphorescence intensity with respect to the toluene sample may be due to increased dynamic self - quenching , because the molecules are much more confined in the lipid bilayer . the explanation of self - quenching is supported by the fact that , for m1 , the highest loss of phosphorescence is observed around the transition temperature , at which the fluidity of the membrane increases most rapidly and diffusion - based processes such as self - quenching are expected to have an increased effect . overall , these results explain that the decrease of tta - uc with rising temperature is most likely due to increased thermal deactivation and self - quenching of 1 . based on these data , we explain the typical maximization of uc around tm in lipid bilayers that have a transition temperature between 5 and 50 c as follows . on one hand , the increase in photosensitizer quenching as a function of temperature is rather linear ( figure 3 ) . on the other hand , the temperature dependence of dt has been described in the literature as sigmoidal , with three orders of magnitude increase when approaching tm , and flattening directly after tm . in other words , upon approaching tm the membrane becomes fluid rather quickly , but once it reaches the liquid crystalline state the fluidity changes negligibly . therefore , above tm the effect of the only minor increase in lateral diffusion coefficient on the upconversion efficiency is completely outcompeted by the increased quenching of the photosensitizer . furthermore , the dissociation of annihilator aggregates results in a rather abrupt and significant increase in fluorescence around tm as well ( figure 3a ) . it is thus concluded that the combination of these three temperature - dependent phenomena results in the maxima that were observed in the uc versus temperature curve at 25 , 33 , and 42 c for samples m12 , pd12 , and p12 , respectively ( figure 2c ) . finally , for the biological application of these upconverting liposomes in bioimaging or phototherapy , it would be beneficial to achieve the highest upconversion intensity at human body temperature ( 37 c ) . from our results , it is evident that the systems o12 , l12 , and m12 achieve similar upconversion quantum yields at 37 c , while pd12 , p12 , and s12 exhibit lower quantum yields . altogether , the results suggest that even though uc maximizes around tm ( for m12 , pd12 , and p12 ) , choosing a lipid with a tm near 37 c does not result in an optimized upconverting liposome formulation . finally , considering that little has been reported about the biocompatibility of dlpc , we conclude that o12 and m12 upconverting liposomes are the most promising for biological applications . the temperature dependence of red - to - blue tta - uc was studied in pegylated liposomes with pc lipids with different lipophilic chain lengths and transition temperatures , and it was found that the upconversion efficiency maximizes around the order disorder transition temperature of the membrane , tm . three major effects contribute to this temperature dependency : ( 1 ) an increase in lipid bilayer fluidity above tm results in higher diffusion rates and thus in higher rates of ttet and tta and higher upconverted intensity ; ( 2 ) perylene aggregates dissociate when t approaches tm , which results in higher annihilator emission intensity ; and ( 3 ) higher thermal deactivation and self - quenching rates of the photosensitizer at higher temperatures lead to a lower ttet rate and lower upconversion intensity beyond tm . measuring the point at which iuc maximizes may be exploited for probing the transition temperature of phospholipid membranes . furthermore , for tta - uc applications that require high performance at elevated temperatures , the results underline the importance of selecting photosensitizers that are minimally affected by temperature . finally , the upconverted intensity in dopc , dlpc , and dmpc liposomes were very similar at 37 c , which highlights that not being at the optimum temperature for a given lipid composition does not necessarily mean that the upconverted intensity is lower than when being at the optimum temperature for another lipid composition . overall , tta - uc in liposomes can be realized with many different lipids of different tm , and for both saturated and unsaturated lipids . for applications in bioimaging and phototherapy , the phospholipid can be rather freely chosen among dlpc , dmpc , and dopc , while dppc , dpdpc , and dspc lead to slightly lower upconverted intensities . such versatility allows for further optimizing the liposomal formulation in terms of other properties such as stability to medium , biocompatibility , toxicity , clearance from the bloodstream , and/or surface functionalization . OUTPUT:

understanding the temperature dependency of triplet triplet annihilation upconversion ( tta - uc ) is important for optimizing biological applications of upconversion . here the temperature dependency of red - to - blue tta - uc is reported in a variety of neutral pegylated phospholipid liposomes . in these systems a delicate balance between lateral diffusion rate of the dyes , annihilator aggregation , and sensitizer self - quenching leads to a volcano plot , with the maximum upconversion intensity occurring near the main order disorder transition temperature of the lipid membrane .

PubMed_Summ6564

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: ccug 11284 is a wild - type strain that was originally isolated from bovine feces . before each experiment , bacteria were grown on conventional blood agar plates ( columbia agar ii containing 8% vol / vol whole horse blood ) at 42c for 20 h in a microaerobic environment , using a campygen gas generating system ( cn0025a ; oxoid ltd . , basingstoke , uk ) and a bbl gaspak system ( bd , franklin lakes , nj ) . bacterial cells were harvested and diluted in a peptone - yeast extract - glucose ( pyg ) medium and used as stock solution for all treatments . the stock solution was striven to obtain a concentration of approximately 10 cfu / ml , as were detected by plate counting . a. polyphaga stock cultures were maintained in pyg medium at 27c in 75 cm culture flasks ( sarstedt , nrnbrecht , germany ) , as described by axelsson - olsson et al . , a. polyphaga were seeded into 12-well culture plates ( fischer scientific gtf ab , switzerland ) in pyg medium ( 1 ml / well ) and incubated at 27c for 24 h , until the trophozoites formed confluent layers at the bottom of the wells . commercially available milk with a ph of 6.4 ( protein 3.4 g , sugar 5 g , fat 1.5 g , ca 120 mg , vitamin a 25 g , vitamin d 0.38 g ) and orange juice with a ph of 3.9 ( protein 0.7 g , sugar 18 g , fat < 0.5 g , na 0.003 g , vitamin c 30 mg ) were used for all experiments . basingstoke , uk ) was added to the products to inhibit growth of other bacteria than c. jejuni . to mimic the conditions of storage in the fridge or at the bench , experiments were incubated at room temperature and 4c . to test whether the presence of amoeba in two different beverage products , milk and orange juice , influenced the survival of c. jejuni , the following three treatments were used : c. jejuni preincubated with a. polyphaga before the addition of product ( treatment a ) , c. jejuni mixed with a. polyphaga after the addition of product ( treatment b ) , and c. jejuni in product without a. polyphaga ( treatment c ) . for treatment a , 12-well plates with confluent a. polyphaga layers in pyg medium were inoculated with 100 l of the c. jejuni stock solution , generating a concentration of 10 cfu / ml and a multiplicity of infection ( moi ) of one bacteria per amoeba , in each well . before inoculation with c. jejuni , the medium in all wells were gently removed and replaced with 1 ml fresh pyg medium . the plates were incubated for 3 h at 32c to allow the bacterial cells to attach to and invade amoebae , and thereafter the pyg medium was gently removed and replaced by 2 ml of product . plates with confluent a. polyphaga were prepared by gently removing the pyg medium and replacing it with 2 ml of product . for the control treatment ( treatment c ) , plates without amoebae after the addition of product , the plates for treatment b and c were inoculated with 100 l of the c. jejuni stock solution generating a concentration of 510 cfu / ml and an moi of one bacteria per amoeba in treatment b , in each well . three plates ( treatments a c ) were incubated at room temperature and at 4c , respectively . all plates were incubated in an aerobic environment and each treatment was done in triplicate wells , resulting in three similar wells for each temperature , treatment and product . from each well , a 100-l sample was taken at time zero ( the addition of product ) and at 3 , 6 , 18 , 24 , and 48 h. all samples were 10-fold serially diluted in pyg medium and spread on blood agar plates for colony counting . three independent experiments were performed on separate occasions . to make sure that the ph level was not affected , the ph level of the fluid in each well was measured after 48 h , when experiments were completed . compared to initial ph ( milk : 6.41 and juice : 3.89 ) only a small increase in ph was observed ( milk : 0.4 and juice : 0.1 ) . for pasteurization experiments , the same settings were used , as described above for treatments a , b , and c. directly after the addition of product , samples of 100 l were taken from the different treatments , a , b , and c and added to tubes containing 500 l of milk or juice . the tubes were gently shaken at 1,400 rpm ( ms2 minishaker ika , germany ) and then incubated in a water bath ( heto dt hetotherm , denmark ) . incubation conditions for milk tubes were 7274c for 15 sec ( equivalent to swedish low pasteurization guidelines ) . incubation conditions for juice tubes were 85c for 15 sec ( equivalent to swedish pasteurization guidelines ) . after heating , the sample tubes were put on ice and 100-l samples were spread on blood agar for colony counting . all experiments were done in triplicates , resulting in three similar wells for each treatment and product . for each well and each time point , a measure of c. jejuni cell survival was calculated by dividing the bacterial concentration of the sample ( estimated from colony counts ) by the bacterial concentration of that well at time 0 h ( the addition of product ) . the c. jejuni strain ccug 11284 and the a. polyphaga strain ( linc ap-1 ) were used in all experiments . ccug 11284 is a wild - type strain that was originally isolated from bovine feces . before each experiment , bacteria were grown on conventional blood agar plates ( columbia agar ii containing 8% vol / vol whole horse blood ) at 42c for 20 h in a microaerobic environment , using a campygen gas generating system ( cn0025a ; oxoid ltd . , basingstoke , uk ) and a bbl gaspak system ( bd , franklin lakes , nj ) . bacterial cells were harvested and diluted in a peptone - yeast extract - glucose ( pyg ) medium and used as stock solution for all treatments . the stock solution was striven to obtain a concentration of approximately 10 cfu / ml , as were detected by plate counting . a. polyphaga stock cultures were maintained in pyg medium at 27c in 75 cm culture flasks ( sarstedt , nrnbrecht , germany ) , as described by axelsson - olsson et al . , a. polyphaga were seeded into 12-well culture plates ( fischer scientific gtf ab , switzerland ) in pyg medium ( 1 ml / well ) and incubated at 27c for 24 h , until the trophozoites formed confluent layers at the bottom of the wells . commercially available milk with a ph of 6.4 ( protein 3.4 g , sugar 5 g , fat 1.5 g , ca 120 mg , vitamin a 25 g , vitamin d 0.38 g ) and orange juice with a ph of 3.9 ( protein 0.7 g , sugar 18 g , fat < 0.5 g , na 0.003 g , vitamin c 30 mg ) were used for all experiments . basingstoke , uk ) was added to the products to inhibit growth of other bacteria than c. jejuni . to mimic the conditions of storage in the fridge or at the bench , experiments were incubated at room temperature and 4c . to test whether the presence of amoeba in two different beverage products , milk and orange juice , influenced the survival of c. jejuni , the following three treatments were used : c. jejuni preincubated with a. polyphaga before the addition of product ( treatment a ) , c. jejuni mixed with a. polyphaga after the addition of product ( treatment b ) , and c. jejuni in product without a. polyphaga ( treatment c ) . for treatment a , 12-well plates with confluent a. polyphaga layers in pyg medium were inoculated with 100 l of the c. jejuni stock solution , generating a concentration of 10 cfu / ml and a multiplicity of infection ( moi ) of one bacteria per amoeba , in each well . before inoculation with c. jejuni , the medium in all wells were gently removed and replaced with 1 ml fresh pyg medium . the plates were incubated for 3 h at 32c to allow the bacterial cells to attach to and invade amoebae , and thereafter the pyg medium was gently removed and replaced by 2 ml of product . plates with confluent a. polyphaga were prepared by gently removing the pyg medium and replacing it with 2 ml of product . for the control treatment ( treatment c ) , plates without amoebae after the addition of product , the plates for treatment b and c were inoculated with 100 l of the c. jejuni stock solution generating a concentration of 510 cfu / ml and an moi of one bacteria per amoeba in treatment b , in each well . three plates ( treatments a c ) were incubated at room temperature and at 4c , respectively . all plates were incubated in an aerobic environment and each treatment was done in triplicate wells , resulting in three similar wells for each temperature , treatment and product . from each well , a 100-l sample was taken at time zero ( the addition of product ) and at 3 , 6 , 18 , 24 , and 48 h. all samples were 10-fold serially diluted in pyg medium and spread on blood agar plates for colony counting . three independent experiments were performed on separate occasions . to make sure that the ph level was not affected , the ph level of the fluid in each well was measured after 48 h , when experiments were completed . compared to initial ph ( milk : 6.41 and juice : 3.89 ) only a small increase in ph was observed ( milk : 0.4 and juice : 0.1 ) . for pasteurization experiments , the same settings were used , as described above for treatments a , b , and c. directly after the addition of product , samples of 100 l were taken from the different treatments , a , b , and c and added to tubes containing 500 l of milk or juice . the tubes were gently shaken at 1,400 rpm ( ms2 minishaker ika , germany ) and then incubated in a water bath ( heto dt hetotherm , denmark ) . incubation conditions for milk tubes were 7274c for 15 sec ( equivalent to swedish low pasteurization guidelines ) . incubation conditions for juice tubes were 85c for 15 sec ( equivalent to swedish pasteurization guidelines ) . after heating , the sample tubes were put on ice and 100-l samples were spread on blood agar for colony counting . all experiments were done in triplicates , resulting in three similar wells for each treatment and product . for each well and each time point , a measure of c. jejuni cell survival was calculated by dividing the bacterial concentration of the sample ( estimated from colony counts ) by the bacterial concentration of that well at time 0 h ( the addition of product ) . the experimental setup included three different treatments ( a , b , and c ) ; see materials and methods section . in milk , the highest c. jejuni survival was seen in treatment a , where bacteria were pre - incubated with amoebae before addition of milk ( 2.8% , 18 h ; 3.8% , 24 h ; 0.8% , 48 h ; table 1 ; fig . treatment b showed 0.05% survival at 18 h and reached a fraction of 6.710of the inoculum at 48 h ( equivalent to 14 cfu / ml ; table 1 ) . after 3 h , the survival of c. jejuni without amoebae ( treatment c ) decreased more rapidly compared to co - cultures ( treatments a and b ) , and the fraction of the inoculum surviving after 18 h was only 3.510 ( equivalent to 6 cfu / ml ; table 1 ) . no bacteria could be detected after 24 h. at 1848 h , treatment a had significantly higher bacterial survival than treatment c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests ; 18 h , p=0.0003 ; 24 h , p<0.0001 ; 48 h , p=0.0007 ; fig . . survival of c. jejuni co - incubated with a. polyphaga in milk ( a ) or orange juice ( b ) at room temperature after 0 h , 3 h , 6 h , 24 h , and 48 h. data are based on three independent experiments with c. jejuni treated in three different ways treatment a ( dots ) , c. jejuni preincubated with a. polyphaga before the addition of product ; treatment b ( squares ) , c. jejuni inoculated to a. polyphaga after the addition of product ; and treatment c ( triangles ) , c. jejuni in product without a. polyphaga . to use the log10 scale , a constant meanssem ( missing data points : one out of nine replicates for : milk treatment b at 0 h , milk treatment a at 3 h and juice treatment b at 3 h ) . mean fraction of the c. jejuni inoculum surviving after 18 h , 24 h , and 48 h for treatments a , b , and c when incubated in milk and juice at room temperature ( rt ) and at 4c c. jejuni incubated in juice showed similar trends as in milk albeit with more pronounced differences between co - cultures and bacteria incubated alone . the highest c. jejuni survival was seen in treatment a ( 88.4% , 18 h ; 36.9% , 24 h ; 0% , 48 h ; table 1 ; fig . 1b ) and the lowest survival was found in treatment c , c. jejuni without amoebae . after 3 h , the survival of c. jejuni incubated without amoebae decreased rapidly compared to co - cultures ( treatments a and b ) and no viable bacteria could be detected after 18 h ( table 1 , fig . 1b ) . the relative survival of c. jejuni in treatment b ( 4.1% , 18 h ; 2.0% , 24 h ; 0.02% , 48 h ; table 1 ) was lower than in treatment a but higher than in c. however , due to the higher start concentration in treatment b , compared to treatment a , the bacterial concentration in the juice was still 45 cfu / ml at 48 h. statistically significant differences in survival were seen between : a and b ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests : 18 h , p=0.0428 ; 24 h , p=0.0428 ; 48 h , p=0.0029 ; a and c : 18 h , p<0.0001 ; 24 h , p<0.0001 ; b and c : 18 h , p=0.0428 ; 24 h , p=0.0428 ; 48 h , p=0.0029 ; fig . 1b ; table 1 ) . at 4c , c. jejuni generally survived better in both milk and juice and the differences were less pronounced between co - cultures and bacteria incubated alone . in milk , the highest c. jejuni survival was seen in treatment a for time point up to 24 h ( 90.3% , 18 h ; 34.3% , 24 h ; table 1 ; fig . at these time points , treatment c ( 24.1% , 18 h ; 20.1% , 24 h ; table 1 ) gave a higher survival than treatment b ( 19.2% , 18 h ; 18.2% , 24 h ; table 1 ) . at 48 h , the highest c. jejuni survival was seen in treatment c ( 3.3% table 1 ) , and the survival in treatments a and b were 0.4 and 0.6% , respectively ( table 1 ) . statistically significant differences in survival were seen at 18 h between : a and b as well as a and c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests : a and b:18 h , p=0.001 ; a and c : 18 h , p=0.0045 ; fig . survival of c. jejuni co - incubated with a. polyphaga in milk ( a ) or orange juice ( b ) at 4c after 0 h , 3 h , 6 h , 24 h , and 48 h. data are based on three independent experiments with c. jejuni treated in three different ways treatment a ( dots ) , c. jejuni preincubated with a. polyphaga before the addition of product ; treatment b ( squares ) , c. jejuni inoculated to a. polyphaga after the addition of product ; and treatment c ( triangles ) , c. jejuni in product without a. polyphaga . to use the log10 scale , a constant 1 had to be added to all cfu values to manage zeros . meanssem ( missing data points : one out of nine replicates for juice treatment c at 18 h ) . when c. jejuni were incubated in juice at 4c , the differences seen between co - cultures ( treatments a and b ) and c. jejuni incubated without amoebae ( treatment c ) , were similar to those seen in juice at room temperature , although the bacteria in treatment c survived longer compared to incubation at room temperature . the highest c. jejuni survival was seen in treatment a : 90.6% , 18 h ; 56.7% , 24 h ; 0.35% , 48 h ; table 1 ) and the lowest survival was found in treatment c : 3.3% , 18 h ; 2.0% , 24 h ; 0.00074% ; 1 cfu / ml ; 48 h ; table 1 ) . the survival of c. jejuni in treatment b : 7.4% , 18 h ; 3.4% , 24 h ; 0.01% , equivalent to 18 cfu / ml ; 48 h , table 1 ) was lower than a but higher than c. statistically significant differences in survival were seen at 1824 h between a and b , and 1848 h between a and c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests ; a and b : 18 h , p=0.0125 ; 24 h , p=0.005 ; a and c : 18 h , p=0.0001 ; 24 h , p=0.0002 ; 48 h , p=0.0489 ; fig . a. polyphaga did not show any protective effect on c. jejuni when heated to recommended pasteurization temperatures , neither in milk nor in orange juice ( data not shown ) . growth was totally inhibited in all samples from treatments a , b , and c. results were based on three independent experiments . the experimental setup included three different treatments ( a , b , and c ) ; see materials and methods section . in milk , the highest c. jejuni survival was seen in treatment a , where bacteria were pre - incubated with amoebae before addition of milk ( 2.8% , 18 h ; 3.8% , 24 h ; 0.8% , 48 h ; table 1 ; fig . treatment b showed 0.05% survival at 18 h and reached a fraction of 6.710of the inoculum at 48 h ( equivalent to 14 cfu / ml ; table 1 ) . after 3 h , the survival of c. jejuni without amoebae ( treatment c ) decreased more rapidly compared to co - cultures ( treatments a and b ) , and the fraction of the inoculum surviving after 18 h was only 3.510 ( equivalent to 6 cfu / ml ; table 1 ) . no bacteria could be detected after 24 h. at 1848 h , treatment a had significantly higher bacterial survival than treatment c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests ; 18 h , p=0.0003 ; 24 h , p<0.0001 ; 48 h , p=0.0007 ; fig . . survival of c. jejuni co - incubated with a. polyphaga in milk ( a ) or orange juice ( b ) at room temperature after 0 h , 3 h , 6 h , 24 h , and 48 h. data are based on three independent experiments with c. jejuni treated in three different ways treatment a ( dots ) , c. jejuni preincubated with a. polyphaga before the addition of product ; treatment b ( squares ) , c. jejuni inoculated to a. polyphaga after the addition of product ; and treatment c ( triangles ) , c. jejuni in product without a. polyphaga . to use the log10 scale , a constant meanssem ( missing data points : one out of nine replicates for : milk treatment b at 0 h , milk treatment a at 3 h and juice treatment b at 3 h ) . mean fraction of the c. jejuni inoculum surviving after 18 h , 24 h , and 48 h for treatments a , b , and c when incubated in milk and juice at room temperature ( rt ) and at 4c c. jejuni incubated in juice showed similar trends as in milk albeit with more pronounced differences between co - cultures and bacteria incubated alone . the highest c. jejuni survival was seen in treatment a ( 88.4% , 18 h ; 36.9% , 24 h ; 0% , 48 h ; table 1 ; fig . 1b ) and the lowest survival was found in treatment c , c. jejuni without amoebae . after 3 h , the survival of c. jejuni incubated without amoebae decreased rapidly compared to co - cultures ( treatments a and b ) and no viable bacteria could be detected after 18 h ( table 1 , fig . 1b ) . the relative survival of c. jejuni in treatment b ( 4.1% , 18 h ; 2.0% , 24 h ; 0.02% , 48 h ; table 1 ) was lower than in treatment a but higher than in c. however , due to the higher start concentration in treatment b , compared to treatment a , the bacterial concentration in the juice was still 45 cfu / ml at 48 h. statistically significant differences in survival were seen between : a and b ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests : 18 h , p=0.0428 ; 24 h , p=0.0428 ; 48 h , p=0.0029 ; a and c : 18 h , p<0.0001 ; 24 h , p<0.0001 ; b and c : 18 h , p=0.0428 ; 24 h , p=0.0428 ; 48 h , p=0.0029 ; fig . 1b ; table 1 ) . at 4c , c. jejuni generally survived better in both milk and juice and the differences were less pronounced between co - cultures and bacteria incubated alone . in milk , the highest c. jejuni survival was seen in treatment a for time point up to 24 h ( 90.3% , 18 h ; 34.3% , 24 h ; table 1 ; fig . at these time points , treatment c ( 24.1% , 18 h ; 20.1% , 24 h ; table 1 ) gave a higher survival than treatment b ( 19.2% , 18 h ; 18.2% , 24 h ; table 1 ) . at 48 h , the highest c. jejuni survival was seen in treatment c ( 3.3% table 1 ) , and the survival in treatments a and b were 0.4 and 0.6% , respectively ( table 1 ) . statistically significant differences in survival were seen at 18 h between : a and b as well as a and c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests : a and b:18 h , p=0.001 ; a and c : 18 h , p=0.0045 ; fig . survival of c. jejuni co - incubated with a. polyphaga in milk ( a ) or orange juice ( b ) at 4c after 0 h , 3 h , 6 h , 24 h , and 48 h. data are based on three independent experiments with c. jejuni treated in three different ways treatment a ( dots ) , c. jejuni preincubated with a. polyphaga before the addition of product ; treatment b ( squares ) , c. jejuni inoculated to a. polyphaga after the addition of product ; and treatment c ( triangles ) , c. jejuni in product without a. polyphaga . to use the log10 scale , a constant 1 had to be added to all cfu values to manage zeros . meanssem ( missing data points : one out of nine replicates for juice treatment c at 18 h ) . when c. jejuni were incubated in juice at 4c , the differences seen between co - cultures ( treatments a and b ) and c. jejuni incubated without amoebae ( treatment c ) , were similar to those seen in juice at room temperature , although the bacteria in treatment c survived longer compared to incubation at room temperature . the highest c. jejuni survival was seen in treatment a : 90.6% , 18 h ; 56.7% , 24 h ; 0.35% , 48 h ; table 1 ) and the lowest survival was found in treatment c : 3.3% , 18 h ; 2.0% , 24 h ; 0.00074% ; 1 cfu / ml ; 48 h ; table 1 ) . the survival of c. jejuni in treatment b : 7.4% , 18 h ; 3.4% , 24 h ; 0.01% , equivalent to 18 cfu / ml ; 48 h , table 1 ) was lower than a but higher than c. statistically significant differences in survival were seen at 1824 h between a and b , and 1848 h between a and c ( kruskal wallis test with dunn 's multiple comparison test and bonferroni correction for multiple tests ; a and b : 18 h , p=0.0125 ; 24 h , p=0.005 ; a and c : 18 h , p=0.0001 ; 24 h , p=0.0002 ; 48 h , p=0.0489 ; fig . a. polyphaga did not show any protective effect on c. jejuni when heated to recommended pasteurization temperatures , neither in milk nor in orange juice ( data not shown ) . growth was totally inhibited in all samples from treatments a , b , and c. results were based on three independent experiments . campylobacter causes approximately 200,000 human infections annually in the european union , with sometimes very severe chronic complications such as guillain barre syndrome ( gbs ) ( 36 , 37 ) . in this study , we investigated the protective effect of the free - living amoeba a. polyphaga on c. jejuni survival in milk and orange juice . it is well known that drinking unpasteurized milk is a risk for acquiring c. jejuni infections ( 38 ) ; however , the consumption of unpasteurized milk and milk products ( 39 , 40 ) as well as unpasteurized juices is common in many countries ( 12 ) . the acidic ph in orange juice has been considered lethal to c. jejuni ( 23 , 41 ) , and therefore orange juices have not been considered a risk factor for acquiring campylobacteriosis . on the other hand , c. jejuni seem well adapted to survive the acidic milieu of the human stomach as well as disinfection with acid in poultry stables ( 42 , 43 ) . we have previously shown an increased acid tolerance of c. jejuni ccug 11284 in co - cultures with a. polyphaga ( 26 . free - living amoebae are common inhabitants of potable water plumbing systems ( 44 , 45 ) and fruit squeezing machines have surfaces that are difficult to clean , with possible formation of biofilms inhabited by amoebae as a result ( 32 , 3446 ) . hence , such systems could provide entry ports where the presence of amoeba could increase the c. jejuni survival and cause infections . as differences in bacterial survival were observed in a previous study depending on weather the bacteria were added to a. polyphaga before ( treatment a ) or after addition of acidified medium ( treatment b ) , we evaluated the effect of these two treatments in juice and milk ( 26 ) . we found significantly higher bacterial survival in co - cultures compared to when c. jejuni were incubated alone ( treatment c ) . in both products and at both temperatures , the highest survival was found in co - cultures where c. jejuni were added to a. polyphaga before the addition of the product ( treatment a ) . the effect of co - culture was most pronounced in juice stored at room temperature , as no c. jejuni survival was detected after 18 h in cultures with c. jejuni alone . also milk stored at room temperature and juice stored at 4c showed significantly higher bacterial survival in co - cultures , compared to when c. jejuni were incubated alone . however , in milk stored at 4c the bacterial survival at 24 h was not significantly affected by co - culture with amoebae and at 48 h , c. jejuni incubated alone ( treatment c ) actually survived better than in co - culture . this is consistent with previous studies reporting good survival of campylobacter in refrigerated milk ( 41 , 47 ) . in our previous study assessing c. jejuni survival in an acidified medium , we found the highest bacterial survival in co - cultures where c. jejuni were added after the addition of acidic media . in that study we found that the acid milieu triggered c. jejuni motility and uptake into the amoebae . however , the products tested here are more complex than a defined bacterial growth medium and other constituent of milk and juice may likely have affected the results . in the majority of cases , this was not studied by us , and hence possible c. jejuni protection from amoebae present in low concentrations needs to be evaluated in the future . high concentrations of amoebae could be present in contaminated water or by growth of amoebae in beverages stored at room temperature for a longer period of time . in all experiments the survival curves for c. jejuni in treatment a were characterized by an increase in bacterial concentration at the beginning of the experiments ( 3 and 6 h ) . this increase might be explained by extracellular c. jejuni residing in the adherent trophozoite layer . when the medium was changed from pyg to milk or juice these bacteria together , our results suggest that a. polyphaga can prolong c. jejuni survival both in milk and juice . it has been shown that legionellae increase their thermal resistance when co - cultured with acanthamoebae , and that intracellular legionellae pneumophila can survive temperatures up to 80c ( 48 ) . acanthamoebae cysts alone have been shown to survive at temperatures up to 80c and even up to 95c for at least 10 min ( 4850 ) . we studied if c. jejuni in co - culture with a. polyphaga could survive heating to recommended pasteurization temperatures for milk ( 7274c ) and juice ( 85c ) . however , a. polyphaga did not have any effect on c. jejuni survival during pasteurization of milk or orange juice , confirming that this is a good method for eliminating c. jejuni in these products . in conclusion , amoebae associated c. jejuni in milk and juice survived better than free bacteria both at room temperature and at 4c , but a. polyphaga could not protect the bacteria from pasteurization . OUTPUT:

background campylobacter jejuni is a common cause of human bacterial diarrhea in most parts of the world . most c. jejuni infections are acquired from contaminated poultry , milk , and water . due to health care costs and human suffering , it is important to identify all possible sources of infection . unpasteurized milk has been associated with several outbreaks of c. jejuni infection . campylobacter has been identified on fresh fruit , and other gastrointestinal pathogens such as salmonella , e. coli o157:h7 and cryptosporidium have been involved in fruit juice outbreaks . c. jejuni is sensitive to the acidic environment of fruit juice , but co - cultures with the amoeba , acanthamoeba polyphaga , have previously been shown to protect c. jejuni at low ph.methodsto study the influence of a. polyphaga on the survival of c. jejuni in milk and juice , the bacteria were incubated in the two products at room temperature and at 4c with the following treatments : a ) c. jejuni preincubated with a. polyphaga before the addition of product , b ) c. jejuni mixed with a. polyphaga after the addition of product , and c ) c. jejuni in product without a. polyphaga . bacterial survival was assessed by colony counts on blood agar plates.resultsco-culture with a. polyphaga prolonged the c. jejuni survival both in milk and juice . the effect of co - culture was most pronounced in juice stored at room temperature . on the other hand , a. polyphaga did not have any effect on c. jejuni survival during pasteurization of milk or orange juice , indicating that this is a good method for eliminating c. jejuni in these products.conclusionamoebae-associated c. jejuni in milk and juice might cause c. jejuni infections .

PubMed_Summ6565

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: control subjects were consecutive patients seen at the hospital among individuals without diabetes and any retinal or eye pathological conditions . individuals were excluded from participation if they were aged > 70 years , were of nonwhite ethnic background , had a history of epilepsy or glaucoma , had previous vitreal surgery , and/or had a cataract on examination . all participants and control subjects had a standardized clinical examination , measurement of blood chemistry , retinal photographs , and assessment of flicker - induced vasodilation using the dynamic vessel analyzer ( dva ; imedos , jena , germany ) . tenets of the declaration of helsinki were followed , institutional review board approval was granted , and written informed consent was obtained from all participants . the dva measures retinal vessel dilation in response to diffuse luminance flicker ( 12 ) . the participant focused on the tip of a fixation bar within the retinal camera while the fundus was examined under green light . an arteriole and venule segment between one - half and two disc diameters from the margin of the optic disc were selected . the mean diameters of the arterial and venous vessel segments were calculated and recorded automatically . baseline vessel diameter was measured for 50 s , followed by a provocation with flicker light of the same wavelength for 20 s and then a nonflicker period for 80 s. this measurement cycle was repeated twice , with a total duration of 350 s / eye . when the eye blinked or moved , the system automatically stopped the measurement and restarted it once the vessel segments were automatically reidentified . retinal arteriolar and venular dilation in response to flicker light was calculated automatically by the dva software . it was represented as an average increase in the vessel diameter in response to the flicker light during the three measurement cycles and was defined as the percent increase relative to the baseline diameter size . in addition to quantifying the flicker - induced vasodilation , we assessed overall static arteriolar and venular diameter using a computer - assisted program . details of the digital image preparation are described elsewhere ( 15 ) . in brief , diameters of the largest six arterioles and venules passing through the circular zone between one - half and one disc diameter away from the optic disc margin were summarized as the central retinal arteriolar equivalent and central retinal venular equivalent using the parr - hubbard formula further modified by knudtson and colleagues ( 15 ) . fasting blood samples were drawn from participants at suburban pathology centers for measurement of fasting blood glucose level within 2 weeks of their eye testing . all participants with diabetes were patients recruited from the diabetic eye clinics and were managed with oral hypoglycemic mediations and/or insulin . control subjects ( individuals without diabetes ) had confirmed nondiabetic status based on a lack of history of diabetes and fasting glucose < 7.0 mmol / l ( 126 mg / dl ) . in participants with diabetes , diabetic retinopathy was graded from fundus photographs at the centre for eye research australia , by graders masked to clinical details . for each eye , a retinopathy severity score was assigned based on modification of the airlie house classification system ( 16 ) . for our analysis , levels 10 , 11 , and 12 were defined as no diabetic retinopathy , 14 to 20 as minimal nonproliferative diabetic retinopathy ( npdr ) , 31 and 41 as early to moderate npdr , and 5180 as severe npdr ( proliferative diabetic retinopathy ) . a detailed questionnaire was used to obtain participant information , including past medical history , current cigarette smoking , and the use of antihypertensive and lipid - lowering medications . hypertension was defined as systolic blood pressure ( sbp ) > 140 mmhg , diastolic blood pressure ( dbp ) > 90 mmhg , or current use of antihypertensive medications . dyslipidemia was defined as cholesterol > 5.5 mmol / l or triglyceride > 2.0 mmol / l or current use of lipid - lowering medications . fasting blood samples were drawn from participants at suburban pathology centers for fasting blood glucose level , cholesterol and triglyceride levels , and a1c within 2 weeks of their eye testing . induced retinal vasodilation between individuals with diabetes and control subjects and in individuals with diabetes between those with and without dr . flicker - induced arteriolar / venular dilation was analyzed as percent increase over baseline diameter , both as a continuous measure and in categories ( tertiles ) . multiple logistic regression models were constructed using the generalized estimating equation models to account for correlation between the right and left eyes and to assess the odds of diabetes ( vs. nondiabetic control subjects ) or diabetic retinopathy ( vs. no diabetic retinopathy among subjects with diabetes ) , comparing the lower versus upper tertiles of flicker light in addition , multiple linear regression models were used to estimate the mean difference in arteriolar and venular dilation . we initially adjusted for age , sex , and fasting blood glucose level ( model 1 ) and further adjusted for duration of diabetes ( in analysis of diabetic patients ) , use of antihypertensive and lipid - lowering medications , current smoking status , sbp , and cholesterol and triglyceride levels ( model 2 ) . analyses were performed in stata ( version 10.1 ; statacorp , college station , tx ) . the dva measures retinal vessel dilation in response to diffuse luminance flicker ( 12 ) . the participant focused on the tip of a fixation bar within the retinal camera while the fundus was examined under green light . an arteriole and venule segment between one - half and two disc diameters from the margin of the optic disc were selected . the mean diameters of the arterial and venous vessel segments were calculated and recorded automatically . baseline vessel diameter was measured for 50 s , followed by a provocation with flicker light of the same wavelength for 20 s and then a nonflicker period for 80 s. this measurement cycle was repeated twice , with a total duration of 350 s / eye . when the eye blinked or moved , the system automatically stopped the measurement and restarted it once the vessel segments were automatically reidentified . retinal arteriolar and venular dilation in response to flicker light was calculated automatically by the dva software . it was represented as an average increase in the vessel diameter in response to the flicker light during the three measurement cycles and was defined as the percent increase relative to the baseline diameter size . in addition to quantifying the flicker - induced vasodilation , we assessed overall static arteriolar and venular diameter using a computer - assisted program . details of the digital image preparation are described elsewhere ( 15 ) . in brief , diameters of the largest six arterioles and venules passing through the circular zone between one - half and one disc diameter away from the optic disc margin were summarized as the central retinal arteriolar equivalent and central retinal venular equivalent using the parr - hubbard formula further modified by knudtson and colleagues ( 15 ) . fasting blood samples were drawn from participants at suburban pathology centers for measurement of fasting blood glucose level within 2 weeks of their eye testing . all participants with diabetes were patients recruited from the diabetic eye clinics and were managed with oral hypoglycemic mediations and/or insulin . control subjects ( individuals without diabetes ) had confirmed nondiabetic status based on a lack of history of diabetes and fasting glucose < 7.0 mmol / l ( 126 mg / dl ) . in participants with diabetes , diabetic retinopathy was graded from fundus photographs at the centre for eye research australia , by graders masked to clinical details . for each eye , a retinopathy severity score was assigned based on modification of the airlie house classification system ( 16 ) . for our analysis , levels 10 , 11 , and 12 were defined as no diabetic retinopathy , 14 to 20 as minimal nonproliferative diabetic retinopathy ( npdr ) , 31 and 41 as early to moderate npdr , and 5180 as severe npdr ( proliferative diabetic retinopathy ) . a detailed questionnaire was used to obtain participant information , including past medical history , current cigarette smoking , and the use of antihypertensive and lipid - lowering medications . hypertension was defined as systolic blood pressure ( sbp ) > 140 mmhg , diastolic blood pressure ( dbp ) > 90 mmhg , or current use of antihypertensive medications . dyslipidemia was defined as cholesterol > 5.5 mmol / l or triglyceride > 2.0 mmol / l or current use of lipid - lowering medications . fasting blood samples were drawn from participants at suburban pathology centers for fasting blood glucose level , cholesterol and triglyceride levels , and a1c within 2 weeks of their eye testing . we compared flicker light induced retinal vasodilation between individuals with diabetes and control subjects and in individuals with diabetes between those with and without dr . flicker - induced arteriolar / venular dilation was analyzed as percent increase over baseline diameter , both as a continuous measure and in categories ( tertiles ) . multiple logistic regression models were constructed using the generalized estimating equation models to account for correlation between the right and left eyes and to assess the odds of diabetes ( vs. nondiabetic control subjects ) or diabetic retinopathy ( vs. no diabetic retinopathy among subjects with diabetes ) , comparing the lower versus upper tertiles of flicker light in addition , multiple linear regression models were used to estimate the mean difference in arteriolar and venular dilation . we initially adjusted for age , sex , and fasting blood glucose level ( model 1 ) and further adjusted for duration of diabetes ( in analysis of diabetic patients ) , use of antihypertensive and lipid - lowering medications , current smoking status , sbp , and cholesterol and triglyceride levels ( model 2 ) . analyses were performed in stata ( version 10.1 ; statacorp , college station , tx ) . selected characteristics of normal control subjects ( n = 103 ) , participants with diabetes ( n = 224 , 85 with type 1 and 139 with type 2 diabetes ) , and those with ( n = 144 ) and without ( n = 80 ) diabetic retinopathy are shown in table 1 . mean age was 56.5 11.8 years in subjects with diabetes and 48.0 16.3 years in control subjects . the proportion of men was similar for participants with diabetes ( 41.6% ) and control subjects ( 39.4% ) . compared with nondiabetic control subjects , participants with diabetes were less likely to be current smokers but had higher bmi and were more likely to have hypertension , dyslipidemia , lower dbp , and lower total cholesterol levels . compared with those with type 1 diabetes , individuals with type 2 diabetes were older , had greater bmi , but a shorter duration of diabetes , and were more likely to have hypertension and dyslipidemia ( data not shown ) . in participants with diabetes , those with diabetic retinopathy had a longer duration of diabetes , had higher sbp , and were more likely to have hypertension . in addition , participants with diabetes had wider static arteriolar diameter than nondiabetic control subjects , whereas those with diabetic retinopathy had wider retinal venules than those without ( table 1 ) . participant characteristics ( age - adjusted means and proportions ) comparing participants with diabetes and normal control subjects , and , among participants with diabetes , those with and without diabetic retinopathy data are means unless stated otherwise . means and proportions are adjusted for age ( set to mean age of 53.8 years old ) , except for age . * comparing those with diabetic subjects and normal control subjects , adjusted for age . comparing those with and without diabetic retinopathy in those with diabetes , adjusted for age . induced retinal vasodilation was reduced in participants with diabetes compared with that in control subjects ( table 2 ) . induced arteriolar dilation was 1.43 2.10% in participants with diabetes and 3.46 2.36% in normal control subjects ( p < 0.001 after adjustment for age , sex , fasting glucose , cholesterol and triglyceride levels , use of antihypertensive and lipid - lowering medications , and current smoking status ) . retinal arteriolar dilation was not significantly different by type of diabetes : 1.57% in those with type 1 and 1.24% in those with type 2 diabetes ( p = 0.98 ) . induced venular dilation was 2.83 2.10% in individuals with diabetes and 3.98 1.84% in normal control subjects ( p < 0.001 after multivariable adjustment ) and again was not significantly different by type of diabetes : 2.84% in those with type 1 and 2.83% in those with type 2 diabetes ( p = 0.99 ) . mean differences in flicker light induced vasodilation between participants with diabetes and normal control subjects and by grades of diabetic retinopathy severity in participants with diabetes * adjustment for age , sex , fasting cholesterol and triglyceride levels , use of antihypertensive and lipid - lowering medications , current smoking status , and fasting glucose ( for analysis of diabetic retinopathy severity ) . table 3 shows that after multivariable adjustment , individuals with reduced flicker light induced vasodilation were more likely to have diabetes ( odds ratios [ ors ] 19.7 and 8.1 , comparing the lowest versus the highest tertile of arteriolar and venular dilation , respectively ) . among participants with diabetes , those with reduced flicker induced dilation were more likely to have diabetic retinopathy ( ors 2.2 and 2.5 , respectively , for arteriolar and venular dilation ) ( table 4 ) . these associations persisted after further adjustment for static arteriolar / venular diameters ( tables 3 and 4 , model 3 ) . associations between reduced flicker - induced arteriolar and venular dilation and diabetes data are ors ( 95% ci ) unless indicated otherwise . model 2 : adjusted for covariates in model 1 plus diabetes duration , use of antihypertensive and lipid - lowering medications , current smoking status , sbp , and fasting cholesterol and triglyceride levels . model 3 : adjusted for covariates in model 2 plus static retinal arteriolar or venular diameter . associations between reduced flicker - induced arteriolar and venular dilation and diabetic retinopathy data are ors ( 95% ci ) unless indicated otherwise . model 2 : adjusted for covariates in model 1 plus diabetes duration , use of antihypertensive and lipid - lowering medications , current smoking status , sbp , and fasting cholesterol and triglyceride levels . model 3 : adjusted for covariates in model 2 plus static retinal arteriolar or venular diameter . * the distribution of diabetic retinopathy severity was not significantly different between those with type 1 and type 2 diabetes ( p = 0.57 , data not shown ) . however , the association of reduced flicker light induced vasodilation with diabetic retinopathy was stronger in participants with type 1 diabetes ( arteriolar dilation or 3.1 [ 95% ci 1.18.5 ] ; venular dilation or 3.8 [ 95% ci 1.410.0 ] ) compared with those with type 2 diabetes ( arteriolar dilation or 1.8 [ 95% ci 0.84.0 ] ; venular dilation or 1.3 [ 95% ci 0.63.1 ] ) , although the interaction with type of diabetes was not statistically significant ( p value for interaction term : p = 0.50 for arteriolar dilation and p = 0.09 for venular dilation ) . in this study , we demonstrated a reduction in flicker light induced retinal arteriolar and venular dilation in individuals with diabetes compared with nondiabetic control subjects and , among individuals with diabetes , in those with retinopathy signs . importantly , we showed that these associations were independent of major risk factors for either diabetes or diabetic retinopathy and independent of static measurements of retinal arterioles and venular diameters . ( 17 ) examined 26 healthy control subjects and 26 individuals with type 1 diabetes who had none or minimal npdr and were not receiving antihypertensive treatment , whereas mandecka et al . ( 14 ) examined 240 individuals with diabetes ( 68 with type 1 and 172 with type 2 diabetes ) and 58 control subjects . both showed reduced flicker light vasodilation in those with diabetes ( compared with those without diabetes ) . furthermore , mandecka et al . also demonstrated a reduction in flicker light vasodilation with increasing diabetic retinopathy severity , while controlling only for age , sex , and use of antihypertensive medications . we have now shown that the relationship of flicker light induced vasodilation and both diabetes and diabetic retinopathy are independent of major confounders and risk factors for diabetic retinopathy , including duration of diabetes and glycemic control . retinal neuronal stimulation by flicker light results in retinal vessel dilation . this response probably reflects endothelial function ( 14 ) , given the documented role of nitric oxide in this flickering light induced vasodilation ( 13,18,19 ) . in a study by dorner et al . ( 13 ) , n - monomethyl - l - arginine , an inhibitor of nitric oxide synthase , blunted this flicker - induced vasodilation in healthy individuals . in addition , impaired response to flicker light stimulation in individuals with hypertension could be restored by angiotensin ii subtype 1 receptor blockade ( 20 ) . however , this finding has been documented only in individuals without diabetes . it was hypothesized previously that the decreased endothelial dysfunction in subjects with diabetes is associated with impaired nitric oxide action because of its inactivation resulting from increased oxidative stress and that abnormal nitric oxide metabolism is related to advanced diabetic microvascular complications ( 21 ) . this hypothesis is supported by recent data demonstrating similar retinal arteriolar and venular dilation after a single sublingual dose of 0.8 mg nitroglycerin between 20 patients with insulin - treated diabetes with no or only mild npdr and 20 healthy age - matched control subjects ( 22 ) . however , it is becoming increasingly clear that neuronal cells of the retina are also affected by diabetes , resulting in dysfunction and degeneration ( 23 ) , and diabetic retinopathy is a disease of both retinal neurons and microcirculation ( 24 ) . because retinal blood flow is coupled with neuronal activity ( 25 ) , reduced flicker light induced vasodilation can thus also reflect neurodegeneration ( 17,24 ) . in our study , significantly reduced flicker light induced vasodilation was observed in diabetic subjects with diabetic retinopathy compared with those without diabetic retinopathy . this relationship appeared to be stronger among individuals with type 1 diabetes than among those with type 2 diabetes , given the similar distribution of diabetic retinopathy severity between the two groups . this observation could be due to longer diabetes duration in those with type 1 diabetes ( mean 22.1 years for type 2 diabetes vs. 12.6 years for type 2 diabetes ) , resulting in possibly a greater level of impairment of retinal vascular autoregulation ( 26 ) , endothelial damage ( 26 ) , or neurodegeneration ( 17,24 ) . alternatively , the underlying mechanisms of diabetic retinopathy may be different in type 1 and type 2 diabetes . the strengths of this study include quantitative measures of retinal vasodilation after flicker light stimulation , assessment of diabetic retinopathy from fundus photographs using standardized grading protocols , and one researcher ( t.t.n . ) performing all dva measurements . limitations of this study should also be noted . first , the cross - sectional nature of the study provides no temporal information on the associations reported . second , our findings are only applicable to individuals with diabetes who are aged 70 years . thus , further longitudinal studies are needed to ascertain cause and effect and to correlate flicker - induced vasodilation with retinal neuronal functions using tests such as electroretinography . in summary induced retinal vasodilation in individuals with diabetes and , among those with diabetes , in those with retinopathy signs . these findings further support the concept that early endothelial dysfunction is a likely key pathophysiological mechanism that underlies diabetes and its microvascular complications . OUTPUT:

objectiveflicker light induced retinal vasodilation may reflect endothelial function in the retinal circulation . we investigated flicker light induced vasodilation in individuals with diabetes and diabetic retinopathy.research design and methodsparticipants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects . flicker light induced retinal vasodilation ( percentage increase over baseline diameter ) was measured using the dynamic vessel analyzer . diabetic retinopathy was graded from retinal photographs.resultsmean sd age was 56.5 11.8 years for those with diabetes and 48.0 16.3 years for control subjects . mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects ( 1.43 2.10 vs. 3.46 2.36% , p < 0.001 for arteriolar and 2.83 2.10 vs. 3.98 1.84% , p < 0.001 for venular dilation ) . after adjustment for age , sex , diabetes duration , fasting glucose , cholesterol and triglyceride levels , current smoking status , systolic blood pressure , and use of antihypertensive and lipid - lowering medications , participants with reduced flicker light induced vasodilation were more likely to have diabetes ( odds ratio 19.7 [ 95% ci 6.559.1 ] , p < 0.001 and 8.14 [ 3.121.4 ] , p < 0.001 , comparing lowest vs. highest tertile of arteriolar and venular dilation , respectively ) . diabetic participants with reduced flicker light induced vasodilation were more likely to have diabetic retinopathy ( 2.2 [ 1.24.0 ] , p = 0.01 for arteriolar dilation and 2.5 [ 1.34.5 ] , p = 0.004 for venular dilation).conclusionsreduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and , in individuals with diabetes , with diabetic retinopathy . our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations .

PubMed_Summ6566

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: de lamorce dune antirtrovirothrapie prophylactique associative ( arpa ) contenant du raltgravir ( ral ) sur la charge virale ( cv ) du vih chez les femmes enceintes do nt la suppression de la cv est leve ou sous - optimale en fin de grossesse . les chercheurs ont extrait le dossier des femmes enceintes infectes par le vih qui avaient amorc une arap contenant du ral aprs 28 semaines de grossesse dans deux centres hospitaliers universitaires entre 2007 et 2013 . onze femmes infectes ont entrepris un traitement de ral une mdiane de 35,7 semaines de grossesse ( plage de 31,1 38,0 semaines ) . les indications pour entreprendre le ral taient une prsentation tardive au suivi de grossesse ( n=4 ) et une suppression sous - optimale de la cv en raison dun mauvais respect du traitement ou dune rsistance virale ( n=7 ) . la cv moyenne au dbut du traitement au ral tait de 73 959 copies / ml ( plage de moins de 40 copies / ml 523 975 copies / ml ) . les patientes ont pris du ral pendant une mdiane de 20 jours ( plage de un 71 jours ) . la diminution moyenne de la cv entre le dbut du ral et laccouchement tait de 1,93 log , lexception dune patiente qui na reu quune dose de ral et dune patiente do nt la cv ntait pas dcelable au moment dentreprendre le ral . au bout de huit jours de ral , 50 % des femmes prsentaient une cv infrieure 1 000 copies / ml ( le seuil pour recommander une csarienne afin de rduire le risque de transmission prinatale ) . la prsente tude fournit des donnes provisoires pour soutenir lutilisation darpa contenant du ral afin dacclrer la rduction de la cv du vih-1 chez les femmes qui prsentaient une cv leve ou une suppression sous - optimale de leur cv pendant la grossesse , ainsi que pour rduire le risque de transmission prinatale du vih tout en vitant une csarienne . a retrospective review of two canadian hiv perinatal databases ( those of the oak tree clinic at bc woman s hospital , vancouver , british columbia , and of the grossesse avec maladie infectieuse clinic at sainte - justine hospital , montreal , quebec ) was conducted to identify hiv - infected pregnant women who initiated treatment with ral ( 400 mg twice per day orally ) after 28 weeks gestation . data collected between 2007 , the year when ral became available , and december 2013 were reviewed . each patient s chart was then retrospectively abstracted for data including ral indication , tolerance and timing of exposure . the standard of care in both clinics included treatment of hiv - infected pregnant women with cart regardless of baseline cd4 cell - count and hiv-1 vl , as well as assessment of the women s clinical , virological and immunological status every four weeks . infants were evaluated at least at birth , two weeks of age , one month of age and then every three to four months until 18 months of age . hiv - negative status in infants was defined presumptively by at least two negative hiv rna polymerase chain reaction test results before four months of age , and confirmed by the absence of hiv-1 antibody at 18 months of age . maternal and neonatal adverse reactions were systematically addressed according to who criteria ( 27 ) , with specific attention devoted to hematological and hepatic complications . hiv-1 vl was measured either using the ultrasensitive amplicor hiv-1 monitor test or cobas taqman hiv-1 test , v1.0 ( roche molecular systems inc , usa ) for cases in vancouver , and the abott realtime hiv-1 assay ( abbott molecular inc , usa ) for cases in montreal . the study was approved by the institutional review board of each centre . a descriptive analysis of population characteristics a nonparametric survival analysis was then conducted to compute the time to achieve a vl < 50 copies / ml and < 1000 copies / ml , respectively . the statistical analysis was performed using r version 2.11.1 ( r core team , 2013 ) . a descriptive analysis of population characteristics was performed . because of the non - normal distribution , median and range are reported . a nonparametric survival analysis was then conducted to compute the time to achieve a vl < 50 copies / ml and < 1000 copies / ml , respectively . the statistical analysis was performed using r version 2.11.1 ( r core team , 2013 ) . a total of 11 women who initiated ral during the third trimester of their pregnancies were identified . three women ( cases 3 , 5 and 7 ) had a new diagnosis of hiv during the current pregnancy . the median gestational age at their first clinic visit was 24 weeks ( range seven to 35 weeks ) . the median duration of consistent cart received was 42 days ( range seven to 202 days ) . indications for ral were late presentation in pregnancy ( n=4 ) and suboptimal vl reduction secondary to poor adherence or viral resistance ( n=7 ) . all patients received ral in combination with at least two other active antiretroviral agents , started at a median gestational age of 35.7 weeks ( range 31.1 to 38.0 weeks ) . exposure duration was a median of 20 days ( range one to 71 days ) . the median gestational age at delivery was 38.7 weeks ; one patient ( case 9 ) delivered at 35 weeks in a context of spontaneous preterm labor . at the time of delivery , nine women had a hiv vl < 1000 copies / ml , of which seven were < 50 copies / ml . figure 1 summarizes the typical vl evolution after ral initiation . among the 11 women , three had a vaginal delivery , three had a caesarean section for obstetrical indications and five had a caesarean section to further decrease the risk of hiv perinatal transmission . three of these caesarean sections could have been avoided ( ie , the vl was below threshold of 1000 copies / ml ) if the hiv vl had been known at the time of the delivery . there were no cases of hiv perinatal transmission observed in the in utero - exposed infants . one infant ( case 11 ) presented a transient symptomatic cardiac arrhythmia at birth , as well as unilateral hydronephrosis and skin abnormalities ( nevus , four nipples ) , which were not prenatally diagnosed . the following two cases were excluded from subsequent analysis : one woman ( case 3 ) had an undetectable vl at ral initiation . she was initially started with a combination regimen with zidovudine , lamivudine and ritonavir - boosted lopinavir at 28 weeks and four days . however , she had adherence issues in a context of a newly diagnosed hiv infection in pregnancy with hepatitis c coinfection and substance use . the woman was admitted for directly observed therapy and ral was started at 33 weeks to rapidly suppress her vl . at the time of ral initiation , the last available vl result ( measured two weeks previously ) was 1762 copies / ml , and the woman reported poor adherence to her cart regimen during this time period . retrospectively , it was determined that at the time of ral initiation , her vl was undetectable ; however , because of concerns surrounding adherence and risk of resistance rise , ral was pursued . the woman discharged herself from hospital for three days at approximately 35 weeks gestation but returned with a positive urine cocaine screen . she had a vaginal delivery at 38 weeks and five days gestation with a confirmed undetectable vl.one woman ( case 10 ) received only one dose of ral . her pregnancy had been complicated by poor adherence and intolerance to cart . at 37 weeks gestation , she was admitted for supervised cart , and her vl was found to be 232,245 copies / ml . as soon as this result was known , ral was added to her regimen to attempt a rapid and maximal suppression of the hiv vl before delivery . however , 3 h after receiving the first dose of ral the woman experienced spontaneous rupture of membranes and went into active labour . she was initially started with a combination regimen with zidovudine , lamivudine and ritonavir - boosted lopinavir at 28 weeks and four days . however , she had adherence issues in a context of a newly diagnosed hiv infection in pregnancy with hepatitis c coinfection and substance use . the woman was admitted for directly observed therapy and ral was started at 33 weeks to rapidly suppress her vl . at the time of ral initiation , the last available vl result ( measured two weeks previously ) was 1762 copies / ml , and the woman reported poor adherence to her cart regimen during this time period . retrospectively , it was determined that at the time of ral initiation , her vl was undetectable ; however , because of concerns surrounding adherence and risk of resistance rise , ral was pursued . the woman discharged herself from hospital for three days at approximately 35 weeks gestation but returned with a positive urine cocaine screen . she had a vaginal delivery at 38 weeks and five days gestation with a confirmed undetectable vl . her pregnancy had been complicated by poor adherence and intolerance to cart . at 37 weeks gestation , she was admitted for supervised cart , and her vl was found to be 232,245 copies / ml . as soon as this result was known , ral was added to her regimen to attempt a rapid and maximal suppression of the hiv vl before delivery . however , 3 h after receiving the first dose of ral the woman experienced spontaneous rupture of membranes and went into active labour . in the remaining nine women , median vl at ral initiation was 88,707 copies / ml ( range 246 to 523,975 copies / ml ; mean 73,959 copies / ml ) . the mean decline of vl from time of ral initiation to delivery was 1.93 log10 copies / ml ( 95% ci 1.32 to 2.53 log10 copies / ml ) ( figure 1 ) . in the four women who received < 2 weeks of ral , the mean vl decrease was 1.82 log10 copies / ml . in the four women who had an initial vl > 4 log10 copies / ml , the mean decrease was 2.65 log10 copies / ml . after eight days on ral , 50% of the women achieved a vl < 1000 copies / ml ( figure 2 ) . similarly , 50% of the women achieved a vl < 50 copies / ml after 26 days on ral . an asymptomatic elevation of liver enzyme levels ( 11- and fivefold the upper limit of normal of alanine aminotransferase and aspartate aminotransferase , respectively ) was noted in a woman for whom ral was added to a combination of zidovudine , lamivudine and ritonavir - boosted lopinavir because of late presentation . the elevation of liver enzyme levels was first observed after five days on ral , without signs of preeclampsia or cholestasis . the status regarding hepatitis a , b and c infections was confirmed to be negative . in our experience , adding ral to a cart regimen was useful in rapidly reducing hiv-1 vl to prevent perinatal transmission in women who have high vl or suboptimal suppression late in pregnancy . our findings are consistent with previously published cases of ral use late in pregnancy , which are summarized in table 2 ( 8,1518,2022,2426,28 ) . among these , only one case of perinatal transmission has been reported ( 8) ; the clinical presentation in that case suggested in utero hiv transmission . we were able to confirm the drastic and rapid decrease of hiv vl after ral initiation , and computed a median time to achieve vl < 1000 copies / ml ( eight days ) , information that will be useful in the clinical setting . moreover , important limitations of the present case series include the absence of data regarding resistance to integrase inhibitors among the women treated , and regarding maternal and neonatal ral plasma concentrations . published data indicate that , despite a reduction of ral median area under the curve by approximately 50% during pregnancy ( 29 ) , ral readily crosses the placenta and achieves adequate concentrations in the neonate , with mean cord blood - maternal blood drug ratios of 1.5 ( range 0.32 to 9.5 ) ( 15,16,22,28 ) . else et al ( 30 ) found that ral achieves the highest placental / neonatal concentration among available antiretroviral medications . explanations for effective placental transfer of ral include its relatively low protein binding and small molecular weight , as well as its favourable ph - dependent lipophilicity , which results in increased amount of ionized drug in the fetal circulation ( 11,22,30,31 ) . a high cord : maternal serum ratio reflects a high placental transfer but also a neonatal accumulation . the ability of fetuses to metabolize and eliminate ral on their own is likely limited by the immaturity of ugt - glucuronidation pathways ( 22,32 ) . we observed a 1.82 log10 copies / ml decrease in hiv vl within two weeks of receipt of a ral - containing cart regimen , which is faster than the mean time of approximately five weeks to suppression that is typically observed with traditional cart ( 33 ) . this finding is consistent with the vl reductions ( 2 log10 copies / ml within 10 to 14 days of receipt of a ral - based regimen ) observed in randomized controlled trials using ral - based regimens ( 1214 ) and in observational studies investigating ral administration late in pregnancy ( 8,15,16,18,21 ) . the reported case of liver toxicity ( 23 ) is , to our knowledge , the second that has been described with ral use in pregnancy ( 29 ) . although hepatotoxicity is one of the well - recognized side effects of antiretroviral drugs , it has not been commonly associated with ral therapy , with increase of aspartate aminotransferase and alanine aminotransferase levels > 5 times the upper limit of normal seen in only 5% of exposed individuals ( 31,34 ) . sufficient data are not yet available to conclude whether the risk of hepatotoxicity is higher in pregnancy . close follow - up of liver enzyme levels in pregnant women treated with ral would be prudent until more safety data are available . the infant who was diagnosed with cardiac arrhythmia , unilateral hydronephrosis and skin anomalies had been exposed to ral in utero for 35 days , starting at 36 weeks gestation . because of this timing , the congenital anomalies are not likely related to ral exposure . however , safety data regarding ral exposure in pregnancy are weak , and it remains a category c drug ( 31 ) . considering the potential advantages of ral noted above , it remains to be determined whether its ability to rapidly reduce vl in late pregnancy will reduce the need for caesarean delivery and the rate of perinatal transmission for women who present near term with high vl . this would benefit hiv - infected women , particularly those with low cd4 cell counts , considering the increased risk of postpartum complications related to caesarean delivery ( 35,36 ) . an important factor to consider , however , is the availability of rapid hiv quantitative test to follow the vl and allow for a safe vaginal delivery . indeed , in previously published cases of pregnant women treated with ral ( 8,15,16,18,2022,2426 ) as well as in the three cases presented here , vl were retrospectively found to be < 1000 copies / ml after caesarean section was performed to decrease the risk of perinatal transmission . availability of rapid hiv quantitative polymerase chain reaction would assist the clinician to better decide whether caesarean delivery is indicated , according to their national guidelines ( 4,5 ) . our findings support the consideration of the use of ral to reduce the risk of perinatal transmission in late - presenting hiv - infected pregnant women and in women with vl rebound near term . however , long - term data are needed to assess the impact of ral use for short - term therapy in the obstetrical setting on the resistance profile . indeed , there is a legitimate concern about the effectiveness of future ral - based regimens . moreover , current canadian ( 5 ) and united states perinatal guidelines ( 4 ) are permissive but do not advocate for ral use in this setting due to the lack of established data . the results of two ongoing clinical trials ( nct01854762 and nct01618305 ) will help to assess advantages of ral compared with other antiretrovirals in pregnancy . further research needs to be performed to understand the role of ral in women with hiv acquisition in pregnancy , who are at even higher risk for perinatal transmission . OUTPUT:

the use of antiretroviral therapy ( art ) has led to a marked reduction in the incidence of perinatal transmission of hiv . with art , it is possible for the viral load to be reduced to undetectable levels during pregnancy . however , some patients ( eg , those with poor adherence or those who acquired hiv during pregnancy ) may still exhibit high viral loads by the third trimester . the purpose of this study was to examine the effect of raltegravir in a combination art regimen in a series of 11 cases in which women presented with high viral loads in the third trimester of pregnancy .

PubMed_Summ6567

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: massotherapy , defined as a manipulation of the soft tissues , is often provided to specific areas or whole body parts aiming at the following effects : enhanced blood flow , relief of muscle tension , improvement of autonomic nerve functions , prevention of bad conditions or injuries , and easing of pains1,2,3 . in recent years , massages have been admitted in international treatment guidelines4 , 5 as one of the recommended therapies requiring further scientific verification . massages are provided in the following cases : subcutaneous emphysema caused by fracturing the breastbone or ribs , external injuries , chest bruises , and crashes6 ; treatment at childbirth that shortens the delivery time7 ; healing of cobb angle of idiopathic scoliosis8 ; relief of patients suffering from musculoskeletal disorders including back pain9 . massages are reported to be effective to alleviate pain and to enhance bodily functions . however , while these reports refer to the effects of massages , there are some cases which do not actively research the mechanism for how the massage is effective . therefore , there are those who insist that massotherapy lacks scientific evidence and needs to be verified scientifically10,11,12 . in clinical practice , we obtained certain effects such as the relief of pain or improvement of the range of joint motion by providing friction to patients with popliteal edemas due to osteoarthritis of the knees or disorder of venous flow . hammer s report referred to histamine or bradykinin as the elements involved in the effects of friction provided to chronic bursitis of the hip and shoulder joints14 . it was assumed that the effect to alleviate pain or to enhance the range of motion after providing friction would facilitate healing of edemas and relief of pain while enhancing the blood flow of the popliteal vein caused by the vascular dilatation or the vasodilator action by use of histamine or bradykinin . physiologically , the lower legs venous sinuses play a major role in venous return , and venous sinuses in the soleus and gastrocnemius play the main role . anatomically , these venous sinuses flow into the popliteal vein directly and indirectly through the posterior tibial and peroneal veins . accordingly , the condition of lower legs venous return is reflected in the rate of blood flow passing through the popliteal vein . it was clarified that friction massage of the region below the popliteal fossa causes dynamic changes in muscle oxygenation15 , but it was unclear what influence this effect has on venous return . based on this assumption , an aim was set at researching the influences of friction on the popliteal region as a manipulation of the body surface , and at considering the mechanism of friction s effects from the viewpoint of venous flow . during this study , friction massage was performed on the area surrounding the popliteal vein in healthy volunteers . friction massage was performed on the intermediate point between the medial and lateral heads of the gastrocnemius muscle . friction massage was performed by the thumbs , moving them in small circles ( 23 cm ) at a frequency of 3 hz . changes in blood flow velocity of the popliteal vein was monitored before and after intervention ( a comparative study : after versus before ) . fifteen male students who satisfied the selection criteria were gathered from ibaraki prefectural university of health sciences as subjects ( means sd : age=21.4 1.7 years ) . the subjects signed a letter of consent after the purpose of the study , method , benefits and risks , and rights of participants were explained . exclusion criteria were as follows : diagnosis or evidence of any cardiovascular , metabolic , orthopedic , neurological or endocrine disease that are known to affect endothelial function ; use of any medication that can interfere with cardiovascular function ; and a risk of adverse response to exercise . the study protocol was approved in advance by the authors institutional review board and adhered to the declaration of helsinki . written informed consent was obtained from all of the individual participants included in the study . the subjects underwent a single testing session in which all of the experimental procedures were conducted . before reporting to the laboratory , subjects were asked to fast and refrain from caffeine , tobacco , alcohol , and strenuous physical activity for at least 12 h before the experiment . the measurement profiles of the blood flow velocity were obtained from pictures of the right popliteal vein by reference to the international guideline17 . based on all the pictures , the sizes in vein diameter and blood flow were analyzed utilizing a logiq book xp ( ge healthcare products , milwaukee , wi , usa ) system with an 8 mhz linear transducer . the pictures of popliteal veins were identified in the b mode on the location two centimeters from the central region of the popliteal fossa . gain settings were adjusted in order to get appropriate views of the front and the rear of the intimal interfaces of veins , thus identifying the vein in the color doppler - mode . a measurement setting was then conducted for the vascular caliber ( sample volume ) of the popliteal veins . doppler velocity profiles were collected simultaneously using a pulsed signal at a corrected insonation angle of 60 to the vessel , with the velocity cursor positioned mid - artery to sample the volume . all pictures were captured by a usb video board at a frequency of 30 hz , and then saved in the external hard drive in order to be analyzed offline afterwards . measurement of the popliteal vein was conducted using doppler ultrasonography with the subjects in a prone position . initially , the subjects were placed in a prone position for 20 minutes at a constant temperature of 2426 c ( relative humidity at 4060% ) for acclimation according to the experimental protocol ( fig . after that , the blood flow velocity of the popliteal vein was measured for the first time . next , friction was provided for two minutes and then the blood flow velocity was measured for the second time . the transition was then analyzed with the first measured value set as the base line . measurement parameters , such as average blood flow velocity ( v mean ) , pulsatility index ( pi ) , and resistance index ( ri ) , were utilized18 , 19 . experimental protocol statistical analyses focused on differences between pre - friction and post - friction blood flow velocity states of the popliteal veins measured using doppler sonography . changes in parameters were compared using within - subject paired t - tests . participants characteristics are shown in table 1table 1.characteristics of study participantsparameters(n=15)age ( years)21.4 1.7height ( cm)173.6 3.8weight ( kg)59.3 3.2bmi ( kg / m)19.7 0.9values are expressed as means sd.bmi : body mass index . in addition , parameter values before and after friction are shown in table 2table 2.blood flow velocity changes before and after friction massageprepostblood flow velocity ( cm / s)13.8 2.8 23.3 6.9*values are expressed as means sd . significantly different between pre- and post - friction measurements , * p<0.01 . when a t - test was conducted , there were significantly large differences between pre- and post - friction measurements ( t=7.162 , df=14 , p<0.01 ) . based on this result and the average values , it is possible to understand that the blood flow of the popliteal vein had a higher velocity after friction compared to before friction . in this study , regarding the venous flow of the lower legs , the effects of friction on popliteal regions was evaluated , using the blood flow velocity of the popliteal vein as an index . the blood flow velocity of the popliteal vein increased when friction was provided to the popliteal region . based on this result , it was shown that friction is effective to improve the venous flow of the lower legs . due to the fact that the lower legs , including the gastrocnemius and soleus muscles , have anatomical characteristics such as specific forms of vascular channels20 , lower legs compartment syndrome , deep venous thrombosis , edema , and venous congestion are prone to occur . the result of this study showed that friction had an effect to heal these clinical conditions and disorders . moreover , adding to circulatory disorders caused by the anatomical characteristics of the lower legs vascular channels , there are also disorders caused by autonomic nervous system malfunctions21 and disorders of the metabolism22 . diabetes is one disorder of the metabolism which invokes muscle pain or muscle fatigue due to disordered blood circulation . therefore , it is considered that enhancing the venous flow of the lower legs would alleviate pain and relieve muscle fatigue . furthermore , it is expected that friction can be used as physical therapy to facilitate healing of injured parts during the period where muscle contraction is not available due to muscle injury , patients being in the postoperative period , and when body parts are bound in a cast . it is also pointed out that friction has other effects such as an enhancement of the circulation when being provided strongly enough to cause neurogenic inflammation . that is , when the massage is provided to the skin , the nociceptor is stimulated , inducing the discharge of neuropeptide such as substance p from the cell body . this stimulates not only the central nerves but also descends to the peripheral nerves , inducing the peptide from the sensory nerve terminal . it has been explained that as a result of the above process , the mast cells and the internal smooth muscles widen the blood vessels23 . the authors believe it to be necessary to start substantiating the study of these effects . since dysfunction of the lower legs venous system , which plays the main role in venous return , is involved in the development of circulatory disorder in many cases , the indication of friction massage for circulatory disorders , such as lower legs compartment syndrome , edema , and diabetic muscle pain , was suggested . however , the results were obtained from young subjects and the autonomic and blood flow - related nervous systems were not investigated , and these are limitations of this study . OUTPUT:

[ purpose ] friction massage ( friction ) of the popliteal fossa is provided for the purpose of relieving pain related to circulatory disorders by improving venous flow in the lower legs . the purpose of this study is to verify the effects of enhancing the venous flow based on measuring the blood flow velocity of the popliteal vein before and after providing friction to the patients . [ subjects and methods ] fifteen healthy male university students participated in the study . the doppler ultrasonography ( du ) was used to measure the blood flow velocity of the popliteal vein , in order to verify the effects of enhancing the venous flow by comparing the measured values before and after a friction massage . [ results ] the result of comparing the blood flow velocity before and after providing friction showed that there was a significant increase after friction . [ conclusion ] this study proved that friction to the popliteal fossa is effectively enhances venous flow by increasing the blood flow velocity in the popliteal vein .

PubMed_Summ6568

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: holt - oram syndrome ( hos ) is an autosomal dominant condition with complete penetrance . manifested in 1:1 , 00 , 000 live births and characterized by forelimb deformities , congenital heart disease and/or cardiac conduction abnormalities . it is linked to a single - gene tbx5 protein - producing mutation with gene map locus 12q24 and is the most commonly occurring heart - hand syndrome . congenital cardiac and upper limb malformations frequently occur together and are classified as heart hand syndromes . the most common among the heart hand disorders is hos , which is characterized by cardiac septation defects and preaxial radial ray abnormalities . this condition with a high rate ( 3085% ) of new non - familial cases was first described by holt and oram in 1960 in a 4-generation family with atrial septal defects ( asd ) and thumb abnormalities . the most common cardiac disorder is an ostium secundum asd , followed by ventricular septal defect ( vsd ) and ostium primum asd . electrocardiogram ( ecg ) abnormalities such as various degrees of atrioventricular ( av ) block have also been reported . a full term female neonate born out of a nonconsanguineous marriage by cesarean section ( indication - previous cesarean section with polyhydramnios ) to a 25-year - old ( weight 58 kg , height 155 cm ) booked g3p1l1a1 with unremarkable antenatal history . family history revealed that the father has radial ray deformity of left upper limb without any cardiac anomaly . physical examination revealed an active baby weighing 2790 g and length of 49 cm , heart rate of 146/min , blood pressure of 70/30 mm of hg , respiratory rate of 40/min , and systemic oxygen saturation of right upper limb being 83% in room air and that of right lower limb being 74% in room air [ figure 1 ] . on musculoskeletal examination , left upper limb shortening was noticed with absent radius bone , radial flexion deformity of the wrist and also absent thumb [ figure 2 ] . no obvious deformities were noticed elsewhere . on cardio - vascular system examination , the pansystolic murmur of grade iii at the mitral and left parasternal area was heard picture showing the baby of holt - oram syndrome left upper limb showing radial ray deformity with absent thumb right hand showing triphalangeal thumb on further investigation , chest x - ray showed normal thoracic situs with cardiomegaly , plain radiograph of both upper limbs revealed absent radius on left side with absent carpal bones and absent first metacarpal bone and phalanges ( thumb ) , right side showing absent carpal bones and triphalangeal thumb [ figure 4 ] . plain radiograph showing the bony deformities of the upper limb with cardiomegaly the baby developed cyanosis couple of hours after delivery , following which an ecg was done which was normal and a 2d echocardiography was done which revealed severe aortic atresia with hypoplastic arch , large perimembranous vsd and asd as well [ figure 5 ] . the neonate was referred to a cardiac center for further management , however due to lack of resources the baby died on day 4 of life . holt - oram syndrome is an autosomal dominant disorder characterized by distinctive malformation of bones of the upper limbs and abnormalities of the heart . cardinal manifestations of hos are dysplasia of upper limb that ranges from minor findings including hypoplasia of thumb , clinodactyly , brachydactyly , triphalangeal thumbs , carpal bone dysmorphism , shortness of ulna , shortness of humerus , aplasia of radius to phocomelia and cardiac abnormalities . although bilateral , left side is often affected more significantly . in a study of 98 subjects with hypoplastic thumbs , 16% proved to be the cases of hos . there are many well described heart - hand syndromes characterized by deformities of the radial ray and congenital heart defects such as thrombocytopenia absent radius syndrome , roberts syndrome , thalidomide embryopathy , and fanconi anemia . the unique feature that helps to differentiate these from hos is that the radial aplasia is associated with hypoplasia / absence of the thumb without any hematological abnormalities and there is often a family history of heart and limb defects . the associated congenital heart defects are the most important determining factors in morbidity and mortality in these patients . other cardiac associations include pulmonary stenosis , mitral valve prolapse and arrhythmias in the form of atrioventricular blocks . more complex cardiac lesions such as tetralogy of fallot , endocardial cushion defects , and total anomalous pulmonary venous return are observed in 18% of subjects with hos . the association with aortic atresia is extremely rare . as per best of our knowledge , till date there were no cases reported in the literature having a description of hos with aortic atresia . the electrocardiographic abnormalities such as variable degree of av blocks have also been reported , but in our case no conduction defects were noted . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . OUTPUT:

holt - oram syndrome ( hos ) is a rare autosomal dominant disorder that causes abnormalities of the upper limbs and heart . it is seen in 1:1 , 00 , 000 live births . it is linked to a single - gene tbx5 protein - producing mutation with gene map locus 12q24 . most commonly it is characterized by the cardiac septation defects and pre - axial radial ray abnormalities . we are reporting a case of hos with aortic atresia which is a rare association .

PubMed_Summ6569

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: idiopathic dilated cardiomyopathy ( dcm ) is a heart muscle disorder characterized by systolic dysfunction and dilation of the left or both ventricles in the absence of any other possible cause.1 dcm can develop in people of any age or ethnicity , although it is more common in male than female persons ( occurring at a ratio of 3:1 in male to female persons ) and typically manifests in the third to fourth decades of life.2 , 3 dcm is the predominant cause of cardiomyopathy in both adult and pediatric populations.3 , 4 in adults , dcm has an estimated prevalence of 1:2500.3 in contrast , annual incidence in pediatric populations has been reported to be much lower : 1:170 000 in the united states5 and 1:140 000 in australia.6 although pediatric dcm has a lower annual incidence than adult dcm , the outcome for pediatric dcm patients is particularly severe.7 , 8 , 9 dcm is the most frequent cause of heart transplantation ( htx ) in pediatric patients.10 data from international pediatric dcm registries indicate that the rates of death or htx over 1 and 5year periods were 31% and 46% , respectively.4 conversely , recent data showed that the htxfree survival rate in adult dcm patients receiving optimal treatment is > 85% at 8 years.2 comparative studies between pediatric and adult dcm populations are currently lacking in the literature . in fact , because of the difficulty of performing controlled clinical trials with pediatric populations , the number of such trials has been limited.10 consequently , the treatment strategies used for pediatric dcm patients have been extrapolated primarily from data based on clinical trials using adult dcm patients . by better characterizing the baseline and longterm progression and outcome of pediatric dcm patients in comparison to adult dcm patients , for which ample data have already been collected , it is thought that improved treatment strategies could be developed for pediatric patients . the aim of this study was to provide insights into the longterm characterization and outcome of dcm in a pediatric population compared with an adult one to ultimately improve the clinical management of dcm in children . we analyzed data from all dcm patients that had consecutively enrolled in the trieste heart muscle disease registry in italy between 1988 and 2014 , according to the protocol approved by the institutional review board of the trieste hospital administration and the local ethics committee . the investigation was in line with the principles outlined in the declaration of helsinki.11 the diagnosis of dcm was assigned according to the current guidelines.1 , 12 , 13 we excluded patients with a secondary cause of myocardial damage , including coronary artery disease ( investigated with coronary angiography / computed tomography ) , hypertensive disorder , valvular disease , biopsyproven active myocarditis , associated congenital heart disease , history of chemotherapy or pharmacologic cardiotoxicity , pulmonary parenchymal or vascular disease , immunological disease , and mitochondrial disease ( studied by complete neurological examination , plasma lactate and amino acids , urine amino and organic acids , and pyruvate and acylcarnitine profiles , if indicated).2 neuromuscular disease was investigated with a laboratory test ( ie , creatine kinase ) and electromyography and , for final diagnosis , by skeletal muscle biopsy if clinically indicated . in the absence of family history of dcm and in the presence of severe recentonset heart failure ( hf ) , all pediatric patients underwent endomyocardial biopsy and , from 2010 , cardiac magnetic resonance to exclude active myocarditis . at enrollment , all patients underwent an initial screening that included a detailed clinical and family history interview , a complete clinical examination , an electrocardiogram , 24hour holter monitoring , and a comprehensive echocardiographic evaluation . conventional 2dimensional echocardiographic mmode pulsed doppler and tissue doppler imaging were all performed according to international guidelines.14 , 15 after enrollment , if not contraindicated , all patients received standard medical therapy with angiotensinconverting enzyme inhibitors , angiotensin receptor blockers , and beta blockers titrated to the highest tolerated dose . clinical and instrumental data were recorded at enrollment and then after 6 months ( range 38 months ) , 12 months ( range 918 months ) , and 24 months ( range 1936 months ) in followup evaluations . at > 24 months after enrollment , patients were recorded at least once every 2 years . patients who were aged 18 years at enrollment were considered part of the pediatric population.6 , 16 to improve the accuracy of our comparisons between 2 differently sized populations , prognostic assessment statistics compared the pediatric population with a sample of adult controls randomly matched in a 1:3 ratio ( 47 pediatric patients to 141 adult patients ) . this was adjusted for the most relevant baseline differences between the 2 groups , as explained in the statistical analysis section . three outcome measurements were primarily investigated : ( 1 ) death or htx , ( 2 ) sudden cardiac death or malignant ventricular arrhythmia ( mva ) , and ( 3 ) death caused by pump failure or htx . data were collected over followup periods of 1 , 6 , and 9 years . all patients with refractory hf requiring inotropic treatment and/or mechanical support or with lifethreatening arrhythmias unresponsive to medical therapy and/or catheter ablation and who did not have contraindications were listed for urgent htx.2 sudden death was defined as immediate death occurring within 1 hour after the onset of symptoms or during sleep in stable patients with new york heart association ( nyha ) class i to iii disease . mvas were defined as ventricular fibrillation / flutter or sustained ventricular tachycardia ( > 30second duration of > 200 beats per minute or hemodynamically significant ) , as recorded by an implantable cardioverterdefibrillator or external defibrillation . other investigated outcomes included cardiovascular death , noncardiac death , and death from unknown causes . the trieste heart muscle disease registry is a local relational database , active since 1978 , that systematically collects the data of patients affected by dcm and other cardiomyopathies consecutively evaluated in the cardiovascular department of the azienda ospedalierouniversitaria ospedali riuniti of trieste . used as a client interface , the system has all of the characteristics of a rapid application development client / server system . data registration is composed of a table series corresponding to the clinical ( history , family study , clinical examination ) and instrumental evaluation ( laboratory examinations ; electrocardiography ; holter monitoring ; echocardiography ; and , when indicated , cardiac catheterization and endomyocardial biopsy ) and pharmacological therapy at baseline and at scheduled followup evaluations . a section dedicated to fatal and nonfatal events and their causes is also present . continuous variables are presented as means and standard deviations or medians and interquartile ranges , as appropriate . for descriptive comparisons , clinical and instrumental characteristics at baseline were compared between groups of patients . this was achieved by 1way anova for continuous variables or the nonparametric median test , as necessary ; for categorical variables , the chisquare or fisher exact test was used , as appropriate . to assess the longitudinal changes in the investigated parameters , first , simple tests for repeated consecutive measures were calculated separately for each group ( the mcnemar test for binary parameters and the paired t test for continuous parameters ) . second , linear mixedeffects models with time and group as the covariates ( in which time is the followup visit and group was defined as either pediatric or adult ) were used to investigate whether a different behavior was present between the groups over time ( by means of the interaction term timegroup evaluated in the models ) . for the binary parameters , generalized linear mixed models were applied.17 because of the size difference between the pediatric and adult groups , we compared the survival of the pediatric patients with that of a sample of adult patients randomly matched in a 1:3 ratio to increase the efficacy of the survival comparison . the matching procedure accounted for the variables that were significantly different at baseline between the 2 populations and that had known possible relevance for the outcome in dcm patients . eventfree survival curves for the 3 primarily investigated outcomes ( described in the clinical outcomes section ) were estimated and plotted using the kaplan meier method . last , univariate and multivariate cox regression models were estimated in the target population ( pediatric patients ) . the limited sample size and number of events in this group were taken into account using a backwardconditional stepwise procedure to select the subset of the most powerful independent predictors . only univariable hazard ratios were estimated for the secondary end points ( sudden cardiac death or malignant ventricular arrhythmia and death from pump failure or htx ) . statistical analyses were conducted using the ibm spss statistics version 19 ( ibm corp ) and r software version 3.0.2 ( r foundation for statistical computing ) with the matching and rgenoud libraries . we analyzed data from all dcm patients that had consecutively enrolled in the trieste heart muscle disease registry in italy between 1988 and 2014 , according to the protocol approved by the institutional review board of the trieste hospital administration and the local ethics committee . the investigation was in line with the principles outlined in the declaration of helsinki.11 the diagnosis of dcm was assigned according to the current guidelines.1 , 12 , 13 we excluded patients with a secondary cause of myocardial damage , including coronary artery disease ( investigated with coronary angiography / computed tomography ) , hypertensive disorder , valvular disease , biopsyproven active myocarditis , associated congenital heart disease , history of chemotherapy or pharmacologic cardiotoxicity , pulmonary parenchymal or vascular disease , immunological disease , and mitochondrial disease ( studied by complete neurological examination , plasma lactate and amino acids , urine amino and organic acids , and pyruvate and acylcarnitine profiles , if indicated).2 neuromuscular disease was investigated with a laboratory test ( ie , creatine kinase ) and electromyography and , for final diagnosis , by skeletal muscle biopsy if clinically indicated . in the absence of family history of dcm and in the presence of severe recentonset heart failure ( hf ) , all pediatric patients underwent endomyocardial biopsy and , from 2010 , cardiac magnetic resonance to exclude active myocarditis . at enrollment , all patients underwent an initial screening that included a detailed clinical and family history interview , a complete clinical examination , an electrocardiogram , 24hour holter monitoring , and a comprehensive echocardiographic evaluation . conventional 2dimensional echocardiographic mmode pulsed doppler and tissue doppler imaging were all performed according to international guidelines.14 , 15 after enrollment , if not contraindicated , all patients received standard medical therapy with angiotensinconverting enzyme inhibitors , angiotensin receptor blockers , and beta blockers titrated to the highest tolerated dose . clinical and instrumental data were recorded at enrollment and then after 6 months ( range 38 months ) , 12 months ( range 918 months ) , and 24 months ( range 1936 months ) in followup evaluations . at > 24 months after enrollment , patients were recorded at least once every 2 years . patients who were aged 18 years at enrollment were considered part of the pediatric population.6 , 16 to improve the accuracy of our comparisons between 2 differently sized populations , prognostic assessment statistics compared the pediatric population with a sample of adult controls randomly matched in a 1:3 ratio ( 47 pediatric patients to 141 adult patients ) . this was adjusted for the most relevant baseline differences between the 2 groups , as explained in the statistical analysis section . three outcome measurements were primarily investigated : ( 1 ) death or htx , ( 2 ) sudden cardiac death or malignant ventricular arrhythmia ( mva ) , and ( 3 ) death caused by pump failure or htx . data were collected over followup periods of 1 , 6 , and 9 years . all patients with refractory hf requiring inotropic treatment and/or mechanical support or with lifethreatening arrhythmias unresponsive to medical therapy and/or catheter ablation and who did not have contraindications were listed for urgent htx.2 sudden death was defined as immediate death occurring within 1 hour after the onset of symptoms or during sleep in stable patients with new york heart association ( nyha ) class i to iii disease . mvas were defined as ventricular fibrillation / flutter or sustained ventricular tachycardia ( > 30second duration of > 200 beats per minute or hemodynamically significant ) , as recorded by an implantable cardioverterdefibrillator or external defibrillation . other investigated outcomes included cardiovascular death , noncardiac death , and death from unknown causes . the trieste heart muscle disease registry is a local relational database , active since 1978 , that systematically collects the data of patients affected by dcm and other cardiomyopathies consecutively evaluated in the cardiovascular department of the azienda ospedalierouniversitaria ospedali riuniti of trieste . used as a client interface , the system has all of the characteristics of a rapid application development client / server system . data registration is composed of a table series corresponding to the clinical ( history , family study , clinical examination ) and instrumental evaluation ( laboratory examinations ; electrocardiography ; holter monitoring ; echocardiography ; and , when indicated , cardiac catheterization and endomyocardial biopsy ) and pharmacological therapy at baseline and at scheduled followup evaluations . a section dedicated to fatal and nonfatal events and their causes is also present . continuous variables are presented as means and standard deviations or medians and interquartile ranges , as appropriate . for descriptive comparisons , this was achieved by 1way anova for continuous variables or the nonparametric median test , as necessary ; for categorical variables , the chisquare or fisher exact test was used , as appropriate . to assess the longitudinal changes in the investigated parameters , first , simple tests for repeated consecutive measures were calculated separately for each group ( the mcnemar test for binary parameters and the paired t test for continuous parameters ) . second , linear mixedeffects models with time and group as the covariates ( in which time is the followup visit and group was defined as either pediatric or adult ) were used to investigate whether a different behavior was present between the groups over time ( by means of the interaction term timegroup evaluated in the models ) . for the binary parameters , generalized linear mixed models were applied.17 because of the size difference between the pediatric and adult groups , we compared the survival of the pediatric patients with that of a sample of adult patients randomly matched in a 1:3 ratio to increase the efficacy of the survival comparison . the matching procedure accounted for the variables that were significantly different at baseline between the 2 populations and that had known possible relevance for the outcome in dcm patients . eventfree survival curves for the 3 primarily investigated outcomes ( described in the clinical outcomes section ) were estimated and plotted using the kaplan meier method . last , univariate and multivariate cox regression models were estimated in the target population ( pediatric patients ) . the limited sample size and number of events in this group were taken into account using a backwardconditional stepwise procedure to select the subset of the most powerful independent predictors . only univariable hazard ratios were estimated for the secondary end points ( sudden cardiac death or malignant ventricular arrhythmia and death from pump failure or htx ) . statistical analyses were conducted using the ibm spss statistics version 19 ( ibm corp ) and r software version 3.0.2 ( r foundation for statistical computing ) with the matching and rgenoud libraries . of the entire population of 927 dcm patients enrolled between 1988 and 2014 , 47 ( 5.1% ) were pediatric . the median followup time after the first clinical evaluation was 110 months ( interquartile range 54185 months ) . table 1 shows the clinical data of the pediatric population at baseline compared with the adult group.18 a family history of dcm was significantly more common among the pediatric population ( 34.8% versus 17.5% ; p<0.03 ) . the pediatric patients presented with significantly lower systolic arterial blood pressure ( 11620 versus 12517 mm hg ; p<0.01 ) , a lower presence of left bundlebranch block ( 4.4% versus 31.9% ; p<0.001 ) , and a higher occurrence of left ventricular ejection fraction ( lvef ; 3613 versus 3211 ; p<0.03 ) . pediatric patients were also characterized by a shorter duration of hf symptoms ( median 0 months [ interquartile range , 1st3rd quartiles : 06 months ] versus 1 month [ interquartile range , 1st3rd quartiles : 07 months ] ; p<0.04 ) . both groups received optimized treatments for hf without agerelated differences . despite different features at baseline , no significant differences were observed between the pediatric and adult populations regarding the longterm longitudinal trends in nyha functional classes iii iv , left ventricular enddiastolic diameter and volume , lvef , and restrictive filling pattern . an initial improvement under treatment , midterm stabilization , and then a subsequent trend to progressive worsening of these parameters were observed in the long term in both the adult and pediatric populations ( figure 1 ) . the matched sample was built by adjusting for differences in familiar forms , duration of hf , systolic blood pressure , left bundlebranch block , and lvef ; moreover , we checked for others parameters that were different in the original sample and found nonsignificant differences ( diastolic blood pressure in the matched sample was 7412 mm hg in the adult population versus 7211 mm hg in the pediatric patients , p=0.09 ; diabetes mellitus 6% versus 0% , p=0.11 ; smokers 26% versus 10% , p=0.05 ; and diuretics 49% versus 46% , p=0.967 ) . clinical data at baseline for pediatric and adult dcm patients acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dcm , dilated cardiomyopathy ; dbp , diastolic blood pressure ; hf , heart failure ; iqr , interquartile range ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; sbp , systolic blood pressure ; sd , sudden death . the pediatric left ventricular diameters are represented also as z scores18 : lvedd , z=1.87 ; lvesd , z=0.66 . longterm longitudinal trends of clinical and echocardiographic parameters ( nyha classes iii iv class , lvedd_i , lvedvi , lvef , rfp ) in pediatric ( solid line ) and adult ( dotted line ) populations . lvedd_i indicates indexed left ventricular enddiastolic diameter ; lvedv_i , indexed left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; mr , mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern . table 2 shows the incidence of major events in the pediatric population and the entire adult dcm population . the incidence of death or htx was significantly higher for the pediatric patients compared with the adults ( 43.5% [ 5 events per 100 patients per year ] versus 25.8% [ 3.4 events per 100 patients per year ] ; p<0.018 ) . the worst outcomes for the pediatric patients were death caused by hf or htx ( 21% [ 2.5 events per 100 patients per year ] in pediatric patients versus 7% [ 0.8 event per 100 patients per year ] in adults , p<0.001 ) and sudden death or mva ( 21% [ 2.5 events per 100 patients per year ] versus 14% [ 1.7 events per 100 patients per year ] , respectively ; p<0.001 ) . incidence of major cardiovascular outcomes in pediatric and adult patients with idiopathic dilated cardiomyopathy hf indicates heart failure ; htx , heart transplant ; icd , implantable cardioverterdefibrillator ; mva , major ventricular arrhythmias ; sd , sudden death . figure 2a shows that longterm survival free from death or htx was significantly lower among the 47 pediatric dcm patients compared with the matched sample of 141 adults ( p<0.001 ) . notably , a significant survival difference can be seen as early as 12 months after enrollment ( survival rates at 1 year : 82% versus 98% in pediatric versus adult populations , respectively ; p<0.001 ) . at followup time points of 6 and 9 years , the survival rates were 71% versus 89% , respectively , in the pediatric patients and 68% versus 89% , respectively , in the adult patients ( p<0.0001 ) . similar results were obtained when examining survival rates free from the combined end points of sudden death or mva and death from pump failure or htx ( p<0.001 for both ) ( figure 2b and 2c ) . figure 3 shows the effect of the age at enrollment on patient outcome , with pediatric age ( ie , < 18 years ) associated with a significantly decreased mortality rate and increased occurrence of htx . rates of longterm survival free from d / htx ( a ) , dhf / htx ( b ) , and from sd / mva ( c ) in 47 pediatric ( solid line ) vs 141 adult patients ( dotted line ) matched in a 1:3 ratio after adjustment for baseline differences between the 2 subgroups . d / htx indicates death or heart transplantation ; dhf / htx , heartfailure death or heart transplantation ; sd / mva , sudden death or major ventricular arrhythmias . pediatric age ( ie , < 18 years ) was associated with increasing risk of all major events : d / htx ( a ) , dhf / htx ( b ) , sd / mva ( c ) . d / htx indicates death or heart transplantation ; dhf / htx , heartfailure death or heart transplantation ; sd / mva , sudden death or major ventricular arrhythmias . finally , we performed a univariate and subsequent multivariate cox analysis among the pediatric population to identify possible prognostic indicators . iv at baseline were the most powerful independent predictors of the occurrence of death or htx . conversely , the use of beta blockers was found to be a protective factor ( table 3 ) . the pediatric patients received beta blocker treatment throughout the enrollment period ( ie , beta blocker therapy before versus after the year 2000 : 76% versus 84% , p=0.421 ) . the univariate analyses for sudden death or mva and for pumpfailure death or htx are reported in tables 4 and 5 . of note , a positive family history for dcm emerged as the only significant predictor ( hazard ratio 3.79 , 95% ci 1.22414.7 ; p=0.045 ) for arrhythmic events in the pediatric population ( table 5 ) . univariate and multivariate analysis in the pediatric dcm population : predictors of death or heart transplantation em dash indicates no data . acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . univariate analysis in the pediatric dcm population : predictors of death from heart failure or heart transplantation acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundle branch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . univariate in the pediatric dcm population : predictors of major ventricular arrhythmias or sudden death acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . of the entire population of 927 dcm patients enrolled between 1988 and 2014 , 47 ( 5.1% ) were pediatric . the median followup time after the first clinical evaluation was 110 months ( interquartile range 54185 months ) . table 1 shows the clinical data of the pediatric population at baseline compared with the adult group.18 a family history of dcm was significantly more common among the pediatric population ( 34.8% versus 17.5% ; p<0.03 ) . the pediatric patients presented with significantly lower systolic arterial blood pressure ( 11620 versus 12517 mm hg ; p<0.01 ) , a lower presence of left bundlebranch block ( 4.4% versus 31.9% ; p<0.001 ) , and a higher occurrence of left ventricular ejection fraction ( lvef ; 3613 versus 3211 ; p<0.03 ) . pediatric patients were also characterized by a shorter duration of hf symptoms ( median 0 months [ interquartile range , 1st3rd quartiles : 06 months ] versus 1 month [ interquartile range , 1st3rd quartiles : 07 months ] ; p<0.04 ) . both groups received optimized treatments for hf without agerelated differences . despite different features at baseline , no significant differences were observed between the pediatric and adult populations regarding the longterm longitudinal trends in nyha functional classes iii iv , left ventricular enddiastolic diameter and volume , lvef , and restrictive filling pattern . an initial improvement under treatment , midterm stabilization , and then a subsequent trend to progressive worsening of these parameters were observed in the long term in both the adult and pediatric populations ( figure 1 ) . the matched sample was built by adjusting for differences in familiar forms , duration of hf , systolic blood pressure , left bundlebranch block , and lvef ; moreover , we checked for others parameters that were different in the original sample and found nonsignificant differences ( diastolic blood pressure in the matched sample was 7412 mm hg in the adult population versus 7211 mm hg in the pediatric patients , p=0.09 ; diabetes mellitus 6% versus 0% , p=0.11 ; smokers 26% versus 10% , p=0.05 ; and diuretics 49% versus 46% , p=0.967 ) . clinical data at baseline for pediatric and adult dcm patients acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dcm , dilated cardiomyopathy ; dbp , diastolic blood pressure ; hf , heart failure ; iqr , interquartile range ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; sbp , systolic blood pressure ; sd , sudden death . the pediatric left ventricular diameters are represented also as z scores18 : lvedd , z=1.87 ; lvesd , z=0.66 . longterm longitudinal trends of clinical and echocardiographic parameters ( nyha classes iii iv class , lvedd_i , lvedvi , lvef , rfp ) in pediatric ( solid line ) and adult ( dotted line ) populations . lvedd_i indicates indexed left ventricular enddiastolic diameter ; lvedv_i , indexed left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; mr , mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern . table 2 shows the incidence of major events in the pediatric population and the entire adult dcm population . the incidence of death or htx was significantly higher for the pediatric patients compared with the adults ( 43.5% [ 5 events per 100 patients per year ] versus 25.8% [ 3.4 events per 100 patients per year ] ; p<0.018 ) . the worst outcomes for the pediatric patients were death caused by hf or htx ( 21% [ 2.5 events per 100 patients per year ] in pediatric patients versus 7% [ 0.8 event per 100 patients per year ] in adults , p<0.001 ) and sudden death or mva ( 21% [ 2.5 events per 100 patients per year ] versus 14% [ 1.7 events per 100 patients per year ] , respectively ; p<0.001 ) . incidence of major cardiovascular outcomes in pediatric and adult patients with idiopathic dilated cardiomyopathy hf indicates heart failure ; htx , heart transplant ; icd , implantable cardioverterdefibrillator ; mva , major ventricular arrhythmias ; sd , sudden death . figure 2a shows that longterm survival free from death or htx was significantly lower among the 47 pediatric dcm patients compared with the matched sample of 141 adults ( p<0.001 ) . notably , a significant survival difference can be seen as early as 12 months after enrollment ( survival rates at 1 year : 82% versus 98% in pediatric versus adult populations , respectively ; p<0.001 ) . at followup time points of 6 and 9 years , the survival rates were 71% versus 89% , respectively , in the pediatric patients and 68% versus 89% , respectively , in the adult patients ( p<0.0001 ) . similar results were obtained when examining survival rates free from the combined end points of sudden death or mva and death from pump failure or htx ( p<0.001 for both ) ( figure 2b and 2c ) . figure 3 shows the effect of the age at enrollment on patient outcome , with pediatric age ( ie , < 18 years ) associated with a significantly decreased mortality rate and increased occurrence of htx . rates of longterm survival free from d / htx ( a ) , dhf / htx ( b ) , and from sd / mva ( c ) in 47 pediatric ( solid line ) vs 141 adult patients ( dotted line ) matched in a 1:3 ratio after adjustment for baseline differences between the 2 subgroups . d / htx indicates death or heart transplantation ; dhf / htx , heartfailure death or heart transplantation ; sd / mva , sudden death or major ventricular arrhythmias . effect of age on outcome measurements . pediatric age ( ie , < 18 years ) was associated with increasing risk of all major events : d / htx ( a ) , dhf / htx ( b ) , sd / mva ( c ) . d / htx indicates death or heart transplantation ; dhf / htx , heartfailure death or heart transplantation ; sd / mva , sudden death or major ventricular arrhythmias . finally , we performed a univariate and subsequent multivariate cox analysis among the pediatric population to identify possible prognostic indicators . iv at baseline were the most powerful independent predictors of the occurrence of death or htx . conversely , the use of beta blockers was found to be a protective factor ( table 3 ) . the pediatric patients received beta blocker treatment throughout the enrollment period ( ie , beta blocker therapy before versus after the year 2000 : 76% versus 84% , p=0.421 ) . the univariate analyses for sudden death or mva and for pumpfailure death or htx are reported in tables 4 and 5 . of note , a positive family history for dcm emerged as the only significant predictor ( hazard ratio 3.79 , 95% ci 1.22414.7 ; p=0.045 ) for arrhythmic events in the pediatric population ( table 5 ) . univariate and multivariate analysis in the pediatric dcm population : predictors of death or heart transplantation em dash indicates no data . acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . univariate analysis in the pediatric dcm population : predictors of death from heart failure or heart transplantation acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundle branch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . univariate in the pediatric dcm population : predictors of major ventricular arrhythmias or sudden death acei indicates angiotensinconverting enzyme inhibitor ; bsa , body surface area ; dbp , diastolic blood pressure ; dcm , dilated cardiomyopathy ; hr , hazard ratio ; lbbb , left bundlebranch block ; lvedd , left ventricular enddiastolic diameter ; lvedv , left ventricular enddiastolic volume ; lvef , left ventricular ejection fraction ; lvesd , left ventricular endsystolic diameter ; lvesv , left ventricular endsystolic volume ; mr mitral regurgitation ; nyha , new york heart association ; rfp , restrictive filling pattern ( left ventricle ) ; sbp , systolic blood pressure ; sd , sudden death . this study compared the characterizations , longterm progression , and outcomes of adult and pediatric dcm patients . most studies of pediatric dcm populations have been based on registries drawn from the united states or australia , and recent data on european populations , provided in this study , have been less represented . furthermore , in the current literature , comparative studies of adult and pediatric dcm patients are lacking . this issue is relevant because the management of pediatric dcm is based largely on longterm data derived from adult cohorts . in this study , we reported a large and wellselected idiopathic dcm cohort in which pediatric cases are rare , representing only 5% of the whole population ; however , clinical cardiologists have to pay particular attention to pediatric dcm . in fact , in our pediatric population , we saw that the disease was less severe at baseline compared with adults , as suggested by the lower percentage of left bundlebranch block , the higher occurrence of lvef , and the shorter duration of hf symptoms . this could be due to having an earlier diagnosis , which may be partially explained by a systematic and detailed collection of familial history of the probands and thus the earlier screening of relatives . despite these differences at baseline , as seen previously , our pediatric population had a significantly poorer longterm outcome compared with adults . all analyzed combined end points ( ie , death / htx , death from hf / htx , and sudden death / mva ) had higher incidence in the pediatric population , even after adjustment for baseline differences between groups . the longterm incidence of death / htx in the pediatric population reached 5 events per 100 patients per year , which is markedly higher than 3.4 events per 100 patients per year in the adult population . these event rates are similar to those reported in the united states and australia.5 , 6 furthermore , the survival rate curves of both populations start to diverge early after the first evaluation and progressively increase the survival gap in the long term . this was particularly evident considering the combined end point of death / htx ( 82% versus 98% in children versus adults at 1year followup ) . finally , the onset of disease at an age < 18 years clearly emerged as a risk factor for all combined end points ( figure 3 ) . this underscores the relevant role of pediatric age for short and longterm management of dcm . these results apparently contrast with the known beneficial effects on the prognosis from familial screening . the latter usually allows earlier diagnosis , often at a less severe stage of the disease , and subsequent benign outcome.19 one could argue that familial screening is useful for more accurately managing the disease with tighter and more aggressive followup when dcm is discovered at a pediatric age . in adults , familial screening allows diagnosis at an earlier stage of the disease , with a consequently better longterm outcome . notably , in our study , the poorer prognosis in pediatric cases resulted not only from the progression of hf and htx but also from arrhythmic events ( figures 2c and 3c ) . in the current literature , much more attention has been paid to hf than to arrhythmias in pediatric dcm patients . nevertheless , an important arrhythmic profile in the pediatric patients compared with the adults clearly emerged in this study . this topic highlights a challenging issue in the management of dcm : whether to implant an implantable cardioverterdefibrillator for primary prevention in children . the current hf pediatric guidelines10 recommend this procedure for pediatric dcm patients with unexplained syncope and at least moderate left ventricular dysfunction ( class of recommendation iia , level of evidence c ) or with lvef < 35% and nyha class ii they also recommend this procedure for adolescent patients with a familial cardiomyopathy associated with sudden death or for younger patients , considering the risk benefit ratio and technical issues ( class of recommendation iia , level of evidence c ) . the low level of evidence for the guidelines suggests the ethical and technical difficulty of this decision and the necessity of risk stratification models . in particular , a left ventricle thinning and dilation ratio , diagnosis before age 13 to 14 years , and use of antiarrhythmic therapy within 1 month of diagnosis emerged as predictors of sudden cardiac death20 ; however , no univocal statement currently exists on this topic in the literature . the identification of predictors of sudden death and mva in pediatric dcm patients was beyond the scope of our study because of the limited number of events . interestingly , at univariate analysis , family history positive for dcm emerged as the only significant predictor of arrhythmic events in the pediatric population . this could suggest that some clusters of gene mutations have an important role in inducing specific arrhythmic phenotypes . most cases are idiopathic , followed by familial forms3 ; therefore , pediatric forms may be caused by particularly aggressive genetic mutations leading to rapidly progressive disease . accordingly , our study showed twice the prevalence of familial forms of dcm in the pediatric population compared with the adult patients ( 34.8% versus 17.5% ) , encouraging genetic screening in these patients and their relatives . in some cases , a positive result may influence clinical management , as in the presence of lamin a / c ( lmna ) mutations.21 , 22 in other cases , the discovery of a mutation has no impact on the clinical management of the disease because , currently , wide genotype phenotype correlation data are still lacking . furthermore , it is known that active myocarditis in children is more aggressive than in adults , probably caused by a predominant immune response.23 consequently , postinflammatory dcm in children is also likely to be more severe , and more aggressive followup and therapeutic strategies are advised . finally , the resulting independent prognostic factors that emerged from our multivariate analysis ( tolerance of beta blocker therapy , lvef , nyha class ) confirm previous studies24 , 25 and reflect the same features that are included in adult dcm prognostic models.2 the protective role that emerged for beta blockers could confirm their benefit in pediatric as well as adult dcm patients . nevertheless , because of the observational nature of the present study , it is possible that beta blocker intolerance was a surrogate for advanced disease state , and a largescale randomized trial is needed to definitively assess the benefit of beta blockers in a pediatric dcm population . only 5% of the pediatric patients enrolled in the american pediatric cardiomyopathy registry received beta blockers in the 1990s compared with 18% after 2000.26 an increasing burden of studies about the pathophysiological differences of pediatric and adult hf mechanisms characterizes the current literature.27 , 28 , 29 this contributes to our understanding of the different agerelated responses to therapy . performing clinical trials in children with dcm is very difficult , but it appears to be the only way to identify the most useful treatments to improve outcome . our population has some analogies with largescale observational studies in the pediatric dcm population5 , 6 , 16 ; however , some notable differences have to be highlighted . the mean age of our pediatric cohort was 15 years , which is older than most other studies on dcm in children . moreover , there were higher proportions of familial and male cases . these differences should be explained by the fact that ours is a cardiomyopathy referral center that is mostly used to evaluate patients that are affected by idiopathic dcm , without known causes and with an important genetic familial or postmyocarditis background and rarely associated with congenital syndromes or neuromuscular diseases . in this sense , the comparison with the adult population was not previously reported and appears to be particularly relevant to the clinical management of such patients . another relevant discrepancy concerns the prognostic longitudinal trends that are shown in the present study . in our population , there appears to be a continued risk of death or transplant after 1 year of followup after enrollment ; that characteristic is different from other pediatric dcm international registries.5 , 6 , 16 it is particularly interesting and is probably related to the abovementioned characteristics of idiopathic dcm enrolled in the present registry . these characteristics revealed a particularly aggressive nature of the disease in the short and long terms in children more than in adults . moreover , the rarity of this disease among the pediatric population in general influenced the size of the samples studied . to overcome this issue , a casecontrol like strategy was achieved by means of a random matching procedure . another limitation concerns the availability of longterm followup data , which were not complete for all patients because of the event rates and censoring mechanism . consequently , the longterm trends of the main clinical and echocardiographic features shown in figure 1 should be interpreted with caution and confirmed by future studies that go on for a longer time . in our opinion , however , the comparison with the adult population ( affected by the same limit ) is reliable . for most of the patients , the genetic data and cardiac magnetic resonance information were lacking , thus we could not include these data in our analyses . because of the limited number of events , uni and multivariable analyses were presented mainly for exploratory purposes and should be confirmed in larger series . future focused studies are warranted to assess the possible prognostic role of these tools in pediatric populations compared with adults . finally , we included htx in the composite end point even though it is not a fatal event . in our opinion , it remains a major event in the natural history of dcm that has the same impact of death in the prognostic evaluation of the disease , especially considering that only urgent htx examples were included . this study compared the characterizations , longterm progression , and outcomes of adult and pediatric dcm patients . most studies of pediatric dcm populations have been based on registries drawn from the united states or australia , and recent data on european populations , provided in this study , have been less represented . furthermore , in the current literature , comparative studies of adult and pediatric dcm patients are lacking . this issue is relevant because the management of pediatric dcm is based largely on longterm data derived from adult cohorts . in this study , we reported a large and wellselected idiopathic dcm cohort in which pediatric cases are rare , representing only 5% of the whole population ; however , clinical cardiologists have to pay particular attention to pediatric dcm . in fact , in our pediatric population , we saw that the disease was less severe at baseline compared with adults , as suggested by the lower percentage of left bundlebranch block , the higher occurrence of lvef , and the shorter duration of hf symptoms . this could be due to having an earlier diagnosis , which may be partially explained by a systematic and detailed collection of familial history of the probands and thus the earlier screening of relatives . despite these differences at baseline , as seen previously , our pediatric population had a significantly poorer longterm outcome compared with adults . all analyzed combined end points ( ie , death / htx , death from hf / htx , and sudden death / mva ) had higher incidence in the pediatric population , even after adjustment for baseline differences between groups . the longterm incidence of death / htx in the pediatric population reached 5 events per 100 patients per year , which is markedly higher than 3.4 events per 100 patients per year in the adult population . these event rates are similar to those reported in the united states and australia.5 , 6 furthermore , the survival rate curves of both populations start to diverge early after the first evaluation and progressively increase the survival gap in the long term . this was particularly evident considering the combined end point of death / htx ( 82% versus 98% in children versus adults at 1year followup ) . finally , the onset of disease at an age < 18 years clearly emerged as a risk factor for all combined end points ( figure 3 ) . this underscores the relevant role of pediatric age for short and longterm management of dcm . these results apparently contrast with the known beneficial effects on the prognosis from familial screening . the latter usually allows earlier diagnosis , often at a less severe stage of the disease , and subsequent benign outcome.19 one could argue that familial screening is useful for more accurately managing the disease with tighter and more aggressive followup when dcm is discovered at a pediatric age . in adults , familial screening allows diagnosis at an earlier stage of the disease , with a consequently better longterm outcome . notably , in our study , the poorer prognosis in pediatric cases resulted not only from the progression of hf and htx but also from arrhythmic events ( figures 2c and 3c ) . in the current literature , much more attention has been paid to hf than to arrhythmias in pediatric dcm patients . nevertheless , an important arrhythmic profile in the pediatric patients compared with the adults clearly emerged in this study . this topic highlights a challenging issue in the management of dcm : whether to implant an implantable cardioverterdefibrillator for primary prevention in children . the current hf pediatric guidelines10 recommend this procedure for pediatric dcm patients with unexplained syncope and at least moderate left ventricular dysfunction ( class of recommendation iia , level of evidence c ) or with lvef < 35% and nyha class ii they also recommend this procedure for adolescent patients with a familial cardiomyopathy associated with sudden death or for younger patients , considering the risk benefit ratio and technical issues ( class of recommendation iia , level of evidence c ) . the low level of evidence for the guidelines suggests the ethical and technical difficulty of this decision and the necessity of risk stratification models . in particular , a left ventricle thinning and dilation ratio , diagnosis before age 13 to 14 years , and use of antiarrhythmic therapy within 1 month of diagnosis emerged as predictors of sudden cardiac death20 ; however , no univocal statement currently exists on this topic in the literature . the identification of predictors of sudden death and mva in pediatric dcm patients was beyond the scope of our study because of the limited number of events . interestingly , at univariate analysis , family history positive for dcm emerged as the only significant predictor of arrhythmic events in the pediatric population . this could suggest that some clusters of gene mutations have an important role in inducing specific arrhythmic phenotypes . most cases are idiopathic , followed by familial forms3 ; therefore , pediatric forms may be caused by particularly aggressive genetic mutations leading to rapidly progressive disease . accordingly , our study showed twice the prevalence of familial forms of dcm in the pediatric population compared with the adult patients ( 34.8% versus 17.5% ) , encouraging genetic screening in these patients and their relatives . in some cases , a positive result may influence clinical management , as in the presence of lamin a / c ( lmna ) mutations.21 , 22 in other cases , the discovery of a mutation has no impact on the clinical management of the disease because , currently , wide genotype phenotype correlation data are still lacking . furthermore , it is known that active myocarditis in children is more aggressive than in adults , probably caused by a predominant immune response.23 consequently , postinflammatory dcm in children is also likely to be more severe , and more aggressive followup and therapeutic strategies are advised . finally , the resulting independent prognostic factors that emerged from our multivariate analysis ( tolerance of beta blocker therapy , lvef , nyha class ) confirm previous studies24 , 25 and reflect the same features that are included in adult dcm prognostic models.2 the protective role that emerged for beta blockers could confirm their benefit in pediatric as well as adult dcm patients . nevertheless , because of the observational nature of the present study , it is possible that beta blocker intolerance was a surrogate for advanced disease state , and a largescale randomized trial is needed to definitively assess the benefit of beta blockers in a pediatric dcm population . only 5% of the pediatric patients enrolled in the american pediatric cardiomyopathy registry received beta blockers in the 1990s compared with 18% after 2000.26 an increasing burden of studies about the pathophysiological differences of pediatric and adult hf mechanisms characterizes the current literature.27 , 28 , 29 this contributes to our understanding of the different agerelated responses to therapy . performing clinical trials in children with dcm is very difficult , but it appears to be the only way to identify the most useful treatments to improve outcome . our population has some analogies with largescale observational studies in the pediatric dcm population5 , 6 , 16 ; however , some notable differences have to be highlighted . the mean age of our pediatric cohort was 15 years , which is older than most other studies on dcm in children . moreover , there were higher proportions of familial and male cases . these differences should be explained by the fact that ours is a cardiomyopathy referral center that is mostly used to evaluate patients that are affected by idiopathic dcm , without known causes and with an important genetic familial or postmyocarditis background and rarely associated with congenital syndromes or neuromuscular diseases . in this sense , the comparison with the adult population was not previously reported and appears to be particularly relevant to the clinical management of such patients . another relevant discrepancy concerns the prognostic longitudinal trends that are shown in the present study . in our population , there appears to be a continued risk of death or transplant after 1 year of followup after enrollment ; that characteristic is different from other pediatric dcm international registries.5 , 6 , 16 it is particularly interesting and is probably related to the abovementioned characteristics of idiopathic dcm enrolled in the present registry . these characteristics revealed a particularly aggressive nature of the disease in the short and long terms in children more than in adults . moreover , the rarity of this disease among the pediatric population in general influenced the size of the samples studied . to overcome this issue , a casecontrol like strategy was achieved by means of a random matching procedure . another limitation concerns the availability of longterm followup data , which were not complete for all patients because of the event rates and censoring mechanism . consequently , the longterm trends of the main clinical and echocardiographic features shown in figure 1 should be interpreted with caution and confirmed by future studies that go on for a longer time . in our opinion , however , the comparison with the adult population ( affected by the same limit ) is reliable . for most of the patients , the genetic data and cardiac magnetic resonance information were lacking , thus we could not include these data in our analyses . because of the limited number of events , uni and multivariable analyses were presented mainly for exploratory purposes and should be confirmed in larger series . future focused studies are warranted to assess the possible prognostic role of these tools in pediatric populations compared with adults . finally , we included htx in the composite end point even though it is not a fatal event . in our opinion , it remains a major event in the natural history of dcm that has the same impact of death in the prognostic evaluation of the disease , especially considering that only urgent htx examples were included . the data of this italian registry suggest that pediatric dcm patients are rare but have a worse outcome than adult patients . this is despite similar treatments , a less advanced stage of the disease at baseline in children , and similar clinical and echocardiographic longterm progression . these findings were further confirmed after adjusting for other covariates that were significantly different from adults at the time of the onset of the disease . finally , pediatric age emerged as an important prognostic predictor of both death from hf and lifethreatening ventricular arrhythmias . OUTPUT:

backgroundthe longterm progression of idiopathic dilated cardiomyopathy ( dcm ) in pediatric patients compared with adult patients has not been previously characterized . in this study , we compared outcome and longterm progression of pediatric and adult dcm populations.methods and resultsbetween 1988 and 2014 , 927 dcm patients were consecutively enrolled . the pediatric population ( aged < 18 years at enrollment ) included 47 participants ( 5.1% ) . at presentation , the pediatric population compared with adult patients had a significantly increased occurrence of familial forms ( p=0.03 ) , shorter duration of heart failure ( p=0.04 ) , lower systolic blood pressure ( p=0.01 ) , decreased presence of left bundlebranch block ( p=0.001 ) , and increased left ventricular ejection fraction ( p=0.03 ) . despite these baseline differences , longterm longitudinal trends of new york heart association class iii to iv , left ventricular dimensions , left ventricular ejection fraction , and restrictive filling pattern were similar between the 2 populations . regarding survival analysis , because of the size difference between the 2 populations , we compared the pediatric population with a sample of adult patients randomly matched using the abovementioned baseline differences in a 3:1 ratio ( 141 adult versus 47 pediatric patients ) . during a median followup of 110 months , survival free from heart transplantation was significantly lower among pediatric patients compared with adults ( p<0.001 ) . furthermore , pediatric age ( ie , < 18 years ) was found to be associated with an increasing risk of both death from pump failure and lifethreatening arrhythmias.conclusionsdespite the pediatric dcm population having higher baseline left ventricular ejection fraction and similar longterm echocardiographic progression compared with the adult dcm population , the pediatric dcm patients had worse cardiovascular prognosis .

PubMed_Summ6570

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: though limited in efficacy in many cases , the control methods available today represent a major progress when compared to the lack of any means for the control of these plants one or two decades ago . crops can be protected by resistance , by selective fungicides , by biocontrol agents , and by cultural methods that did not existed before . the current focus in applied breeding is leveraging biotechnological tools to develop more and better markers to allow marker assisted selection with the hope that this will speed up the delivery of improved cultivars to the farmer . to date , however , progress in marker development and delivery of useful markers has been slow in legumes . we are now also facing an accelerated progress in the genomic and biotechnological research , which should soon provide important understanding of some crucial developmental mechanisms in both the parasites and their host plants and will provide candidate genes for resistance to ascochyta blight . the application of ngs technologies will provide a new research framework and molecular tools to be applied in resistance to ascochyta blight in legumes . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . OUTPUT:

legume cultivation is strongly hampered by the occurrence of ascochyta blights . strategies of control have been developed but only marginal successes achieved . breeding for disease resistance is regarded the most cost efficient method of control . significant genetic variation for disease resistance exists in most legume crops with numerous germplasm lines maintained , providing an excellent resource for plant breeders . fast and reliable screening methods have been adjusted to fulfill breeding program needs . however , the complex inheritance controlled quantitatively by multiple genes , has been difficult to manipulate . successful application of biotechnology to ascochyta blight resistance breeding in legume crops will facilitate a good biological knowledge both of the crops pathogen interaction and of the mechanisms underlying resistance . the current focus in applied breeding is leveraging biotechnological tools to develop more and better markers to speed up the delivery of improved cultivars to the farmer . to date , however , progress in marker development and delivery of useful markers has been slow in most legumes . the limited saturation of the genomic regions bearing putative qtls in legume crops makes difficult to identify the most tightly linked markers and to determine the accurate position of qtls . the application of next generation sequencing technologies will contribute to the development of new markers and the identification of candidate genes for ascochyta blight resistance .

PubMed_Summ6571

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: marginal zone b - cell malignant lymphoma is a low - grade malignant non - hodgkin 's lymphoma that develops in mucosa - associated lymphoid tissue ( malt ) . this disease frequently develops in the stomach and also occurs in the salivary gland , thyroid , and lung . most cases are diffuse large b - cell lymphoma , and the incidence of hepatic malt lymphoma is low among cases of primary hepatic malignant lymphoma [ 2 , 3 , 4 , 5 ] . here , we describe a rare case in which a lesion was initially thought to be a single tumor but was ultimately diagnosed as 2 contiguous tumors ( malt lymphoma and hemangioma ) using contrast - enhanced ultrasonography ( ceus ) with sonazoid ( daiichi sankyo , tokyo , japan ) . the patient was a 60-year - old female in whom a tumor of 15 mm in diameter was detected in the couinaud 's segment ( s6 ) of the liver on the grayscale us in a medical examination . she had no subjective symptoms , relevant medical or family history , and did not drink alcohol . physical findings on admission were : blood pressure 136/80 mm hg , pulse rate 80/min , and body temperature 36.4c . blood tests on admission showed hb 10.4 g / dl ( normal 14.017.0 g / dl ) , suggesting a mild anemia . tumor markers were normal , tests for hepatitis b virus ( hbv ) and hepatitis c virus ( hcv ) were negative , and there were no other abnormal findings . grayscale us showed a tumor with a snowman - like appearance and a relatively clear boundary in the s6 of the liver , with hypo- and hyperechoic areas in the lateral and medial parts of the lesion , respectively ( fig . the tumor had a pale , low - density area on unenhanced ct , and prolonged enhancement in the equilibrium phases ( fig . , the whole lesion gave a low - intensity signal on t1-weighted imaging , but isointensity in the lateral part and high intensity in the medial part were seen on t2-weighted imaging . similarly , the lateral part showed high intensity and the medial part had a higher intensity on heavy t2-weighted imaging ( fig . the lateral part was enhanced in the arterial phase , and enhancement persisted in the portal phase . in contrast , the medial part was gradually enhanced in the arterial phase , compared to the portal phase . ceus was performed using an aplio xg ( toshiba medical systems , tokyo , japan ) with a convex probe ( pvt-375bt , 3.75 mhz frequency ) . the mechanical index for the acoustic output was set to 0.2 , and a single focus point was set at the lower margin of the lesion . sonazoid ( 0.5 ml ) was injected into the left cubital vein followed by a flushing with 10 ml of normal saline . the lateral hypoechoic region was homogenously hyperenhanced in the vascular phase ( 040 s ) early after injection , and the contrast medium was washed out after about 30 s. the medial hyperechoic region was gradually stained from the margin toward the central region ( fig . the tumor showed a defect in both hypo- and hyperechoic regions in the post - vascular phase ( after 15 min ) . similar findings were observed after a second intravenous injection of 0.5 ml of sonazoid using defect reperfusion imaging in the postvascular phase . liver hemangioma was suspected for the medial part of the lesion based on the typical contrast findings on mri and ceus . in the lateral part , the contrast medium was washed out in the vascular phase on ceus early after the intravenous injection of sonazoid . furthermore , the lateral part showed a defect in the postvascular phase , and this defect led to the suspicion of a malignant tumor , including hepatocellular carcinoma ( hcc ) . thus , surgical resection was performed . in a macroscopic examination of the resected specimen , the medial part was whitish and the lateral part was yellowish - white . on hematoxylin and eosin ( he ) staining , the medial part comprised blood vessels formed by a single layer of flattened endothelial cells and an interstitium formed by thin connective tissue , with the vascular lumen filled with blood . based on these findings , the medial part of the tumor was diagnosed as hemangioma . in the lateral part , lymphocyte infiltration in a dense arrangement was observed on he staining , and most lymphocytes contained a moderately sized nucleus , but some cells contained a large nucleus and noticeable nucleolus ( fig . similar findings were present in the germinal center , with atypical lymphocytes invading the germinal center . based on these findings , the lateral part of the tumor was diagnosed as marginal zone b - cell lymphoma . isaacson and wright first proposed the name of malt lymphoma for extranodal malignant lymphoma of marginal zone b - cell origin in 1983 . malt lymphoma is a low - grade malignant non - hodgkin 's lymphoma that develops in mucosa - associated lymphoid tissue , and accounts for 78% of all cases . malt lymphoma frequently develops in the stomach , and also occurs in the salivary gland , thyroid , and lung . primary hepatic malignant lymphoma is rare , with most cases being diffuse large b - cell lymphoma and less than 10% being malt lymphoma [ 2 , 3 , 4 , 5 ] . many cases of malt lymphoma are solitary , imaging findings are diverse , and it is difficult to make a definite diagnosis based on imaging alone . exclusion of hcc may not be possible and a definite diagnosis can only be made histopathologically after surgical resection in many cases [ 8 , 9 , 10 ] . in our patient , the lesion was initially considered to be a single tumor , but imaging findings indicated that it had 2 distinct regions . a literature search indicated that 2 cases of simultaneous malt lymphoma and hemangioma in the liver have been reported , with focal nodular hyperplasia also present in 1 of these cases [ 11 , 12 ] . in both previous cases , malt lymphoma and hemangioma were separate , and thus there has been no previous case in which the tumors initially appeared to be a single tumor . in our patient , malt lymphoma and hemangioma were in contact , but each tumor was independent , rather than pathologically continuous , on histopathological examination . concomitant malt lymphoma and hemangioma were considered to have no causal relationship in the 2 previous cases [ 11 , 12 ] . the characteristic imaging findings of hepatic malt lymphoma are nonspecific , but include a relatively hypoechoic mass without a clear hypoechoic margin on grayscale us , hypoenhancement of the tumor in the arterial phase on dynamic ct , and low and high intensities on t1- and t2-weighted images on mri , respectively . in ceus using sono view ( bracco , milan , italy ) in 2 patients with hepatic primary malt lymphoma , foschi et al . found that the lesions were inhomogeneously hyperenhanced in the arterial phase and hypoenhanced in the portal and late phases . these 2 patients were hbv - positive : one was an hbv - inactive carrier , and the other had chronic hbv hepatitis . dynamic ct in both patients showed a slight hyperenhancement in the arterial phase , and hypoenhancement in the portal phases , and hcc was suspected . it was difficult to make a preoperative diagnosis , and the tumor was finally diagnosed histopathologically as hepatic malt lymphoma . the development of a malt lymphoma is thought to involve persistent chronic inflammation , and helicobacter pylori infection is well - known in gastric malt lymphoma . in primary hepatic malt lymphoma , chronic liver disorders such as hbv- or hcv - associated chronic hepatitis , hepatic cirrhosis , and primary biliary cirrhosis are occasionally found in the background liver . our patient was negative for viruses and the background liver was normal , but homogenous hyperenhancement was observed in the vascular phase early after sonazoid injection , and the contrast medium was washed out after about 30 s on ceus . a defect was also noted in the postvascular phase , based on which the possibility of a malignant tumor , including hcc , could not be ruled out . however , the presence of 2 contiguous tumors was indicated by real - time evaluation hemodynamics in the tumor using ceus , which indicates the utility of ceus for a proper diagnosis . tumor penetration by existing blood vessels on dynamic ct and mri is a characteristic finding in hepatic malignant lymphoma [ 8 , 10 ] . however , in our case , no blood vessel penetrating the tumor was evident in any imaging . this feature may not have been visualizable in our case , or the absence of blood vessels penetrating the tumor may differentiate primary hepatic malt lymphoma from other malignant lymphomas . only a few reported cases of primary hepatic malt lymphoma have included ceus findings , and no typical enhancement pattern on ceus has been established . the presence of blood vessels penetrating the tumor is useful for the diagnosis of malignant lymphoma , and ceus evaluation of intratumoral hemodynamics in real time may be more likely to visualize penetrating blood vessels , compared to dynamic ct and mri . it is possible that the absence of this feature differentiates primary hepatic malt lymphoma from other malignant lymphomas . confirmation of this possibility will require further evidence from ceus evaluation of more cases of primary hepatic malt lymphoma . the lesion in our patient was initially considered to be a single tumor , but contiguous hepatic malt lymphoma and hemangioma were actually present . the concomitant occurrence of these tumors is rare , and no cases with 2 tumors in contact have been previously reported . the tumors gave different enhancement patterns on ceus and their presence was confirmed histopathologically , based on which we were able to make the final diagnosis . OUTPUT:

primary hepatic marginal zone b - cell malignant lymphoma of mucosa - associated lymphoid tissue ( malt lymphoma ) is extremely rare . we present a case in which a lesion was diagnosed as 2 contiguous tumors ( malt lymphoma and hemangioma ) using contrast - enhanced ultrasonography ( us ) with sonazoid . there has been no previous case of contiguous hepatic malt lymphoma and hemangioma . the present case was a female with no medical history . we detected a snowman - like appearance , which was a tumor of 15 mm in diameter with hypo- and hyper - echogenicities in the lateral and medial parts , respectively , in the couinaud 's segment ( s6 ) of the liver on us . the tumor appeared as a single lesion with a low - density area in the unenhanced phase and prolonged enhancement in the equilibrium phases on dynamic ct . on mri , the whole lesion showed a low - intensity signal on t1-weighted imaging , but isointensity in the lateral part and high intensity in the medial part were seen on t2-weighted imaging . on contrast - enhanced us , the lateral hypoechoic region was homogenously hyperenhanced in the early vascular phase , and the contrast medium was washed out after about 30 s ; in contrast , the medial hyperechoic region was gradually stained from the margin toward the central region . the tumor showed a defect in both hypo- and hyperechoic regions in the postvascular phase . hemangioma was suspected for the medial part based on the typical image findings , but the lateral part was not given a diagnosis . thus , surgical resection was performed . the medial part was a hemangioma , and the lateral part was a malt lymphoma by histopathological findings .

PubMed_Summ6572

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: this study was conducted in tugela ferry , south africa , where tb incidence is 1,100 cases/100,000 population and > 80% of tb mdr tb and xdr tb incidence was 118 cases and 72 cases/100,000 population , respectively , in 2007 ( 4 ) . ethical approval for this study was obtained from albert einstein college of medicine , yale university , university of kwazulu - natal , and the kwazulu - natal department of health . we performed a prospective cross - sectional study actively identifying patients with suspected tb in medical and tb wards , the hiv clinic , and the outpatient department at the tugela ferry district hospital during february 2008april 2009 . a person with suspected tb was defined as someone having a self - reported cough of any duration or > 2 other signs or symptoms , including fever , night sweats , weight loss , or shortness of breath for any duration . patients could be either newly manifesting tb symptoms or have been receiving tb treatment for > 2 months but currently reporting active tb symptoms ( i.e. , treatment failures ) . sputum for this study was tested by microscopic analysis of auramine- and ziehl - nielsen stained smears and middlebrook 7h11 agar and mycobacterial growth indicator tube 960 broth culture . dst of positive cultures was performed by using the 1% proportional method on middlebrook 7h11 agar for isoniazid ( critical concentrations : isoniazid 0.2 g / ml , rifampin 1.0 g / ml , ethambutol 7.5 g / ml , streptomycin 2.0 g / ml , ofloxacin 2 g / ml , kanamycin 5.0 g / ml , capreomycin 10 g / ml , and ethionamide 5.0 g / ml ) . dst was repeated on all drug - resistant isolates to confirm the observed resistance pattern . the proportion of patients with xdr tb and drug - susceptibility patterns were described by using simple frequencies . xdr tb treatment outcomes were reported as of november 2009 ; standard international definitions were used ( 11 ) . of 912 enrolled patients with suspected tb , 209 ( 23% ) had culture - positive tb ( figure 2 ) . of these patients , 30 ( 14% ) had mdr tb , of which 19 ( 63% of those with mdr tb ; 9% with culture - positive results ) had xdr tb . determination of prevalence of tuberculosis ( tb ) and drug resistance among persons with suspected tb , tugela ferry , south afica , 20082009 . dst , drug susceptibility testing ; mdr tb , multidrug - resistant tb ; xdr tb , extensively drug - resistant tb . among xdr tb isolates , all 19 ( 100% ) were resistant to all 6 drugs routinely tested in kwazulu - natal province ( isoniazid , rifampin , ethambutol , streptomycin , ofloxacin , and kanamycin ) , which extended the trend seen in previous years toward increasing drug resistance ( figure 1 ) . of these isolates , 4 ( 21% ) were also resistant to capreomycin , and 13 ( 68% ) were resistant to capreomycin and ethionamide ( table 1 ) . thus , an 8-drug resistance pattern was the predominant dst type among xdr tb patients in this cohort . * xdr tb , extensively drug - resistant tuberculosis ; inh , isoniazid ; rif , rifampin ; emb , ethambutol ; sm , streptomycin ; ofl , ofloxacin ; km , kanamycin ; cap , capreomycin ; eto , ethionamide . of 13 patients with 8-drug resistance xdr tb , 5 ( 38% ) were women ( median age 33.5 years , range 2451 years ) ( table 2 ) . although 5 ( 38% ) had previously received ( or currently showed failure to ) first - line tb treatment , none had ever received treatment with second - line drugs for mdr tb . twelve ( 92% ) patients were hiv infected ( median cd4 cell count 183.5 cells / mm , range 22670 cells / mm ) ; only 2 ( 17% ) were receiving antiretroviral therapy at the time of tb screening . * mdr tb , multidrug - resistant tuberculosis ; xdr tb , extensively drug - resistant tb . 6-drug resistance , resistance to isoniazid , rifampin , ethambutol , ofloxacin , kanamycin , and streptomycin ; 7-drug resistance , resistance to isoniazid , rifampin , ethambutol , ofloxacin , kanamycin , streptomycin , and capreomycin ; 8-drug resistance , resistance to isoniazid , rifampin , ethambutol , ofloxacin , kanamycin , streptomycin , capreomycin , and ethionamide . first - line drugs used for treatment of persons with new tb cases or confirmed drug - susceptible tb include isoniazid , rifampin , ethambutol , and pyrazinamide . second - line drugs used for treatment of persons with confirmed mdr tb include ofloxacin , kanaymycin , ethionamide , p - aminosalicylic acid , and cycloserine or terizidone . among 13 xdr tb patients with 8-drug resistance , 7 ( 54% ) died ( median time to death 59 days , range 16205 days ) . two patients were lost to follow - up , and 4 ( 31% ) are still living and receiving xdr tb treatment ( range 190502 days of follow - up ) . no trend in survival of patients with xdr tb was observed by drug - resistance pattern ( 6-drug vs 7-drug vs. 8-drug ) . routine drug - resistance surveillance to first- and second - line drugs is conducted in tugela ferry , which has a high incidence of tb and hiv co - infection . in this study , we expanded second - line testing for 2 additional bactericidal drugs ( capreomycin and ethionamide ) for treatment of patients with xdr tb . resistance to 8 first - line and second - line drugs is the predominant pattern for xdr tb in tugela ferry , thereby severely limiting effective therapeutic options with available medications . according to the standard xdr tb regimen used in this province , patients were receiving <3 active drugs ( pyrazinamide , p - aminosalicylic acid , and cycloserine ) , which increases the risk for treatment failure and further amplification of drug resistance . these findings underscore the need for routine surveillance for resistance to all first - line and second - line drugs used and for tailoring regimens accordingly to improve treatment success and reduce emergence of more drug - resistant xdr tb strains . first , the reliability of second - line dst is variable , and only recently have methods and critical concentrations been standardized ( 12 ) . however , all drug - resistant isolates in this study had dst repeated to confirm observed results . second , dst for other first - line drugs , such as pyrazinamide , and other second - line drugs was not conducted , although these drugs are often used for xdr tb treatment . thus , the degree of drug resistance was likely to be only a minimum estimate . third , although the proportion of xdr tb cases in this survey was high , the absolute number of xdr tb cases was low . this small sample size limits our ability to make conclusions about treatment outcomes for patients with increasing drug - resistant isolates . however , previous studies from our site have shown poorer survival rates with increasing drug resistance ( 4 ) . expanded dst for second - line and third - line drugs is critical for xdr tb patient care . given continued high and rapid number of deaths from xdr tb , better and more rapid methods for second - line dst are urgently needed to improve diagnosis and guide treatment . although new drugs are being developed , efforts must target prevention of xdr tb and its transmission , earlier identification of cases , support of treatment completion for tb and mdr tb , and greater use of antiretroviral therapy for patients who are co - infected with hiv . OUTPUT:

we expanded second - line tuberculosis ( tb ) drug susceptibility testing for extensively drug - resistant mycobacterium tuberculosis isolates from south africa . of 19 patients with extensively drug - resistant tb identified during february 2008april 2009 , 13 ( 68% ) had isolates resistant to all 8 drugs tested . this resistance leaves no effective treatment with available drugs in south africa .

PubMed_Summ6573

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: proteus syndrome ( ps ) is a rare and sporadic disorder that causes postnatal overgrowth of tissues in a mosaic pattern . the complications of ps include , progressive skeletal deformities , invasive lipomas , benign and malignant tumors , and deep venous thrombosis with pulmonary embolism . we report a rare case of ps that presented with hypertrophy of index and middle finger without any other abnormalities or complications . incidentally we noticed that he had enlarged index and middle fingers of both hands and thumb of right hand [ figure 1 ] . on probing patient revealed that it was present since childhood with onset around the age of 5 years and gradual progression over years to the present size . no similar tissue growth in other parts of the body and there was no one in the family with similar features . on examination hypertrophy of index and middle finger of both the hand ( a , b , c ) and thumb of the right hand ( c ) laboratory investigations revealed normal renal and liver function tests . his x - ray of hands showed hyperostosis of involved fingers [ figure 2 ] . x - ray hands showing hyperostosis of both index and middle fingure ( a , b ) and thumb of right hand ( b ) proteus who had the ability to change his shape and was proposed by wiedemann , et al . in 1983 . happle , et al . in 1987 hypothesized that the syndrome might be due to somatic alteration of a gene leading to mosaic effects that would be lethal if the mutation were carried in nonmosaic fashion . the dysregulated tissue growth in mosaic pattern results in various phenotypic presentations and hence the clinical manifestations of ps are highly variable . the tissue overgrowth is usually absent or mild at birth and progressive in nature but usually appears to plateau after adolescence . the disproportionate overgrowth of tissue is usually asymmetrical and involves the arms , legs , hands , feet , and digits . characteristic manifestations include hyperostoses , often near epiphyses with associated impaired mobility and cerebriform connective tissue nevus seen most commonly on plantar surface . other findings are lipomas , epidermal nevi and capillary vascular malformations [ table 1 ] . criteria for the diagnosis of proteus syndrome there is no specific molecular marker , or laboratory test , for the diagnosis of ps . the diagnosis is mainly based on history , clinical examination and imaging studies . because of its variable presentation , ps may be confused with other conditions . the two disorders most commonly confused with ps are klippel - trenaunay syndrome and hemihyperplasia / lipomatosis syndrome . the important points in ps that help in the differential diagnosis are : differential diagnosis of proteus syndrome sporadic and progressive nature of tissue overgrowththe absent or mild tissue growth at birthabsence of bone tumor , enchondromasabsence of specific gene mutations differentiates from neurofibromatosisabsence of familial inheritance ( postzygotic somatic mutation of genes ) sporadic and progressive nature of tissue overgrowth the absent or mild tissue growth at birth absence of bone tumor , enchondromas absence of specific gene mutations differentiates from neurofibromatosis absence of familial inheritance ( postzygotic somatic mutation of genes ) there are no effective treatment modalities for ps . the patients should be followed up regularly for development of complications and their management . the management is also challenging because of progressive nature of tissue growth . both benign and malignant two relatively common tumors include cystadenomas of the ovary and monomorphic adenomas of the parotid gland . presented with macrodactyly of index and middle finger of both the hands and thumb of right hand ( one criteria of category b ) and he met all the three general criteria . his skeletal survey was normal except for hyperostosis of index and middle finger and there were no associated complications except for the limitation of his affected finger movements . although the patient did not satisfy the proposed criteria [ table 1 ] , a literature search revealed that out of the 205 cases reported 90 satisfied the criteria highlighting the variability in clinical presentation in cases of ps . our patient was managed as a case of inferior wall mi and is presently on anti - ischemic medications with no new complications . in conclusion , ps is a very rare and highly variable , progressive tissue overgrowth disorder . patients should be kept under regular follow - up for the development of complications and their management . OUTPUT:

proteus syndrome ( ps ) is a rare hamartomatous disorder characterized by various cutaneous and subcutaneous lesions , including vascular malformations , lipomas , hyperpigmentation , and several types of nevi . partial gigantism with limb or digital overgrowth is pathognomonic of ps . we report a rare case of ps in a 50-year - old man who presented with inferior wall myocardial infarction and was incidentally detected to have hypertrophy of index and middle fingers of both the hands .

PubMed_Summ6574

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: it is characterised by the production of abnormal hb referred to as sickle hb or hbs.123 the prevalence of sca is high in sub - saharan africa with nigeria having the highest burden.45 sca has been associated with hyperhaemolysis , cerebrovascular disease , acute chest syndrome , vaso - occlusive crisis , pulmonary hypertension and premature death among others.67 relatively , individuals with sca enjoy a compensated state of ill health interspersed with periods of acute exacerbation characterised by hyperhaemolytic ( anaemic ) or vaso - occlusive ( voc ; painful crisis ) with infection , tissue hypoxia and micro - vascular occlusion as important predisposing events.68 abnormal lipid homeostasis has been reported in sca as well as other haematological disorders such as -thalassemia and this has been suggested to have the potential to alter membrane fluidity and function of red blood cell ( rbc ) in individuals with sca.91011 earlier studies reported significant increase in plasma triglyceride ( tg ) levels and concurrent significant decrease in plasma levels of total cholesterol ( tc ) , high - density lipoprotein - cholesterol ( hdl ) and low - density lipoprotein - cholesterol ( ldl ) in sca subjects.91112 several inconclusive mechanisms such as heightened erythropoiesis ( causing increased cholesterol utilization ) , defective liver function ( due to iron overload ) and defects in postabsorptive plasma homeostasis of fatty acids have been put forward to explain the pathogenesis of this sca - associated lipid abnormalities.913 however , it is worthy of note that this lipid phenotype is generally recognized as a risk factor for cardiovascular diseases . zorca et al.11 reported that elevated plasma tg is a potential risk factor for pulmonary hypertension ( ph ) in sca subjects . the impact of disordered lipid metabolism on the course of sca and its numerous complications are not yet clearly defined . also , there is little information on the lipid profile of sca subjects in voc . due to the present dearth of knowledge ; this study determined the lipid profile of adult nigerians with sca in vaso - occlusive crisis ( voc ) and in steady state ( ssca ) . eighty - two participants comprising 58 adults with sca ( 30 in steady state and 28 in voc ) and 24 age - matched healthy individuals with hbaa genotype were recruited into this study . the sca ( hbss ) subjects were recruited from the hematology day care unit , department of hematology , university college hospital , ibadan after approval by university college hospital ( ui / uch ) joint ethics review committee , and informed consent by participant . steady state ( ssca ) and vaso - ooclusive crisis ( voc ) were defined as earlier reported.14 subjects with other forms of genotype apart from hbss and hbaa , diabetes mellitus , hypertension , human immunodeficiency virus ( hiv ) , hepatitis , cancer and with established endocrine dysfunctions were excluded from the study . blood pressure ( bp ) was obtained using a mercury sphygmomanometer after at least 10 minutes of rest . after an overnight fast of about 10 hr , 5 ml of venous blood was obtained from each sca subject in steady state ( ssca ) and the controls . samples were collected upon admission in the voc group as voc is an acute clinical condition hence ; could not have been predicted for possible overnight fast . most subjects in voc would probably be anorexic because of the acute pain they were going through . blood samples were dispensed into edta - containing samples bottles and after determining the packed cell volume ( pcv ) and total white blood cell count ( wbc ) , plasma was appropriately obtained and stored at 20c until analyses were done . haemoglobin phenotype of each subject was determined using standard electrophoretic method at ph 6.8 while pcv and wbc were determined as described by cheesbrough.15 plasma lipid profile was determined using enzymatic method while ldl was calculated using friedwald equation.16 the distribution of the data was assessed using histogram with normal curve . results are presented as mean standard deviation or as median ( interquartile range ) for gaussian and non - gaussian distributed data , respectively . analysis of variance ( anova ) or kruskal - wallis test was used to compare all the three groups while differences between two groups were determined using independent student 's t - test or man - whitney u as appropriate . results are presented as mean standard deviation or as median ( interquartile range ) for gaussian and non - gaussian distributed data , respectively . analysis of variance ( anova ) or kruskal - wallis test was used to compare all the three groups while differences between two groups were determined using independent student 's t - test or man - whitney u as appropriate . pcv , tc , hdl and ldl were significantly lower while wbc was significantly higher in sca compared with the control subjects . there was slight , but insignificant elevation of tg in sca compared with the control subjects . in table 2 , all the components of the lipid profile between the three groups ( ssca , voc and controls ) were significantly different . other components of the lipid profile had no specific pattern of differences . characteristics of the subjects in table 3 , tc and hdl were significantly lower while tg / hdl was significantly higher in sca subjects in steady state ( ssca ) compared with the control subjects . similarly , tc and ldl were significantly lower in sca subjects in vaso - occlusive crisis ( voc ) compared with controls . however , tc , tg , ldl and tg / hdl were significantly lower while hdl was significantly higher in voc compared with ssca . comparison of lipid profile in ssca , voc and control subjects using anova to find out if there is any interaction between wbc and lipid profile , sca subjects were classified into two groups based on the mean wbc value ; 11.97 ( 10/l ) [ table 1 ] into 11.97 ( 10/l ) and > 11.97 ( 10/l ) groups . as shown in table 4 , the two groups had similar lipid profile but they exhibited a similar pattern to that observed when ssca were compared with voc . there was insignificant reduction in the levels of tc , tg , ldl , tg / hdl and insignificant elevation of hdl level in sca subjects with > 11.97 ( 10/l ) wbc compared with sca subjects with 11.97 ( 10/l ) lipid profile in ssca , voc and control subjects pattern of lipid profile based on mean total white blood cell count ( wbc ) in sca subjects despite intense research for over 4 decades , mechanism of lipid homeostasis alteration in sca subjects is not yet fully understood.11 the observed lower levels of tc , hdl and ldl in the combined sca subjects ( ssca and voc ) are not novel findings . hypocholesterolemia has been widely reported in sca subjects1112 and was thought to be due to increased cholesterol utilization consequent to increased erythropoiesis of sca . however , the reports of westerman17 and ngogang et al.,18 showed that hypocholesterolaemia is a common feature of both haemolytic and non - haemolytic anaemia and that serum cholesterol is in equilibrium with the cholesterol content of total red cell mass . it was , therefore , suggested that sca - associated hypocholesterolemia is a consequence of anaemia itself and not increased erythropoiesis.1117 the interaction between sca complications such as voc and disturbed metabolic homeostasis in individuals with sca has been reported.1419 in this study , tc and ldl decreased progressively from control - to - ssca - to - voc . ssca had lower tc and hdl while voc had lower tc and ldl compared with the control subjects . this observation further confirms that sca - associated hypocholesterolemia might be anaemia dependent as intense haemolysis has been associated with various complications of sca.20 also , tg / hdl was higher in ssca than the control groups . the ratio of tg to hdl has been reported to be relevant in determining the risk of clinical vascular disease . it has been used to identify diabetic patients with an atherogenic lipid profile and has been found suitable in selecting patients needing earlier and aggressive treatment of lipid abnormalities.21 our observation is not surprising as the ssca group had slightly higher tg with concurrent lower hdl compared with the control subjects . zorca et al.11 reported that high tg / hdl is associated with endothelial dysfunction and suggested that high tg / hdl is a potential risk factor for pulmonary hypertension . although ldl is usually low in sca subjects , belcher et al.22 showed that ldl from sca subjects is more susceptible to oxidation and cytotoxicity to endothelium . our observation , together with earlier reports , indicates that anaemia - associated lipid homeostasis disturbance could predispose sca subjects to various vascular diseases . unfavorable plasma fatty acid composition has been associated with clinical severity of sca.23 similarly , nouraie et al.20 reported that intensity of haemolytic anaemia is an independent risk factor for the development of sca complications such as ph and hypoxaemia . in this study , plasma levels of tc , ldl and tg / hdl were lower in voc compared with ssca . this observation could be as a result of possible intense haemolytic anaemia in voc which would facilitate the attainment of a new equilibrium between the serum cholesterol and cholesterol content of total red cell mass.1117 the observed higher hdl in voc compared with ssca supports the report of darbari et al.3 which showed that higher hdl is independently associated with frequent voc . the observed elevated plasma hdl could be a marker of less marrow activity in sca subjects since formation of erythroid cell membrane requires cholesterol.1124 the reason for the observed lower tg in voc compared with ssca is presently unclear . however , intake of drugs and/or reduced food intake ( due to possible anorexia ) before presentation may be responsible for this observation . further research work is still required to properly understand the disturbance in lipid homeostasis following voc as standard fasting period could not be ensured in our voc subjects . also , the small sample size used in this study could limit proper data interpretation . our study further confirms the widely reported defective lipid homeostasis in adults with sickle cell anaemia . it also showed that the alteration in the lipid metabolism becomes pronounced with vaso - occlusive crisis . OUTPUT:

background : abnormal lipid homeostasis has been reported in sickle cell anaemia ( sca ) as well as in other haematological disorders . however , there is little information on the lipid profile of sca subjects in vaso - occlusive crisis ( voc ) . this study determined the lipid profile of adult sca subjects in voc and in steady state ( ssca).materials and methods : fifty - eight ( 58 ) adults with hbss ( 30 in steady state and 28 in vaso - occlusive crisis ) and 24 age - matched healthy individuals with hbaa genotype were recruited into this study . standard methods were used for the determination of blood pressure ( bp ) , packed cell volume ( pcv ) , total white blood cell count ( wbc ) and haemoglobin phenotype . after an overnight fast , 5 ml of venous blood was obtained from each ssca and the controls while samples were collected upon admission in the voc group . plasma lipid profile was determined using enzymatic method . differences between two groups were determined using independent student 's t - test or man - whitney u as appropriate . p - values less than 0.05 were considered significant.results:plasma total cholesterol ( tc ) and high density lipoprotein ( hdl ) were significantly lower while the ratio of triglyceride ( tg ) to hdl ( tg / hdl ) was significantly higher in ssca compared with the controls . low density lipoprotein ( ldl ) and tc were significantly lower in sca subjects in voc compared with controls . however , tc , tg , ldl and tg / hdl were significantly lower while hdl was significantly higher in voc compared with ssca.conclusion:sickle cell anaemia subjects have defective fasting lipid metabolism which becomes pronounced with voc .

PubMed_Summ6575

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: obesity is a key public health issue for us youth , particularly among specific sociodemographic groups , including some racial / ethnic and sexual orientation groups [ 1 , 2 ] . obesity is operationalized as having a body mass index ( bmi ) equal to or greater than the 95th percentile among individuals younger than age 18 years or a bmi of 30 or greater for individuals age 18 years or older . previous research in a primarily white cohort of youth and young adults , age 1223 years , found that sexual minority ( nonheterosexually identified ) females had higher bmi than heterosexual females throughout adolescence , similar to patterns seen in adult females . among males in this cohort , gay males had higher bmi in early adolescence compared to heterosexual males , but by late adolescence bmi among gay males was lower than their heterosexual peers , similar to patterns seen in adult males . however , little is known about the intersection of race / ethnicity and sexual orientation and its impact on youth weight status . a small number of studies have investigated sexual orientation patterns in bmi among multiethnic samples of adults [ 7 , 8 ] . one such study found that among females , white and african american sexual minorities were at increased risk of being overweight compared to same - race / ethnicity heterosexual individuals , whereas among adult males , gay males were less likely than heterosexuals to be overweight among white , african american , asian , and latino men . we are aware of only one study with a representative sample of adolescents examining sexual orientation disparities in bmi in a multiethnic sample , which found that bisexual female and male youth were at elevated risk for obesity compared to same - gender heterosexual youth across race / ethnicity groups . however , no research has explored whether an age - by - orientation interaction effect exists in racial / ethnic minority youth . disparities in bmi among sexual minorities have been explained primarily using the minority stress model , which suggests that experiences of prejudice and discrimination based on minority status negatively affect health . sexual minorities who are also racial / ethnic minorities may be at greater risk for negative health outcomes due to experiences of minority stress based on being a member of multiple minority groups [ 11 , 12 ] . indeed , research on sexual orientation , body image , and eating disorders in primarily white samples of adults has suggested that compared with heterosexuals , gay males indicated greater body dissatisfaction and eating disorder symptomatology [ 13 , 14 ] . an alternative explanation is that sexual orientation disparities in bmi are related to sociocultural ideals regarding body appearance . for instance , sexual minority male youth reported greater desire for muscularity , but fewer attempts to gain weight , compared to heterosexual male youth . among adult females , lesbian and bisexual individuals indicated lower internalization of sociocultural appearance ideals for a thin body type compared to heterosexual females . these findings may help to explain why sexual minority females have higher bmi and sexual minority males have lower bmi , compared to their same - gender heterosexual counterparts . however , similar to research on sexual orientation - by - gender disparities in obesity more research is needed to first identify whether sexual orientation - by - gender disparities in obesity exist in nonwhite racial / ethnic groups and then to examine whether explanations for these disparities apply across racial / ethnic groups . previous obesity prevention and intervention efforts have been only marginally successful , in part because they tend not to be appropriately tailored and instead use a one size fits all approach . in a recent review of school - based internet obesity prevention programs for adolescents , a number of programs targeted racial / ethnic minorities who are at greater risk for obesity and the majority of programs included content on nutrition and physical activity . however , none of the programs reviewed seemed to address issues related to sexual orientation and obesity , such as body image or sociocultural ideals of thinness and muscularity . more research is needed to identify subgroups most at risk for obesity by determining whether sexual orientation - by - gender disparities exist across race / ethnicity groups , such that intervention and prevention efforts can be more effectively tailored for these groups . the transition from adolescence to young adulthood is a critical period for weight gain and the development of obesity , with long - term negative health implications for excessive weight gain during young adulthood [ 17 , 18 ] . in addition , previous research has indicated that associations between sexual orientation and bmi change across adolescence and into young adulthood . longitudinal research with nationally representative samples of adolescents is needed to address whether age - by - sexual orientation effects exist among nonwhite youth . to address this question and to inform obesity prevention and weight - loss intervention efforts , the current study used longitudinal data from waves i iv of the national longitudinal study of adolescent health ( add health ) to examine sexual orientation disparities in bmi over time within female and male race / ethnicity groups . specific sexual minority subgroups were compared separately to heterosexual individuals because previous research has found bmi and obesity prevalence to differ among these subgroups , with bisexual individuals at particularly high risk for elevated bmi and obesity [ 9 , 19 ] . we hypothesized that female sexual minorities , particularly bisexual individuals , would have consistently higher bmi over time than heterosexual females . we further hypothesized that heterosexual males would experience greater one - year increases in bmi compared to gay males . finally , we hypothesized that these patterns would be similar across all three racial / ethnic groups . after exclusion criteria were applied ( described below ) , the current sample included 7,140 females and 6,166 males , who contributed data to at least one of the four waves of add health , a us nationally representative longitudinal cohort . participants were age 1121 years at wave i ( 1995 ) and age 2434 years at wave iv ( 2008 - 2009 ) . analyses were restricted to participants who provided a report of sexual orientation identity at wave iii and self - identified as non - latino white ( 59% ) , non - latino black / african american ( 23% ) , and latino ( 18% ) at wave i. other race / ethnicity groups were excluded due to a small sample size within some sexual orientation groups . descriptive statistics for age and bmi by race / ethnicity , gender , and sexual orientation are reported in table 1 . sexual orientation identity was assessed at wave iii with one item asking participants to choose the description that best fits how they think about themselves , with the following response options : 100% heterosexual ( straight ) ; mostly heterosexual ( straight ) , but somewhat attracted to people of your own sex ; bisexual , that is , attracted to men and women equally ; mostly homosexual ( gay ) , but somewhat attracted to people of the opposite sex ; 100% homosexual ( gay ) ; not sexually attracted to either males or females . race and ethnicity were assessed separately at wave i but recoded and combined into the following groups for analysis : non - latino white , non - latino black / african american , and latina / o . age in years and age - specific bmi ( kg / m ) calculated from self - reported height and weight were assessed at each wave . self - reported height and weight were used because measured height and weight were not available at all four waves . to test the hypotheses , we conducted longitudinal unweighted linear generalized estimating equation analyses in sas ( version 9.3 ; cary , nc ) . analyses were stratified by gender and race / ethnicity , with heterosexual as the reference group . for the current study , participants who responded that they were not sexually attracted to either gender were excluded from the analyses , and mostly homosexual and 100% homosexual were combined into lesbian / gay due to small sample sizes , yielding the following sexual orientation identity groups : heterosexual , mostly heterosexual , bisexual , and lesbian / gay . to address the nonlinearity of bmi across development [ 2123 ] , age was modeled both linearly and quadratically and sexual orientation - by - age was used to model repeated measures of continuous bmi across ages 1134 years , with age and bmi updated at each wave . weights are typically used in analysis of data from add health to allow for population estimates . we conducted unweighted analyses because the complexity of the models in examining bmi trajectories across waves and accounting for clustering by schools did not allow for the incorporation of weights . in addition , a model - based analysis is reasonable if design effects are taken into account , which the current analysis did by adjusting for gender , race / ethnicity , and age . sexual orientation and race / ethnicity group differences in mean age at each wave were found . among females , bisexuals and mostly heterosexual individuals were significantly younger ( bisexual range : 0.33 to 0.43 years ; mostly heterosexual range : 0.25 to 0.30 years ) than completely heterosexual individuals at all waves , p < 0.02 to p < 0.0001 . no significant sexual orientation group differences were found among males for mean age at each wave . among both females and males , latinos were significantly older ( female range : 0.43 to 0.49 years ; male range : 0.36 to 0.44 years ) than same - gender non - latinos at all waves , p < 0.0001 . in addition , non - latina black / african american females were significantly older ( 0.15 years ) than non - latina white females at wave ii only , p < 0.01 . descriptively , among both females and males across sexual orientation and race / ethnicity groups , age - specific bmi increased substantially across time from age 11 to 34 years ( table 1 , figure 1 ) . among females , the association between sexual orientation and bmi did not differ significantly by age , so sexual orientation - by - age interaction terms were not included in the final models . non - latina white and latina bisexual individuals had higher bmi compared to their heterosexual female counterparts , while no sexual orientation differences were observed among non - latina black / african american females ( see table 2 , figure 1 ) . among males , the association between sexual orientation and bmi differed significantly by age within each of the three race / ethnicity groups . gay males had higher bmi than heterosexual males in early adolescence . however , heterosexual males showed greater one - year bmi gains over time surpassing gay males by approximately age 17 years , with disparities widening further as participants aged into adulthood ( see table 2 , figure 1 ) . bisexual individuals showed a different pattern , with bisexual males showing greater one - year bmi gains over time compared to heterosexual males , but only among non - latino white participants . previous research with a predominantly white cohort of youth found that age modified sexual orientation disparities in bmi in males . the current research extended these findings to non - latino black / african american and latino young men . during adolescence and young adulthood , heterosexual males demonstrated greater yearly increases in bmi compared to gay males , putting them at excess risk for obesity . it is not clear why these patterns are emerging , but reporting bias could be one factor . a prior add health analysis found that gay males underreport their bmi by an estimated 0.37 bmi units more than heterosexual males ; nevertheless , bias of this magnitude would not be sufficiently large to explain the differences observed in the current study . another potential explanation for smaller increases in bmi among gay males may be that compared to heterosexual males , gay males are at greater risk for body dissatisfaction and eating disorder symptomatology , which may result in lower bmi over time [ 13 , 14 ] . other research has suggested that sexual minority male adolescents and young adults are less likely to attempt to gain weight compared to completely heterosexual male youth , which may represent a protective factor against the development of obesity among sexual minority male youth . this study also found higher bmi among bisexual non - latina white and latina females compared to same - race / ethnicity heterosexual females , but not in other sexual minority female subgroups . it is possible that bisexual females may be responding to sexual minority stressors ( e.g. , increased rates of victimization ) by engaging in obesogenic behaviors ( e.g. , stress - induced binge eating ) , more so than other sexual minority females or gay males . higher bmi among bisexual females may also be attributable to comorbidity of obesogenic behaviors with other health risk behaviors and negative health outcomes . for instance , other research has indicated that bisexual females are at greater risk for psychological distress and health risk behaviors , including substance use and self - injurious behavior , compared to other sexual orientation groups . a recent study found that compared to lesbians , bisexual women are more likely to use maladaptive coping strategies , which may explain more adverse mental and physical health outcomes in bisexual females compared to lesbian females . results from the current study highlight the need for research on health outcomes within sexual minority subgroups , in addition to comparing sexual minorities with completely heterosexual individuals . in addition , more research is needed to understand why bisexual females and males and heterosexual males have greater risk for increased bmi and whether membership in other sexual orientation groups may confer specific protective factors against weight gain and development of obesity . findings from this study demonstrated that sexual orientation and gender differences in bmi are not limited to non - latino white youth and young adults . among males , heterosexual males showed greater one - year bmi gains than gay males across all race / ethnicity groups . among females , non - latina white and latina bisexual individuals had higher bmi than same - race / ethnicity heterosexual individuals regardless of age ; there were no sexual orientation differences in non - latina black / african americans . it is clear from these results that sexual orientation disparities in bmi are a public health concern across race / ethnicity groups . obesity prevention and intervention efforts should target healthy body image and weight - management methods for all youth , but additional resources may be needed for sexual minority youth . in particular , interventions should be designed in such a way as to not exacerbate risk of unhealthy weight control behaviors and eating disorders . in summary , obesity prevention initiatives and treatment interventions addressing unhealthy weight gain in adolescence and young adulthood must be relevant for all sexual orientations and race / ethnicities . OUTPUT:

obesity is a key public health issue for us youth . previous research with primarily white samples of youth has indicated that sexual minority females have higher body mass index ( bmi ) and sexual minority males have lower bmi than their same - gender heterosexual counterparts , with sexual orientation differences in males increasing across adolescence . this research explored whether gender and sexual orientation differences in bmi exist in nonwhite racial / ethnic groups . using data from waves i iv ( 19952009 ) of the us national longitudinal study of adolescent health ( n = 13,306 , ages 1134 years ) , we examined associations between sexual orientation and bmi ( kg / m2 ) over time , using longitudinal linear regression models , stratified by gender and race / ethnicity . data were analyzed in 2013 . among males , heterosexual individuals showed greater one - year bmi gains than gay males across all race / ethnicity groups . among females , white and latina bisexual individuals had higher bmi than same - race / ethnicity heterosexual individuals regardless of age ; there were no sexual orientation differences in black / african americans . sexual orientation disparities in bmi are a public health concern across race / ethnicity groups . interventions addressing unhealthy weight gain in youth must be relevant for all sexual orientations and race / ethnicities .

PubMed_Summ6576

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: nontuberculous mycobacteria ( ntm ) have emerged as an increasingly important pathogen in the last two decades . unlike other environmental pathogens that are largely opportunistic in patients with malignancy and immunodeficiency , as well as transplant recipients , ntm can cause significant disease in otherwise healthy individuals . the ntm most commonly associated with pulmonary infection is the mycobacterium avium complex ( mac ) , which is a microbial complex of mycobacterium avium and mycobacterium intracellulare . there have been many reports concerning its radiologic findings.123 ) although uncommon , several cases of solitary pulmonary nodules ( spn ) caused by mac pulmonary infections have been reported,456 ) which is different from the typical presentation of mac . however , a case of a multiple cavitating nodular infection with neither a fibrotic change nor nodular bronchiectasis associated with m. intracellulare has not been reported . we present the case of a 67-year - old asian woman who had a m. intracellulare infection presenting with multiple cavitating pulmonary nodules , which was differentiated from metastatic lung disease by percutaneous transthoracic needle aspiration ( pcna ) . she presented to a local clinic after a single occurrence of hemoptysis 10 days prior . the color of the hemoptysis was scarlet and the amount was 1/2 cup of soju , korean distilled spirits . she had been diagnosed with type 2 diabetes mellitus ( dm ) 2 years prior at a local clinic , and had since been taking metformin 500 mg after breakfast and dinner . glycosylated hemoglobin was 6.7% , and she had good control of her blood sugar levels during hospitalization . after a chest ct was obtained at the local clinic , she was transferred to our hospital to investigate the multiple cavitary pulmonary nodules that were found on the ct scan . when the patient visited our hospital , her initial vital signs showed a blood pressure of 110/70 mm hg , heart rate of 80 beats / min , respiratory rate of 16 breaths / min , and body temperature of 36.8. both pupil responses to light were normal and there was no abnormality in the conjunctivae and sclerae . on auscultation , neither crackles nor wheezing was heard in both lung fields , and the heart sound was regular without murmur . at the first visit to our hospital , the patient did not have any symptoms . there were several round nodules in both the upper lung zone and right middle lung zone , and patch consolidation in the left lower lung zone on the chest radiography , which is suggestive of mycobacterium tuberculosis ( mtb ) or metastatic lung disease ( figure 1 ) . similarly , the chest ct showed centrilobular nodules with a tree - in - bud appearance and three round cavitary nodules in the left apex , the right upper lobe posterior segment , and the right lower lobe superior segment , suggestive of mtb or metastatic lung disease ( figure 2 ) . we isolated the patient because we could not exclude the possibility of mtb along with metastatic lung disease . the initial laboratory parameters were as follows : total leukocyte count 7,500/mm ( neutrophil 64.6% , lymphocyte 21.1% , monocyte 0.44% ) ; hemoglobin level 12.8 g / dl ; and platelet count 217,000/mm . the level of c - reactive protein was 0.03 mg / dl and other parameters were within the normal limit on the blood chemistry tests . additionally , the coagulation profile was checked , and the prothrombin time was 11.1 seconds ( international normalized ratio 1.35 ) . for further evaluation , we planned to perform a bronchoscopy and pcna , and the additional imaging examinations were not performed because chest imaging was obtained on the day of the initial hospital visit . the results of three smears for acid - fast bacilli , and a nucleic acid amplification test for mtb and ntm in sputum were all negative . for further evaluation , a bronchoscopy was performed on the left upper lobe apical segmental bronchus , the right upper lobe posterior segmental bronchus , and the right lower lobe superior segmental bronchus . the smear test of the bronchoscopic washing fluid was positive for acid - fast bacilli . the result of nucleic acid amplification was negative for mtb , but positive for ntm . therefore , the patient was diagnosed with ntm , so the patient 's quarantine was lifted . after 7 days , heavy colonies with confluent growth in ogawa 's egg medium were detected in the bronchial washing fluid culture . after 2 weeks , several colonies with confluent growth in the mycobacterium growth indicator tube 's egg medium were detected in the bronchial washing fluid culture . the precise species was identified using a polymerase chain reaction - restriction fragment length polymorphism - based method that identified differences in the rpob gene.7 ) the colonies were subsequently identified as m. intracellulare . to rule out metastatic lung disease , the lung tissue from the biospy showed chronic granulomatous inflammation with caseating necrosis ( figure 3a , b ) . for further evaluation , a nucleic acid amplification for mtb and ntm with a stain for acid - fast bacilli was conducted using tissue from the pcna . the additional report showed that both the nucleic acid amplication for ntm and the stain for acid - fast bacilli were positive ( figure 3c ) , and there were no malignant cells . this finding was consistent with ntm infection , and we could exclude metastatic lung disease . in conclusion , the lung tissue from the biospy confirmed the diagnosis obtained from the bronchial washing fluid culture . with the diagnosis of ntm infection the patient was prescribed a medication regimen that included rifampin ( 450 mg ) , ethambutol ( 800 mg ) , and clarithromycin ( 1,000 mg ) . a drug susceptibility test for clarithromycin was performed , and the result showed that the m. intracellulare was sensitive to clarithromycin . the patient started to complain of nausea and vomiting , and had poor oral intake 7 days after taking the medication for ntm . we changed the time for taking the medication from before meals to before bed , after which her symptoms improved . there were no other complications such as an abnormal liver function test or optic neuritis . we have performed blood tests and chest radiography to monitor the side effects and the disease progression . m. avium is the more important pathogen in a disseminated disease , whereas m. intracellulare is the more common respiratory pathogen . the chest radiography and ct scans showed abnormalities typical of the two forms of mac lung disease . the traditionally recognized presentation of mac lung disease is as an apical fibrocavitary lung disease with large cavities , located in the upper lobe . this form of the disease usually occurs in men with a history of cigarette smoking , excessive alcohol use , and underlying lung disease in their late 40s and early 50s . if not treated , this form of mac is rapidly progressive within a relatively short time period , 1 to 2 years mac lung disease also presents with bronchiectatic nodular infiltrates , usually involving the right middle lobe or the lingula segment , predominantly in postmenopausal and non - smoking women . this form of the disease has a tendency to progress much slower than the fibrocavitary disease , therefore long - term follow - ups lasting from months to years may be necessary to determine clinical or radiographic changes . in this indolent form of the disease spn is identified as focal , round , or oval areas of increased opacity in the lung that measure 3 cm in diameter . these nodules are frequently discovered incidently on chest radiography or chest ct.8 ) spn is often assumed to be attributable to mtb infection.9 ) however , it has been shown in case reports that spn can be attributable to mac lung infection.456 ) in 2009 , sekine et al.10 ) reported a case of a mac pulmonary infection presenting with multiple nodules , which was an unusual presentation of a mac pulmonary infection . unlike mtb therefore , the isolation of mac species from a respiratory sample is not sufficient evidence of ntm lung disease . in 1997 , the american thoracic society issued a revised set of diagnostic criteria for ntm pulmonary disease . according to these criteria , a patient with ntm lung disease must have compatible symptoms and signs , and a compatible chest radiography or chest ct abnormalities . the current case did not strictly satisfy the diagnostic criteria proposed by the american thoracic society in terms of radiographic findings . the diagnostic criteria of ntm lung disease must be expanded to such cases of spn , multiple nodules , and multiple cavitary nodules , as in our case . in our case , we could not initially rule out mtb lung infection due to the chest ct findings , which showed multiple cavitating nodules with centrinodular nodules . we did not suspect mac lung infection because there was neither bronchiectasis in the right upper lobe or the left lingular segment nor a fibrotic change in the upper lobe . while the bronchoscopy findings were sufficient to diagnose the patient with mac lung infection , we also conducted a pcna to rule out metastatic lung disease . , we differentiated the atypical presentation of mac lung infection from mtb lung disease or metastatic lung disease . ntm have emerged as an increasingly important pathogen in the last two decades . in korea , there has been an increasing prevalence of mac infections , and an increasing number of cases presenting with atypical findings . our case report highlights the importance of differentiating among mtb , mac infection , and metastatic lung disease in cases of multiple cavitary nodules . clinicians should consider the possibility of mac lung infection with various findings on chest radiography and chest ct . we believe that pcna can be a valuable diagnostic tool for differentiating mtb and mac , and differentiating between malignant diseases and infectious diseases when a pulmonary nodule is revealed on chest radiography or chest ct scans . in conclusion , to the best of our knowledge , this is a very rare report of a mac pulmonary infection presenting with multiple cavitary nodules . as the prevalence of mac infections increases , more cases start to show atypical radiographic findings , compared to the typical apical fibrocavitary or bronchiectatic nodular forms . other forms of mac have been reported , such as spn and multiple nodules . in this report , we present another form of mac pulmonary infection . therefore , clinicians should consider the possibility of mac lung disease with various findings on chest radiography or chest ct scans . in addition , pcna can be a useful diagnostic tool for evaluating multiple nodules to differentiate metastatic lung diseases from infectious diseases such as mtb or mac lung infections . OUTPUT:

nontuberculous mycobacteria ( ntm ) have been increasingly recognized as an important cause of chronic pulmonary infections . the mycobacterium avium complex ( mac ) , which is composed of two species , mycobacterium avium and mycobacterium intracelluare , is the most commonly encountered pathogen associated with ntm lung disease . mac pulmonary infection typically presents in a fibrocavitary form or a nodular bronchiectatic form . however , there have been atypical presentations of mac pulmonary infections , including solitary pulmonary nodules ( spn ) . there have been several previous reports of spn due to mac infection in the united states , japan , and korea . in 2009 , sekine and colleagues reported a case of mac pulmonary infection presenting with multiple nodules . to date , however , there have been no cases of ntm lung infection with multiple cavitary pulmonary nodules , and neither a fibrotic change nor nodular bronchiectasis . the present case showed a multiple cavitating nodular lung infection due to mac , which is very rare and different from the typical presentation of mac pulmonary infections . we also showed that percutaneous transthoracic needle aspiration can be a useful diagnostic tool to evaluate a case of multiple cavitary nodules .

PubMed_Summ6577

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: despite better knowledge of the neurobiology of pain , progress of pharmacology and techniques of pain treatment , consensus and guidance of experts , inadequate control and underestimation of pain more often is the rule rather than the exception ( 1 ) . approximately 30 - 40% of patients with cancer have pain at the time of setting the diagnosis . in the advanced stage of the disease 75 - 90% of patients suffer pain , despite data from the institution of palliative medicine around the world that 95% of cancer pain can be effectively controlled ( 2 ) . in 40 - 50% of cases the pain was rated as medium - severe to severe , whereby in 70% of cases occurring in the form of nociceptive cancer pain wherein the cancerous cells released endothelin , prostaglandins and tumor necrosis factor alpha ( tnf ) , proteolytic enzymes and other algogene substances . compression and nerve injury or cancer pain due to infiltration of bone nerve are the cause of the neuropathic cancer pain ( 3 ) . mild ( weak ) opioid analgesics are intended for the treatment of moderate pain and are used in case of treatment failure with non - opioid analgesics or if the initial pain intensity was 4 to 6 by the ias , either alone or in combination with non - opioid , with or without other analgesics . tramadol is mild opioid analgesic with effects on the central nervous system , acting as a non - selective pure agonist of , and opioid receptors with higher affinity for the receptor . by inhibiting the reuptake of norepinephrine and is used in the treatment of moderately severe pain , and can suppress the cough , while in wide range of analgesic doses not suppress respiration . depending on the method of application to date has been proven the involvement of paracetamol in five different analgesic mechanisms : ( a ) inhibition of isoenzymes of cyclooxygenase ( cox ) in the cns without interaction with the binding sites ; ( b ) activation of serotonin bulbospinal time periods ; ( c ) activation of nitric oxide ( no ) activation path ; ( d ) activation or modulation of endogenous opioid periods , and ( e ) increase the tone of the endogenous cannabinoid ( 5 ) . metabolism of paracetamol releases n - acetyl - p - benzoquinone imine ( napqi ) , which if it is not detoxified , binds to hepatocytes leading to cell necrosis . this binding is cause poisoning and liver weakness in case of paracetamol overdose ( 6 ) . also proven is link between hypertension and paracetamol ( 7 , 8) , which is probably caused by an significant amount of sodium which each paracetamol tablet contain . due to the frequent occurrence of mixed nociceptive - neuropathic pain , one analgesic may not be efficient enough to cover all of the causal mechanisms of pain . combined analgesics may be more effective because they can offer a wider range of relieving pain , activation of analgesic process and reduce the negative effects ( 9 ) . the effect of analgesics combination may be higher , lower or the same as the intended total extent of the impact . this effect can be calculated mathematically , based on the concept of equal dose , which is defined as the dose of each drug that contributes to the total extent of the effect when each is used separately . the combined use of tramadol and paracetamol in one product , taking into account the pharmacokinetic and pharmacodynamic criteria can improve the benefit : risk ratio , increase efficiency by synergistic mechanisms , improve the tolerability of the drug ( lower individual dose ) and patient compliance ( 11 ) . combining tramadol and paracetamol is achieved a synergistic analgesia by three different mechanisms of action : binding of the -opioid receptors ; activation of the descending pain control pathways ; inhibition of cox-3 . the combination ensures rapid onset of action , longer efficacy , better efficiency then individual components and a good safety profile . it can be administered alone or can be added to nsaids in patients with inadequate analgesia care must be taken that tramadol may increase the risk of convulsive spasms due to a decrease of convulsive threshold and lead to serotonin syndrome in combination with other selective serotonin reuptake inhibitors ( antidepressants ) ( 12 ) . paracetamol as the second component of the fixed combination in therapeutic doses has just few side effects , while the maximum recommended dose for adults ( 4 grams per day ) is associated with cases of hepatotocicity ( 13 , 14 ) . palliative stage of the disease involves interruption of targeted oncology treatments and the limited lifespan of the patient with the dominant aim of improving the quality of life , regardless of the duration of life ( 15 ) . pain of medium severe intensity is dominant symptom in patients with advanced stages of cancer . progression of the disease in these patients requires frequent evaluation of symptoms of pain and adjustment of therapeutic doses of weak opioids or switch to strong opioid analgesics . the goal of the research was to determine the efficacy of a fixed combination tramadol and acetaminophen in the treatment of pain in patients with the advanced stage of cancer . a prospective study was conducted at the center for palliative care , university clinical center tuzla , bosnia and herzegovina , from january 1 to december 31 2013 . study entered 369 patients who were due to pain intensity 4 - 8 ( medium severe to severe pain ) on the numeric rating scale ( nrs ) , treated with a fixed combination of tramadol and acetaminophen ( 37.5 mg and 325 mg ) in the initial dose 3x1 tablets for pain intensity 4 , up to 4x2 tablets for pain intensity 7 and 8 . every day ( 10 days ) pain intensity was recorded and if the previous day was patient had two or more episodes of pain , the dose of fixed combination tramadol and paracetamol was increased to a maximum of 8 tablets daily . during the first 10 days of study 16 patients patients excluded from the study during the first ten days of treatment . * of the total respondents , 369 patients the study ended 353 patients , with mean age of 65.3412.15 years ( 24 - 92 years ) , 211 ( 59.77% ) males and 142 ( 40.23% ) females . from the baseline 102 patients ( 28.89% ) had verified metastatic changes in bones while 251 patients ( 71.11% ) had no bone metastases ( p<0.0001 ) . in the study was 33.43% of patients with tumors of the gastrointestinal system , 25.22% with lung tumor , while the tumors of other organs account for less than 10% , with varying percentages of bone metastases ( table 2 ) . tumor localization . * from total of 353 patients ; * * from total of 102 patients ; o * * * = other tumors of bones and connective tissue , unknown localization , non cancer pain ; & esophagus , stomach , intestines ; liver , gallbladder , pancreas from total sample 158 ( 44.76% ) patients were in the palliative stage of cancer disease in period less than 12 months , and 195 or 55.24% of the patients in the period after 12 months ( p=0.067 ) ( table 3 ) . time from ph * diagnosis until psd * * from total of 353 patients ; * ph = histopathological diagnosis ; psd * * = palliative stage of the disease in 13 ( 3.68% ) of patients palliative stage of the disease is verified in less than three months , with 126 ( 35.69% ) in the period up to 36 months , while in 48 ( 13:59% ) patients specific oncological treatment lasted up to 72 months and in 21 ( 5.96% ) cases for more than six years . all patients were previously informed about the aims and nature of research , and they provided their approval with written informed consent to participate in the study . statistical analysis was performed by biomedical software medcalc for windows version 9.4.2.0 . for testing the repeated measurements of dependent samples , depending on the distribution of variables the statistical hypotheses were tested at the level of significance of =0.05 or the difference between samples was considered significant if p<0.05 . a ) the duration of treatment with a fixed combination tramadol and acetaminophen the average duration of treatment with a fixed combination tramadol and paracetamol for all 353 patients was 57 days ( from the shortest treatment duration of 13 to the longest of 330 days ) . most common duration of treatment was between 31 - 100 days ( in 225 patients or 63.74% ) , while 2 patients ( 0.57% ) had treatment duration was longer than 300 days ( table 4 ) . duration of treatment with a fixed combination tramadol and acetaminophen . * total 353 patients ; * * transfer to morphine ; * * * fixed combination used until death in patients with bone metastases , the average duration of treatment with a fixed combination tramadol and acetaminophen was 69 days ( 14 - 330 ) , and in patients without bone metastases , the median duration of treatment was 52 days ( 13 - 278 ) , which is significantly lower than compared to patients with bone metastases ( p=0.0047 ) . in our study , disease progression and higher pain intensity was sign for transfer to strong opiates in 57 ( 16.15% ) patients , while until the end of life the pain was adequately treated with a fixed combination tramadol and acetaminophen in 51 patients ( 14.45% ) ( table 4 ) . b ) analysis of the pain intensity by days of treatment for all patients the average pain score in all patients for 10 days of treatment was 2.121:34 where there was a statistically significant difference ( p=0.0001 ) compared to the total intensity of pain in patients with metastatic changes in bones ( 2.261.47 ) compared to patients without bone metastasis ( 2.061.27 ) . on the first day of treatment the average intensity of pain in all patients was 5.541.18 , significantly more ( p<0.0001 ) compared to the pain intensity on the tenth day of treatment 1.50.53 ( table 5 ) . average pain intensity by days of treatment among all patients . measured outside of pain breakthrough ; * median , wilcoxon test ; * * paired samples t - test comparing the average values of pain intensity by days of treatment of patients with and without bone metastases , on the day of admission the pain intensity was significantly higher ( p<0.0001 ) in patients with bone metastases [ median 6.00 ( 4.00 to 8.00 ) ] versus patients without bone metastases [ median 5.00 ( 4.00 to 8.00 ) ] ( table 6 ) . comparison of average pain intensity of patients with and without bone metastases . presented as median ; * mann - whitney test ( independent samples ) significantly greater pain intensity was also observed in patients with bone metastases on fifth , sixth and eighth days of treatment with a fixed combination of tramadol and paracetamol compared to patients without bone metastases ( figure 1 ) . mean pain intensity by days of treatment of patients with and without bone metastases analysis of the optimal dose of fixed combination tramadol and paracetamol as the base of analgesics in the treatment of moderate pain the average dose of the fixed combination tramadol and paracetamol ( 1 tablet = 37.5 mg and 325 mg ) for all 353 patients for 10 days of treatment was 4.81.8 tablets ( 180 mg of tramadol and 1560 mg of paracetamol ) . the average dose of fixed combination tramadol and paracetamol ( for both groups of patients ) was higher with each subsequent day of treatment of 4.171 - 53 tablets ( 156.4 mg tramadol and 1355.3 mg paracetamol ) on first to 5.62 1.95 tablets ( 210.8 mg tramadol and 1826.5 mg paracetamol ) on the tenth day of treatment ( table 7 ) . mean number of tablets for fixed combination tramadol and acetaminophen * by days of treatment . * 1 tablet of fixed combination = tramadol 37.5 mg and paracetamol 325 mg in all patients with confirmed bone metastasis mean dose of fixed combination tramadol and acetaminophen was statistically significantly higher ( p<0.0001 ) compared to patients without bone metastasis [ 5.421.83 ( 203.25 mg tramadol and paracetamol 1761.5 mg ) in patients with metastases versus 4.59 1.79 ( 172.13 mg of tramadol and paracetamol 1491.8 mg ) in patients without bone metastases ] ( table 8) . comparison of mean dose of fixed combination tramadol and paracetamol by days of treatment in the groups with and without bone metastases . * mann - whitney test ( independent samples ) on the tenth day of treatment in the group of patients without bone metastases average dose of tramadol in fixed combination tramadol and paracetamol was 200.25 mg of tramadol , while on the same day in a group of patients with bone metastases average dose of tramadol was significantly higher ( p<0.0001 ) and amounted to 236.3 mg of tramadol ( figure 2 ) . the average dose of tramadol in a fixed combination tramadol and paracetamol by groups and days of treatment in the group of patients without bone metastases , on the tenth day of treatment , the average dose of paracetamol in a fixed combination tramadol and paracetamol was 1735.5 mg of paracetamol , while on the same day in a group of patients with bone metastases average dose of paracetamol were statistically significantly higher ( p<0.0001 ) and amounted to 2047.5 mg of paracetamol ( figure 3 ) . the average dose of paracetamol in a fixed combination tramadol and paracetamol by groups and days of treatment from a total of 353 patients surveyed , during the first 10 days of treatment , side effects of mild to moderately high intensity ( corrected with additional targeted therapy and did not jeopardize the continuation of treatment with a fixed combination tramadol and paracetamol ) occurred in 103 patients ( 29.18% ) ( table 9 ) . the frequency of side effects in the treatment of pain with a fixed combination of tramadol and paracetamol . * from 103 patients with side effects ; * * from total of 353 patients nausea that was present in 39.8% and vomiting with 34.9% were the dominant side effects in the treatment of pain with a fixed combination tramadol and acetaminophen , while the dizziness was observed in 8 ( 7.77% ) and somnolence in 2 ( 1.94% ) patients ( table 9 ) . a study published in 2011 on the efficacy and safety of a fixed combination tramadol and acetaminophen in the treatment of medium to severe pain ( 16 ) states a significant analgesic efficacy of this combination with a reduction in average pain intensity from an initial 6.1 to 3.1 , with 64.8% of patients described significant pain relief . data from the same study indicate that 90.5% of patients have a high degree of satisfaction with treatment and 78.7% of patients assessed the general situation as much better . of the surveyed 2663 patients with an average age of 73.66.6 years , 119 ( 4.5% ) reported at least one side effect in form of as known and foreseeable ones . similar results were also confirmed by our research , while in our research at the start of the study ( the first day of treatment ) average pain intensity in all patients was 5.541.18 which was significantly higher ( p<0.0001 ) compared to the pain intensity on the tenth day of treatment 1.500:53 . already after 24 hours of treatment by a fixed dose of tramadol and acetaminophen , the average pain intensity of all patients was significantly lower p<0.0001 [ 5.00 ( 4.00 to 8.00 ) on the first day compared to the average pain intensity 2.00 ( 1.00 to 7.00 ) on the second day of treatment ] which indicates the rapid onset of the drug action . review paper , published in 2008 ( 17 ) , the efficiency of a fixed combination tramadol and acetaminophen in the treatment of mild to moderate pain included 15 studies . nine studies ( double - blind trials with a treatment duration of 1 - 10 days ) includes a total of 2537 patients with chronic degenerative diseases ( with the emergence of pain ) after trauma or postoperatively , showed that the most common average dose of fixed combination tramadol and paracetamol ( 37.5 mg and 325 mg ) was from 4.34.5 tablets . in six studies in which the duration of treatment was 4 - 13 weeks for the bone muscle pain , it was followed 1890 patients , and the mean daily dose of fixed combination tramadol and acetaminophen ( 37.5 mg and 325 mg ) was 3.54.2 tablets daily . in our study an average dose of fixed combination tramadol and paracetamol for all 353 patients during 10 days of treatment was 4.8 1.8 tablets ( 180 mg of tramadol and paracetamol 1560 mg ) . the average dose of fixed combination tramadol and paracetamol was higher with each subsequent day of treatment with 4.171.53 tablets ( 156.4 mg of tramadol and 1355.3 mg of paracetamol ) on the first to 5.6 1.95 tablets ( 210.8 mg of tramadol and paracetamol 1826.5 ) on the tenth day of treatment . in a study by ajay et al . ( 18 ) a total of 204 patients with moderate to severe pain of muscle marrow origin was treated with a combination of phentermine ( 50 mg ) and diclofenac sodium ( 75 mg ) ( group a ) and a fixed combination of tramadol and acetaminophen ( 37.5 and 325 mg ) ( group b ) . the intensity of pain with the use of a fixed combination tramadol and paracetamol after 5 days of treatment ( measured by vas scale ) is reduced from an average of 74 on the first day to 36.72 on the fifth day of treatment . however a combination of phentermine ( 50 mg ) and diclofenac sodium ( 75 mg ) showed better efficacy in the treatment of pain , wherein the average intensity of pain on the first day was 70.74 and 20.74 of the fifth , which is statistically better ( p = 0.0001 ) compared to treatment than with fixed combination of tramadol and paracetamol . similar results on the efficacy of a fixed combination tramadol and paracetamol in the treatment of pain in a group of patients with bone metastases ( muscle bone pain ) shows our research . in our study , the average pain intensity in patients with bone metastases ( muscle bone pain ) on the first day of treatment was 6.07841.1831 , on the fifth day significantly lower 1.94120.6265 ( p<0.001 ) and on the tenth day of treatment 1.58820.5691 ( p<0.001 ) which supports the analgesic efficacy of a fixed combination tramadol and paracetamol . this claim is confirmed by a study carried out on 336 patients with chronic back pain ( 19 ) where the initial pain intensity was 67.8 ; immediately after the start of treatment was reduced to 47.4 and after 3 months of treatment at even 1.8 . in this study followed side effects of which the most common were nausea ( 12.0% ) , dizziness ( 10.8% ) and constipation ( 10.2% ) . the average daily dose of tramadol and paracetamol was 4.2 tablets ( 158 mg of tramadol and 1369 mg of paracetamol ) . our findings show that the side effects , during the treatment of pain with a fixed combination tramadol and paracetamol were registered in 103 patients or 29.18% , with the dominance of nausea and vomiting . ( 20 ) reported frequency of side effects in 35.88% of patients in the treatment of pain with a fixed combination of tramadol and acetaminophen , wherein the dominant was vomiting ( 27.35% ) and nausea ( 25.88% ) , but much less common headache ( 5.88% ) , dizziness ( 3.82% ) and somnolence ( 1.47% ) . ( 21 ) vomiting occurred in 28.8% , nausea in 25.8% , dizziness in 15.9% and somnolence in 9.1% of patients with pain treated with fixed combination tramadol and paracetamol . limitations of the research there are a small number of studies in which was compared the use of fixed - dose drug treatment of the moderate to severe cancer pain , and lot more research on the treatment of some forms of non - carcinoma pain , especially skeletal and muscle . this study did not presented , nor the frequency nor the ways of cropping breakthrough of pain in our patients . duration of life and other disorders that accompany the advanced carcinoma limit the accuracy of research . fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain , with frequent dose evaluation and mild side effects . OUTPUT:

goal : the goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol ( acetaminophen ) in the treatment of pain of patients with the advanced stage of cancer.material and methods : a prospective study was conducted at the center for palliative care , university clinical center tuzla , bosnia and herzegovina , from january 1st to december 31st 2013 . a total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen ( 37.5 mg and 325 mg ) at the initial dosage 3x1 tablet ( 112.5 mg tramadol and 975 mg acetaminophen ) for pain intensity 4 , up to 4x2 tablets ( 300 mg of tramadol and 2600 mg paracetamol ) for pain intensity 7 and 8 . if the patient during previous day has two or more pain episodes that required a rescue dose of tramadol , increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily ( 300 mg of tramadol and 2600 mg paracetamol ) . statistical analysis was performed by biomedical software medcalc for windows version 9.4.2.0 . the difference was considered significant for p<0.05.results : the average duration of treatment with a fixed combination tramadol and acetaminophen was 57 days ( 13 - 330 days ) . already after 24 hours of treatment the average pain score was significantly lower ( p<0.0001 ) compared to the admission day [ 5.00 ( 4:00 to 8:00 ) during the first days versus 2.00 ( 1:00 to 7:00 ) during the second day of treatment ] . the average dose of the fixed combination tramadol and acetaminophen tablets was 4.8 1.8 ( 180 mg of tramadol and 1560 mg paracetamol ) . side effects , in the treatment of pain with a fixed combination tramadol and acetaminophen , were found in 29.18% of patients , with a predominance of nausea and vomiting.conclusion:fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain , with frequent dose evaluation and mild side effects .

PubMed_Summ6578

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the term amyotrophic lateral sclerosis ( als ) was first coined by charcot , who postulated the primacy of the upper motor neuron ( umn ) in als pathogenesis.1 assessment of cortical function in als and identification of the characteristic clinical phenotype involving combined upper and lower motor neuron abnormalities remain the key for als diagnosis.24 however , despite charcot 's initial observations , the site of disease onset and mechanisms underlying als pathophysiology remain areas of intense study and debate.5 in this setting , assessment of motor cortical and corticospinal function using non - invasive techniques , such as transcranial magnetic stimulation ( tms ) , has enhanced our understanding of als pathophysiology and resulted in novel diagnostic approaches . single- , paired- and multiple - pulse tms techniques have all been used ( figure 1 ) with the following measures taken to reflect corticomotoneuronal function : motor threshold ( mt ) , motor evoked potential ( mep ) amplitude , central motor conduction time ( cmct ) , cortical silent period ( csp ) , intracortical inhibition and facilitation . the present review will focus on the mechanisms underlying the generation of these tms measures , while at the same time assessing the contributions tms has made in the understanding of als pathophysiology . with an eye towards the future , the review will also consider the potential diagnostic utility of tms in als and incorporation of tms as a disease biomarker in the assessment of neuroprotective medications in a clinical trial setting . transcranial magnetic stimulation excites a network of neurons in the underlying motor cortex with motor evoked potentials recorded over the contralateral abductor pollicis brevis muscle . the motor cortex is preferentially stimulated when the current flows in a posterior anterior direction within the motor cortex . mt reflects the ease with which corticomotoneurons are excited and is proposed to be assessed by the international federation of clinical neurophysiology as the minimum stimulus intensity required to elicit a small ( usually > 50 v ) mep in the target muscle in 50% of trials.6 with the recent adaptation of threshold tracking techniques , mt can also be measured as the stimulus intensity required to elicit and maintain a target mep response of 0.2 mv.79 mt reflects the density of corticomotoneuronal projections onto the spinal motor neuron with the highest density of projections to intrinsic hand muscles having the lowest mts.1012 mts are lower in the dominant hand12 and correlate with the ability to perform fine ( fractionated ) finger tasks,13 so that mt has the potential to map corticomotoneuronal representation and function . as well as reflecting the density of corticomotoneuronal projections , mts may also be a biomarker of cortical neuronal membrane excitability.1416 mts are influenced by the glutamatergic neurotransmitter system , through -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid ( ampa ) receptors , whereby excessive glutamate activity reduces mts.17 in contrast , pharmacological blockade of voltage - gated sodium channels raises mt.18 in als , abnormalities in mt have been inconsistent . while some tms studies reported an increased mt or even an inexcitable motor cortex,1926 others have documented either normal or reduced mt.2732 these discrepancies likely relate to heterogeneity of the als phenotype and the stage of disease at time of testing and rate of progression . longitudinal studies have documented a reduction of mts early in the disease course , increasing to the point of cortical inexcitability with disease progression.29 the early reduction in mt appears most pronounced in als patients with profuse fasciculations , preserved muscle bulk and hyper - reflexia.33 fasciculations may precede other features of als by many months and taken in association with reduced mt suggest a cortical origin of fasciculations in als.34 reduced mt may be modulated by increased glutamate excitation , reduced gamma - aminobutyric acid ( gaba ) inhibition or a combination of both . reduced mt early in als supports an anterograde transsynaptic process , whereby cortical hyperexcitability underlies the development of progressive neurodegeneration . mep amplitude reflects a summation of complex corticospinal volleys consisting of d ( direct)- and i ( indirect)-waves.14 35 at threshold , tms elicits i - waves at intervals of 1.5 ms , which increase in amplitude with increasing stimulus intensity.35 the increase in mep amplitude with increasing stimulus intensity may be used to generate a stimulus response curve that follows a sigmoid function.36 as with mt , the mep amplitude reflects the density of corticomotoneuronal projections onto motor neurons.37 when compared with mt , the meps probably assess the function of neurons that are less excitable or further away from the centre of the tms induced electrical field.38 the mep amplitude should be expressed as a percentage of the maximum compound muscle action potential ( cmap ) evoked by electrical peripheral nerve stimulation.6 doing so takes into account any lower motor neuron pathology and provides insight into the percentage of the motor neurone pool activated in the mep . normative values for the mep to cmap ratio demonstrate a large inter - subject variability thereby reducing the sensitivity and limiting the value of this measure for detecting abnormalities of the corticomotoneurons.38 39 the mep responses are modulated by a variety of neurotransmitter systems within the central nervous system.37 40 specifically , gabaergic neurotransmission via gabaa receptors suppresses while glutamatergic and noradrenergic neurotransmission enhances the mep amplitude.41 of interest , these changes in mep amplitude occur independently of changes in mt , suggesting that physiological mechanisms underlying the generation of the mep amplitude and mt are varied . abnormalities of meps have been extensively documented in als.38 increases in mep amplitude have been reported in sporadic and familial forms of als ( figure 2a ) , most prominently early in the disease course.30 31 42 mep amplitude correlates with surrogate biomarkers of axonal degeneration , such as the strength duration time constant , thereby providing an association between cortical hyperexcitability and motor neuron degeneration.30 43 the increase in mep amplitude in als is not seen in mimic disorders despite a comparable degree of lower motor neuron dysfunction ( figure 2b ) . this suggests that the mep amplitude changes in als are excitotoxic in nature.4447 ( a ) the motor evoked potential ( mep ) amplitude , expressed as a percentage of compound muscle action potential ( cmap ) response , is significantly increased in sporadic amyotrophic lateral sclerosis ( als ) and familial als ( fals ) when compared with healthy controls . ( b ) the mep amplitude is significantly increased in als when compared with pathological and healthy controls , thereby distinguishing als from als mimic disorders . * cmct represents the time from stimulation of the motor cortex to the arrival of corticospinal volley at the spinal motor neuron.6 multiple factors contribute to the cmct including time to activate the corticospinal cells , conduction time of the descending volley down the corticospinal tract , synaptic transmission and activation of spinal motor neurons.48 cmct may be measured using either the f - wave or cervical ( or lumbar ) nerve root stimulation methods;49 50 both methods provide only an estimation of the cmct,48 51 and given that a variety of technical , physiological and pathological factors influence cmct,48 there is a range of normative data . in als , cmct is typically modestly prolonged,21 29 52 probably reflecting axonal degeneration of the fastest conducting corticomotoneuronal fibres and increased desynchronisation of corticomotoneuronal volleys secondary to axonal loss.28 53 54 the d90a - sod1 als mutation is a unique exception ; in this disorder cmct is typically very prolonged.55 the sensitivity of detecting a prolonged cmct may be improved by recording from both upper and lower limb muscles , or from cranial muscles in als patients with bulbar onset disease.26 56 csp refers to the interruption of voluntary electromyography activity in a target muscle induced by stimulation of the contralateral motor cortex.57 the csp duration is measured from the onset of the mep response to resumption of voluntary electromyography activity37 57 and increases with stimulus intensity.5759 the csp is mediated by both spinal mechanisms , in its early part , and cortical inhibitory neurons acting via gabab receptors in the latter part.57 58 6063 since the duration is determined by the latter part , the csp is a measure of cortical inhibition . in addition , the density of the corticomotoneuronal projections onto motor neurons also influences the csp , with the csp duration being the longest for upper limb muscles.38 abnormalities of the csp duration are well established in als.37 absence or reduction in csp duration has been reported in both sporadic and familial als , with the reduction of csp duration being the most prominent early in the disease course.3032 44 46 52 6467 the reduction of csp duration appears to be specific for als among neuromuscular disorders , being normal in x - linked bulbospinal muscular atrophy ( kennedy 's disease ) , acquired neuromyotonia and distal hereditary motor neuronopathy with pyramidal features.4447 although the mechanisms underlying csp duration reduction in als remain to be established , decreased motor drive and reduced gabaergic inhibition , either due to degeneration of inhibitory interneurons or dysfunction of gabab receptors , may underlie the reduction of csp duration in als . an absent or delayed ipsilateral csp has also been reported as an early abnormality in als.67 68 the ipsilateral csp depends on functioning of transcallosal glutamatergic fibres projecting onto inhibitory interneurons in the non - stimulated motor cortex,69 and degeneration of these transcallosal fibres or their targeted inhibitory interneurons may account for abnormalities of the ipsilateral csp in als . the previous section has covered conventional tms parameters that can be assessed through activation of the motor cortex by single impulses . motor cortical excitability may also be assessed using paired - pulse techniques , in which a conditioning stimulus modulates the effect of a second test stimulus . several different paired - pulse paradigms have been developed,37 38 but short interval intracortical inhibition ( sici ) , intracortical facilitation ( icf ) and long interval intracortical inhibition have been most frequently used in als clinical research as methods to determine cortical excitability . to identify sici and icf , a subthreshold conditioning stimulus is typically delivered at predetermined time intervals prior to a suprathreshold test stimulus.8 7072 in the early tms paradigms,70 72 73 the conditioning and test stimuli were kept constant , and changes in the test mep amplitude were evaluated . typically , if the interstimulus interval ( isi ) was between 1 and 5 ms , the test response was inhibited ( sici ) . increasing the isi to between 7 and 30 ms resulted in the facilitation of the test response ( icf).38 by recording the descending corticospinal volleys through epidural electrodes at the level of the cervical spinal cord , it has been deduced that both sici and icf originate at the level of the motor cortex.35 72 specifically , sici is associated with a reduction in the number and amplitude of late i - waves , namely i2 and i3 , with i - wave suppression remaining up to an isi of 20 ms , which is the typical duration of the inhibitory postsynaptic potential mediated through gabaa receptors.71 74 sici and icf appear to be physiologically distinct processes as evident by lower thresholds for activation of sici and sici remains independent of the direction of current flow in the motor cortex induced by a subthreshold conditioning pulse in healthy subjects , while icf appears to be preferentially generated by current flowing in a posterior constant stimulus paired - pulse technique has been the marked variability in mep amplitudes with consecutive stimuli.71 75 to overcome this limitation , a threshold tracking technique was developed whereby a constant target mep response ( 0.2 mv ) was tracked by a test stimulus.7 8 using threshold tracking , two phases of sici were identified,7 8 76 77 a smaller phase at isi 1 ms and a larger phase at isi 3 ms ( figure 3a ) . although synaptic neurotransmission through the gabaa receptor mediates the second phase of sici,74 7880 the precise mechanisms underlying the first phase of sici remain uncertain . it was initially suggested that the first phase of sici reflected local excitability properties , particularly relative refractoriness of cortical axons , with resultant resynchronisation of cortico - cortical and corticomotoneuronal volleys.7 81 subsequently , it has been argued that synaptic processes best explain the development of the initial phase of sici , possibly driven by activation of cortical inhibitory circuits that were distinct to those that mediated the later sici phase.76 77 82 ( a ) short interval intracortical inhibition ( sici ) , defined as the stimulus intensity required to maintain a target motor evoked potential of 0.2 mv , as assessed by the threshold tracking transcranial magnetic stimulation technique . intracortical inhibition is illustrated by an increase in the conditioned test stimulus intensity required to track the target response , while intracortical facilitation is indicated by a reduction in test stimulus intensity . in healthy controls , sici develops between interstimulus intervals ( isi ) of 1 and 7 ms , with two peaks evident at 1 and 3 ms as indicated by the arrows . sici is significantly reduced in both sporadic amyotrophic lateral sclerosis ( sals ) and familial amyotrophic lateral sclerosis ( fals ) . ( b ) averaged sici , between isi 1 and 7 ms , was reduced in two presymptomatic superoxide dismutase-1 ( sod-1 ) mutation carriers 6 months prior to the development of als . ( c ) normalised sici , expressed as a fraction of the sici value measured at the first study , was reduced 8 months prior to development of als in a third presymptomatic sod-1 mutation carrier . a reduction or absence of sici , together with an increase in icf , indicative of cortical hyperexcitability has been documented in cohorts of sporadic and familial als patients ( figure 3a).3032 44 45 8388 of relevance , cortical hyperexcitability appears to be an early feature in sporadic als , correlating with measures of subsequent peripheral neurodegeneration.30 in addition , cortical hyperexcitability appeared as an early feature in familial als due to mutations linked to the superoxide dismutase-1 ( figure 3a ) and fused in sarcoma ( fus ) genes,31 preceding the clinical development of familial als ( figure 3b).31 neuropathological studies in als have identified degeneration of inhibitory cortical interneurons89 and this could account for the reduction in sici . separately , glutamate - mediated excitotoxicity may also contribute to sici reduction , as was suggested by partial correction of sici abnormalities in als patients treated with the glutamate antagonist riluzole.87 a recent study documenting sici reduction at low ( 40% of resting mt ( rmt ) ) , medium ( 70% of rmt ) and high ( 90% of rmt ) conditioning stimulus intensities in als patients provided further support for the notion that abnormalities in sici appeared to be mediated by a combination of glutamate excitotoxicity and degeneration of inhibitory cortical circuits.90 as such , preserving the integrity of intracortical inhibitory circuits , and counteracting excitatory cortical circuits , may serve as potential therapeutic options in als . a peristimulus time histogram technique can assess the function of a select subset of corticomotoneurons by recording the perturbation of voluntarily recruited motor units induced by a threshold cortical stimulation.53 in healthy controls , there is a well synchronised primary peak with a latency of approximately 2030 ms recording from hand or forearm muscles.28 53 analysis of this primary peak in disease states such as als provides information on corticomotoneuronal conduction time , the extent of desynchronisation of corticomotoneuronal descending volleys , the degree of corticomotoneuronal synaptic input onto the anterior horn cell and the timing of excitatory and inhibitory inputs to the motor neuron.33 in als , the primary peak becomes desynchronised , prolonged in duration and delayed.28 91 92 in addition , the amplitude of the primary peak may be increased with additional subcomponents both suggestive of corticomotoneuronal hyperexcitability.53 93 these primary peak abnormalities appear early in als , accompanied by reduced mts . with progression of disease , there is prolongation and increased desynchronisation of the primary peak , findings possibly specific to als when compared with healthy controls and kennedy 's disease.53 94 over recent years , collision techniques such as the triple stimulation technique ( tst ) have been used to reduced the degree of mep desynchronisation which normally occurs following a single cortical stimulus.95 96 this complex technique is performed by first delivering a high - intensity magnetic stimulus to motor cortex followed by supramaximal electrical stimulation of the peripheral nerve supplying the target muscle at the wrist such that the descending corticomotoneuronal volley is collision takes place along the proximal segment of the peripheral nerve at the upper arm . a third stimulus is subsequently delivered to erb 's point ( axilla ) after an appropriate delay , eliciting a highly synchronised motor response in those fibres in which the collision had occurred . the amplitude and area of this test cmap response are compared with the response induced by the conditioned tst paradigm ( erb 's point - wrist erb 's point stimulation ) yielding an amplitude ratio of > 93% and area ratio of > 92% in healthy controls.95 96 in als , the tst is sensitive at detecting subclinical corticomotoneuronal dysfunction.54 97 corticomotoneuronal dysfunction was also reported in kennedy 's disease using the tst technique,98 99 potentially limiting the diagnostic utility of tst in als . recently , however , a combination of tst with single- and paired - pulse tms techniques has reaffirmed the functional integrity of corticomotoneuronal tracts in kennedy 's disease,100 and thereby the diagnostic utility of tst . given the well documented tms abnormalities in als patients , the tms techniques may be of utility in the diagnostic process of als . although umn signs may be clinically evident in als , in some phenotypes such as the flail arm variant , this may not be the case , and detection of subclinical umn dysfunction may facilitate the diagnosis.42 abnormalities of cortical excitability , including an increase in mep amplitude along with reduction of sici and rmts , have been reported in the flail - arm variant of als , underscoring the utility of tms in detecting subclinical umn dysfunction.42 of further relevance , subclinical umn dysfunction has been reported in progressive muscular atrophy ( pma),101103 suggesting that pma may be a phenotype of als . while corticomotoneuronal integrity was recently reported to be intact in pma using a -band intermuscular coherence technique,104 assessment of cortical function with tms techniques may be of diagnostic utility , especially in light of presence of subclinical umn pathology in pma.102 103 importantly , single- and paired - pulse tms techniques reliably distinguish als from the mimic disorders ( table 1 ) , hastening the diagnosis of als by up to 8 months.47 a reduction in averaged sici , between isi 1 and 7 ms , and peak sici at isi 3 ms were the most robust diagnostic tms parameters , with the finding of absent sici exhibiting a sensitivity of 97%.47 of further relevance , tms studies have established the presence of early and subclinical dysfunction of cortico - bulbar and cortico - respiratory tracts in als,26 105107 thereby suggesting a potential diagnostic utility of bulbar and diaphragmatic mep recordings . in addition , combining tms with radiological techniques , such as mr spectroscopy , may further add to the diagnostic yield especially given the sensitivity of mr spectroscopy in detecting subclinical umn dysfunction.108110 consequently , combining tms techniques , in particular the recording of sici as well as bulbar and diaphragmatic meps , together with radiological techniques , such as mr spectroscopy , may enable an earlier diagnosis of als and thereby commencement of neuroprotective therapies and recruitment into clinical trials . transcranial magnetic stimulation ( tms ) techniques in amyotrophic lateral sclerosis ( als ) mimic disorders single - pulse tms studies have established a normal resting motor threshold ( rmt ) and cortical silent period ( csp ) duration in all als mimic disorders . the motor evoked potential ( mep ) amplitude was reported to be increased in spinal muscular atrophy ( sma ) , a finding attributed to greater corticomotoneuronal projections onto the surviving motor neurons . in addition , the central motor conduction time ( cmct ) was reportedly prolonged in distal hereditary motor neuronopathy with pyramidal features ( dhmnp ) . short interval intracortical inhibition ( sici ) and intracortical facilitation ( icf ) , assessed by the paired - pulse tms technique , have been universally normal in als mimic disorders . in contrast , triple stimulation techniques ( tst ) have been reportedly abnormal in kennedy 's disease , suggesting subclinical upper motor neuron dysfunction , although a recent study has reaffirmed functional integrity of corticomotoneuronal tracts in kennedy 's disease ( see utility of peristimulus time histograms section ) . single- and paired - pulse techniques have also been normal in facial onset sensory motor neuronopathy ( fosmn ) syndrome . * neuromuscular disorders include demyelinating neuropathy , myasthenia gravis , lead toxicity and hirayama 's disease . in addition to its diagnostic utility , it has been suggested that tms may exhibit a clinical utility in assessing disease progression in als.111 specifically , longitudinal tms studies in als patients reported a significant reduction in mep amplitude , mt and cmct , and suggested that reduction in mep amplitude may be an objective biomarker of disease progression in als.111 in contrast , others have failed to document any significant longitudinal changes in tms parameters , thereby arguing against tms utility in the monitoring of disease progression in als.52 prospective longitudinal studies are indicated to further clarify the role for tms in monitoring disease progression in als . in his original writings , charcot concluded that als was a disorder of the brain and that the lower motor neuron component resulted from a downstream affect . not all his contemporaries agreed and in particular gowers was adamant that the demise of upper and lower motor neurons were independent events . in the past 2 decades the site of als onset has been revisited , to a large extent precipitated by the advent of tms . three schools of thought have developed pertaining to the role of the umn , and related pathophysiological processes in als : ( i ) the dying forward hypothesis , ( ii ) the dying back hypothesis and ( iii ) the independent degeneration hypothesis ( figure 4 ) . while the site of disease onset in als remains uncertain , tms studies have tended to favour a cortical origin , with excitotoxicity mediating motor neuron degeneration in als.5 112 the dying forward and dying back hypothesis of amyotrophic lateral sclerosis ( als ) . the dying forward hypothesis proposed that als was primarily a disorder of the corticomotoneurons ( highlighted in red ) , with anterior horn cell degeneration mediated via an anterograde glutamate - mediated excitotoxic process . in contrast , the dying back hypothesis proposes that als begins within the muscle or neuromuscular junction , with pathogens retrogradely transported from the neuromuscular junction to the cell body where these pathogens may exert their deleterious effects . the dying forward hypothesis proposes that als is primarily a disorder of the corticomotoneurons , which connect monosynaptically with anterior horn cells.113 corticomotoneuronal hyperexcitability was postulated to induce anterior horn cell degeneration transsynaptically via an anterograde glutamate - mediated excitotoxic process.113 most tms studies have demonstrated that cortical hyperexcitability is an early feature in sporadic and familial als , linked to motor neuron degeneration.27 30 31 43 65 112 114 115 in addition , longitudinal studies in asymptomatic sod-1 mutation carriers revealed that cortical hyperexcitability developed prior to the clinical onset of als,31 also seen in the g93a sod-1 mouse model.116 of relevance , loss of parvalbumin - positive inhibitory interneurons in the motor cortex of als patients would contribute to the development of cortical hyperexcitability.117 in keeping with a cortical origin of als is the now accepted view that als and frontotemporal dementia ( ftd ) represent an overlapping continuum of the same disorder,118 119 an observation underscored by recent genetic findings establishing that increased hexanucleotide repeat expansion in the first intron of c9orf72 gene on chromosome 9p21 is associated with both als and ftd.120 121 of further relevance , accumulation of tdp-43 ubiquitinated inclusions in anterior horn cells appears to be a pathological hallmark of als.119 122 interestingly , identical tdp-43 inclusions may also be evident in cortical neurons within the frontal ( betz cells ) and temporal lobes of als patients,119 122 123 underscoring the link between ftd and als , and thereby a cortical origin of als . of relevance , molecular approaches have provided further corroborating evidence for glutamate excitotoxicity in als . specifically , a significant reduction in the expression and function of the astrocytic glutamate transporter , excitatory amino acid transporter 2 ( eaat2 ) , has been reported in the sod-1 mouse model and the motor cortex and spinal cord of als patients.124128 in addition , dysfunction of eaat2 transporter appeared to be a preclinical feature in the sod-1 mouse model.129 130 further underscoring the importance of astrocytes in als pathophysiology are recent stem cell studies documenting that motor neuron degeneration appears to be initiated by dysfunction of astrocytes.131 on the postsynaptic side , increased expression of glutamate receptors permeable to excessive influx of na and ca ions132 have been reported in als,133137 potentially rendering the motor neurons more susceptible to glutamate excitotoxicity.138 further support for a role for glutamate excitotoxicity has been indirectly provided by the clinical benefit of riluzole , a glutamate antagonist , in als patients.139142 for the glutamate hypothesis to be a plausible mechanism of motor neuron degeneration , the issue of selectivity of motor neuron involvement in als , together with sparing of motor neurons in non - als conditions exhibiting cortical hyperexcitability,38 must be explained . a number of molecular features may render the motor neurons vulnerable to glutamate toxicity in als . first , motor neurons preferentially express glutamate receptors , such as the ampa receptors , which are more permeable to influx of ca ions.133 134 136 137 in addition , motor neurons in als patients lack the intracellular expression of ca binding proteins parvalbumin and calbindin d28k , both required to buffer intracellular ca.143 144 aberrant activity of the inositol 1,4,5-triphosphate receptor type 2 receptor has been reported in als,145 146 thereby resulting in higher intracellular concentrations of ca within the motor neurons . ultimately , an influx of ca ions through the ionotropic glutamate receptors nmda occurs in the motor neurons,147 148 resulting in increased intracellular ca concentration and activation of ca - dependent enzymatic pathways that mediate neuronal death.149151 glutamate excitotoxicity may also result in production of free radicals that can further damage intracellular organelles and thereby cause cell death.152154 it could be argued that the finding of widespread fasciculations in als , an important diagnostic criterion,155 may argue against a dying forward mechanism given that fasciculations are thought to originate from the distal motor axon , are associated with abnormalities of sodium and potassium conductance , and may precede the onset of lower motor neuron dysfunction.156162 it seems unlikely that cortical hyperexcitability could lead to changes in distal axonal excitability that would result in widespread fasciculations . importantly , a supraspinal mechanism for triggering fasciculations in als has been previously reported.34 in agreement with this notion are findings that fasciculations in als may originate at the level of the motor neuron cell body.157 as such , it could be hypothesised that hyperexcitability of descending motor pathways may contribute to generation of fasciculation in als , thereby providing additional support for a dying forward process . in conjunction with glutamate excitotoxicity , there is compelling evidence that mitochondrial dysfunction may exert an important role in the pathophysiology of als.163168 under conditions of excessive ca load , as may be evident with glutamate excitotoxicity,169 mitochondrial production of free radicals increases resulting in injury of critical neuronal cellular proteins and dna . mitochondrial dysfunction may in turn enhance glutamate excitotoxicity by disrupting the normal resting membrane potential , resulting in loss of the voltage - dependent mg - mediated block of nmda receptor channels.170 from a therapeutic perspective , dexpramipexole , a pharmacological agent that enhances mitochondrial function,171 was effective in slowing als progression in a recent phase ii trial.172 a phase iii , multicentre , international trial was commenced in march 2011 to determine the clinical efficacy of dexpramipexole in als ( clinicaltrials.gov-nct01281189 ) . taken further , it is anticipated that tms studies will be used to determine the efficacy of dexpramipexole in the modulation of cortical excitability in an attempt to provide further insight into als pathophysiology . the dying back hypothesis proposes that als is primarily a disorder of the lower motor neurons , with pathogens retrogradely transported from the neuromuscular junction to the cell body where they exert their deleterious effects.173 although some pathological studies have indirectly supported a dying back process,174176 no pathogens of any type have been identified in relation to als . the presence of widespread dysfunction within the frontal cortex , including the primary , supplementary and prefrontal motor cortices in als , remains difficult to reconcile with a dying back process.3 110 177 in addition , the absence of central pathology in other lower motor neuron disorders such as kennedy 's disease or poliomyelitis provides a further argument against a dying back process.33 44 the independent degeneration hypothesis suggests that the upper and lower motor neurons degenerate independently.178 some 100 years after the original gowers publication , neuropathological studies provided support for the independent degeneration hypothesis whereby the degeneration of upper and lower motor neurons appeared to be independent.179 180 these correlative morphological techniques , however , may be confounded by the anatomical and functional complexity of the corticomotoneuronal system.181 in particular , there remains considerable variability in the corticomotoneuronal to anterior horn cell ratio , due to synaptic changes , and as such attempts to correlate upper and lower motor neurons on autopsy studies may not be meaningful.33 in addition to the three competing theories of als pathogenesis , a prion - like propagation hypothesis has also been suggested.182 specifically , the previously documented contiguous spread of als5 183 could be explained by direct neuron - to - neuron transmission of pathogenic proteins via exosomes , defined as small lipid membranous microvesicles.182 the pathogenic exosomes could spread in either a rostral direction , explaining the rostral - to - caudal spread of als , or in a lateral horizontal direction accounting for the lateral - to - medial spread of disease . in addition , non - contiguous propagation of als could also be explained by spread of pathogenic proteins or toxic molecules through the blood or csf via exosomes.182 interestingly , the genes implicated in als pathogenesis , including tdp-43 and fus , possess a putative prion domain.184 although a prion - like propagation mechanism may seem an attractive explanation for the spread of als , at present there is no direct evidence to support such a process in als . although first described by charcot some 150 years ago , the pathophysiological mechanisms underlying als , variability , rate of progression and site of disease onset remain obscure . objective assessment of umn function in als remains a difficult task in clinical neurophysiology.185 while tms is mainly used as a clinical research tool , conducted in specialised neurophysiological laboratories , there is an urgent need to objectively assess umn function in als . this has been underscored by the recent awaji diagnostic criteria.155 186 although needle electromyography is used by the criteria to objectively assess lower motor neuron dysfunction , the detection of umn involvement is based solely on clinical examination . much has recently been learnt about als from mri , especially diffusion tensor mri , functional imaging and network analysis,110 187198 but these tools remain prohibitively expensive , not readily available and may exhibit a modest diagnostic sensitivity.190 commercially available tms systems that will enable an objective assessment of umn function could be readily developed , facilitating the diagnosis of als . such tms systems may result in the development of more functional als biomarkers that could be used in future drug trials for early patient recruitment and monitoring of drug efficacy . although first described by charcot some 150 years ago , the pathophysiological mechanisms underlying als , variability , rate of progression and site of disease onset remain obscure . objective assessment of umn function in als remains a difficult task in clinical neurophysiology.185 while tms is mainly used as a clinical research tool , conducted in specialised neurophysiological laboratories , there is an urgent need to objectively assess umn function in als . this has been underscored by the recent awaji diagnostic criteria.155 186 although needle electromyography is used by the criteria to objectively assess lower motor neuron dysfunction , the detection of umn involvement is based solely on clinical examination . much has recently been learnt about als from mri , especially diffusion tensor mri , functional imaging and network analysis,110 187198 but these tools remain prohibitively expensive , not readily available and may exhibit a modest diagnostic sensitivity.190 commercially available tms systems that will enable an objective assessment of umn function could be readily developed , facilitating the diagnosis of als . such tms systems may result in the development of more functional als biomarkers that could be used in future drug trials for early patient recruitment and monitoring of drug efficacy . OUTPUT:

amyotrophic lateral sclerosis ( als ) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex , brainstem and spinal cord . a combination of upper and lower motor neuron dysfunction comprises the clinical als phenotype . although the als phenotype was first observed by charcot over 100 years ago , the site of als onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated . transcranial magnetic stimulation ( tms ) enables non - invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections . to date , tms studies have established motor cortical and corticospinal dysfunction in als , with cortical hyperexcitability being an early feature in sporadic forms of als and preceding the clinical onset of familial als . taken together , a central origin of als is supported by tms studies , with an anterograde transsynaptic mechanism implicated in als pathogenesis . of further relevance , tms techniques reliably distinguish als from mimic disorders , despite a compatible peripheral disease burden , thereby suggesting a potential diagnostic utility of tms in als . this review will focus on the mechanisms underlying the generation of tms measures used in assessment of cortical excitability , the contribution of tms in enhancing the understanding of als pathophysiology and the potential diagnostic utility of tms techniques in als .

PubMed_Summ6579

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: macrophages ( m ) are one of the resident cell types in synovial tissue , along with fibroblasts . while quiescent in health , m become activated in the inflamed joint , where they make up around 3040% of the cellular content , and regulate secretion of pro - inflammatory cytokines and enzymes involved in driving the inflammatory response and joint destruction ( firestein and zvaifler , 1990 ) . their position throughout the sub - lining layer and lining layer at the cartilage it is estimated that rheumatoid arthritis ( ra ) and psoriatic arthritis ( psa ) each affects approximately 1% of the population ( firestein , 2003 ; gladman , 2009 ) , leading to patient pain and disability as well as contributing to a great economic burden in terms of lost working days and patient health services ( cooper , 2000 ) and therefore is an area of intense investigation . as our understanding of inflammation progresses , including the recent concept that resolution of inflammation is an active process rather than a passive return to homeostasis , the role of m is increasingly appreciated . the inability to resolve acute inflammation may lead to a chronic inflammatory state . depending on their phenotype , m can secrete either pro- or anti - inflammatory cytokines and mediate matrix destruction or deposition . synovial m participate in many of the events driving inflammation including the stimulation of angiogenesis , leukocyte and lymphocyte recruitment , fibroblast proliferation , and protease secretion leading to eventual joint destruction ( burmester et al . , 1997 ; vallejo et al . , 2003 ; abeles and pillinger , 2006 ) . while ra and psa are considered more inflammatory than osteoarthritis ( oa ) , it can still contain an inflammatory component , of which m play a large part . in all of these conditions depletion of m from both ra and oa synovial cell cultures leads to reduced synovial fibroblast responses such as cytokine and mmp production ( janusz and hare , 1993 ; bondeson et al . , both macrophages and fibroblasts display an activated cell phenotype with increased cell surface expression of hla - dr and leukocyte adhesion molecules ( athanasou et al . , 1988 ; interaction of m with t - cells potentiates the expression of several pro - inflammatory mediators such as il-1 and and mmps ( mcinnes et al . important pro - inflammatory cytokines like tnf and il - l are abundant in the inflamed synovium and are characteristically released by classically activated ( m1 ) m . the importance of m in driving the inflammatory response has been highlighted by several quantitative microscopic studies , where they have shown that m number ; correlates with disease activity ( tak et al . , 1997 ) , has potential use as a biomarker for disease ( kruithof et al . , 2006 ; bresnihan et al . , 2009 ) and declines in response to therapy ( goedkoop et al . , 2004 ; canete et al . , , a prominent feature of the inflamed joint , promotes the survival of monocytes / macrophages and induces their anaerobic adaptations including glycolysis ( roiniotis et al . , it is long appreciated that m play an important role in the pathogenesis of arthritis and this observation was supported by studies showing that the number of m was increased in clinically affected joints compared to non - affected joints ( kraan et al . , 1998 ) . several studies also linked the number of synovial m to inflammatory cytokine production joint destruction ( mulherin et al . , the culmination of this work has led to sub - lining cd68 positive synovial m currently being the only validated biomarker for disease severity ( tak et al . , 1997 ) and response to therapy in arthritis ( haringman et al . , 2005 ) , further confirming their importance in the pathogenesis of this disease , a finding which is independent of treatment type ( haringman et al . , 2005 ; thurlings et al . , several studies have concluded that m number is decreased in psa synovial tissue following therapy ( goedkoop et al . besides the abundant pro - inflammatory cytokines and chemokines present in inflamed synovial tissue , activation , and survival of m can be achieved through acetylation or de - acetylation of histones . downstream effects of tnf and other molecules results in the induction of histone acetyltransferase ( hat ) activity in m which causes acetylation of histones and subsequent modulation of transcriptional activity . two recent studies have found evidence of depressed hdac activity in ra , particularly in synovial macrophages and fibroblasts . the ratio of hdac : hat activity was significantly lower in ra synovial tissue compare to healthy controls . in combination with this , hdac inhibition decreases il-10 production from whole tissue synovial explants cultures , indicating a negative effect on anti - inflammatory pathways , which would lead us to believe that a lack of hdac may contribute to perpetuation of inflammation ( huber et al . , 2007 ; grabiec et al . hdac inhibitors reduced il-6 production from tnf stimulated m and induced apoptosis of ra synovial fluid ( sf ) m , even in the presence of a pro - inflammatory stimulus ( grabiec et al . , 2010 ) . this is of interest considering the ability of synovial cells and infiltrating cells to evade apoptosis during joint inflammation contributing to synovial hypercellularity ( salmon et al . , 1997 ; the potential use of hdac inhibitors has been further promoted by their success in suppressing synovial inflammation and cartilage destruction in a cia mouse model ( nasu et al . , 2008 ) . toll like receptors ( tlr ) are pattern recognition receptors that mediate response to infection . however , it is becoming apparent that some of these receptors may become activated by non - infectious agents from within the body and may therefore play a role in autoimmune conditions such as ra . engagement of tlrs induces signaling through a well defined pathway involving myd88 that leads to transcriptional activation ( joosten et al . , tlr knockout and arthritis mouse models , or a combination of both , have highlighted the position of tlrs in the pathogenesis of arthritis . in a model of spontaneous arthritis due to il-1 receptor antagonist knockout , simultaneous knockout of tlr4 attenuated inflammation while tlr2 knockout produced a more severe arthritis . knockout of tlr9 had no effect ( abdollahi - roodsaz et al . , 2008 ) . however the role of tlr2 seems less defined as other studies have shown that knockdown of tlr2 produces beneficial effects in arthritis ( joosten et al . , 2003 ) . further to this , many tlr ligands have been identified in synovial inflammation ( okamura et al . , 2001 ; park et al . , 2004 ) . acute serum amyloid a ( saa ) , which is significantly upregulated in arthritis and propagates pro - inflammatory effects similar to tnf ( ohara et al . , 2000 ; mullan et al . , 2006 ; connolly et al . , 2011 ) , is a functional ligand for tlr2 and may contribute to the deleterious effects of saa in arthritis ( cheng et al . , 2008 ) . ra m are more responsive to stimulation than m from other forms of inflammatory arthritis , despite no difference in m number ( huang et al . , 2007 ) . therefore , engagement of tlr2 and 4 may contribute to m activation and a sustained m response in ra . rheumatoid factor ( rf ) is one of the diagnostic criteria for ra and can help to distinguish ra from similar arthropathies like psa . classification of ra as an autoimmune disease came initially from the discovery of igg auto - antibodies in the blood of patients ( waaler , 1940 ; franklin et al . , 1957 ) . rf is mostly igm - rf , but igg - rf and iga - rf can also be detected in some patients . the cellular receptors for igg are the fc receptors , fcri ( cd64 ) , fcrii ( cd32 ) , and fcriii ( cd16 ) . fcriii has been demonstrated to play a role in the development of arthritis through animal models . mice deficient in fcriii are protected from the development of collagen induced arthritis without alteration of their humoral response , and therefore the protection is not due to alterations in t - cell responses ( sthl et al . , 2002 ; andrn et al . , polymorphisms in fc receptors are associated with incidence of ra as well as response to therapy ( morgan et al . , 2006 ; canete et al . , 2009 ; thabet et al . in the immune system m are effective antigen presenting cells with phagocytic activity which respond to lymphocyte derived cytokines . however , the responses elicited by m are variable and depend entirely on the tissue environment . dedicated reviews on this topic discuss in more detail the cytokines and chemokines involved in promoting one phenotype over another ( mantovani et al . , 2004 ; murray and wynn , 2011 ) but an overview of the main components are outlined in figure 1 . classically activated m1 m have a pro - inflammatory phenotype , producing high levels of tnf , il-1 , il-6 , il-12 , il-23 , reactive oxygen species , and low levels of il-10 . alternatively activated m , of which there are three subsets ( mantovani et al . , 2004 ; martinez et al . , 2008 ) , display and anti - inflammatory phenotype , producing high levels of il-10 , il-1 receptor antagonist , decoy il-1rii , tgf , and low levels of il-12 . an interesting , and potentially useful , property of these m is that they remain plastic and polarization into one phenotype does preclude re - polarization ( stout et al . , 2005 ) . therefore , if we could elucidate the exact pathways and transcription factors involved in promoting one phenotype over the other in vivo , this system could be exploited for therapeutic gain . ifn along with lps or tnf drive polarization of m1 ( classically activated ) macrophages which participate in pro - inflammatory activities . on the other hand , il-4 + il-13 , il-10 , or immune complexes drive m2 ( alternatively activated ) macrophages , which participate in anti - inflammatory responses . there appears to be a lack of evidence for m polarization in either direction in the inflamed joint . it has been suggested that spondyloarthropathies such as psa display a more m2 profile compared to ra patients and that m1 mediators correlate with joint inflammation in ra ( vandooren et al . , 2009 ) . however , in general , most studies of m in arthritis focus on important m functions and not polarization . the mediators that can control m polarization are indeed present in the synovium and some show potential as therapeutic targets . synovial lining layer thickness is greater in ra , compared to psa or healthy control subjects , which is associated with an increase in synovial m and fibroblasts . ( 2000 ) also found similar levels of il-10 in ra and psa synovium , despite the difference in synovial lining layer m numbers , however levels were described as being quite low . it is difficult to determine if this lack of il-10 is a contributor to or consequence of the overwhelming inflammation in the joint . a study by mottonen et al . ( 1998 ) found that 68% of m isolated from ra sf were cd86 positive and that sf m can take on a dendritic cell phenotype when exposed to a combination of il-4 and gm - csf and that these cells were more effective at activating t - cells than control or tnf stimulated m . the effects of il-4 + gm - csf were mediated through cd86 , a marker of classically activated m . il-10 was able to inhibit the observed effects with il-4 + gm - csf as it downregulated the expression of cd86 , as well as cd-40 and hla - dr which also participate in m mediated t - cell activation . this is consistent with the classification that m2c m , which are driven by il-10 are involved in suppression of the immune response ( mantovani et al . , 2004 ) . these results may appear confusing as il-4 along with il-13 drive the m2a or alternative m phenotype which should be involved in anti - inflammatory responses . however gm - csf drives the m1 phenotype in monocyte derived macrophages so this may be the driving force for inflammatory responses in these experiments . the m1 m phenotype is induced by interferon- ( ifn ) in combination with either lipopolysaccharide ( lps ) or tnf. ifn is highly expressed in ra synovial tissue and its levels significantly correlate with disease severity ( milman et al . , 2010 ) . exposure to inf increases the response of m exposed to other stimuli by either upregulating pro - inflammatory cytokines , like tnf , or downregulating anti - inflammatory cytokines , like il-10 ( erwig et al . tnf is a master cytokine in inflammation and as such is a potent inducer of other pro - inflammatory cytokines ( nawroth et al . , 1986 ; butler et al . , 1995 ) , is chemotactic for leukocytes , is a potent inducer of angiogenesis ( leibovich et al . , 1987 ) , stimulates adhesion molecule expression in sfc in vitro ( marlor et al . , 1992 ) , and lymphoid migration into inflamed synovial tissue in vivo ( wahid et al . , 2000 ) . within the inflamed joint macrophages , fibroblasts , lymphocytes , and endothelial cells produce tnf. an important role for tnf in arthritis was confirmed by studies which showed its potential to degrade both cartilage ( dayer et al . , 1985 ) and bone ( bertolini et al . , 1986 ) . further rationale for the involvement of tnf in the progression of inflammatory arthritis was provided when transgenic mice expressing a modified human tnf gene spontaneously developed arthritis which exhibited increased human tnf protein , joint inflammation , bone erosion , and cartilage destruction . in this study , antibodies specific for human , but not mouse tnf reduced disease severity ( keffer et al . , 1991 ) . in subsequent studies administration of a monoclonal antibody to tnf ameliorated inflammation and joint damage after disease onset in a cia model of arthritis ( williams et al . , 1992 ) . tnf cytokine targeted therapies have now been developed for inflammatory arthritis . the first clinical trial was undertaken in the uk in 1992 and demonstrated that targeted biologic therapy decreased serum il-6 levels , swollen joint numbers and levels of the acute phase proteins crp and a - saa which are markers of inflammation ( elliott et al . , 1993 ) . alternatively , anti - inflammatory and m2 polarizing cytokines like il-10 are lowly expressed in arthritis as its signaling is blocked during fc receptor ligation ( ji et al . , 2003 ) , and treatment with the pro - resolving mediator annexin a1 stimulates release of il-10 ( ferlazzo et al . , 2003 ) . treatment of pbmc with il-10 caused a change in the ratio of th17:treg cells in favor of treg cells and decreased production of the pro - inflammatory cytokine il-17 ( heo et al . , 2010 ) . animal models of arthritis have also demonstrated how treatment with il-10 can suppress the development and progression of joint inflammation , even in established disease ( walmsley et al . , 1996 the cytokines involved in promoting polarization are well defined , however less is known about which transcription factors are utilized to induce polarization . irf5 ( interferon regulatory factor 5 ) has been implicated in driving the m1 phenotype as well as actively suppressing m2 polarization and driving th1 and th17 responses ( krausgruber et al . , ( 2011 ) was not performed in synovial m , animal studies suggest that inflammation in ra is driven by th1 cytokines such as ifn , which is upregulated early in the disease process ( miltenburg et al . , 1992 ; schulze - koops and kalden , 2001 ) and a rapid growth in interest in the th17 pathway and indeed il-17 itself in the last few years would suggest that this would warrant investigation in the inflamed joint . recent reports confirm that alterations in the irf5 gene confers susceptibility to ra ( dieguez - gonzalez et al . 2011 ) as well as many related illnesses such as inflammatory bowel disease , sjogrens syndrome , and systemic lupus erythematosus ( dideberg et al . , 2007 ; , 2006 ) and irf4 ( satoh et al . , 2010 ) have been implicated in promoting m polarization in other disease settings , and irf family members contribute to determination of dendritic cell fate ( tamura et al . , 2005 ) . these findings make the irf family attractive candidates to study in the context of m s in arthritis . nr4a is part of the orphan nuclear receptor superfamily which have roles in lipid metabolism and inflammation ( desreumaux et al . , 2001 ; receptors in the same superfamily as nr4a are downregulated in arthritic tissue and their activation appears to play a role in inhibiting disease progression ( bonnelye et al . however members of the nr4a subfamily appear to have less clearly defined effects to the anti - inflammatory family members liver x receptor and peroxisome - proliferator - activator receptor and drive inflammation in human synovial tissue ( murphy et al . , 2001 ) . the role of nr4a receptors specifically in m polarization has not yet been elucidated , however , any role for nr4a in m polarization would be an interesting finding due to the modulation of nr4a by both dexamethasone and methotrexate , which are effective treatments for joint inflammation in some patients . , 2006 ) where it promotes transcription of pro - inflammatory genes . in arthritis , and inflammation in general , nfb can be considered a master transcription factor as it is utilized by many ligand tnf and il-1 which are abundant in the inflamed joint employ this transcription factor and in turn can be regulated by it . nfb activation has been detected prior to the clinical onset of arthritis in animal models ( tsao et al . , 1997 ; han et al . , 1998 ) and the nfb pathway has been directly targeted as a treatment method for ra confirming its essential role in the pathogenesis of this disease ( wakamatsu et al . , 2005 ) . immunohistochemical staining has confirmed nuclear expression of nfb subunits in synovial m ( handel et al . , 1995 ) . the nfb family consists of five proteins ; p50 , p52 , rela ( p65 ) , relb , and c - rel . rela , relb , and c - rel contain a transcriptional activation domain and therefore upregulate gene expression , however p50 and p52 do not contain the transcriptional activation domain and homodimers of these proteins can sometimes have a repressing function ( bohuslav et al . , nfb p50 activation has been linked to promoting m2 polarizing genes in m ( porta et al . , 2009 ) . this study found that knockout of the nfb p50 subunit prevented the development of tolerance in lps challenged m by restoring m1 mediators and inhibiting m2 cytokines . ( 2006 ) found that accumulation of the p50 homodimer occurred in the nuclei of tumor associated m and that these m expressed an m2 phenotype . therefore due to the prominence of the nfb pathway in ra there is a growing understanding of the molecular drivers of inflammation and an appreciation that the resolution of inflammation is an active process rather than a passive return to homeostasis . endogenously produced mediators that actively promote the resolution of inflammation are now under investigation for their therapeutic use . lipoxin a4 ( lxa4 ) is an eicosanoid produced by the transcellular metabolism of arachidonic acid by 15/5- or 5/12-lipoxinagese ( serhan et al . , 1984 ) . its biosynthesis is co - incident with the resolution phase of inflammation and many of its bioactions are mediated through ligation of its receptor , alx / fpr2 ( fiore et al . , 1994 ) . lxa4 is produced in inflamed synovial tissue ( thomas et al . , 1995 ) where it can downregulate pro - inflammatory activities of activated fibroblasts and upregulate anti - inflammatory activities , even in the presence of a pro - inflammatory stimulus which acts through the same receptor ( sodin - semrl et al . , 2004 ; kronke et al . , 2009 ; chan and moore , 2010 ) . in other disease models , lxa4 has been shown to induce anti - inflammatory / pro - resolving actions such as inhibition of neutrophil recruitment and activation ( filep et al . , 1999 ) , regulation of nfb activation ( decker et al . , 2009 ) , and the clearance of apoptotic cells by m ( godson et al . , 2000 ) once these cells have carried out their functions in regard to host defense they are programmed to die by apoptosis . resolution of inflammation and return to homeostasis involves phagocytosis of apoptotic neutrophils to prevent the persistence to necrosis and leakage of cellular contents , which may itself begin an inflammatory reaction . despite the lack of apoptosis occurring in all cell types in the inflamed synovium , resident synovial m retain the capacity to phagocytose apoptotic cells , even at an early timepoint after arthritis induction ( van lent et al . , 2001 ) . if normal apoptosis and phagocytosis could be induced in the inflamed synovium , possibly by native lxa4 or its stable analogs , this process may trigger a normal resolution of inflammation . in order to encourage phagocytosis , apoptotic cells release mediators that attract phagocytes toward them , essentially flagging themselves for engulfment . one such mediator is the anti - inflammatory compound annexin a1 ( arur et al . , 2003 ; annexin a1 is a 37-kda protein of the annexin superfamily where all family members contain a similar core region and a distinct n - terminal region which confers specificity of function . generally annexin a1 is localized to the cytoplasm where , upon stimulation , it is mobilized to the cell membrane and secreted ( for an extensive review on annexin a1 see perretti and dalli , 2009 ) . interestingly annexin a1 also signals through alx / fpr2 , the same receptor utilized by lxa4 and saa . immunohistochemical analysis has demonstrated an increased expression of annexin a1 in the ra synovial lining layer macrophages and fibroblasts compared to oa and normal joints . this may , however , be due to the increased lining layer thickness in this condition ( goulding et al . , 1995 ) as other studies have shown decreased binding of annexin a1 to several cell types in ra ( goulding et al . glucocorticoid stimulation causes annexin a1 mobilization to the cell surface and secretion where it mediates glucocorticoid induced anti - inflammatory effects . this is of particular interest in arthritis as glucocorticoid therapy is one of the current treatments for this condition ( flower , 1988 ; podgorski et al . , 1992 ; yang et al . , 1998 , 1999 ; maderna et al . , 2005 ) . however , as is increasingly the case for many mediators , the role of annexin a1 may not be as unambiguous as initially described and it may also potentiate pro - inflammatory actions in arthritis . ( 2008 ) has revealed synergistic actions with tnf and annexin a1 in terms of mmp production from synovial fibroblast cells . they saw firstly that tnf can induce expression of endogenous annexin a1 and secondly that tnf along with the annexin a1 mimetic peptide ac2 - 26 enhanced secretion of mmp-1 which was dependent on fpr2/alx , erk , jnk , and nfb ( tagoe et al . , as mentioned , this study was not performed in synovial m , but as they have similar actions to synovial fibroblasts , the same results may be produced by these cells once investigated . further to this , it has also been shown that administration of human recombinant annexin a1 during the immunization phase of the collagen induced arthritis model perpetuated the development of the signs and symptoms of arthritis . this may have been due to the increased t - cell activation and skewing toward a th1 phenotype by annexin a1 acting through fpr2/alx ( dacquisto et al . , 2007 ) . t - cells from ra patients 48 h post steroid therapy demonstrated depressed expression of annexin a1 ( dacquisto et al . , 2008 ) further lending support to the possibility that annexin a1 may also mediate pro - inflammatory actions . however we must be careful to acknowledge the actions of specific cleavage products from full length annexin . one such cleavage product has been identified as causing neutrophil extravasation , an important event in inflammation , where other truncated forms of annexin can not ( williams et al . , 2010 ) . in the study of inflammation and our efforts to promote its normal resolution , m remain to the fore of our interest . in the inflamed joint , m will continue to be a focal point for therapeutic intervention which , currently , centers around cytokine blockade but now has the possibility of extending into m re - programming . this remains an interesting and a yet to be fully explored option in terms of treatment for synovial inflammation . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . OUTPUT:

synovial macrophages are one of the resident cell types in synovial tissue and while they remain relatively quiescent in the healthy joint , they become activated in the inflamed joint and , along with infiltrating monocytes / macrophages , regulate secretion of pro - inflammatory cytokines and enzymes involved in driving the inflammatory response and joint destruction . synovial macrophages are positioned throughout the sub - lining layer and lining layer at the cartilage pannus junction and mediate articular destruction . sub - lining macrophages are now also considered as the most reliable biomarker for disease severity and response to therapy in rheumatoid arthritis ( ra ) . there is a growing understanding of the molecular drivers of inflammation and an appreciation that the resolution of inflammation is an active process rather than a passive return to homeostasis , and this has implications for our understanding of the role of macrophages in inflammation . macrophage phenotype determines the cytokine secretion profile and tissue destruction capabilities of these cells . whereas inflammatory synovial macrophages have not yet been classified into one phenotype or another it is widely known that tnf and il - l , characteristically released by m1 macrophages , are abundant in ra while il-10 activity , characteristic of m2 macrophages , is somewhat diminished . here we will briefly review our current understanding of macrophages and macrophage polarization in ra as well as the elements implicated in controlling polarization , such as cytokines and transcription factors like nfb , irfs and nr4a , and pro - resolving factors , such as lxa4 and other lipid mediators which may promote a non - inflammatory , pro - resolving phenotype , and may represent a novel therapeutic paradigm .

PubMed_Summ6580

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: a critical component of successful patient care in total knee arthroplasty ( tka ) is a blood management strategy . tka can result in substantial perioperative blood loss , rendering patients at increased risk of requiring allogenic blood transfusion12 ) . total knee and hip arthroplasty and fracture surgery is the number one reason for transfusion in patients undergoing surgery and accounts for 9.8% of all transfused red blood cell units3 ) . complications of allogenic blood transfusion include the risk of disease transmission , hemolytic reaction , fluid and hemodynamic overload , acute lung injury , coagulopathy , allergic reaction and febrile non - hemolytic reaction4 ) . allogenic transfusion is associated with immunomodulation , and an increased incidence of prosthetic infection56 ) . bierbaum et al.7 ) reported a transfusion rate of 39% following tka , with an increased risk of fluid overload , infection rate and duration of hospitalization in the patients who received allogenic transfusion . several studies have highlighted the disadvantages of allogenic blood including a negative effect on postoperative complications , length of hospital stay , cost and mortality8910 ) . the fundamental aim of blood management is to eliminate the need for allogenic blood whilst at the same time preventing anaemia . thereby the risk of transfusion is removed , hemoglobin ( hb ) status and oxygen carrying capacity is maximized , leading to a positive effect on the patient 's recovery and both early and long - term outcomes . blood management strategies should be individualized , based on patient specific risk factors including preoperative hb level , anticipated difficulty of the procedure and expected blood loss , and associated medical comorbidities . hb loss in routine primary tka has been calculated to be 3.8 g / dl11 ) . the transfusion trigger should be individualized based on the risks and benefits for each patient . two recently published studies highlighted the benefits of evidence - based , multidisciplinary , multimodal approach to optimizing care in joint replacement patients potentially requiring allogenic transfusion1213 ) . both studies stressed the importance of optimizing preoperative red cell mass , minimizing perioperative blood loss and being judicious with the threshold for transfusion based on each individual 's clinical status . by introducing a multimodal program supported by evidence - based guidelines , transfusion rate was markedly reduced with a significant reduction in complications , 30-day readmission rates , length of hospital stay and mortality . available blood management strategies can be broadly divided into 3 stages : preoperative optimisation , intraoperative and postoperative protocols14 ) . several studies have highlighted the significant influence of preoperative hb on the requirement for transfusion in tka1115 ) . g / l preoperatively required allogenic blood whilst patients with preoperative hb level less than 110 similarly , pierson et al.11 ) found an algorithm - based strategy aimed at improving preoperative hb level was most effective in reducing transfusion rate . other risk factors associated with an increased need for transfusion include weight , age greater than 75 years , male gender , hypertension and body mass index less than 27 kg / cm16 ) . whilst many factors are non - modifiable , pola et al.17 ) showed more than one risk factor had a compounding effect on transfusion rate . therefore , in patients with multiple risk factors , it is vitally important to correct anaemia and maximize preoperative red cell mass . correcting anaemia not only reduces the risk of allogenic transfusion but also has a positive impact on the patient 's rehabilitation and functional recovery . patients with postoperative hb between 8 to 10 g / dl may not be low enough to warrant transfusion but often feel lethargic , with a higher risk of syncopal episodes , impairing their ability to mobilize and undergo rehabilitation . in our centre , patients are screened 3 months prior to surgery with full blood count , proceeding to iron studies if the preoperative hb is less than 120 g / dl . any patient identified with anaemia is referred to the hematology unit for further investigation of the underlying cause and management . a common reason in elderly patients is iron deficiency , as a result of poor dietary intake and occult gastrointestinal bleeding secondary to non - steroidal anti - inflammatory drug use . the parameters measured to investigate iron deficiency are listed in table 2 with threshold cut - off values . both have been shown to be effective , however , oral iron may not be efficacious in patients with malabsorption such as coeliac disease . another disadvantage of oral iron supplements is the slow effect and therefore it needs to be implemented well in advance of surgery . a cohort study of 156 patients treated with ferrous sulfate 256 mg / day for 1 month preoperatively , in with combination vitamin c which enhances iron absorption , showed a reduced transfusion rate for non - anemic patients18 ) . for our patients with deficient iron stores , the hematologists administer 5001,000 mg ferritin carboxymaltose as a rapid intravenous infusion over 15 minutes . the infusion needs to be given minimum of 3 weeks preoperatively , and is expected to improve the hb 1 g / dl over 10 days . we have observed intravenous iron to be more effective than oral supplements ( d'costa e , unpublished data ) . munoz et al.19 ) reported a significant increase of 1.8 g / dl in hb level and 67% resolution of anaemia using intravenous iron sucrose . erythropoietin is a synthetic hormone , stimulating progenitor cells in the bone marrow to differentiate into red blood cells and activating hematopoiesis . erythropoietin is a powerful agent in correcting anaemia . in a systematic review , spahn20 ) showed erythropoietin to be successful in improving mean preoperative hb and postoperative hb with reduced transfusion rates when combined with iron therapy in patients undergoing tka . the main disadvantage of erythropoietin is cost and at this stage , its routine use in australia is not approved in tka patients unless the patient suffers anaemia secondary to chronic renal failure . patients undergoing tka frequently take antiplatelet and anticoagulant medications that affect the risk of bleeding . the decision and timing of cessation of antiplatelelet and anticoagulant therapy needs to take into consideration risks of thrombosis versus risk of bleeding . platelet activation occurs with non - cardiac surgery , making myocardial infarction the most common major vascular complication after surgery . under usual circumstances , warfarin should be discontinued 5 days prior to tka21 ) and recommenced postoperatively when the risks of acute bleeding are believed to be stable . bridging anticoagulation therapy is commonly used in the interim period with agents such as low molecular heparin , which has a shorter half - life22 ) . there are no clear guidelines or consensus on the optimal bridging therapy for patients on warfarin for conditions such as atrial fibrillation , previous embolic cerebrovascular events or mechanical valve replacement , and further clinical trials are required to clarify the optimal regime . with regards to aspirin and antiplatelet therapy , its cessation prior to surgery is believed to result in an increased risk of cardiovascular complications and major cardiac events2324 ) . however , a recent large randomized controlled trial of 10,010 patients including 39% orthopaedic procedures , comparing aspirin versus placebo with 30-day follow - up after surgery , found conflicting results25 ) . there was no difference in the primary outcome of death or myocardial infarction between the 2 groups , regardless of whether the patient was taking aspirin prior to surgery or not . the most common reported site of bleeding was the surgical site in 78.3% and gastrointestinal tract in 9.3% . the authors concluded aspirin administration before surgery and throughout the early postsurgical period had no significant effect on the rate of composite of death or nonfatal myocardial infarction but increased the risk of major bleeding . allogeneic transfusion rates were reduced from 40%52% to 3%18% in the preoperative autologous donor group in two cohort studies2627 ) . however preoperative autologous donation is associated with a high rate of wasted blood and is no longer deemed to be cost effective . there remains the potential for wrong blood being returned to the patient due to clerical errors2829 ) . the use of preoperative autologous blood donation has therefore fallen out of favour and we no longer use it in our tka patients . the risk of intraoperative bleeding is influenced by difficulty of the procedure and patient factors such as obesity , comorbidities and bleeding disorders . meticulous efficient surgical technique with careful dissection , soft tissue handling and bleeding control assists with diminishing blood loss . maintaining steady blood pressure and normothermia is accepted to be important in limiting blood loss , we found rigid temperature control is not necessary in a prospective consecutive observational cohort study of patients undergoing primary tka30 ) . as long as patient axillary temperature is maintained within the range of 34.737.8 during the perioperative period , our study demonstrated no effect of patient temperature on transfusion rate or blood loss . the technique of acute normovolemic hemodilution attempts to achieve a similar effect to preoperative autologous blood donation without the preoperative inconvenience . blood is collected from the patient in the immediate preoperative period and volume is replaced with colloid or crystalloid fluid . the rationale is surgical blood loss will have a lower hematocrit , and the collected whole blood is transfused in the immediate postoperative period , negating the downsides of blood storage . however , the effectiveness of acute normovolemic hemodilution in reducing allogenic transfusion is debatable20 ) . it may be appropriate in selected cases where blood cross matching is difficult due to the presence of antibodies however we do not recommend its routine use . perioperative red cell salvage collects blood lost during the operative procedure and immediate postoperative period , and returns the blood to the patient . perioperative red cell salvage reinfuses fresh blood , thereby avoiding problems associated with storage , seen with autologous predonation and allogeneic blood . this translates to more efficacious oxygen carrying capacity with a higher mean erythrocyte viability31 ) and increased preservation of 23 diphosphoglycerate32 ) . red cell salvage also incorporates washing the blood loss volume . washing the blood removes biochemical , cellular and non - cellular debris31 ) . unwashed cell salvage is associated with adverse postoperative effects due to the presence of cytokines including hypotension , hyperthermia , increased postoperative bleeding and non - cardiogenic pulmonary edema3334 ) . we have been using intraoperative red cell salvage for primary and revision tka , with success in reducing allogenic transfusion requirement ( dan m , unpublished data ) . the efficacy of cell salvage in tka in our cohort compared to previously published studies353637 ) is outlined in table 3 . we concluded perioperative red cell salvage reduces but does not eliminate the need for allogenic blood . the effectiveness of intraoperative red cell salvage is dependent on preoperative hb and hematocrit of blood lost and actual blood loss volume , which in turn determine the ability to return red cells . we believe intraoperative red cell salvage is most effective in patients with preoperative hb between 120 to 150 g / dl , further emphasizing the importance of correcting preoperative hb above 120 g / dl prior to tka . above 150 g / dl , topical fibrin sealant , composed of fibrinogen and thrombin , mimics the final step of coagulation cascade when mixed together during the application process . randelli et al.38 ) performed a randomized trial of topical fibrin versus control group in tka and found no difference in hb levels , postoperative decrease in hb , drainage or mean total blood loss . in particular , the transfusion rate was 32.3% in the control group compared with 25.8% in the fibrin group , with no significant difference . the authors concluded topical application of fibrin sealant was not effective in reducing perioperative blood loss in tka . another randomized study comparing topical fibrin spray to intravenous tranexamic acid ( txa ) demonstrated comparable reduction in blood loss but the cost of the fibrin spray was significantly greater39 ) . the routine use of intra - articular wound drainage in tka has been shown to increase blood transfusion requirement40 ) . this needs to be balanced with the reported increased risk of persistent ooze , bruising and hematoma formation41 ) . evidence for use of an intra - articular drain in tka therefore remains inconclusive and very much an individual decision based on surgeon preference . postoperative reinfusion drains are commonly employed in tka and previous investigations suggest reduction in allogeneic transfusion rate . a meta - analysis by huet et al.33 ) showed a relative risk reduction of 0.35 for allogeneic transfusion need with reinfusion drains . zacharopoulos et al.42 ) performed a prospective randomized controlled trial with reinfusion drains , demonstrating a decrease in allogenic blood transfusion . in contrast , hazarika et al.43 ) showed reinfusion drains had no significant benefit with the downside of additional cost . reinfusion drains carry the potential for transfusion reaction , as the unwashed blood contains fibrin degradation products and other potential contaminants4445 ) . the drained blood needs to be reinfused with 6 hours of commencement to avoid the potential for hemolysis . we no longer use reinfusion drains , as the cost does not seem to be justified , especially with the increasing use of txa in reducing postoperative blood loss . txa is one such agent , being a synthetic plasminogen - activator inhibitor , showing both clinical efficacy and an acceptable safety profile . txa inhibits the activation of plasminogen to plasmin by blocking the lysine binding sites of plasminogen to fibrin . the result is decrease proteolytic action on fibrin monomers and fibrinogen , leading to clot stabilization46 ) . the use of txa in primary tka is associated with reduced transfusion rates , increased discharge to home , and reduced costs47 ) . txa has desirable features of ease of administration , minimal effect on operative procedure workflow , and extremely low cost as a generic medicine . intravenous txa has been demonstrated to significantly reduce the amount of blood loss and blood transfusion requirements without an increase in venous thromboembolic risk in multiple studies for tka4849 ) . there is however no clear consensus on ideal dosage , timing , frequency and route of administration for txa in tka . the current recommendation for intravenous use is 10 to 15 mg / kg as a single dose . however significant heterogeneity exists in currently available studies , with doses ranging from 700 to 10,500 mg and often with multiple dosages . several contra - indications preclude the use of intravenous txa at the time of surgery , including renal insufficiency , history of previous deep venous thrombosis , cerebrovascular and cardiac disease . one study reported 28% of patients were contraindicated to intravenous txa51 ) and in these patients topical administration may be more appropriate due to delay in systemic absorption after application into the knee . intra - articular application limits systemic exposure and maximizes drug concentration and activity directly at the site of bleeding . wong et al.52 ) proved the efficacy of intra - articular txa in a double - blind , placebo - controlled randomized trial in tka . the authors demonstrated a significant difference in hb reduction and blood loss using 3.0 g of txa in 100 ml of normal saline compared to 1.5 g of txa and placebo , with no difference in thromboembolic complications . plasma levels of txa following topical administration were 70% less than an equivalent intravenous dose . more recently , a retrospective study found intra - articular and pericapsular injection of txa after capsular closure resulted in a transfusion rate reduction from 17.5% to 5.5% as well as a significantly higher postoperative hb in the txa group51 ) . alshryda et al.53 ) performed a systematic review and meta - analysis showing topical txa to significantly reduce the rate of blood transfusion and was safe . a number of studies have directly compared intravenous txa with topical txa demonstrating the efficacy and safety of topical administration in tka545556 ) . both patel et al.51 ) , using a single intravenous dose , and soni et al.57 ) , using a 3 dose intravenous regimen , concluded topical txa had similar efficacy to intravenous txa in terms of perioperative change in hb , lowest postoperative hb , total drain output and transfusion rate , and no increase in complications in randomized prospective studies . in a study comparing 3 methods of administration in tka , single dose intravenous txa was more effective than topical and intra - articular txa injected via the drain in reducing hb drop58 ) . local administration through the drain yielded least blood drainage postoperatively compared to intravenous and topical application , with 80% reduction of drainage volume compared to 45% and 18% , respectively . in contrast , maniar et al.59 ) found single intravenous dose did not give effective results . a 3-dose regimen of preoperative , intraoperative and postoperative doses of 10 mg / kg produced maximum effective reduction of drain loss and total blood loss in tka . the authors concluded a preoperative dose prior to tourniquet inflation was important to inhibit the activation of the fibrinolysis cascade . our preference in tka is to use topical txa , with no patients contraindicated to its use . 3.0 g of txa combined with 20 ml normal saline is administered to the operative site after prosthesis cementation and final washout for 5 minutes . after 5 minutes , any residual fluid is removed and wound closure performed without further lavage or intra - articular drain insertion . another principal arm of effective blood management is to restrict allogenic transfusion to patients meeting well - established transfusion criteria . adherence to evidence - based transfusion guidelines and utilization of appropriate transfusion triggers is the key element in achieving this . the recommendations for a restrictive transfusion protocol include transfusion in patients with hb<7 g / dl , hb<8 g / dl in setting of cardiac disease , or specific patient situations where additional oxygen carrying capacity is needed . transfusion of a single unit of packed red blood cells at a time is advised12 ) . the blood management strategy algorithm used in our hospital a blood management program in tka aims to reduce allogenic transfusion rate and its associated risks , whilst at the same time maximizing hb level and oxygen carrying capacity in the postoperative period . effective blood conservation encompasses optimizing preoperative red cell mass , salvaging blood lost during the perioperative period , minimsing blood loss with hemostatic measures and individualizing the transfusion trigger according to the patient 's clinical status and medical comorbidities . we use a combination of preoperative intravenous iron infusion , intraoperative red cell salvage , and topical txa . a proactive approach to blood management will lead to a positive effect on early and long - term outcomes and greater success in care of tka patients . OUTPUT:

a perioperative blood management program is one of a number of important elements for successful patient care in total knee arthroplasty ( tka ) and surgeons should be proactive in its application . the aims of blood conservation are to reduce the risk of blood transfusion whilst at the same time maximizing hemoglobin ( hb ) in the postoperative period , leading to a positive effect on outcome and cost . an individualized strategy based on patient specific risk factors , anticipated blood loss and comorbidities are useful in achieving this aim . multiple blood conservation strategies are available in the preoperative , intraoperative and postoperative periods and can be employed in various combinations . recent literature has highlighted the importance of preoperative hb optimization , minimizing blood loss and evidence - based transfusion guidelines . given tka is an elective procedure , a zero allogenic blood transfusion rate should be the aim and an achievable goal .

PubMed_Summ6581

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: this infection is re - emerging in china , japan , australia , india , and europe . leptospirosis is a common cause of acute febrile illness in india , especially during the monsoon months and outbreaks have been reported from the andamans , tamil nadu , karnataka , maharashtra , andhra pradesh , and orissa after heavy rains . severe disease occurs in 510% of patients associated with high mortality rate in this group and leptospiremia occurs during the 1 week of illness . the majority of the patients present with nonspecific symptoms of acute fever , headache , abdominal pain , myalgia , and conjunctival suffusion , which makes it difficult to differentiate this illness from other causes of acute fever like scrub typhus , dengue , and malaria . thus , laboratory confirmation of disease is important as clinical management is different for these conditions . direct detection includes isolating the organism in culture or detecting specific dna while indirect method includes detection of antibodies . the use of culture as a diagnostic method is limited by its long turnover time , requiring at least 68 weeks for growth . polymerase chain reaction ( pcr ) targeting the 16s rrna has been used to detect the presence of leptospires in serum , urine , cerebrospinal fluid , and autopsy tissue . pcr has been done with 16s rrna as the target having a sensitivity of 52.794.4% and a specificity of 90100% , secy gene , lipl32 gene , and rrs gene with the highest sensitivity of 94.8% . its value lies in the fact that it can diagnose the disease very early in the 1 week of illness before the appearance of antibodies and hence helps in early initiation of treatment . loop - mediated isothermal amplification ( lamp ) an isothermal dna amplification method has high specificity and not inhibited by pcr inhibitors . the utility of lamp for the rapid and specific diagnosis of leptospirosis has been evaluated by only five different groups of researchers . microscopic agglutination test ( mat ) is the reference method for serological diagnosis of leptospirosis . the mat suffers from drawbacks like complex and labor intensive test procedure , requirement of a large library of strains and paired sera for confirmation . detection of igm antibodies by elisa is the most widely used method for diagnosis of leptospirosis especially as a part of modified faine 's criteria . like faine 's criteria it includes clinical features such as a headache , fever , temperature , conjunctival suffusion , meningism , joint pain , jaundice , albuminuria , and epidemiological features but unlike faine 's criteria which use culture and mat for laboratory diagnosis , in addition , modified faine 's criteria uses igm elisa also . the advantage of elisa is that it can be performed easily with less infrastructure and technical expertise and is inexpensive and less laborious compared to mat . in addition , the elisa can be automated , the result is objective , especially once a diagnostic cutoff has been decided on , therefore having less inter- and intra - observer variation . as no single test by itself can diagnose all cases of leptospirosis , composite diagnostic criteria , which includes clinical , epidemiological , and laboratory parameters , have been defined called as faines and modified faines criteria . the aim of this study was to compare the utility of lamp , pcr , and elisa for diagnosis of leptospirosis and to correlate clinical features with the diagnosis of leptospirosis . serum was collected from 150 patients with acute febrile illness from december 2012 to july 2014 . these patients had a fever ( 100f ) of duration 15 days without eschar , who were malaria and blood culture negative . after the study was approved by the institutional review board , clinical information , and 4 ml blood was collected from these patients ( after obtaining informed consent ) in a red capped tube with clot activator ( bd vacutainer , franklin lakes , nj , usa ) . igm antibodies to leptospira were detected by elisa ( panbio ltd , brisbane , australia ) in 150 acute serum samples and 32 convalescent sera . each elisa run was validated only if the relevant controls ( positive , negative , and cutoff controls ) were within the range described by the manufacturer . in addition , an in - house qc ( close to the cutoff value ) sample was used for assay validation . the igm elisa for leptospira was considered to be positive if the value was 20 panbio units . dna was extracted from the serum samples ( 200 l ) using the qiaamp blood mini kit ( qiagen , hilden , germany ) and stored at 70c . a nested pcr was performed targeting and amplifying a 547 bp segment of the 16s rrna gene ( rrs gene ) . the primer sequence used was as described by boonsilp et al . in each cycle of the nested pcr , the reaction volume was 50 l which contained 2 pcr mix ( thermo fisher scientific , marietta , usa ) , 20 pmol of each of the primers , 4 mm mgcl2 and pcr grade water along with 5 l of dna . the cycling conditions used for both ( first and second round ) were the same and included 95c for 2 min for initial denaturation , followed by 95c for 10 s , 67c for 15 s , 72c for 30 s for a total of 40 cycles and one cycle of 72c for 7 min for the first run . the final extension of 72c for 7 min was performed before detection of amplification products . gel electrophoresis was performed in a 2% agarose gel containing ethidium bromide ( 10 g / ml ) , and the 547 bp product was visualized using a gel documentation system ( gel doc , bio - rad laboratories , hercules , ca , usa ) . the lipl32 and lipl41 lamp assay was performed at 63c using the protocol and primer sequence described by chen et al . in each run positive control which was leptospira interrogans strain icterohemorrhagiae obtained from regional medical research centre , port blair , india and a negative control were used . the detection of the lamp products was done by visual detection for turbidity , centrifugation at 14,000 rpm for 1 min for pellet formation and gel electrophoresis using a 2% agarose gel containing ethidium bromide ( 10 g / ml ) . the product was visualized using a gel documentation system ( gel doc , bio - rad laboratories , hercules , ca , usa ) . l. interrogans serovar pomona , serovar icterohemorrhagiae , and serovar hardjo ( kindly provided by rmrc , port blair , india ) were used as positive controls for the nested pcr and the lamp assay . two amplified products for rrs gene were sequenced to confirm the appropriateness of the target amplified . the abi 310 genetic analyzer ( applied biosystems , foster city , ca , usa ) was used to enumerate the sequences . the homology of the sequence obtained with that of the existing leptospira sequence in the gene bank was performed using the basic local alignment search tool ( blast , available from www.ncbi.nlm.nih.gov/blast ) program with the available standard reference sequences in the genebank for homology . the case definition used in this study included the samples which were positive by pcr or lamp or fulfilling modified faine 's criteria based on clinical features , epidemiological features and igm elisa for leptospirosis . all the data were entered into an excel spreadsheet 2010 ( microsoft office , redmond , washington , usa ) . the sensitivity and specificity of elisa , pcr , and lamp assay were evaluated using latent class analysis ( lca ) using stata version 13 ( statacorp lp , texas , usa ) . chi - square test was used to check the association of categorical variables and a p < 0.05 was taken as statistically significant . serum was collected from 150 patients with acute febrile illness from december 2012 to july 2014 . these patients had a fever ( 100f ) of duration 15 days without eschar , who were malaria and blood culture negative . after the study was approved by the institutional review board , clinical information , and 4 ml blood was collected from these patients ( after obtaining informed consent ) in a red capped tube with clot activator ( bd vacutainer , franklin lakes , nj , usa ) . igm antibodies to leptospira were detected by elisa ( panbio ltd , brisbane , australia ) in 150 acute serum samples and 32 convalescent sera . each elisa run was validated only if the relevant controls ( positive , negative , and cutoff controls ) were within the range described by the manufacturer . in addition , an in - house qc ( close to the cutoff value ) sample was used for assay validation . the igm elisa for leptospira was considered to be positive if the value was 20 panbio units . dna was extracted from the serum samples ( 200 l ) using the qiaamp blood mini kit ( qiagen , hilden , germany ) and stored at 70c . a nested pcr was performed targeting and amplifying a 547 bp segment of the 16s rrna gene ( rrs gene ) . the primer sequence used was as described by boonsilp et al . in each cycle of the nested pcr , the reaction volume was 50 l which contained 2 pcr mix ( thermo fisher scientific , marietta , usa ) , 20 pmol of each of the primers , 4 mm mgcl2 and pcr grade water along with 5 l of dna . the cycling conditions used for both ( first and second round ) were the same and included 95c for 2 min for initial denaturation , followed by 95c for 10 s , 67c for 15 s , 72c for 30 s for a total of 40 cycles and one cycle of 72c for 7 min for the first run . the final extension of 72c for 7 min was performed before detection of amplification products . gel electrophoresis was performed in a 2% agarose gel containing ethidium bromide ( 10 g / ml ) , and the 547 bp product was visualized using a gel documentation system ( gel doc , bio - rad laboratories , hercules , ca , usa ) . the lipl32 and lipl41 lamp assay was performed at 63c using the protocol and primer sequence described by chen et al . in each run positive control which was leptospira interrogans strain icterohemorrhagiae obtained from regional medical research centre , port blair , india and a negative control were used . the detection of the lamp products was done by visual detection for turbidity , centrifugation at 14,000 rpm for 1 min for pellet formation and gel electrophoresis using a 2% agarose gel containing ethidium bromide ( 10 g / ml ) . the product was visualized using a gel documentation system ( gel doc , bio - rad laboratories , hercules , ca , usa ) . l. interrogans serovar pomona , serovar icterohemorrhagiae , and serovar hardjo ( kindly provided by rmrc , port blair , india ) were used as positive controls for the nested pcr and the lamp assay . two amplified products for rrs gene were sequenced to confirm the appropriateness of the target amplified . the abi 310 genetic analyzer ( applied biosystems , foster city , ca , usa ) was used to enumerate the sequences . the homology of the sequence obtained with that of the existing leptospira sequence in the gene bank was performed using the basic local alignment search tool ( blast , available from www.ncbi.nlm.nih.gov/blast ) program with the available standard reference sequences in the genebank for homology . the case definition used in this study included the samples which were positive by pcr or lamp or fulfilling modified faine 's criteria based on clinical features , epidemiological features and igm elisa for leptospirosis . all the data were entered into an excel spreadsheet 2010 ( microsoft office , redmond , washington , usa ) . the sensitivity and specificity of elisa , pcr , and lamp assay were evaluated using latent class analysis ( lca ) using stata version 13 ( statacorp lp , texas , usa ) . chi - square test was used to check the association of categorical variables and a p < 0.05 was taken as statistically significant . among the 150 patients recruited , 52 were diagnosed to have leptospirosis based on our case definition . of these three were positive by igm elisa , pcr , and lamp , two were positive only by pcr for rrs gene ( 547 bp ) , and 7 were positive only by lamp assay for lipl32 and lipl41 genes , another forty fulfilled modified faine 's criteria ( clinical criteria plus igm elisa positive ) . only , decreased urine output , jaundice , renal compromise , and low platelet count were found to be significantly related to leptospirosis as given in table 1 . the test results were analyzed using lca for the three tests elisa , pcr , and lamp for diagnosis of leptospirosis . however , the specificity was highest for pcr with 98.64% , followed by lamp 95.24% and least for elisa ( modified faines criteria ) 72.79% . as all patients positive by igm elisa for leptospirosis ( as per the inclusion and exclusion criteria ) were having a clinical picture compatible with leptospirosis , the lca results for elisa have been extrapolated as results obtained for modified faines criteria for leptospirosis . clinical features among those with leptospirosis and those without ( based on study case definition ) it was seen that lamp assay was positive for all 10 ( 100% ) within the 1 week of illness . in case of pcr , three samples were positive in the 1 week of illness and other two in the 2 week of fever . by elisa , igm antibodies were detectable within 47 days of illness for 20 ( 46.5% ) , including the three positive by molecular assays and 23 ( 53.5% ) were positive between 8 and 15 days of fever . sequencing done for two samples ( genbank accession numbers kr780767 and kr780768 ) confirmed the identity with the available sequences as 98% and 97% respectively with l. interrogans . according to the world health organization , the case definition of leptospirosis includes an acute febrile illness with a headache , myalgia , conjunctival suffusion , anuria / oliguria , jaundice , cough , hemoptysis , breathlessness , hemorrhage , rash , nausea , vomiting , abdominal pain , diarrhea , and meningeal irritation . however , only renal compromise ( oliguria and raised creatinine ) , low platelet count and jaundice ( bilirubin > 3 mg% ) were significantly related to the patients with leptospirosis in this study . in this study , among the leptospirosis patients , in addition to fever , 48.08% had myalgia , 36.54% had a headache , 28.85% had oliguria , 59.61% had raised bilirubin , and 42.3% had renal compromise as evidenced by raised creatinine level . observed that myalgia was seen in 78.4% , icterus in 74.5% , headache in 41.2% , and oliguria in 29.4% of leptospirosis patients . chaudhry et al . reported that the common clinical features were vomiting / nausea ( 49.4% ) , headache ( 50.5% ) , myalgia ( 52.8% ) , renal involvement ( 54% ) , and raised bilirubin ( 59.7% ) . using modified faine 's criteria , debmandal et al . found that the most common features were a headache ( 100% ) , jaundice ( 93.92% ) , whereas 25.23% leptospirosis cases had increased bilirubin . although all three assays showed excellent sensitivity , the specificity of the lamp and pcr was far superior to that of the igm elisa . in a study done by lin et al . the detection limit of the lamp assay was similar to the pcr ( 100 genome equivalents ) the target being lipl41 gene . reported that with the target rrs gene and lipl41 gene , the sensitivity was 43.6% and 37.6% , and specificity was 83.5% and 90.2% , respectively for the two targets . in another study conducted by koizumi et al . , the specificity of lamp assay with rrs gene as target was 66.7% . from the last two studies , it is evident that lipl41 has higher specificity compared to rrs gene for detection of leptospira dna by lamp assay . in the present study , the lamp assay had a high specificity as it had two targets lipl32 and lipl41 which is similar to the findings of chen et al . this explains the reason of it picking up the samples which were neither picked up by pcr nor elisa . interestingly , there were two samples which were positive for rrs gene by pcr but negative by lamp assay and igm elisa , despite being repeated twice . the noteworthy point regarding the molecular assays used in this study is that all 10 samples positive by leptospira lamp assay occurred in individuals whose duration of illness did not exceed 1 week . this suggests that lamp assay is more likely to be positive in those with fever < 7 days . the two samples which were negative by lamp but positive by pcr were from patients whose duration of illness was beyond 7 days . igm antibodies to leptospira are detectable from the 2 week onward , the same was observed in this study . this confirms the finding that all cases of leptospira can not be detected in blood by nucleic acid amplification tests like pcr or lamp after the 1 week of illness . hence , igm elisa is still a useful tool for diagnosis of leptospirosis in a tertiary care center like ours . this is of great importance as most of these patients are referred to a tertiary care center in the 2 week of illness as they have not responded to treatment at the primary or secondary health - care level . a robust inclusion and exclusion criteria for recruiting study subjects were used in this prospective study , reference test for leptospirosis diagnosis like culture and mat were not performed . therefore to assess the efficacy of each test ( igm elisa , pcr , and lamp ) for diagnosis of leptospirosis , lca was employed . an expert formulated case definition was used to assess the significance of clinical features in those with and without leptospirosis . among 52 patients diagnosed as cases of leptospirosis , 40 were positive only by igm elisa / modified faines criteria . using lca , all the three tests had a sensitivity of 100% , whereas a specificity of 98.64% , 95.24% , and 72.79% could be attributed to pcr , lamp , and igm elisa / modified faines criteria for leptospirosis . in the 1 week of illness , lamp assay performed best , whereas igm elisa was the mainstay of diagnosis of leptospirosis from the 2 week onward . our preliminary data suggest that a combination of lamp and igm elisa is likely to pick up most cases of suspected leptospirosis especially when they have no eschar , are blood culture and malaria negative . future studies including paired sera for a demonstration of rise in titer or seroconversion and detection of leptospiral dna in urine are required to assess the validity of these findings . institutional review board , christian medical college , vellore ( min no 8109 dated 05.12.2012 ) for funding the study . institutional review board , christian medical college , vellore ( min no 8109 dated 05.12.2012 ) for funding the study . OUTPUT:

background : leptospirosis is a zoonotic disease which requires laboratory diagnosis for confirmation.materials and methods : in this study serum samples from adults with acute undifferentiated fever ( duration 15 days ) were tested for igm antibodies to leptospira by elisa , pcr for rrs gene and loop - mediated isothermal amplification ( lamp ) assay for lipl32 and lipl41.results:among the 150 sera tested , three were positive by pcr , lamp and igm elisa / modified faines criteria , two by only pcr ; seven only by lamp assay and forty fulfilled modified faine 's criteria ( illness clinically compatible and igm elisa positive for leptospirosis ) . clinical correlation revealed renal compromise , low platelet count and severe jaundice were significantly related to leptospirosis ( p < 0.05).conclusion : this study suggests that lamp assay could be useful for diagnosis of leptospirosis during the 1st week of illness whereas igm elisa forms the mainstay of diagnosis from the 2nd week onward . further studies especially community based , comparing elisa , pcr , lamp , culture and microscopic agglutination test are required to evaluate the veracity of these findings .

PubMed_Summ6582

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: periodontal diseases comprise of a group of inflammatory diseases affecting the supporting tissues of the teeth resulting from a complex interplay between specific gram - negative microorganisms , their by products , and the host - tissue response . earlier , periodontitis had been considered as a disease confined to the oral cavity . however , in the past several years , substantial scientific data have emerged to indicate that the localized infections characteristic of periodontitis can have a significant effect on the systemic health . this increase in systemic inflammation has been implicated in having a modulating role in cardiovascular disease ( cvd ) , on an adverse pregnancy outcome , and on diabetes mellitus and in respiratory disease . in recent years evidence suggests that plasma osteopontin levels are associated with the presence and extent of cvd , an inflammatory mediator whose levels are also found to commensurate with the progression of periodontal disease in gingval crevicular fluid as well as in plasma . the concomitant increase of osteopontin in plasma is caused by spillage or overflow of osteopontin from the diseased periodontal tissues , or produced by circulating activated macrophages . osteopontin ( opn ) is a non - collagenous , calcium binding , glycosylated phosphoprotien produced by osteoblasts . studies have shown that opn is a component of human atherosclerotic plaque and could be a mediator of arterial neointima formation . opn is synthesized by resident macrophages , smooth muscle , and endothelial cells in primary and restenotic human coronary atherosclerotic plaques , which contribute to cellular accumulation and dystrophic calcification in atherosclerotic plaques . opn levels in blood serum also correlate positively with the extent of coronary atherosclerotic disease , suggesting a role of opn in cvds . osteopontin levels also reflect active lesions of aggravated periodontal disease accompanied by alveolar bone resorption . thus by treating periodontal disease , we may lower the risk of future cardiovascular events by reducing opn levels after periodontal therapy . this study is planned with an objective to provide a diagnostic tool which is expected to play an important role in the assessment of periodontal disease severity and it may also help in prevention and control of systemic diseases such as cvd , inflammatory kidney disease , diabetes mellitus , and respiratory disease etc . the study was conducted with the following aims : to estimate and compare the levels of opn in plasma of subjects with healthy periodontium and generalized chronic periodontitis.to estimate opn levels in plasma of generalized chronic periodontitis subjects 2 months after scaling and root planing.to compare opn levels in plasma of generalized chronic periodontitis subjects before and after two months after scaling and root planing.to correlate opn with periodontal disease index before and two months after scaling and root planing . to estimate and compare the levels of opn in plasma of subjects with healthy periodontium and generalized chronic periodontitis . to estimate opn levels in plasma of generalized chronic periodontitis subjects 2 months after scaling and root planing . to compare opn levels in plasma of generalized chronic periodontitis subjects before and after two months after scaling and root planing . to correlate opn with periodontal disease index before and the study was conducted with the following aims : to estimate and compare the levels of opn in plasma of subjects with healthy periodontium and generalized chronic periodontitis.to estimate opn levels in plasma of generalized chronic periodontitis subjects 2 months after scaling and root planing.to compare opn levels in plasma of generalized chronic periodontitis subjects before and after two months after scaling and root planing.to correlate opn with periodontal disease index before and two months after scaling and root planing . to estimate and compare the levels of opn in plasma of subjects with healthy periodontium and generalized chronic periodontitis . to estimate opn levels in plasma of generalized chronic periodontitis subjects 2 months after scaling and root planing . to compare opn levels in plasma of generalized chronic periodontitis subjects before and after two months after scaling and root planing . to correlate opn with periodontal disease index before and in the present study , 40 subjects were selected from the outpatient department of periodontology ( post- graduate section ) of bharati vidyapeeth university dental college and hospital , pune . screening examination included : ( 1 ) medical history ( 2 ) dental history , and ( 3 ) periodontal disease index ( ramfjord ) systemically healthy patientspatients in age group of 20 - 45 yearsrandom selection of male and female patientstwenty subjects with healthy periodontiumtwenty subjects with generalized chronic periodontitis . systemically healthy patients patients in age group of 20 - 45 years random selection of male and female patients twenty subjects with healthy periodontium twenty subjects with generalized chronic periodontitis . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertensionhistory of any bone disorderssubjects who had undergone periodontal treatment in the last six monthssubjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six monthssubjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate)pregnant or lactating femalessmokers . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertension history of any bone disorders subjects who had undergone periodontal treatment in the last six months subjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six months subjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate ) pregnant or lactating females informed consent was obtained from those subjects who agreed to participate voluntarily in this study after institutional ethical clearance was obtained . based upon the periodontal disease index scores , the subjects were divided into two groups : group i- 20 subjects with healthy periodontium . group ii- 20 subjects with generalized chronic periodontitis . for opn assessment , non - fasting , venous blood samples were collected from the subjects at the time of clinical examination ( group i , ii ) and two months after scaling and root planing in group ii . blood was withdrawn by venepuncture from the anterior cubital vein using a sterile syringe and needle at the pathology laboratory at the bharati hospital . five ml of blood sample was transferred to the vials containing anticoagulant and transferred immediately to the laboratory at interactive research school of health affairs ( irsha ) . the stored plasma was used for estimation of opn levels at a later date . plasma opn level thereafter , scaling and root planing was carried out for subjects with generalized chronic periodontitis and oral hygiene instructions were given to the subjects . periodontal disease index was assessed after two months of scaling and root planing and plasma samples were also collected to estimate levels of opn . the data obtained was subjected to statistical analysis using two sample t - tests , paired t - test to compare opn levels in group ii before and after treatment and un - paired t - test to compare opn levels in group i and ii . correlation of the opn levels with the clinical parameter in each group was analyzed by pearson 's correlation coefficient . in the present study , 40 subjects were selected from the outpatient department of periodontology ( post- graduate section ) of bharati vidyapeeth university dental college and hospital , pune . screening examination included : ( 1 ) medical history ( 2 ) dental history , and ( 3 ) periodontal disease index ( ramfjord ) systemically healthy patientspatients in age group of 20 - 45 yearsrandom selection of male and female patientstwenty subjects with healthy periodontiumtwenty subjects with generalized chronic periodontitis . systemically healthy patients patients in age group of 20 - 45 years random selection of male and female patients twenty subjects with healthy periodontium twenty subjects with generalized chronic periodontitis . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertensionhistory of any bone disorderssubjects who had undergone periodontal treatment in the last six monthssubjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six monthssubjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate)pregnant or lactating femalessmokers . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertension history of any bone disorders subjects who had undergone periodontal treatment in the last six months subjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six months subjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate ) pregnant or lactating females informed consent was obtained from those subjects who agreed to participate voluntarily in this study after institutional ethical clearance was obtained . based upon the periodontal disease index scores , the subjects were divided into two groups : group i- 20 subjects with healthy periodontium . group ii- 20 subjects with generalized chronic periodontitis . for opn assessment , non - fasting , venous blood samples were collected from the subjects at the time of clinical examination ( group i , ii ) and two months after scaling and root planing in group ii . blood was withdrawn by venepuncture from the anterior cubital vein using a sterile syringe and needle at the pathology laboratory at the bharati hospital . five ml of blood sample was transferred to the vials containing anticoagulant and transferred immediately to the laboratory at interactive research school of health affairs ( irsha ) . the stored plasma was used for estimation of opn levels at a later date . plasma opn level thereafter , scaling and root planing was carried out for subjects with generalized chronic periodontitis and oral hygiene instructions were given to the subjects . periodontal disease index was assessed after two months of scaling and root planing and plasma samples were also collected to estimate levels of opn . systemically healthy patientspatients in age group of 20 - 45 yearsrandom selection of male and female patientstwenty subjects with healthy periodontiumtwenty subjects with generalized chronic periodontitis . systemically healthy patients patients in age group of 20 - 45 years random selection of male and female patients twenty subjects with healthy periodontium twenty subjects with generalized chronic periodontitis . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertensionhistory of any bone disorderssubjects who had undergone periodontal treatment in the last six monthssubjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six monthssubjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate)pregnant or lactating femalessmokers . history of systemic diseases ( e.g. , diabetes mellitus , ischemic heart disease , other cvds contributing to arthrosclerosis , stroke , hypertension history of any bone disorders subjects who had undergone periodontal treatment in the last six months subjects who had taken antibiotics , anti - inflammatory drugs , steroids and contraceptives in the last six months subjects who are on antiresorptive drugs such as bisphosphonates ( eg , alendronate ) pregnant or lactating females informed consent was obtained from those subjects who agreed to participate voluntarily in this study after institutional ethical clearance was obtained . based upon the periodontal disease index scores , the subjects were divided into two groups : group i- 20 subjects with healthy periodontium . group ii- 20 subjects with generalized chronic periodontitis . for opn assessment , non - fasting , venous blood samples were collected from the subjects at the time of clinical examination ( group i , ii ) and two months after scaling and root planing in group ii . blood was withdrawn by venepuncture from the anterior cubital vein using a sterile syringe and needle at the pathology laboratory at the bharati hospital . five ml of blood sample was transferred to the vials containing anticoagulant and transferred immediately to the laboratory at interactive research school of health affairs ( irsha ) . the stored plasma was used for estimation of opn levels at a later date . plasma opn level thereafter , scaling and root planing was carried out for subjects with generalized chronic periodontitis and oral hygiene instructions were given to the subjects . periodontal disease index was assessed after two months of scaling and root planing and plasma samples were also collected to estimate levels of opn . the data obtained was subjected to statistical analysis using two sample t - tests , paired t - test to compare opn levels in group ii before and after treatment and un - paired t - test to compare opn levels in group i and ii . correlation of the opn levels with the clinical parameter in each group was analyzed by pearson 's correlation coefficient . in this study , an attempt was made to evaluate opn levels in subjects with healthy periodontium and generalized chronic periodontitis and its assessment after scaling and root planing using an osteopontin enzyme immunometric assay kit ( quantikine ) . a total of 40 subjects between 18 to 45 years were included in this study . the mean concentration of opn in plasma was observed to be higher in the generalized chronic periodontitis group ( 153.08 ng / ml ) as compared with the subjects with healthy periodontium ( 55.09 ng / ml ) [ table 1 ] . the difference in the mean of opn levels in group i and ii was 98.00 ng / ml ; with t value as 9.249 and p value=0.00 which is statistically significant [ table 2 ] . the opn level in plasma of generalized chronic periodontitis subjects was found to be significantly higher than that of healthy subject . opn levels in plasma of group i and ii subjects at baseline comparison of opn levels in plasma of group i and ii subjects at baseline opn levels decreased to 91.52 ng / ml in group ii , two months after scaling and root planing . the difference in mean of opn levels was 61.5566 ng / ml witht value as 6.843 and p value as 0.00 which is statistically significant [ table 3 ] . comparison of opn levels in plasma of group ii at baseline and two months after scaling and root planing the mean periodontal disease index ( pdi ) score in the generalized chronic periodontitis group was 5.118650.469 , whereas the mean pdi score in healthy subjects was 1.000.245 [ table 4 ] . a significant difference ( p<0.05 ) was found in the mean pdi scores between the healthy and generalized chronic periodontitis group . the mean pdi score in the generalized chronic periodontitis group i.e. group ii was 5.118650.469 which reduced to 3.681.126 as assessed two months after scaling and root planing [ table 5 ] . statistically significant difference ( p<0.05 ) in the pdi scores between the healthy and generalized chronic periodontitis group with the p=0.00 with higher values in the subjects with generalized chronic periodontitis . pdi scores in group i and ii subjects at the baseline pdi scores in group ii at baseline and two months after scaling and root planing the opn levels in plasma were correlated with the pdi scores using pearson 's correlation coefficient . when all the subjects ( group i and ii ) were considered together at baseline , the pearson 's correlation coefficient was 0.893 was statistically significant ( p<0.05 ) . when only the generalized chronic periodontitis group i.e. group ii ( at baseline ) was considered , the pearson 's correlation coefficient was 0.731 which is also statistically significant ( p<0.05 ) . this suggests that opn levels in plasma show a positive correlation with the severity of the periodontal disease . when the generalized chronic periodontitis group ( group ii ) was considered two months after scaling and root planing , the pearson 's correlation coefficient was 0.181 which is statistically not significant ( p>0.05 ) after two months of scaling and root planing [ table 6 ] . this result indicates that the rate of change of pdi is not similar to the rate of change of opn . both the parameters show improvement after scaling and root planing , but correlation could not be established which can be attributed to the other factors such as hosts response or patients compliance in the resolution of periodontitis after treatment of the same . the results of this study demonstrated the elevated opn levels in plasma in subjects with generalized chronic periodontitis as compared with subjects with healthy periodontium . the results of the study are consistent with outcomes of recent investigations which reported which reported an elevation of opn in periodontitis patients . they found a highly significant elevation of opn plasma in subjects with chronic periodontitis group as compared with the healthy group . the assessment of opn concentration was determined using a sandwich type human osteopontin enzyme immunoesssay kit ( titrezyme ) which is different from our study where osteopontin enzyme immunometric assay kit ( quantikine ) was used to assess opn levels . the highest mean plasma opn concentrations observed in the periodontitis group in their study were 1273.21 ng / ml , and in the healthy group was 476.35 ng / ml . this was statistically significant ( p0.05 ) . in addition they also assessed and correlated opn levels in plasma with opn levels in gingival crevicular fluid ( gcf ) . the highest mean gingival crevicular fluid concentrations were observed in the periodontitis group 1575.01 ng / ml , and the lowest in the healthy group 1194.80 ng / ml . they postulated that the concomitant increase of opn in plasma may be caused by the spillage or overflow of opn from the diseased periodontal tissues , or produced by the circulating activated macrophages . subjects in the periodontitis group were treated by scaling and root planing , and strict oral hygiene measures were instituted . the mean concentration of opn in the plasma in the generalized chronic periodontitis group decreased from 153.09 ng / ml to 91.52 ng / ml , which showed a statistically significant relation . the findings of our study are also in agreement with sharma and pradeep . who found that the level of opn decreased from 1273.21 ng / ml to 1051.68 ng/ ml in plasma of chronic periodontitis patients after treatment i.e. two months after scaling and root planing . these results also showed a positive correlation with opn levels in gcf which were significantly reduced from 1575.01 ng / ml to 1194.80 ng / ml after treatment of subjects with chronic periodontitis . also the mean pdi score of generalized periodontitis group decreased from 5.19 to 3.68 as assessed two months after scaling and root planing . statistically significant positive correlation between opn in plasma and pdi was found at the baseline in subjects with generalized chronic periodontitis . however , weak positive correlation was observed between opn and pdi two months after scaling and root planing in subjects with generalized chronic periodontitis . the result of this study indicates a significant association between inflammatory marker opn and periodontal disease and a tendency for significant reduction of plasma opn levels after treatment of periodontitis . however , a weak correlation was observed between opn and pdi in generalized chronic periodontitis subjects after scaling and root planing . as the correlation between opn and cardiovascular disease has already been established and the opn levels also increase periodontal diseases which is evident from our results ; this may indicate a strong correlation between periodontitis and cvd with one of the mediator as opn . thus , it is clear that the risk of cvd can be reduced in otherwise healthy individuals with prevention/ treatment of periodontitis at an early stage . scaling and root planing may also help in reducing the severity of pre - existing cvd . this implies that the assessment of periodontal status at the time of cardiovascular examination should also be incorporated in routine practice . from the above observation , it can be concluded that elevated levels of opn were seen in subjects with periodontitis as compared with healthy individuals . it was also found that the opn levels significantly decreases two months after periodontal therapy . as the correlation between opn and cardiovascular disease has already been established and the opn levels also increases in periodontal diseases which is evident from our results ; this may indicate a strong correlation between periodontitis and cvd with one of the mediator as opn . thus , it is clear that the risk of cvd can be reduced in otherwise healthy individuals with prevention / treatment of periodontitis at an early stage . this implies that the assessment of periodontal status at the time of cardiovascular examination should also be incorporated in routine practice . for clinical application of this approach , a long term study of large sample size is required with relevant laboratory investigations to evaluate cardiovascular status . studies could also be carried out in relation to the subjects with periodontitis and pre - existing cvd to evaluate the effect of periodontal therapy on severity of cvd . OUTPUT:

background : osteopontin ( opn ) is a bone matrix derivative , whose levels reflect active lesions of aggravated periodontal disease accompanied by alveolar bone resorption . opn is also a component of human atherosclerotic plaque , suggesting a role of opn in cardiovascular diseases . the present study was conducted to assess and compare plasma opn levels in subjects with healthy periodontium and generalized chronic periodontitis and to evaluate the effect of scaling and root planing on plasma opn levels of generalized chronic periodontitis subjects.materials and methods:40 gender matched subjects were divided into two equal groups , group i- healthy and group ii- generalized chronic periodontitis , based on the periodontal disease index . blood samples were collected from the subjects at the time of clinical examination ( group i , ii ) and two months after scaling and root planning of group ii . plasma opn level was determined using a opn enzyme immunometric assay kit ( quantikine).results : the mean value of plasma opn levels in subjects with generalized chronic periodontitis was higher ( 153.08 ng / ml ) as compared to the subjects with healthy periodontium ( 55.09 ng / ml ) . after treatment of generalized chronic periodontitis group , the level of plasma opn decreased to 91.53 ng / ml.conclusion : the findings from the study suggest that plasma opn levels were highest in plasma from sites with periodontal destruction ; however , scaling and root planing resulted in the reduction of opn levels .

PubMed_Summ6583

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the development of the spinal cord plays a central role towards execution coordinated movements and of sensory inputs as well . together with sensory inputs from the eye and ear in human they produce a movement output as a consequence of reflexes or higher brain cognitive functions . these circuits are mainly disturbed in motoneuron diseases like amyotrophic lateral sclerosis ( als ) , spinal muscular atrophy ( sma ) or in cases of lesions caused by accidents . the restauration of such disturbed motor output functions is the main goal for physicians and scientists all over the world . if we therefore take a closer look at the time cell differentiation and establishment of those motor circuits , this may help to restore the original function in disease . the spinal cord as a central nervous system ( cns ) structure builds up connections to the periphery of the body . this includes muscle movement , breathing and rhythmic activities of muscle cells with a constant feed back to the higher brain regions . disorders affecting the function of the motor system including als or sma are characterized by the progressive inability not only to walk and move but also suffer from the increasing inability to breathe or speak . the complexity of dysfunctions affecting the motor system makes it unable to apply cures on single cell type level but rather needs a more systemic approach . the fact that the motor system has great abilities to compensate dysfunctions for a longer time even makes it harder to start curing a disease as the loss of functional cells has started sometimes even years before . for example usually more than 50% of all motoneurons are already dysfunctional for a longer period before a patient comes to the clinic due to compensatory effects of the remaining functional cells in the spinal cord . orphaned muscle cells are taken over by neighboring motoneurons as they send out new axonal side tribes to innervate these muscle fibers . knowledge on the development of the spinal motor circuits might help to understand and might even help finding cures against such degenerative diseases . the cns epithelial cells of the neural tube are pseudo stratified cells and perform symmetric cell divisions to increase the number of neural precursor cells ( npcs ) . different regional signals along the rostro - caudal axis start to instruct the positional identity of the cells defining forebrain , midbrain , hindbrain , and spinal cord . caudalization is induced by the vitamin a derivative retinoic acid ( ra ) followed by expression of pax3 by neuroepithelial cells . subsequently , mutant mice deficient for retinaldehyde dehydrogenase 2 ( raldh2 ) show severe alterations in hindbrain and spinal cord patterning . the second early molecule necessary for the specification of the spinal cord is the fibroblast growth factor ( fgf ) . both fgf and ra form antagonizing gradients to determine the anterior hindbrain and the posterior spinal cord along the rostro - caudal axis . regionalization within the caudal part is performed by expression of the homeobox domain transcription factors ( hoxgenes ) ( diez del corral et al . , 2003 ) . these hox transcription factors represent the concept for a neuronal subtype identity of the embryonic hindbrain and spinal cord ( wu et al . , 2008 ) . while fgfs and ra define the cellular identity for the rostro - caudal axis , cellular identities along the dorso - ventral axis of the developing hindbrain and spinal cord are defined by members of the bone morphogenetic protein ( bmp ) and of the wingless / int-1 ( wnt ) family , secreted from the roof plate cells . the respective antagonizing signal comes from the notochord and later on from the floor plate cells which secrete sonic hedgehog ( shh ) as a ventralization signal for the spinal cord cells ( dessaud et al . , 2008 ) . the resulting progenitor cells , as well as the resulting cells from these progenitor pools are characterized by a specific expression patterning of homeodomain transcription factors . consequently , mutations in patched 1 or smoothened , both being receptor parts of the shh pathway , induce severe patterning defects during embryogenesis . this homeodomain transcription factor concept has been considered as the essential mechanism for specification of neuronal and the latter glial subtype identities . definition of cells might be in general performed by the transcription factor code but it does not clarify the way towards a specialized cell type . such signals have to be positioned outside the cells and therefore the extracellular matrix most probably plays a pivotal role in this process . for example , heparan sulfate proteoglycans ( hspgs ) are found in almost all mammalian cells . they are on cell surfaces ( glypicans , syndecans ) and in the extracellular space ( perlecan , collagen type xviii or agrin ) . they are composed of a core protein with covalent o - linked heparan sulfate glycosaminoglycan side chains . the fgf2 and fgf4 , the wnt and the notch signaling pathways have been reported to be affinity- and position - dependent on the presence of hspgs . the matrix binds and places these factors to the optimal positions and thereby enhances specificity and availability of these factors ( androutsellis - theotokis et al . , 2006 ) . additionally , neuroepithelial cells start their differentiation into neurons , by changing their 6-o - sulfation profile and their hs chain length . alterations in n - sulfation , 3-o - sulfation and 6-osulfation have been detected during stem cell differentiation . the elimination of sulfation during in vitro neural stem cell differentiation changes the relative proportion of early neurons generated from the stem cell pool and appears to block the further differentiation of these post - mitotic cells . hspgs have to pass the golgi apparatus as their side chains are sulfated by a subset of ( sulfotransferase ) enzymes ( karus et al . , 2012 ; karus et al . , 2013 future research will have to focus not only on the transcription factor code but rather on the matrix and their specific discrete changes influencing position , differentiation and the total number of cells . more motoneurons than necessary are generated during embryonic development to serve the needs for adulthood . the excess in cells is reduced first due to the limited amount of trophic support and second by electric activity and connectivity to the target cells , the skeletal muscle . the motoneuron subtypes are well organized along the rostro - caudal and dorso - ventral axis in the spinal cord sorted by function and innervation targets . neurons innervating the same target are together in a column ( jessell , 2000 ) ( see also figure 1 ) . for example the motoneurons of mediomedial column present throughout the spinal cord innervate the axial trunk muscles while the lateral motor column ( lmc ) , which is positioned in the brachial and lumbal part of the spinal cord innervates the skeletal muscles of the limbs and thereby regulates fine motor skills ( bonanomi and pfaff , 2010 ) . segmentation and motoneuron connection during spinal cord development in mice . motoneurons are positioned in motoneuron pools within the segments of the spinal cord from rostral to caudal . eight cervical segments ( c1 to c8 ) followed by 12 thoracic ( t1 to t12 segments and 7 lumbal segments ( l1 to l7 ) . the expression of the homeobox protein hoxc8 marks the area of motoneurons necessary for forelimb prehension efficiency ( tiret et al . , 1998 ) . the more rostrally positioned motor columns innervate the forelimbs while the motoneurons of the thoracic segments innervate the sympathetic ganglia , the dermomyotome and the peripheral trunk muscles . the different motor columns along the rostro - caudal axis are characterized by expression of different homeobox transcription factors : isl-1 and isl- 2 , ( islet-1 and -2 ) , lim-1 , lim-3 ( lim homeobox transcription factor-1 and -3 ) , lhx4 ( lim homeobox transcription factor 4 ) . three motoneuron subtypes exist in the motor columns , the - , - , and -motoneurons . the large multipolar -motoneurons innervate the extrafusal skeletal musculature receiving input from the proprioceptive sensory afferent neurons . up to 30% of all motoneurons are smaller -motoneurons controlling the intrafusal muscle fibers in the muscle spindles . they modulate the response of the muscle spindle in accordance to the muscle extension and receive no direct input from proprioceptive sensory afferents . -motoneurons express the spindle - derived glial - derived neurotrophic factor ( gdnf ) for their survival during the early postnatal period . experiments with conditional transgenic knock out mice also indicated that - and possibly also -motoneurons in part depend on factors generated from the muscle spindle . the skeleto - fusi motoneurons ( -motoneurons ) project both on the skeletal muscle and the muscle spindle . they can only hardly be distinguished from the -motoneurons and only little is known about their specific properties ( kanning et al . , 2010 ) . apart from the terminal differentiation and positioning of the motoneuron cell bodies within the motor columns the growth of axons combined with correct targeting is critical for the latter function of the body . the pathfinder structures are capable of recognizing different signals from their surrounding and subsequently react to them . sperry postulated in 1963 his chemo - affinity theory , by which the axons find their target cells according to the receptors in the growth cone so that they can recognize the guiding molecules along their way ( sperry , 1963 ) . nowadays we know that axonal growth is not exclusively dependent on guidance molecules but also depends on molecules on the cell surface , diffusible trophic factors , electric activity and last not least extracellular matrix molecules ( faissner , 1997 ; klausmeyer et al . , 2011 ) . diffusible factors can influence growth behavior and survival of neurons over long distances . basically , diffusible factors and linked signals can act attractively or repulsively on the growing axon and the composition of the receptors on a growth cone determines the chemo - attractively or chemo - repulsively behavior . the combination of attraction and repulsion reveals that the growing axon finds the exit point from the spinal cord to target the muscle tissue . ( bcs ) , make sure that the motor axons pass the neuroepithelium while the cell bodies stay in the neural tube . when they are not present , this leads to emigration of the cell bodies along the growing axons . therefore the bcs not only influence the correct axon growth but rather take over responsibility for the resting behavior of the cell bodies of motoneurons . in contrast , the dorsal root ganglionic neurons behave totally different . when taken into culture the interaction of the bcs and the growing motor axons is performed by semaphorins and their receptors neuropilin 2 ( nrp2 ) and/or plexin - a2 . the protein family of semaphorins includes membrane bound and soluble proteins and represents one of the largest protein families involved in axonal pathfinding . the metametric segmental patterning of the spinal nerves correlates with the typical segmentation including a repetitive rostro - caudal growth patterning and projection through the anterior part of the somites . inhibiting factors are the peanut agglutinin ( pna)-binding glycoprotein and semaphorin 3f ( sema3f ) . positioning of motoneuron cell bodies is mainly mediated by signals from the slit and robo family . the slits prevent migration of the motoneurons towards the ventral floor plate and thereby help them to stay in their correct columns . in contrast , the netrin / dcc ( deleted in colorectal cancer ) system attracts spinal motoneurons . the correct positioning and function of interneurons is important for coordination and gait . here , the eph / ephrins and netrin / dcc act as important mediators . effects were observed in knock out mice and could show for developing commissural interneurons aberrant midline axon guidance capabilities while the missing di6 interneuron marker dmrt3 ( double sex / male - abnormal-3 related transcription factor ) results in divergent gait patterning ( vallstedt and kullander , 2013 ) . while the axons of the medio - medial motor column ( mmc ) target to the dorsal trunk musculature , axons of the lateral motor column ( lmc ) project ventrally towards the limb musculature . fibroblast growth factor has been identified as a chemotrophic factor for targeting the mmc motoneuron axons . repulsive signals originate from the dorsal root ganglionic cells ( drgs ) and the ventral mesenchyme by receptor tyrosine kinases epha3 and epha4 and their respective ligand ephrina . epha3/epha4 double mutants display a misguided axon growth as they can not react to the repulsive signals of ephrina . as a consequence the growing motor axons of the mmc artificially target the drgs . motor axons of the lmc grow ventrally to the limb musculature as they express other receptors compared to the motoneurons of the mmc . they do not react to the repulsive signals which prevent growth of the mmc motor axons into the limbs . the limb target tissue provides cell adhesion molecules of the immunglobulin superfamily like l1 and the neuronal cell adhesion molecule ncam . if this direct cell to cell interaction is inhibited it results in a stronger fasciculation and a wrong projection pattern . the concerted activity of soluble factors , membrane- bound factors , receptors on the cell surface and finally electric activity of the target cell establish the correct connection to the muscle cells . experiments have shown that even on the level of already reduced axon numbers on the muscle so that one fiber is innervated by only one axon of a motoneuron there is still possible substantial alteration . this is mainly due to the fact that the initially made synapses have different stabilities . experiments have shown that synapses at the skeletal muscle can be discriminated into fast synapsing ( fasyn ) and slow synapsing ( desyn ) terminals . treatment of younger mice with -bungarotoxin resulted in selective and permanent denervation of the desyn synapses when applied before 3 months of age . interestingly the actual more stable fasyn synapses appear more vulnerable in a mouse model for spinal muscular atrophy ( murray et al . , 2008 ) . OUTPUT:

the development of the spinal cord needs a concerted interaction of transcription factors activating diverse genes and signals from outside acting on the specification of the different cells . signals have to act on the segments of the embryo as well as on the cranial - caudal axis and the dorso - ventral axis . additionally the axons of the motoneurons have to cross the central nervous system barrier to connect to the periphery . intensive anatomical studies have been followed by molecular characterization of the different subsets of transcription factors that are expressed by cells of the developing spinal cord . here , intensive studies for the most important appearing cells , the motoneurons , have resulted in a good knowledge on the expression patterns of these proteins . nonetheless motoneurons are by far not the only important cells and the concert activity of all cells besides them is necessary for the correct function and integrity of motoneurons within the spinal cord . this article will briefly summarize the different aspects on spinal cord development and focuses on the differentiation as well as the functionalization of motoneurons .

PubMed_Summ6584

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: humans have domesticated animals and plants through selective breeding , producing individuals with specific traits deemed beneficial ( hazel 1950 ) . hunting and plant harvesting can have selective , evolutionary effects on wildlife behavior and wildlife and plant morphology ( skogland 1989 ; mcgraw 2001 ; harris et al . 2002 ; coltman et al . 2003 ) . fishing can also be selective on certain life history traits ; many types of fishing gear are designed to remove some individuals in preference to others ( todd and larkin 1971 ; hamley 1975 ; law 2000 ; kuparinen et al . overall , human exploitation can cause significant changes to life history and morphological traits of wild populations , including fish ( darimont et al . larger fish are preferentially harvested to ( i ) avoid growth and recruitment overfishing , ( ii ) reduce harvesting and processing costs , and ( iii ) meet market demands for bigger fish ( walters and martell 2004 ) . the common phenotypic effect of fishing ( i.e. , reduction in mean age and size ) is widely known ( trippel 1995 ; hutchings 2004 ) , but more recently the possible genetic effects of fishery selection on life history traits such as age and size at maturity have received attention ( policansky 1991 ; law 2000 ; olsen et al . 2004 ; kuparinen and merila 2007 ) . experimental exploitation studies on captive atlantic silversides ( menidia menidia ) showed evolutionary effects of size - selective mortality on somatic growth , yield , and population biomass , among other traits ( conover and munch 2002 ; walsh et al . the researchers concluded that these effects were caused by selection of genotypes with variable growth rates . among wild populations , significant reductions in age and size at maturity in many canadian atlantic cod ( gadus morhua ) stocks coincided with dramatic decreases in abundance , and some scientists have suggested that heavy , size - selective fishing contributed to these life history changes ( hutchings and myers 1994 ; olsen et al . 2004 ) . most forms of fishing gear can be size - selective , but few studies have quantified fishery selection ( but see sinclair et al . such quantifications , though rare ( fenberg and roy 2008 ) , are necessary to reliably evaluate the consequences of fisheries - induced selection ( law 2007 ; hutchings and fraser 2008 ; kuparinen et al . comparison of the sizes and ages of fish that are caught with those that are not caught is essential for understanding the patterns of size selection , but such data are very difficult to obtain in most wild fish populations and fisheries . gillnets are especially size - selective because a fish is only caught if it is small enough to enter the mesh but large enough to become entangled by it ( hamley 1975 ; ricker 1981 ; bromaghin 2005 ) . however , selectivity curves for gillnets of specific sizes are difficult to determine , even with experimental fishing using gillnets of known mesh size ( todd and larkin 1971 ) . additionally , the use of multiple sizes of gillnets , as is frequently the case in commercial fisheries , makes the gillnet selectivity curves even more difficult to estimate . fishermen are often secretive about the sizes of gillnets they use and may change gear during a season . finally , many characteristics of fish and fisheries can further complicate size selection patterns , including seasonal migration timing of components of fish stocks that differ in age and size , temporal variation in fishing schedule and intensity , and the efficiency of the fishery when open . studies of gillnet fishery selection on pacific salmon ( oncorhynchus spp . ) are aided by their anadromous and semelparous life history . all salmon that pass through the fisheries and migrate into freshwater ( termed the escapement ) are maturing adults . these salmon can be counted and sampled for size and age , and those data can then be directly compared with data on samples from the catch because little natural mortality or growth typically takes place during this brief period . ricker ( 1981 ) used catch and escapement data from british columbia , canada populations of all five pacific salmon species and reported that fishery selection contributed to decreasing trends in age and body size in many populations , though he noted that these traits are affected by numerous factors . given the effects of density ( i.e. , competition ) and climate on growth and age at maturity of salmon ( e.g. , rogers and ruggerone 1993 ; pyper and peterman 1999 ; reviewed in quinn 2005 ) , it is important to carefully document fishery selection patterns over sufficient time periods that enable evolutionary changes to occur before associating fisheries with life history trait changes . in this study , commercial gillnet fishery catch and escapement data from 1946 to 2005 were used to quantify the magnitude and nature of selection on age and size at maturity for a commercially important and biologically diverse population complex of sockeye salmon ( o. nerka ) from the nushagak district of bristol bay , southwest alaska . this is an ideal study system because ( i ) there are long term data on size , age , and sex of sockeye in both the catch and the escapement ; ( ii ) the fishery exploits a large percent of the run each year ; and ( iii ) excellent records on the management of the fishery have been maintained over time , allowing us to examine the effects of covariates on the magnitude and direction of selection . first , few studies have quantified harvest selection in wild populations over the extended time periods needed to assess possible long term effects . previous studies in bristol bay , for example , only examined data over short time periods ( burgner 1964 ; bue 1986 ; hamon et al . most commercial fisheries occur over long time periods and experience many changes in environmental conditions , fishing technologies , and management schemes , so variation in selection may occur for a number of reasons . ( 2009 ) postulated that harvest selection can be a consistent force , and we wanted to explore annual patterns of selection over many years on a wild population . second , in many harvest selection studies , only the ages and sizes of individuals that are caught are known ; life history traits of individuals that are not caught are unidentified or only indirectly estimated ( but see carlson et al . 2007 ; we employed traditional methods to calculate yearly selection metrics , including selection differentials and vulnerability profiles , and we measured long term trends in these metrics . using this information we first determined whether the fishery has been generally size - selective over the past six decades . we then assessed the extent to which this selection has changed over the period of record , considering specifically the effects of changes in gear , fishing rate , and average fish body size . we did not seek to determine explicitly whether fishery selection in this system is leading to changes in age and size at maturity , as that topic can only be fully addressed after the selection itself has been quantified ( hutchings and fraser 2008 ) , and the effects of selection are integrated with the environmental factors that also affect growth and maturation . however , we present data to help assess the possible evolutionary and ecological consequences of the size - specific fishing pressure at a basic level . 1 ) , produces one of the most abundant and biologically diverse sockeye salmon runs in the world , and these salmon have been exploited by a commercial gillnet fishery since 1884 ( bue 1986 ) . the recent 25-year average total run size was 35 million fish , with an average annual catch of 24 million . 1 ) . sockeye salmon migrate through the nushagak bay on their way to spawn in three separate basins : the igushik , nushagak , and wood river systems ( fig . one other basin , the snake river , is so small and supports so few salmon that it is not considered . most sockeye salmon spawning in these systems spend 1 or , less frequently , 2 years rearing in lakes before migrating to sea , where they spend 14 ( typically 2 or 3 ) more years , returning in june - july and spawning in july - september ( quinn et al . the five fishing districts , and associated freshwater systems , of bristol bay , alaska , including the nushagak district . the history of the bristol bay sockeye fishery is well documented and knowledge of its management and its many changes allows greater understanding of the nature of fishery selection . commercial fishing began in the 1880s using fish traps and gillnets fished from wooden sailboats . motorized boats were not permitted until 1951 , at which time 32 feet was fixed as their maximum length . motorized vessels have evolved with technology , though the length regulation remains in effect ( link et al . mesh size has been regulated in bristol bay since 1924 , first at a minimum of 5 inches ( 146 mm ) and then , in 1962 , at a minimum of 5 inches ( 136.5 mm ) to lessen fishing pressure on larger sockeye . these early regulations were intended to increase profitability without reducing spawning success by increased the catch of longer sockeye , including more males , and allowed smaller fish , mostly females , to escape ( bue 1986 ; link et al . after the 1984 season , minimum gillnet mesh size regulations were ended and , since then , for the majority of the season , mesh size is not standardized , though in some years regulations to reduce exploitation of chinook salmon ( o. tshawytscha ) are enacted for short periods of time ( tim sands , alaska department of fish and game , pers . prior to 1951 most gillnets were made of cotton or linen twine , which caught fish of a narrow size range . multi - strand nylon web gillnets came into use in 1952 , followed by multi - strand nylon monofilament web in 1981 . these materials were superior to cotton and linen , catching more fish of a greater range of sizes because they were lighter , more transparent , and more elastic ( bue 1986 ) . since the 1950s the bristol bay sockeye salmon fisheries have been managed to achieve an escapement goal based on the carrying capacity of the system for spawning by adults and rearing by juveniles ( link et al . fisheries are opened conservatively based on predicted run timing to ensure that escapement goals are met ; after that , fisheries are opened to a greater extent . therefore , fishing rate often changes over the course of the season ( quinn et al . the fishery has also seen different levels of sockeye abundance over time , and the varying proportions of the run being caught may affect selectivity . since 1946 , 1986% of the annual sockeye salmon run in the nushagak district was caught , with an average harvest of 54% ( fig . this harvest percentage was high in the first years of this dataset , decreased in the 1960s and 1970s , and has been increasing since the late 1970s . changing ocean environments and other factors caused increased sockeye salmon runs to bristol bay after 1978 , also escalating catch rates ( hilborn et al . number of sockeye salmon in the nushagak district run and proportion of the run caught by the fishery , 19462005 . since 1946 scientists and fishery managers have estimated the nushagak district sockeye salmon catch and escapement , and collected age , sex , and length ( asl ) data on individual fish on a daily basis throughout the fishing and escapement periods . at fish processing plants , catch numbers are estimated and a sample ( range : 10656643 fish per year ) is measured for length and weight , scales are collected to be read for age determination , and sex of each fish is recorded . the wood , nushagak , and igushik rivers have counting towers or sonar devices to enumerate upstream migrating salmon that have escaped the fisheries . beach seine nets , which collect adults of all sizes , are used to sample the escapement for asl data each day ( range : 1503542 fish per year per river ) . daily catch and escapement counts were available from 1946 to 1959 but raw asl data were not available during this time . ( 1963 ) by measuring a sample of the salmon for asl and expanding these by the overall counts during the sampling time periods . therefore , from 1946 to 1959 these calculations , rather than data on individual fish , were used to characterize fishery selection . no data were available from 1960 to 1962 , and daily counts and asl data from individual fish were used from 1963 to 2005 . we used the yearly asl data to characterize length and length at age for all sockeye salmon in the nushagak district , treating males and females separately . because sockeye salmon of different ages , sizes , and sexes may enter the fishery and migrate upriver at different times ( older and larger fish generally enter earlier ; quinn 2005 ) and fish abundance varies greatly throughout the season , it would be imprecise to average length and age data on a seasonal basis to characterize the catch and escapement . therefore , daily asl data were used to estimate the distribution and abundance of all sockeye sizes and ages by weighting the number of fish sampled daily of a given age , length , and sex by the total number of caught or escaped on that day . on days when asl data were not collected , we estimated sockeye salmon length by interpolation from adjacent days with data . we characterized the age , sex , and length of all individuals escaping into each of the three rivers to avoid biases resulting from variation in proportions migrating to each river among years . to calculate the total escapement on a given day we first performed analyses on fish of all ages and then grouped fish by the number of years that they had been in the ocean ( ocean age ) . because salmon put on > 99% of their weight at sea , ocean age largely determines their overall size ( quinn 2005 ) , and thus vulnerability to being caught in a gillnet . if < 40 fish of each of these ages were examined for asl within a given year for the escapement into any of the three river systems , calculations were not made for that year . to calculate the total number of fish being caught or escaping of a given age , we multiplied the total catch or escapement by the proportion of fish of a given age group on a daily basis . we assumed that fish of all sizes and age groups , had , on average , equal contact with the fishery ( i.e. , opportunity to get caught ) in a given year and that differential fishing mortality was due to the effects of the gillnet fishery rather than some other attribute , such as migration route . fishing occurs throughout the nushagak fishing district , close to shore and in the open water , and the fishery is very effective at catching fish ( tim sands , alaska department of fish and game , pers . doctor ( 2008 ) provided evidence of subtle differences in migration timing among some populations within the nushagak fishing district but this complex , like others in bristol bay , is characterized by compressed migration timing and broad overlap among the components . for each year that data were available , we calculated exploitation ratio ( total proportion caught ) for fish of each age group ( all ages , ocean age 2 , and ocean age 3 ) and sex on a yearly basis ( py , a , s ) ( equation 1 ) . where cy , a , s is the number of fish of a certain age and sex caught in a given year and ey , a , s is the number of fish of a given age and sex in the escapement in that year . we also created yearly length and length at age frequency histograms ( in 10 mm bins ) of sockeye salmon in the catch and escapement to reconstruct their distribution in the total run . next we constructed yearly gillnet vulnerability profiles for each sex and age group showing , for each length bin , the proportion of fish that were caught ( lagler 1968 ) . proportions caught were calculated for a given length and age ( py , a , l ; equation 1 ) . for each year , proportions were scaled to 1 by dividing the proportion for each length by the maximum proportion within that year , allowing comparisons between years . the proportion caught was calculated only for length bins for which more than 3000 fish of all ages or 2000 fish of ocean ages 2 or 3 were caught on a given day to prevent inaccurate results due to small sample sizes . we calculated yearly length - based standardized selection differentials ( ssdy ) for each sex and ocean age ( equation 2 ) . this value is the difference in mean length of fish in the run ( , where ) versus those in the escapement ( ) ( i.e. , before versus after fishing ) ( law and rowell 1993 ) divided by the standard deviation of length of fish in the run ( ) to allow comparison between years . confidence bands about the vulnerability profiles and ssds were determined by bootstrapping the asl data on a daily basis , with 500 replicates per year ( 0.025 and 0.975 quantiles of the replicates ) . to better understand how changing fishery management , run size , fish size , and catch levels have affected selection over time , we performed ordinary least squares regression analysis of the form : these models regressed ssds and year - specific subsets of the following factors : ( i ) gillnet mesh size regulations ( as a categorical variable ) , ( ii ) run size , ( iii ) length deviation from the long term average , and ( iv ) date at which half of the total catch is reached ( catch date, which describes fishery timing ) . all regressions were performed for fish of each sex and ocean ages 2 and 3 separately because these groups were selected differently by the fishery . interactions among all factor combinations were examined for significance along with temporal autocorrelation , and the best models were chosen based on akaike information criterion with a second order correction for small sample sizes ( aicc ) ( burnham and anderson 2002 ) and r values . aicc values show how well a model fits the data without being overparameterized and r values show how much of the variation in the data is explained by each model . we picked the model that had the lowest aicc value and used the r value to support these decisions . 1 ) , produces one of the most abundant and biologically diverse sockeye salmon runs in the world , and these salmon have been exploited by a commercial gillnet fishery since 1884 ( bue 1986 ) . the recent 25-year average total run size was 35 million fish , with an average annual catch of 24 million . 1 ) . sockeye salmon migrate through the nushagak bay on their way to spawn in three separate basins : the igushik , nushagak , and wood river systems ( fig . one other basin , the snake river , is so small and supports so few salmon that it is not considered . most sockeye salmon spawning in these systems spend 1 or , less frequently , 2 years rearing in lakes before migrating to sea , where they spend 14 ( typically 2 or 3 ) more years , returning in june - july and spawning in july - september ( quinn et al . the five fishing districts , and associated freshwater systems , of bristol bay , alaska , including the nushagak district . the history of the bristol bay sockeye fishery is well documented and knowledge of its management and its many changes allows greater understanding of the nature of fishery selection . commercial fishing began in the 1880s using fish traps and gillnets fished from wooden sailboats . motorized boats were not permitted until 1951 , at which time 32 feet was fixed as their maximum length . motorized vessels have evolved with technology , though the length regulation remains in effect ( link et al . mesh size has been regulated in bristol bay since 1924 , first at a minimum of 5 inches ( 146 mm ) and then , in 1962 , at a minimum of 5 inches ( 136.5 mm ) to lessen fishing pressure on larger sockeye . these early regulations were intended to increase profitability without reducing spawning success by increased the catch of longer sockeye , including more males , and allowed smaller fish , mostly females , to escape ( bue 1986 ; link et al . after the 1984 season , minimum gillnet mesh size regulations were ended and , since then , for the majority of the season , mesh size is not standardized , though in some years regulations to reduce exploitation of chinook salmon ( o. tshawytscha ) are enacted for short periods of time ( tim sands , alaska department of fish and game , pers . prior to 1951 most gillnets were made of cotton or linen twine , which caught fish of a narrow size range . multi - strand nylon web gillnets came into use in 1952 , followed by multi - strand nylon monofilament web in 1981 . these materials were superior to cotton and linen , catching more fish of a greater range of sizes because they were lighter , more transparent , and more elastic ( bue 1986 ) . since the 1950s the bristol bay sockeye salmon fisheries have been managed to achieve an escapement goal based on the carrying capacity of the system for spawning by adults and rearing by juveniles ( link et al . fisheries are opened conservatively based on predicted run timing to ensure that escapement goals are met ; after that , fisheries are opened to a greater extent . therefore , fishing rate often changes over the course of the season ( quinn et al . the fishery has also seen different levels of sockeye abundance over time , and the varying proportions of the run being caught may affect selectivity . since 1946 , 1986% of the annual sockeye salmon run in the nushagak district was caught , with an average harvest of 54% ( fig . this harvest percentage was high in the first years of this dataset , decreased in the 1960s and 1970s , and has been increasing since the late 1970s . changing ocean environments and other factors caused increased sockeye salmon runs to bristol bay after 1978 , also escalating catch rates ( hilborn et al . number of sockeye salmon in the nushagak district run and proportion of the run caught by the fishery , 19462005 . since 1946 scientists and fishery managers have estimated the nushagak district sockeye salmon catch and escapement , and collected age , sex , and length ( asl ) data on individual fish on a daily basis throughout the fishing and escapement periods . at fish processing plants , catch numbers are estimated and a sample ( range : 10656643 fish per year ) is measured for length and weight , scales are collected to be read for age determination , and sex of each fish is recorded . the wood , nushagak , and igushik rivers have counting towers or sonar devices to enumerate upstream migrating salmon that have escaped the fisheries . beach seine nets , which collect adults of all sizes , are used to sample the escapement for asl data each day ( range : 1503542 fish per year per river ) . daily catch and escapement counts were available from 1946 to 1959 but raw asl data were not available during this time . ( 1963 ) by measuring a sample of the salmon for asl and expanding these by the overall counts during the sampling time periods . therefore , from 1946 to 1959 these calculations , rather than data on individual fish , were used to characterize fishery selection . no data were available from 1960 to 1962 , and daily counts and asl data from individual fish were used from 1963 to 2005 . we used the yearly asl data to characterize length and length at age for all sockeye salmon in the nushagak district , treating males and females separately . because sockeye salmon of different ages , sizes , and sexes may enter the fishery and migrate upriver at different times ( older and larger fish generally enter earlier ; quinn 2005 ) and fish abundance varies greatly throughout the season , it would be imprecise to average length and age data on a seasonal basis to characterize the catch and escapement . therefore , daily asl data were used to estimate the distribution and abundance of all sockeye sizes and ages by weighting the number of fish sampled daily of a given age , length , and sex by the total number of caught or escaped on that day . on days when asl data were not collected , we estimated sockeye salmon length by interpolation from adjacent days with data . we characterized the age , sex , and length of all individuals escaping into each of the three rivers to avoid biases resulting from variation in proportions migrating to each river among years . to calculate the total escapement on a given day we first performed analyses on fish of all ages and then grouped fish by the number of years that they had been in the ocean ( ocean age ) . because salmon put on > 99% of their weight at sea , ocean age largely determines their overall size ( quinn 2005 ) , and thus vulnerability to being caught in a gillnet . if < 40 fish of each of these ages were examined for asl within a given year for the escapement into any of the three river systems , calculations were not made for that year . to calculate the total number of fish being caught or escaping of a given age , we multiplied the total catch or escapement by the proportion of fish of a given age group on a daily basis . we assumed that fish of all sizes and age groups , had , on average , equal contact with the fishery ( i.e. , opportunity to get caught ) in a given year and that differential fishing mortality was due to the effects of the gillnet fishery rather than some other attribute , such as migration route . fishing occurs throughout the nushagak fishing district , close to shore and in the open water , and the fishery is very effective at catching fish ( tim sands , alaska department of fish and game , pers . doctor ( 2008 ) provided evidence of subtle differences in migration timing among some populations within the nushagak fishing district but this complex , like others in bristol bay , is characterized by compressed migration timing and broad overlap among the components . for each year that data were available , we calculated exploitation ratio ( total proportion caught ) for fish of each age group ( all ages , ocean age 2 , and ocean age 3 ) and sex on a yearly basis ( py , a , s ) ( equation 1 ) . where cy , a , s is the number of fish of a certain age and sex caught in a given year and ey , a , s is the number of fish of a given age and sex in the escapement in that year . we also created yearly length and length at age frequency histograms ( in 10 mm bins ) of sockeye salmon in the catch and escapement to reconstruct their distribution in the total run . next we constructed yearly gillnet vulnerability profiles for each sex and age group showing , for each length bin , the proportion of fish that were caught ( lagler 1968 ) . proportions caught were calculated for a given length and age ( py , a , l ; equation 1 ) . for each year , proportions were scaled to 1 by dividing the proportion for each length by the maximum proportion within that year , allowing comparisons between years . the proportion caught was calculated only for length bins for which more than 3000 fish of all ages or 2000 fish of ocean ages 2 or 3 were caught on a given day to prevent inaccurate results due to small sample sizes . we calculated yearly length - based standardized selection differentials ( ssdy ) for each sex and ocean age ( equation 2 ) . this value is the difference in mean length of fish in the run ( , where ) versus those in the escapement ( ) ( i.e. , before versus after fishing ) ( law and rowell 1993 ) divided by the standard deviation of length of fish in the run ( ) to allow comparison between years . confidence bands about the vulnerability profiles and ssds were determined by bootstrapping the asl data on a daily basis , with 500 replicates per year ( 0.025 and 0.975 quantiles of the replicates ) . to better understand how changing fishery management , run size , fish size , and catch levels have affected selection over time , we performed ordinary least squares regression analysis of the form : these models regressed ssds and year - specific subsets of the following factors : ( i ) gillnet mesh size regulations ( as a categorical variable ) , ( ii ) run size , ( iii ) length deviation from the long term average , and ( iv ) date at which half of the total catch is reached ( catch date, which describes fishery timing ) . all regressions were performed for fish of each sex and ocean ages 2 and 3 separately because these groups were selected differently by the fishery . interactions among all factor combinations were examined for significance along with temporal autocorrelation , and the best models were chosen based on akaike information criterion with a second order correction for small sample sizes ( aicc ) ( burnham and anderson 2002 ) and r values . aicc values show how well a model fits the data without being overparameterized and r values show how much of the variation in the data is explained by each model . we picked the model that had the lowest aicc value and used the r value to support these decisions . length frequency histograms showed variation in the length and length at age distributions of males and females over time . as expected , ocean age 3 fish were longer than ocean age 2 fish and males were longer than females for a given age , though overlap was observed among these groups . patterns of catch and escapement length distributions have also varied greatly among years , suggesting differing patterns of fishery selection . total yearly exploitation rates , or proportions of the fish that were caught , increased significantly over the years for males and females and fish of all age groups ( p < 0.05 ; fig . 3 ) , but they increased more for ocean age 2 fish ( of both sexes ) than for ocean age 3 fish . in most years , the proportion of males caught was higher than that of females . this difference was attributable to ocean age 2 fish ; from 1963 to 2005 , an average of 51% of ocean age 2 males were caught compared to 42% of ocean age 2 females . for ocean age 3 fish , an average of 62% of males and 64% of females were caught , and on average 57% of males and 54% of females of all ages were caught . proportion of the nushagak district sockeye salmon run caught of ( a ) all ages , ( b ) ocean age 2 , and ( c ) ocean age 3 as a function of ocean age and sex , 19632005 . vulnerability profiles revealed significant differences by length within and between sex and age groups over time ( fig . 4 ) , 1s . for females of all ages , longer fish ( > 550 mm ) were most vulnerable during earlier years , indicating directional selection favoring smaller fish ( fig . 4a ) . in later years vulnerability peaked at medium - long lengths , indicating disruptive selection favoring shorter and also the very longest fish . in only 2 years , 1991 and 2001 , vulnerability was highest for the shortest females ( < 450 mm ) and decreased for longer fish . vulnerability profiles for males of all ages were generally similar to those of females ( fig . 4b ) . however , in most years , even the early ones , the longest males ( > 600 mm ) were less vulnerable than the longest females , and male vulnerability curves peaked for the medium - long fish rather than the longest . this suggests that fishery selection on males has been less directional and more disruptive , compared to females . in recent years length vulnerability profiles of female ( a ) and male ( b ) sockeye salmon of all ages from 1946 to 2005 in the nushagak district . dotted black lines indicate the 95% confidence intervals ; data were insufficient for calculations in the early years . we found inconsistent patterns of vulnerability to the fishery over time for ocean ages 2 and 3 sockeye salmon . longer ocean age 2 fish were , in many years , most vulnerable to the fishery . however , in other years vulnerability profiles were dome - shaped or showed that shorter fish were most vulnerable . in the early years ( < 1979 for females , < 1973 for males ) , longer ocean age 3 fish were consistently more vulnerable than smaller fish . this pattern then weakened for both sexes , and in the later years smaller fish were most vulnerable , especially males . the different size selection patterns between ocean age 2 and 3 fish were consistent with the greater size of the ocean age 3 fish . however , the overlap in length distributions of the two ages and the generally greater length of males than females made overall fishery vulnerability patterns complicated . thus , the fishery has been size - selective but the most vulnerable length was not always the largest ; it depended on the combination of year , sex , and age of the fish . in 91% of the years ( 52 of 57 ) , ssds for female sockeye salmon of the nushagak district were negative , indicating that the fishery was catching longer than average fish ( fig . however , ssds for females have decreased in magnitude over time and in some recent years they have been positive . however , since 1965 positive or 0 ssds were evident in many years , showing that length selection has become weaker and less directional . standardized selection differentials for female and male sockeye salmon of all ages ( 19462005 ) and ocean age 2 and 3 ( 19632005 ) of the nushagak district . ocean age 2 females that escaped to spawn were , for the most part , shorter than fish in the run as a whole ( i.e. , before fishing ; fig . selection changed direction in 1982 . in 85% of the years ( 11 of 13 ) before that year ssds were positive , indicating that on average shorter males were caught than escaped . however , after 1982 ssds were mostly negative ( in 88% of years ) , so longer males were caught . in the most recent years , the selective trend has weakened and become variable . size selection on females and males of ocean age 3 was inconsistent over time ( fig . 5c ) . for females , in earlier years ( < 1979 ) all ssds were negative , but in 14 of 27 ( 52% ) years since then ssds were positive . a similar long term pattern was revealed for males . before 1973 , all 8 years with data had negative ssds but since then ssds were positive in most years ( 20 of 31 or 65% ) . regression models were consistent for male and female sockeye salmon of the same age group ( table 1 ) . factors most often included in the best fit models to explain ssds included gillnet mesh size regulation , run size , and fish length deviation from the long term average . for ocean age 2 fish , the best models included length deviation from the long term average and gillnet mesh size regulation . ssds increased , becoming more positive ( signifying weaker selection on big fish ) , as length deviation increased , mesh size decreased , and abundance of salmon increased . more complex models , which had higher r values of 0.540.56 , including ( i ) both gillnet mesh size regulation and run size and ( ii ) mesh size regulations , run size , and length deviation , explained selection best for ocean age 3 sockeye ; the factors affected ssds in the same way they did for ocean age 2 fish . significant first - order temporal autocorrelation was found for ssd regressions of ocean age 2 male fish . however , such autocorrelations were not detected for females of any age , nor for ocean age 3 males , so we did not analyze this factor further . models that best predicted standardized selection differentials ( ssds ) for sockeye salmon in the nushagak district , 19632005 , based on aicc and r values aicc , akaike information criterion with a second order correction ; ar1 , significant first - order autocorrelation coefficient . our study fills a need for quantifying the intensity of harvest selection and estimating selection differentials directly ( law 2007 ; kuparinen et al . examination of age- and size - selective harvest of sockeye salmon in a commercial gillnet fishery over 57 years revealed higher susceptibility and exploitation of older and larger fish in most years . this overall result confirmed the general belief that larger is more vulnerable, but the details of our findings revealed a much more intricate and variable pattern of exploitation and vulnerability ( fig . sockeye salmon runs with varying sex ratios and proportions of age classes experienced different selection patterns due to sex- and age - specific difference in fishery selectivity . the gillnet vulnerability curve and the selectivity of the fishery depend on the size distribution of fish that encounter the nets . in the nushagak district fishery , age composition , and thus length frequency , can change dramatically from year to year due to ocean conditions and the strength of different brood years , which can affect the vulnerability curves and size - selectivity . in most years more males than females and more ocean age 3 than ocean age 2 fish were caught ( fig . fishery selection was strongly directional in the early years ( 1946early 1970s ) ; longer fish were more vulnerable to the fishery than smaller fish ( fig . 4 ) . however , during and after the 1970s size selection became less directional and more disruptive , especially for males ; fish of intermediate lengths have been the most vulnerable . in many years more large females were caught than large males ( figs 4 and 5 ) because male sockeye salmon are , on average , longer than females . recently , the magnitude of fishery selection has decreased and the fishery has not consistently selected for or against fish of a given length ( fig . 5 ) . in this fishery , gillnet mesh size regulations , salmon abundance , and deviation in fish length from long term average were the most important variables affecting selectivity ( table 1 ) . when salmon were very numerous , larger fish experienced less selection than in years when there were fewer fish . the likely explanation is that when salmon were abundant the overall exploitation increased ( because the number allowed to escape to spawn is fixed ) and so the more intense fishing pressure caught more fish of all sizes . the effects of gillnet mesh size regulations were more obvious ; mandates for larger mesh sizes and regulations prohibiting the use of smaller mesh increased the catch of larger fish . finally , in years when the fish were larger , the largest fish tended to escape , likely because they were too big to be caught . short - term variability in size - selection patterns was due to different combinations of these factors . delta aic values were < 2 for all models shown in table 1 , indicating that each had similar support . for female fish , significant interactions were detected between year and length deviation and between year and run size . this suggests that for females , the effects of length deviation and run size on selectivity varied over time . just as age composition and length frequency changes can affect fishery selection patterns , changes in population composition over time different patterns of fishery selection and exploitation will be revealed at different spatial scales . assessing fishery selection on a fishing district scale is important because that is the level at which management actions occur ( minard and meacham 1987 ) . examining harvest selection on a population - level scale is important because that is the scale at which many processes of natural and sexual selection act . yearly estimates of the proportion of each spawning population passing through the fishery are not available . however , catch and escapement for the three main rivers that drain into the nushagak district ( thus a finer spatial scale than the district as a whole but not as fine as discrete spawning populations ) have been estimated ( adfg unpublished data ; kendall and quinn , in press ; branch and hilborn , in review ) . to assess how different proportions of fish returning to these river influenced fishery selection , we quantified the run size for each watershed and included the proportion of the run migrating to the wood river system ( the watershed typically with the largest run size ) as an additional parameter in our linear regressions of nushagak district - wide ssds . we found that for females , but not males , the proportion of the run heading to the wood river was a significant parameter in models explaining ssds . we also extended our fishery selection quantification to the finer spatial scale , quantifying population - specific exploitation rates , ssds , and vulnerability profiles ( kendall and quinn , in press ) . these analyses revealed that fishery selection and exploitation have not been uniform on populations that differ in average age and length . a long term , decadal perspective of harvest selection on a wild population is necessary to understand potential genetic changes that can result . short term studies may draw incomplete conclusions about the selective nature of harvest , and studies that examine only life history or morphological endpoints of wild populations ( e.g. , yoneda and wright 2004 ; hamilton et al . 2007 ) may not reveal annual variability and intermediary processes within a population that can have broader ecosystem impacts . for example , burgner ( 1964 ) found that gillnets in the nushagak district fishery were highly selective on larger , ocean age 3 fish , particularly females during 19461959 . thus , using only burgner 's results may produce different conclusions about fishery selection patterns and their potential implications than are indicated by a longer perspective . much recent research has focused on evolution of life history traits in wild fish stocks , both marine and freshwater ( law 2000 ; olsen et al . 2007 ) , and in wildlife ( coltman et al . 2003 ) due to size - selective harvest . in some studies size - selectivity was not directly measured but was assumed to be directional due to gear type used . our results demonstrate that even when size - selective gear is used and a large proportion of the stock is exploited , harvest selection is not necessarily consistent or predictable . thus , in modeling the effects of fishery and harvest selection and understanding ecosystem effects of such exploitation , scientists and managers can not assume consistent , directional selection and the consequences of such . in general , large size at seawater entry or rapid early growth at sea results in early age at maturation , and the older ( and ultimately larger ) fish are the slower - growing members of the cohort . the effects of disruptive harvest selection on norms of reaction are further complicated by differences in selection between males and females , resulting in uncertain overall consequences for the fish . thus , the variable nature of fishery selection over time in the nushagak district fishery , and likely many other fisheries , may hinder evolution of fish towards an optimal life history . an additional consideration is that there are many spawning populations within the nushagak district that were sampled collectively in our study . here we have assessed fishery selection at the fishing district scale and grouped all populations together . however , these populations have consistent differences in average age at maturity and length at age , and so their patterns of exploitation and selection also vary ( kendall and quinn , in press ) . we estimated length - based gillnet fishery selection , but a fish 's girth probably has more influence on its vulnerability to a gillnet rather than length per se . unfortunately , girth data are not available in the nushagak district , nor are they in many fisheries data sets , and they can not be calculated from the available data . regier ( 1969 ) found that unless precise girth measurements can be taken at the mesh mark , it is better to use length to understand fishery selection . still , girth is an important consideration in fishery selectivity , and because male and female salmon of the same length may have a different girth and shape , the actual selectivity patterns of male and female salmon may differ from those estimated from length data . our results revealed that the nushagak district fishery has caught longer than average fish during most of the past 60 years . from an ecological standpoint , beyond the reduction in abundance of spawning adults that inevitably results from fishing , size - selective fishing can reduce per capita productivity if the small fish that survive to breed produce fewer eggs than would have been produced by the prefishery size distribution . using the mean and maximum selection differentials observed for female sockeye salmon in the nushagak district , we estimated the decrease in egg production by females of average length due to such fishery selection using extensive length - fecundity data from the wood river system ( quinn et al . the average fishery selection differential from 1946 to 2005 was 8 mm , reducing the fecundity of an average female by only 5% ( 104 eggs ) . at the greatest observed selection differential ( 29 mm ) , the average female spawner would have 12% fewer eggs . there are undoubtedly other kinds of ecological effects of size - selection ( for example , larger females dig deeper nests than smaller females ; steen and quinn 1999 ) but these lines of evidence suggest that the numerical consequences of the selective fishery in this system have not been great . from an evolutionary viewpoint , it is of great interest whether nushagak district sockeye salmon , and others subject to size - selective harvest , have become smaller and younger as a direct result of such harvest . size selection patterns by the nushagak fishery , and likely many other fisheries , have varied over time , in part due to stochasticity of environmental and management conditions . in addition , they have also been affected by variation in population contribution over time ( kendall and quinn , in press ) . size and age at maturity of adult salmon are influenced by many factors , including but not limited to density of conspecifics , density of other salmon species , and ocean conditions ( rogers and ruggerone 1993 ; pyper and peterman 1999 ; ruggerone et al . thus , evolutionary effects of fishing can not be revealed without careful consideration of the many factors affecting growth and maturation . calculation of probabilistic maturation reaction norms ( dieckmann and heino 2007 ) is a way to integrate these effects with fishery selection ( e.g. , fukuwaka and morita 2008 ) . also from an evolutionary perspective , fish whose maturation size coincides with that of maximum vulnerability to its fishery could adjust their size or age to reduce the probability of being caught . a fish given age or mature at an earlier or later age and thus at a different size . overall , the nushagak district fishery has caught larger than average , but not the largest , sockeye salmon . in general this corresponds to large ocean age 2 fish and smaller ocean age 3 fish , and thus to reduce the probability of being caught , ocean age 2 fish should grow slower and ocean age 3 fish should grow faster . this would seem to require a complex change in the reaction norm between growth and probability of maturation that controls variation in age and size within and among populations ( quinn et al . nushagak district sockeye salmon have become both longer and older in recent decades ( fig . 6 ; p = 0.0004 and r = 0.27 for age of males , p = 0.07 and r = 0.09 for age of females ) , consistent with the hypothesis that density - dependent effects in the ocean depress growth and result in a phenotypic shift in age at maturation ( pyper et al . 1999 ; holt and peterman 2004 ) . this finding is inconsistent with the expectation that fisheries - induced evolution causes harvested fish populations to become shorter and younger , as was expressed for iteroparous species ( law and grey 1989 ) . however , the effects of such evolution on anadromous , semelparous fishes such as pacific salmon may be different and should be explored further . proportion of ocean age 3 sockeye salmon in the nushagak district run ( the vast majority of the remaining fish are of ocean age 2 ) , 19632005 . for fish and wildlife populations under size - selective exploitation , it may be important to maintain large numbers of phenotypically diverse breeders to buffer against the detrimental effects of selection ( darimont et al . the nushagak district fishery is managed using biologically - robust escapement goals , which have been increasing in recent years , allowing more sockeye salmon onto the spawning grounds . 1 ) met or exceeded its escapement goal in 85% of the years from 1962 to 2005 ( tim baker , alaska department of fish and game , pers . additionally , for most of the past 60 years , the fishery has not harvested the biggest fish returning to spawn , benefiting the nushagak district stocks in the short- and long - term ( law 2007 ) . the suite of populations thus seems to be very healthy , to the benefit of the ecosystems that depend on them ( naiman et al . thus , the biologically robust escapement goals used to manage the fishery and prevention of harvest of the largest individuals may contribute to the weaker and less consistent size - selectivity in recent years . such escapement goals and gear that spares the largest individuals may be included in a manager 's toolbox to prevent negative effects of size - selective harvest . finally , fishery and natural , including sexual , selection may act in opposition ( carlson et al . 2007 ; hutchings and rowe 2008 ) , and evolutionary trait changes may result from their combined effects ( edeline et al . 2007 ) . for bristol bay sockeye salmon and many other species , age at maturity and length at age result from a blend of natural , sexual , and anthropogenic selection . ecological processes on the spawning grounds that favor large individuals may compensate to some degree for the reduction in the overall numbers of these individuals . the fact remains the larger than average fish have been harvested in most years from the nushagak district sockeye salmon stock . the effects of such harvest selection on wild populations must be examined from many angles , and conclusions must be drawn using long term studies that incorporate ecological , ecosystem , and evolutionary considerations . OUTPUT:

life history traits of wild animals can be strongly influenced , both phenotypically and evolutionarily , by hunting and fishing . however , few studies have quantified fishery selection over long time periods . we used 57 years of catch and escapement data to document the magnitude of and trends in gillnet selection on age and size at maturity of a commercially and biologically important sockeye salmon stock . overall , the fishery has caught larger fish than have escaped to spawn , but selection has varied over time , becoming weaker and less consistent recently . selection patterns were strongly affected by fish age and sex , in addition to extrinsic factors including fish abundance , mesh size regulations , and fish length variability . these results revealed a more complex and changing pattern of selective harvest than the larger is more vulnerable model , emphasizing the need for quantified , multi - year studies before conclusions can be drawn about potential evolutionary and ecological effects of fishery selection . furthermore , the results indicate that biologically robust escapement goals and prevention of harvest of the largest individuals may help prevent negative effects of size - selective harvest .

PubMed_Summ6585

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: both innate and adaptive immune responses are , in every way , affected by polarization with cytokines . the expression of costimulatory molecules and chemokines , as well as the execution of effector programs , is affected in monocytes . in humans and mice , t helper ( th)1 and th2 polarization with ifn - r and il-4 il-4 polarization , also known as either alternative or m2a activation , stimulates wound recovery and parasite immunity responses . ifn - r polarization , which is referred to as either classical or m1 activation , is responsible for tumor resistance , intracellular killing , and il-12 production in monocytes . m1 macrophages , which are activated by the classical pathway , are shown to be responsive to two signals : type 1 inflammatory cytokines and microbial products . there are three subsets of m2 macrophages : m2a , induced by il-4 or il-13 ; m2b , induced by immune complexes and agonists of tlrs or il-1 receptors ; and m2c , induced by il-10 and glucocorticoid hormones . m1 and m2 macrophages can be differentiated based on their receptors , expression of cytokines and chemokines , and effector function . m1 macrophages are microbicidal and inflammatory , and m2 macrophages are immunomodulators ( m2a and m2c ) and possess minimal microbicidal effects . recently , the activation or polarization of macrophages has been demonstrated to be rapid , plastic , and fully reversible . this shows that macrophages are dynamic when they first engage in the inflammatory response and the resolution process that follows and that changes in function are caused by changes in the microenvironment . low - level laser therapy ( lllt ) is a form of light emission with a power output of less than 500 mw and is therefore considered nonthermal irradiation to living tissue . lllt is known to be a noninvasive treatment modality and has been applied in various fields . lllt was thought to be effective in pain relief and promoting recovery of some pathology , including tendinopathies , osteoarthritis , temporomandibular joint disorders , wound healing , and nerve injuries [ 7 , 8 ] . the exact mechanism is still under investigation , but the mechanism is likely to be photochemically related . this would affect the biological regulation of nitric oxide and adenosine triphosphate and would further affect the inflammatory process or cytokine release . lllt is prevalent in the prevention and treatment of cancer therapy - induced oral mucositis [ 9 , 10 ] and may alter human immunity . lllt has also been shown to have several biological effects that favor the healing process . lllt ( 660 nm ) is able to promote the skin repair of burned rats by decreasing the necrotic area and upregulating cyclooxygenase-2 and vascular endothelial growth factor expression . an in vitro study demonstrated that increased intracellular calcium influx occurred in mast cells , followed by histamine release after laser irradiation , which may explain the biological effect of lllt in promoting wound healing . cytokine expression in short - term muscle remodeling is also modulated by lllt , which leads to a decline in tnf- and tgf- after cryoinjury . similarly , the clinical value of the potential immune modulation effect of laser therapy has recently been studied in the treatment of allergic rhinitis . the ability of the ktp/532 yag laser to reduce nasal congestion and discharge in patients with allergic rhinitis has been identified . the ktp/532 yag laser is effective as an additional treatment for patients who are refractory to medications , and the treatment is extremely well tolerated without significant side effects . after one year , nasal obstruction was improved in 69% of cases and nasal discharge in 40% of cases . 308 nm xenon chloride ( xecl ) uvb irradiation significantly minimized these symptoms , including rhinorrhoea , sneezing , and nasal obstruction , and improved the total nasal scores and the allergen - induced skin prick tests in a dose - dependent manner . the xecl uvb excimer laser may also serve as a new treatment option for treating allergic rhinitis , which is a th2-dominant disease that is suppressed by th1 or m1 immunity . controlled by the action of histone acetyltransferases ( hats ) , histone deacetylases ( hdacs ) , and methyltransferases , histone acetylation and methylation are important epigenetic modifications that influence gene transcription . modifications on histones , such as acetylation or trimethylation at h3k4 , h3k36 , and h3k79 , are associated with gene activation . it is unknown , however , whether lllt modulates human monocyte polarization and immune function via epigenetic regulation . because different types of lasers have been used for the treatment of th2-dominant disease , we evaluate the influence of lllt on monocyte polarization in this study . we investigated the regulatory effects of lllt on monocyte m1 polarization to provide evidence for the use of lllt for immunologic disorders . louis , mo ) supplemented with 10% fetal bovine serum , 100 u / ml of penicillin , and 100 g / ml of streptomycin at 37c with 5% co2 in a humidified incubator . thp-1 cells were centrifuged , resuspended in fresh media , and plated in 24-well plates at a cell density of 5 10/ml 24 hours before experimental use . the cells were pretreated with a low - power gallium - aluminum - arsenide ( gaa1as ) laser ( 03 j / cm ; 660 or 808 nm ) alone or 2 hours before lps ( 0.2 g / ml ) stimulation . cell supernatants were collected 12 , 24 , and 48 hours after lps stimulation . to investigate epigenetic regulation , the cells were pretreated with methylthioadenosine ( mta , a histone methyltransferase inhibitor ) or anacardic acid ( aa , a histone acetyltransferase inhibitor ) 1 hour before lllt . to investigate the mitochondria involvement in lllt - related monocyte polarization , the cells were pretreated with oligomycin ( 1 and 2.5 g / ml , sigma - aldrich , st . louis , mo , usa ) or antimycin ( 0.1 and 0.5 g / ml , sigma - aldrich , st . the gaa1as ultra red laser with wavelengths of 660 nm and gaa1as near - infrared laser with wavelengths of 808 nm ( transverse ind . a total volume of 1 ml of cell - containing media for 12-well plates was added into each well to decrease the refraction during the low - level laser irradiation treatment . the distance between the gaa1as laser source and the culture plate was adjusted to ensure homogeneous laser exposure in 12-well plates . the cells were treated with the gaa1as laser beam to reach a total energy of 0 , 1 , 2 , and 3 j / cm , respectively . thp-1 cells were treated with different doses of lllt and total rna was isolated from cells immediately ( t = 0 ) or 6 hours after lps stimulation . total rna was extracted from cells using trizol ( invitrogen , carlsbad , ca ) according to the manufacturer 's instruction . three g of rna from each sample was then reverse - transcribed into first - strand cdna in 20 l of reaction mixture using the superscript first - strand synthesis system with the real - time pcr kit ( invitrogen ) . measurements were performed by an abi prism 9700 ht sequence detection system ( applied biosystems , foster city , ca ) using a predeveloped taqman probe / primer combination for m1-related genes and glyceraldehyde 3-phosphate dehydrogenase ( g3pdh ) from the same cdna samples . taqman pcr was performed in 10 l using amplitaq gold polymerase and the universal master mix ( applied biosystems ) . threshold cycle numbers were transformed using the comparative threshold cycle and relative value methods according to the manufacturer 's recommendation and expressed relative to g3pdh , which is used as a housekeeping gene by multiplexing single reactions . the m1-related cytokine and chemokine genes are as follows : ccl2/mcp-1 , cxcl10/ip-10 , and tnf-. the ccl2/mcp-1 , cxcl10/ip-10 and tnf- concentrations in the cell supernatants were determined using commercially available elisa - based assay systems ( r&d systems , minneapolis , mn ) 5 10 cells were treated with 1% formaldehyde for 10 min at room temperature , followed by sonication of the dna and immunoprecipitation of chromatin overnight with antibodies against acetylated h3 and h4 and trimethylated h3k4 ( upstate biotechnology , waltham , ma ) . immune complexes were collected using a protein a slurry ( invitrogen ) , and the dna was reverse cross - linked , extracted , and quantified using a taqman sds 7900ht . for pcr amplification of chip products , primers and probes were designed to analyze the proximal promoter and intronic enhancer regions of the tnf- gene as previously described [ 19 , 20 ] , encompassing the following subregions relative to the transcription start site : tnf1 ( t1 , + 99 to 42 ) ; tnf2 ( t2 , + 32 to 119 ) ; tnf3 ( t3 , 100 to 250 ) ; tnf4 ( t4 , 195 to 345 ) ; and + 1417 , + 720 , and 1700 . primers and probes were also designed to analyze the proximal promoter regions of the cxcl10/ip-10 gene ( cxcl10/ip-10 - 1 : + 9 to 172 and cxcl10/ip-10 - 2 : 444 to 622 ) . ( 1 ml / well ) , treated with lllt ( 660 nm ) , and incubated for 24 h. the cells were harvested and washed 3 times with pbs for direct immunofluorescence staining using labeled monoclonal antibodies to cd14 , cd45ro , ccr7 , or cd86 . the cell surface markers were analyzed using a facscan flow cytometer and the cellquest software ( becton dickinson , franklin lakes , nj , usa ) . according to the manufacturer ( invitrogen , carlsbad , ca ) , an anchored oligo - dt primer was used to reverse - transcribe total rna ( 1 g ) using superscript ii . primer pairs were designed using primer3 ( http://frodo.wi.mit.edu/primer3/ ) and were validated using in silico pcr ( http://genome.ucsc.edu/cgi-bin/hgpcr ) and blast ( http://blast.ncbi.nlm.nih.gov/blast.cgi ) . the following primer sequences were used : mt - nd1nadh dehydrogenase , subunit 1 ( mt complex i ) fw : accatttgcagacgccataa and re : tgaaattgtttgggctacgg ; sdha succinate dehydrogenase complex , subunit a , flavoprotein ( mt complex ii ) fw : caaacaggaacccgaggtttt and re : cagcttggtaacacatgctgtat ; mt - cytb mitochondrial cytochrome b ( mt complex iii ) fw : gccctcggcttacttctctt and re : gacggatcggagaattgtgt ; cox1 ( mt - coi)cytochrome c oxidase i ( mt complex iv ) fw : ttcgccgaccgttgactattctct and re : aagattattacaaatgcatgggc ; mt - atp6atp synthase , h+ transporting , mitochondrial fo complex , subunit f6 ( mt complex v ) fw : tttgcggaggaacattggtgt and re : tccagatgtctgtcgcttagat ; ucp2uncoupling protein 2 ( mitochondrial , proton carrier ) fw : cctgaaagccaacctcatgac and re : caatgacggtggtgcagaag ; and 18 s rrna fw : tagagggacaagtggcgttc and re : cgctgagccagtcagtgt . for q - pcr time course samples ( n = 3 ) , 10 l reactions consisting of 3 l of diluted cdna and 0.3 m of forward and reverse gene - specific primers combined with 2 power sybr green pcr master mix ( applied biosystems , foster city , ca ) were aliquoted into 96-well plates using a biomeck 2000 laboratory automation workstation ( beckman coulter inc . , fullerton , ca ) . applied biosystems prism 7900ht sequence detection system was used for the amplification process that included a ten - minute 95c denaturation stage , then forty repetitions of 95c for fifteen seconds , and lastly 60c for one minute . quantifications were obtained by the comparative ct method ( ct ) ( applied biosystems , foster city , ca ) . the geometric mean of housekeeping gene ( gapdh ) expression served as the internal control . the relative copy number of mtdna was computed via normalizing the crossing points in the quantitative pcr curves between the mitochondrial nd1 gene and the nuclear 18s rrna gene , and the ratio was normalized to the control . differences between experimental and control groups were analyzed by using the mann - whitney u test . changes in chemokines and cytokines at different doses of lllt alone were analyzed using the wilcoxon signed rank test . a p - value < 0.05 was considered indicative of a significant difference between groups . we first tested whether lllt ( 03 j / cm , 660 and 808 nm ) influenced the m1-related chemokine and cytokine expression in thp-1 cells . real - time pcr data showed that the m1-related chemokine ccl-2 was enhanced by 660 nm ( 1 - 2 j / cm ) and 808 nm ( 1 - 2 j / cm ) lllt 24 hours after irradiation . the most powerful effect was produced by 1 j / cm of 660 nm lllt and 2 j / cm of 808 nm lllt ( figures 1(a ) and 1(b ) ) . however , 3 j / cm of lllt ( 660 and 808 nm ) suppressed ccl-2 expression in thp-1 cells . cxcl-10 mrna expression was enhanced by 660 nm lllt but suppressed by 808 nm lllt ( figures 1(c ) and 1(d ) ) . tnf- , an m1-related pro - inflammatory cytokine , was also enhanced by 660 nm lllt but suppressed by 808 nm lllt 24 hours after irradiation ( figures 1(e ) and 1(f ) ) . the effect of lllt on m1-related cytokine and chemokine mrna expression was observed at 12 , 24 , and 48 h time points ( figures 2(a ) , 2(b ) , and 2(c ) ) . there were no differences between the control group and all of the other groups with different doses of lllt treatment , indicating that cell viability was not affected by lllt ( data not shown ) . because lllt could induce m1-related cytokine and chemokine mrna expression in monocytes , we examined whether lllt could also induce m1-related cytokine and chemokine protein expression . one j / cm of 660 nm lllt significantly induced ccl2 and cxcl10 production in human monocytes , whereas 2 j / cm and 3 j / cm did not ( figures 3(a ) and 3(b ) ) . tnf- protein production was also enhanced by 660 nm lllt 24 h after irradiation ( figure 3(c ) ) . the influence of lllt on m1-related chemokine and cytokine production may also involve mitochondrial biogenesis and activation . it is known that oligomycin hinders atp synthase by blocking its proton channel ( fo subunit ) , which is necessary for oxidative phosphorylation of adenosine diphosphate to atp and leads to an increased proton gradient , which decreases both respiratory activity and oxidative phosphorylation , thereby resulting in mitochondrial dysfunction . antimycin is a mitochondrial inhibitor that binds in the energy - coupling site and inhibits the flow of electrons from cytochrome b to cytochrome c1 . low - intensity laser irradiation has been reported to improve mitochondrial dysfunction and leads to mitochondrial alterations [ 24 , 25 ] . the inhibition of lllt - induced ccl2 mrna expression by oligomycin and antimycin suggested mitochondrial involvement ( figure 4 ) . as shown in figures 5(a ) and 5(b ) , 1 j / cm of lllt significantly increased the copy number of mitochondria , but 2 j / cm of lllt did not . the data are similar to the lllt - induced production of m1-related chemokine and cytokine . next , we evaluated the involvement of respiratory chains including complexes i to v and uncoupling protein . one j / cm of lllt increased the mrna amount of complexes i to v and uncoupling protein , whereas 2 j / cm did not ( figures 5(c ) and 5(d ) ) . it has been shown that epigenetic modification at the tnf- gene locus occurs by a coordinated and complicated network of regulation involving dna methylation , histone modification , and chromatin remodeling . studies in monocytes and macrophages have shown that although there are different patterns of histone modifications , the main regulatory regions associated with histone modifications could be identified in lllt - treated monocytes . in fact , the involvement of histone acetylation in the regulation of tnf- expression was further supported by the finding that aa significantly suppressed tnf- expression in lllt - treated thp-1 cells ( figure 6(a ) ) . to determine whether histone modifications occurred in thetnf- gene locus in monocytes , chip analysis of thp-1 cells treated with lllt was conducted ; pcr primers corresponding to four overlapping subregions ( 1700 and tnf14 , covering the region between 345 and + 99 ) in the tnf- promoter and two intronic regions ( + 720 and + 1417 ) in the tnf- gene were used . compared to the histone modifications found in the medium control cultures , significant histone modifications were detected at the tnf- gene locus in lllt - treated thp-1 cells . as shown in figures 6(b ) and 6(c ) , upregulated tnf- expression in lllt - treated thp-1 cells was associated with an increased level of histone 3 acetylation primarily in the t1 , t4 , and intron sequence ( + 1720 ) of the tnf- gene ; however , increased histone 4 acetylation was found to be mostly associated with the proximal promoter regions of the tnf- gene in the t1 , t2 , and intron sequence ( + 1417 ) . we next examined whether the effects of lllt on tnf- expression were due to histone methylation . moreover , chip analysis also showed elevated levels of tri - methylated h3k4 at the proximal promoter subregion , as well as the tnf1 , tnf3 , and tnf4 regions of the tnf- gene in lllt - treated cells ( figure 6(e ) ) . next , we investigated whether lllt - induced ip-10 expression in human monocytes was induced by increasing histone acetylation and trimethylation . pretreatment with aa reversed lllt - induced ip-10 expression in thp-1 cells ( figure 7(a ) ) . chip analysis also showed increased levels of h3 at the proximal promoter subregion cxcl10 - 1 in the ip-10 gene in lllt - treated cells , whereas h4 occupation did not increase ( figures 7(b ) and 7(c ) ) . pretreatment with mta did not reverse lllt - induced ip-10 expression in thp-1 cells ( figure 7(d ) ) . therefore , these findings suggested that the effect of lllt on m1 polarization is associated with the cellular regulation of differential histone modification . polarization of t cells and macrophages with cytokines influences every aspect of the immune response , including innate and adaptive immunity [ 13 ] . it is important to understand and be able to control macrophage polarization to eventually be able to enhance our immunity and treat immune disorders . over the last decades , we have witnessed an increasing prevalence of allergic diseases , which are relatively common and often debilitating diseases . allergic diseases are caused by elevated th2 cells , but the reason for this preferential activation is unclear . macrophages are the major antigen - presenting cells involved in the induction of the primary immune response and play a critical role in immunity . ifn - r polarization , occurring through either classical or m1 activation , programs monocytes for phagocytosis , tumor resistance , and allergy suppression . it is also important to understand how to modulate the function of macrophages , induce m1 immunity to promote intracellular killing and tumor resistance , and prevent allergic reaction . lllt is a form of light therapy with therapeutic effects on living tissues . in this study , 660 nm lllt promoted m1 polarization and cytokine and chemokine mrna and protein expression . therefore , the effect of lllt on monocyte polarization may be a potential treatment for allergic diseases and may also promote immunity to viral infections and tumors . the optimal dose of 1 j / cm may be more effective for promoting m1 immunity than 2 j / cm or 3 j / cm . tnf- is an endotoxin - induced cytokine that causes necrosis and death of tumors and is also a pro - inflammatory cytokine predominantly released by macrophages . not only is tnf- a pro - inflammatory cytokine , but it is also an immunoregulatory molecule that can modify the balance of t regulatory cells . in addition , tnf- is a central cytokine that triggers inflammation in rheumatoid arthritis ( ra ) , indicating that the inhibition of tnf- is an effective treatment strategy for ra . following a viral infection , cxcl10/ip-10 is secreted by bronchial epithelial cells , and th1 cells are recruited via cxcr3 to eliminate the intracellular pathogen . baseline cxcl10 serum concentration is linked to the outcome of antiviral therapy in monoinfected hepatitis patients , as well as in patients coinfected with hiv [ 30 , 31 ] . mcp-1/ccl2 is one of the key chemokines that regulate migration and infiltration of monocytes and macrophages . both ccl2 and its receptor ccr2 have been shown to play vital roles in numerous diseases . the movement of monocytes from the blood stream across the vascular endothelium is required for both regular immunological surveillance and inflammatory response . ccl2 inhibits the viral attachment of human immunodeficiency virus ( hiv-1 ) to the ccr2 and ccr5 coreceptors . additionally , the expression of all m1 polarization cytokines and chemokines is promoted by lllt . therefore , lllt may be useful to promote antiviral immunity but may not be a suitable therapy for autoimmune or rheumatoid diseases . considering the importance of m1-polarized macrophages in various disease contexts , especially immunity to intracellular microorganisms and tumors , we examined the effects of different doses of lllt on the expression of m1-polarized macrophages related cytokines and chemokines by using human thp-1 monocytes and provided evidence supporting the effects of lllt on macrophage function . in this study , our results showed that after five days of muscular lesion , the activities of complex ii and succinate dehydrogenase elevated considerably in contrast to the control group . moreover , our results demonstrated that lllt significantly increased the activities of complexes i , ii , iii , and iv and succinate dehydrogenase compared to the muscle injury group without treatment . this study also shed light on the mechanisms of epigenetic regulation by lllt in immune cells . modifications on histones , such as acetylation or trimethylation at h3k4 , h3k36 , and h3k79 , are associated with gene activation . recently , histone modification has become a new target for antiallergy drug development . in this study , lllt induced histone h3 and h4 acetylation and h3k4 trimethylation in the tnf- gene promoter area . lllt also induced histones h3 acetylation in the ip-10 gene promoter region but did not induce acetylation of histone h4 . these results suggest that epigenetic regulation could be one of the important mechanisms by which lllt modulates m1-related cytokine and chemokine expression . in this study , 660 nm lllt appeared to be a potent enhancer of the production of pro - inflammatory cytokines and m1-related chemokines in monocytes . m1-related immunoregulations play important roles in the antiviral and antitumor immunity and the pathogenesis of inflammation in autoimmune diseases . because tnf- , mcp-1 , and ip-10 are important indicators of lllt - induced m1 polarization , lllt may promote anti - viral and anti - tumor immunity but enhance autoimmune and rheumatoid diseases . lllt may be a potent immune - enhancing agent that is suitable for the treatment of allergic diseases but may not be a good therapy for autoimmune and rheumatoid disorders . OUTPUT:

low - level laser therapy ( lllt ) has been used in the treatment of radiotherapy - induced oral mucositis and allergic rhinitis . however , the effects of lllt on human monocyte polarization into m1 macrophages are unknown . to evaluate the effects of lllt on m1-related cytokine and chemokine production and elucidate the mechanism , the human monocyte cell line thp-1 was treated with different doses of lllt . the expression of m1-related cytokines and chemokines ( ccl2 , cxcl10 , and tnf- ) was determined by elisa and real - time pcr . lllt - associated histone modifications were examined by chromatin immunoprecipitation ( chip ) assays . mitochondrial involvement in the lllt - induced m1-related cytokine expression was evaluated by quantitative real - time pcr . flow cytometry was used to detect the cell surface markers for monocyte polarization . the results showed that lllt ( 660 nm ) significantly enhanced m1-related cytokine and chemokine expression in mrna and protein levels . mitochondrial copy number and mrna levels of complex i - v protein were increased by lllt ( 1 j / cm2 ) . activation of m1 polarization was concomitant with histone modification at tnf- gene locus and ip-10 gene promoter area . this study indicates that lllt ( 660 nm ) enhanced m1-related cytokine and chemokine expression via mitochondrial biogenesis and histone modification , which may be a potent immune - enhancing agent for the treatment of allergic diseases .

PubMed_Summ6586

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: craniopharyngioma is an uncommon tumor of the nervous system ; it is well - known to recur even several years after surgery . we are here with reporting a case of craniopharyngioma which recurred at a site removed from the original site 5 years after surgery and radiotherapy . a 4-year - old girl was admitted for progressive deterioration of vision of 2 months duration . in addition there was no history of endocrinopathy , fits or any symptom of raised intracranial pressure . on examination , visual acuity was questionable perception of light on the right side and counting fingers at 3 m distance on the left . imaging revealed a solid and cystic craniopharyngioma in the sellar - suprasellar region [ figure 1a and b ] . she underwent a right frontotemporal craniotomy and transsylvian exploration and almost total excision of the tumor . postoperative mr showed a tiny residual tumor adherent to the pons [ figure 2a and b ] . ( a and b ) showing the preoperative images ( before first surgery ) ( a and b ) images after first surgery showing no residual tumour in the primary site but a small fragment adherent to the pons she was given a course of radiotherapy for this residue 54 gy in 30 fractions . follow - up imaging at the end of 2 years did not reveal any residual tumor [ figure 3 ] . two years after surgery and radiotherapy no recurrence imaging was being done periodically to check for recurrence . the 5-year surveillance imaging showed a recurrence in the right sylvian fissure along the route taken during the first surgery . there was no evidence of tumor in the sellar - suprasellar area [ figure 4a and b ] . she underwent reexploration by the same route , and a tiny fragment densely adherent to the middle cerebral artery was left behind . ( a and b ) showing remote recurrence five years after first surgery and radiotherapy . although craniopharyngiomas are benign tumors they are known to recur even after years and even after the administration of radiotherapy , recurrence rates ranging from 25% to 70% . recurrences at a site removed from the original site are very rare < 25 cases have been reported . these ectopic recurrences are not to be misinterpreted as ectopic primary occurrences since craniopharyngioma can occur anywhere along the obliterated rathke 's pouch . these ectopic recurrences may occur along the surgical pathway or at a site , not along the surgical pathway . the cells of the tumor may get implanted and may subsequently metamorphose into a fresh neoplasm . these tumor cells may in turn give rise to the regrowth of the tumor . the usual time to recurrence is around 4 years . but why this has to be a peculiarity of craniopharyngiomas can not be explained . another way the tumor may get seeded at a distant site the evidence for this is strong since tumor cells have been observed in the csf . although most recurrences are along the surgical corridor an instance where the recurrence has occurred in the spine has been recorded . when the transsphenoidal route is used , the csf spaces are not violated this may explain the absence of recurrences after transsphenoidal route . it is not surprising to observe that the histologic examination of the primary and recurrent lesions are the same . recurrences rates are said to be low after total surgical excision . but recurrences even decades after a quiescent period are well - known . it can be assumed that radiotherapy would have sterilized the surgical corridor and ectopic recurrences will not occur . but this was not the case in our patient , and in the few that have been reported . total excision is not an assurance that recurrences at ectopic or primary site will not occur . certain measures have been proposed to minimize these ectopic recurrences , protecting the operative field with patties to prevent seeding , emptying the cyst prior to removal of tumor , thorough irrigation of the field before dural closure . probably , a higher mib-1 index and expression of p53 may predispose to these recurrences . but eternal vigilance and regular imaging are mandatory to detect recurrences . another point worthy of note is why this phenomenon is not seen with respect to other benign tumors like meningiomas or even malignant tumors . OUTPUT:

the aim was to present a rare case of recurrent craniopharyngioma remote from the primary site of origin . a young girl was operated for sellar region craniopharyngioma . for a small residual tumor , she underwent radiotherapy . follow - up imaging did not reveal any residual tumor or recurrence . surveillance magnetic resonance imaging after 5 years revealed a recurrence in the right sylvian fissure . this tumor was totally excised . recurrence of craniopharyngioma is well - known , but recurrence at a site remote from the original site after radiotherapy is extremely rare . one such case is being presented .

PubMed_Summ6587

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: pathological tissue fibrosis is the abnormal accumulation of collagen - rich extracellular matrix ( ecm ) after a chronic or misregulated response to injury that progressively disrupts tissue architecture , leading to tissue stiffness , impaired organ function , and eventually organ failure . fibrosis is featured in diverse conditions , accounts for as much as 45% of all deaths worldwide , and appears to be increasing in prevalence . fibrosis complications arise in very different disease settings , from autoimmunity and environmentally induced inflammation to cancer , spanning multiple organs . to date , the treatment options are extremely limited for attenuating or reversing this process . thus , there is an urgent need to delineate underlying pathological mechanisms that may lead to new therapeutic approaches . both the initiation and persistence of pathological fibrosis involves the activation and differentiation of progenitors to myofibroblasts , the key effectors in fibrosis . myofibroblasts play an important role in executing physiologic tissue repair , leading to matrix deposition , wound contraction , and healing on one hand , and pathological fibrogenesis leading to chronic fibrosing conditions on the other . accordingly , prominent molecular pathways in acute tissue repair often recapitulate their fibrogenic function in chronic fibrotic conditions , essentially conditions in which wound healing has gone awry ; these include platelet derived growth factor receptor beta ( pdgfr ) and transforming growth factor beta ( tgf- ) . however , there are still many gaps in our understanding of the mechanisms underlying fibrogenesis . due to their morphology and function , these cells are incredibly difficult to study in vitro . recently , elegant fate mapping studies pointed to a role for pericytes as a significant progenitor pool for myofibroblasts after injury in a variety of organ systems . liver pericytes , also known as hepatic stellate cells ( hscs ) , have been shown to be the major progenitor pool for myofibroblasts after carbon tetrachloride ( ccl4)-induced liver injury and fibrosis,5 , 6 and gene expression profiling of these cells isolated at various time points after ccl4 administration identified molecular alterations that might be functionally relevant to fibrogenesis . likewise , myofibroblasts and their precursors have been transcriptionally profiled during kidney fibrosis in mice using translational ribosome affinity purification technology . isolation of this cell type induces a lot of alteration in what these cells express ; therefore , it is important to study the function of the genes in their native disease environment without disrupting cell - cell and cell - matrix interactions . we aimed to identify novel modifiers of tissue fibrosis expressed in myofibroblasts or their progenitors through rna silencing in vivo . although much more challenging than conducting a cell - based screen in vitro , this in vivo approach was pursued to enable the interrogation of gene function in the context of the complex tissue environment and thereby yield physiologically relevant fibrosis modifiers . in order to achieve this objective , we employed recently generated transcriptomes from myofibroblasts and their precursors in models of liver and kidney injury and fibrosis.6 , 7 to achieve effective gene silencing in vivo , we used small interfering rna ( sirna ) delivery with lipid nanoparticles ( sirna - lnps ) , an emerging technology for gene silencing in vivo , particularly in the liver , and hence deployed this technology in a model of liver fibrogenesis . the sirna - lnp technology has been previously used to show that silencing of the collagen type i alpha 1 gene ( col1a1 ) reduced its mrna levels and collagen accumulation in liver fibrosis models.9 , 10 however , the use of sirna - lnp technology in a targeted assay for identifying novel fibrosis modifiers has not yet been reported . herein , we report our use of a platform composed of novel sirna targets , sirna - lnp delivery technology , and ccl4-induced liver fibrosis , resulting in the identification of novel modifiers of fibrogenesis in vivo . we aimed to silence genes in key fibrogenic cell lineages , myofibroblasts , and pericytes to identify novel mediators of tissue fibrosis . candidate genes were selected by the intersection of gene expression datasets for this cell lineage in two different organ systems . we identified genes that were commonly at least 2-fold upregulated in activated hscs isolated from livers of mice treated with ccl4 for 2 months and myofibroblasts and pericytes , their precursors , in the mouse kidney 2 and 5 days after unilateral ureteral obstruction ( uuo ) . we excluded transcripts that were not associated with a gene product , had no human homolog , or had well - known functions in fibrosis ( figure 1 ) . ultimately , we unbiasedly tested 24 genes by sirna - mediated gene knockdown ( kd ) in vivo ( table s1 ) . ccl4-induced liver injury and fibrosis in mice is a well - characterized model consisting of repeated ccl4 administration that injures hepatocytes , followed by a fibrogenic reaction . hscs are activated to expand , differentiate to myofibroblasts , and produce increased levels of ecm and pro - inflammatory mediators , thereby also promoting macrophage accumulation ; all of these reactions constitute a coordinated response to tissue injury and the progressive accumulation of collagen . we found that animals dosed orally with 1 ml / kg of ccl4 in mineral oil on day 0 and day 7 and euthanized on day 10 exhibited significant liver fibrosis based on increased picrosirius red ( psr ) and collagen immunopositivity in liver tissue as compared to vehicle - treated mice . percent area of tissue immunoreactive with asma , the hallmark of myofibroblasts , and iba-1 , a macrophage - specific marker , were also increased in ccl4-treated animals , suggesting an increase in myofibroblasts and macrophage numbers in the tissue ( figures s1a s1c ) . corresponding to increased collagen deposition in tissue , col1a1 mrna was markedly upregulated ( figure s2a ) . the assessment of col1a1 mrna levels was used as an expedient approach to functionally assess a relatively large number of sirna targets and flag fibrogenic genes of interest . given the sirna - lnp delivery system targets multiple liver cell types , including hscs , hepatocytes , kupffer cells , but not endothelial cells,11 , 12 , 13 , 14 we validated the ability to kd genes expressed in hscs in mice using sirna - lnps ( figures s1d s1h ) . mice were injected with a single dose of sirna - lnp ( 1 mg / kg ) against reelin ( reln - lnps ) , a gene prominently expressed in hscs . animals receiving reln - lnps , but not luc - lnps ( negative control ) , showed significant reduction in reln mrna in both oil- and ccl4-treated animals ( figure s1e ) . we also demonstrate the ability to kd the hsc - specific gene col1a1 in liver . col1a1-lnp reduced col1a1 mrna by 50% , with no effect on reln mrna . because the tgf- pathway is a recognized fibrogenic mediator , we tested whether kd of transforming growth factor beta receptor 1 ( tgfbr1 ) decreased the transcription and accumulation of collagen indeed , administration of tgfbr1-lnps and col1a1-lnps , but not luc - lnps , reduced the transcription of col1a1 mrna ( figure s1f ) as well as collagen accumulation ( figures s1 g and s1h ) . to test the role of genes identified in our transcriptomic analysis , we modified the sirna administration protocol to allow pre - existing protein to be turned over and therefore achieve pre - clearance of proteins encoded by the genes of interest and ensure continued kd throughout the experiment ( figure 2a ) . we first used luc - lnps to validate this protocol for detecting differences between oil- and ccl4-treated cohorts , with respect to the levels of col1a1 mrna , our primary parameter for defining target genes . we similarly evaluated differences in the mrna levels for a panel of other genes ( figure s2a ) . the strictly standardized mean difference ( ssmd ) values for col1a1 , collagen type iii alpha 1 ( col3a1 ) , tissue inhibitor of metalloproteinases 1 ( timp1 ) , and platelet derived growth factor receptor beta ( pdgfrb ) , but not tgfbr1 , integrin subunit alpha m ( itgam ) , or alpha - actin-2 ( acta2 ) , suggested that these genes were suitable to use as readout genes ( figure s2b ) . having established the suitability of the ccl4 treatment with the sirna - lnp kd platform , we proceeded to test our candidate genes . we tested the effect of kd of 24 individual genes in vivo ( figure 2a ) . we identified seven genes that significantly reduced the amount of col1a1 mrna ( table 1 ) . five of these seven genes , namely , early growth response 2 ( egr2 ) , fk506-binding protein ( fkbp10 ) , atpase na / k transporting subunit alpha 2 ( atp1a2 ) , follistatin like 1 ( fstl1 ) , and hyaluronan synthase 2 ( has2 ) , were silenced by 75%100% in whole liver tissue and significantly reduced col1a1 mrna levels . silencing of these genes did not elicit any overt toxicity , as measured by body weight loss ( figure s3 ) . because the other 19 genes did not meet these criteria ( tables 1 and s1 ) , we focused on further analyzing the five modifiers of fibrosis . the kd of the transcription factor ( tf ) egr2 had the broadest effect by reducing the levels of col1a1 and col3a1 mrna as well as the percent area immunopositive for asma , iba-1 , and collagen proteins , although the reduction in collagen by half did not achieve significance ( figure 2 ; table 1 ) . egr2 silencing also reduced pdgfrfb mrna levels ( figure 3a ) , suggesting a mechanism of decreased fibrosis and macrophage accumulation due to reduced expansion of activated hscs . given that egr2 has structural similarities to its family members , egr1 and egr3 , we confirmed the specificity of the egr2 sirna by transfecting human 293 t cells with plasmids encoding mouse egr1 , egr2 , or egr3 under the transcriptional control of the cmv promoter . in the tested construct , the expression of mouse egr1 , egr2 , and egr3 is not under the control of the endogenous promoter . thus , reduction in gene expression is due to the binding of the sirna egr2 to the mrna . using the same egr2 sirna that was used for the in vivo experiments , we found that this sirna reduced egr2 mrna levels , but not egr1 or egr3 mrna , unambiguously demonstrating that egr1 and egr3 were not targeted by our egr2 sirna ( figures s4a s4c ) . interestingly , even though the sirna against egr2 was specific , egr2-lnp treatment in vivo also reduced egr1 and egr3 mrna levels ( figures s4d s4f ) , suggesting transcriptional co - regulation of egr family members . similar to egr2 , kd of fkbp10 or atp1a2 reduced the collagen and iba-1 positive areas as did that of egr2 ( figure 2 ; table 1 ) ; however , kd of fkbp10 or atp1a2 did not alter the percent immunopositivity for asma . fkbp10 kd also decreased pdgfrb mrna levels , but this effect was somewhat weaker than that of egr2 ( 28% versus 45% reduction ; figures 3a and 3b ) , possibly accounting for its lack of effect on asma immunopositivity . these results suggest that egr2 , fkbp10 , and atp1a2 regulate fibrogenesis through different mechanisms . kd of either of the two other fibrosis modifiers , fstl1 and has2 , decreased col1a1 mrna levels as well as macrophage and collagen accumulation in the tissue , although has2 kd did not achieve significance for the latter ( figure 2 ) . notably , kd of these genes showed increased amounts of asma immunopositivity , which was highly significant for has2 kd , suggesting increased numbers of myofibroblasts . corresponding with the increased myofibroblasts , we detected higher levels of the timp1 mrna in the livers of both fstl1 and has2 kd animals ( figures 3d and 3e ) . despite the increased myofibroblast and timp1 mrna levels , , we also conducted in parallel in vitro studies and showed that three independent fstl1 sirnas reduced col1a1 mrna levels . thus , the direct reduction of collagen transcription may be sufficient to reduce overall collagen accumulation , despite the elevated number of myofibroblasts and reduced collagen degradation ( figure s5 ) . egr2 emerged as the strongest modifier of fibrosis in the ccl4 liver fibrosis / sirna kd platform . we aimed to directly demonstrate that egr2 kd in an hsc would reduce col1a1 and pdgfrb mrna levels . we tested the effect of egr2 kd in the human hsc line lx-2 using three independent sirnas ( figure 4 ) . this experiment required a different sirna to be used because no species cross - reactive sirna was designed ( see materials and methods ) . all sirnas against erg2 reduced its mrna levels as well as col1a1 and pdgfrb mrna levels . these results are consistent with the effect of egr2 kd in our in vivo ccl4 assay platform . as expected , kd of col1a1 reduced its own expression , but not that of egr2 . interestingly , col1a1 silencing also reduced pdgfrb mrna levels , suggesting a regulatory feedback loop . taken together , these data support that egr2 is fibrogenic in both rodents and humans . myofibroblasts are key effectors of fibrosis and therefore the elucidation of pathways that promote this cell lineage would be a significant advance in the field . here , we report the use of a targeted in vivo sirna kd platform to identify novel mediators of fibrogenesis . we leveraged novel biology - targeting genes upregulated during liver and kidney fibrosis in myofibroblasts and their progenitors and sirna - lnp technology to silence these genes in ccl4-induced liver injury and fibrosis in mice . we identified five genes , namely egr2 , atp1a2 , fkbp10 , fstl1 , and has2 , which modified fibrogenesis in this system because their kd reduced col1a1 mrna levels and collagen accumulation in the liver . prior to our study , egr2 , atp1a2 , and fkbp10 had not been functionally validated in fibrosis in vivo , and our study is the first to validate fstl1 and has2 in liver fibrosis . we further directly demonstrated that egr2 kd in human hscs reduced the expression of fibrotic genes . we conclude that in vivo sirna kd using sirna - lnp is a powerful tool to identify disease - relevant modifiers in vivo . studying myofibroblasts is extremely difficult because they are in direct contact with multiple cell types , including other myofibroblasts , myeloid cells , mesothelial cells , endothelial cells , epithelial cells , and circulating fibrocytes in situ . myofibroblasts respond to chemo - mechanical stimuli , and therefore disruption of their native environment during cell isolations alters their activation state . to circumvent these shortcomings this approach allowed us to study functional consequences of silencing of specific genes of interest in vivo in their native environment . it is of note that our sirna - lnp delivery approach allows us to silence gene expression in hscs ; however , this lnp formulation also targets other cells in the liver , including kupffer cells and hepatocytes , but not endothelial cells.11 , 12 , 13 , 14 therefore , we can not rule out the contribution of gene silencing in kupffer cells and hepatocytes on the anti - fibrotic outcome . our strategy to identify novel players in tissue fibrosis took advantage of recent transcriptomic datasets for myofibroblasts and their precursors isolated from fibrotic liver or kidney in mouse models.6 , 7 using sirna - lnp delivery technology , we tested the effect of gene silencing in a physiologically relevant context in vivo . we employed a ccl4 administration model that featured significant collagen accumulation and established several robust rna and histological measures of fibrogenic activity to identify fibrosis modifiers . using the criteria of significant reduction of col1a1 mrna levels of greatest interest are those that also reduced collagen accumulation in the tissue , namely , egr2 , atp1a2 , fkbp10 , fstl1 , and has2 . notably , these five genes were the most strongly silenced in vivo ( by 75% or greater ) that significantly reduced col1a1 mrna levels . it is possible that we might have achieved a greater degree of in vivo gene silencing for other target genes with a higher dose or a different dosing paradigm . thus , although we can not draw conclusions about the functional role of genes whose silencing was incomplete , our results clearly identify five genes as novel fibrogenic mediators in liver fibrosis in vivo . these genes fell into different groups based on the effects of their silencing on a mini mrna array and histological measures . we propose grouping them as follows : egr2 , a gene with potential function in hsc expansion ; atp1a2 and fkbp10 , genes that regulate mechanosensing ; and fstl1 and has2 , genes involved in matrix - cell signaling . egr2 , a tf of the egr family , emerged as the strongest effector in the sirna screen . egr tfs are important for the induction of cellular programs , including cell proliferation , differentiation , and death , in response to stimuli such as cytokines , growth factors , and toxic substances.17 , 18 , 19 egr2 has not been previously reported to play a role in tissue fibrosis in vivo . rather , egr2 is prominently known for its role in early myelination of the peripheral nervous system in humans and mice.21 , 22 , 23 egr2 kd silenced its expression by 94% , reduced col1a1 and col3a1 mrna levels , and diminished accumulation of myofibroblasts and macrophages , each to 15% of control . thus , our demonstration of reduced fibrogenic activity by egr2 silencing reveals a novel egr2 function . the downregulation of pdgfrb mrna levels by 45% suggests that egr2 may promote hsc expansion . this mechanism would explain the reduced asma - expressing hsc and thereby reduced signals for macrophage accumulation , all of which may have contributed to the reduction in fibrosis . importantly , we also directly demonstrate that egr2 kd in a human hsc line reduces col1a1 and pdgfrb transcripts , supporting the regulation of a fibrogenic program in hscs by this tf . the comparatively weaker effect of col1a1 silencing in vitro ( 50% ) versus in vivo sirna - lnp- mediated kd ( 80% ) of egr2 is due to the use of different delivery methods as well as the use of different sirna sequences to achieve gene silencing in human cells versus in vivo in mice . interestingly , col1a1 kd also reduced pdgfrb mrna levels . because ecm accumulation and expression of pdgfr are linked , it is feasible that decreased collagen production would decrease pdgfr expression in a feedback loop . the relevance of our finding to fibrogenesis in humans is also supported by a prior in vitro study , in which overexpression of egr2 in human skin fibroblasts upregulated collagen gene expression and myofibroblast differentiation , and these profibrotic tgf--induced responses were attenuated by egr2-depletion . we unambiguously confirmed that our sirna is specific for egr2 ( figures s4a s4c ) and also found that egr2 kd in human hscs reduces col1a1 and egr2 , but not egr1 or egr3 mrna ( data not shown ) , confirming the anti - fibrotic effect . however , in vivo egr2 kd also decreased the mrna levels of egr1 and egr3 , supporting the co - regulation of these transcription factors . it has been shown previously in vitro that overexpression of egr1 induced egr2 and egr3 expression and likewise egr3 overexpression induced egr1 and egr2 expression , whereas overexpression of egr2 did not have such an effect.25 , 26 , 27 here , we report that egr2 kd also reduces egr1 and egr3 mrna levels in vivo , a novel aspect of egr tf co - regulation . although egr2 has not been previously reported to play a role in tissue fibrosis in vivo , egr1 and egr3 have been implicated in the fibrotic response in vitro and in vivo previously.27 , 28 , 29 therefore , the extent of the anti - fibrotic effect may be due the co - regulation of egr tf . atp1a2 and fkbp10 were identified as fibrogenic modulators , with mechanisms of action distinct from that of egr2 . atp1a2 is the large catalytic subunit of an enzyme that catalyzes the hydrolysis of atp , coupled with the exchange of na and k ions across the plasma membrane . atp1a2 has a known function in the contractility of skeletal and cardiac muscle . on the basis of our results , it is intriguing to speculate that atp1a2 silencing may have reduced the contractility of myofibroblasts , effectively mimicking their behavior in a more compliant matrix environment and hence resulting in a less fibrogenic program.31 , 32 supporting this theory , we found that atp1a2 kd reduced fibrogenesis in vivo by significantly limiting the transcription of the col1a1 and timp1 genes , macrophage accumulation , and collagen deposition . however , in contrast to egr2 , atp1a2 silencing had no effect on asma expression . this theme of altered mechanosensing may also explain the alleviated fibrosis upon silencing of fkbp10 . fkbp10 is a molecular chaperone in the endoplasmatic reticulum that directly interacts with collagen i , contributing to the maturation and molecular stability of type i procollagen , promoting normal secretion , stable inter - molecular crosslinking , and collagen deposition in the ecm . fkbp10 has a well - established role in bone mass in humans and mice , but its role in tissue fibrosis is largely unexplored . fkbp10 mouse embryos are post - natally lethal and display reduced collagen crosslinking in calvarial bones . in this study , we report our novel finding that fkbp10 silencing reduces collagen deposition to 64% ; however , we found no reduction in asma expression . we speculate that fkbp10 silencing alters the quantity or crosslinking of the ecm and thereby alters mechanosensing . consistent with our in vivo results , a prior in vitro study showed that inhibition of fkbp10 in primary human fibroblasts from pulmonary fibrosis patients attenuates expression of pro - fibrotic genes and decreases collagen secretion . thus , our findings expand the scope of atp1a2 and fkbp10 functions by demonstrating their novel roles in fibrogenesis in vivo . fstl1 and has2 silencing also affected multiple fibrogenic readouts in our assay platform , but resulted in a pattern distinct from that of egr2 , atp1a2 , and fkbp10 . both fstl1 and has2 silencing reduced col1a1 mrna , macrophage accumulation , and collagen deposition but counterintuitively increased myofibroblast density as well as the level of timp1 mrna , a profibrotic pathway . fstl1 is a tgf--inducible , secreted , matricellular glycoprotein belonging to the secreted protein acidic rich in cysteines ( sparc ) family , with pleiotropic functions.37 , 38 , 39 during the course of our current study , it was reported that haplodepletion of fstl1 or a neutralizing anti - fstl1 antibody reduced bleomycin - induced pulmonary fibrosis . we found that fstl1 gene silencing reduced collagen transcription and accumulation in the context of liver fibrosis but surprisingly increased myofibroblast density , possibly reflecting a compensatory feedback loop . we hypothesize that the overall reduction in collagen accumulation is a direct result of decreased collagen production by fstl1 silencing , so that the increased number of myofibroblasts and reduced activity of collagen degradation would still result in decreased overall collagen accumulation . indeed , kd of fstl1 in the human hsc line lx-2 resulted in decreased levels of col1a1 mrna . like fstl1 , silencing of has2 resulted in unexpected effects , also likely through a matrix - modifying mechanism . has2 is one of three isoenzymes responsible for cellular hyaluronan ( ha ) synthesis , a matrix component normally highly abundant in joint synovium . ha is well known for its role in wound healing.40 , 41 has2 has been previously reported to be pathological in the bleomycin - induced lung fibrosis model , in which mesenchymal cell - specific deletion of has2 abrogated myofibroblast accumulation and inhibited the development of lung fibrosis . we show that has2 silencing also reduces liver fibrosis . has2 silencing also unexpectedly augmented myofibroblast density . taken together , our studies have identified fstl1 and has2 as fibrosis modifiers in our in vivo liver fibrosis platform and reveal surprising effects of silencing these genes , supporting their complex role in the regulation of fibrogenesis . to the best of our knowledge , our study is the first example of a targeted sirna assay for the discovery of novel fibrosis modifiers in vivo . the results implicate five novel modulators of the fibrogenic process in the liver and demonstrate the feasibility of sirna - lnp for interrogating gene function in the liver . because these genes are commonly upregulated in pericytes and myofibroblasts in both liver and kidney fibrosis models , these genes warrant follow - up to further explore their function and mechanism of action in liver and other organs and to inform their role in both physiological and pathophysiological fibrosis . all animal procedures were conducted in accordance with cambridge laws and the institutional animal care and use committee approved protocol no . 657 . 8- to 10-week - old male balb / c mice ( taconic bioscience ) were given ccl4 by oral gavage ( sigma - aldrich ; 1 ml / kg dissolved in mineral oil ) on days 0 and 7 . sirna - lnps were either given on day 6 at a concentration of 1 mg / kg or on days 7 , 3 , 2 , and 6 at 0.5 mg / kg . these experiments were controlled with cohorts of mice that received sirna targeting luciferase ( luc - lnps ) with oil or ccl4 , respectively . animals were sacrificed on day 10 by co2 asphyxiation , followed by cardiac perfusion with 10 ml of pbs , and liver lobes were harvested for qpcr and histopathological analysis . target fibrosis modifier genes were selected by intersecting transcriptomic data generated from isolated hscs of mice treated with ccl4 for 2 months , and genes specifically expressed in pericytes / myofibroblasts in the mouse kidney 2 and 5 days after uuo.6 , 7 169 genes were common to both datasets and significantly upregulated at least 2-fold . among these , we excluded transcripts that were not associated with a gene product , genes with no known human homolog , and well - known modifiers in fibrosis ( validated in vivo by independent investigators ) , resulting in 24 genes for further evaluation . a set of ten sirnas with canonical sirna structures was defined for each target gene . all sirnas were directed against the coding sequence of their respective target mrna and perfectly matched all known mrna transcript variants of the target gene available in the ncbi reference sequence database ( refseq db , release 65 , may 2014 ) . the sirnas used in this study were designed to be a perfect match only to their target mrna and to have 2 mismatches within positions 218 of the 19-mer sequence to any other genes . the design as described above is sufficient to ensure specificity.44 , 45 specifically , at least four mismatches between the sirna sequences of each of the genes of interest ( atp1a2 , egr2 , fkbp10 , fstl1 , and has2 ) and the readout genes col1a1 , col3a1 , tgfbr1 , pdgfrb , and timp1 . further , there were three mismatches between egr2 sirna and egr1 sequence and more than four mismatches between egr2 sirna and egr3 sequence . the sirna antisense strands lacked a seed region ( nucleotides 27 ) identical to a seed region ( nucleotides 27 ) of known mouse mirnas ( mirbase , release 20 , june 2013 ) . additional similarity analysis showed that there were at least four mismatches between the sirna sequences of each of the genes of interest ( atp1a2 , egr2 , fkbp10 , fstl1 , and has2 ) and the readout genes col1a1 , col3a1 , tgfbr1 , pdgfrb , and timp1 . further , there were three mismatches between egr2 sirna and egr1 sequence and more than four mismatches between egr2 sirna and egr3 sequence . from sirnas fulfilling those criteria , the sirnas for each final screening were selected for predicted activity based on analysis with proprietary algorithms ( axolabs , gmbh ) . in vivo grade sirnas each of the ten aforementioned sirna molecules / target gene was screened for its potency to kd gene expression in a cell - based reporter assay . for each target gene , the regions of their coding sequences targeted by the sirnas were synthesized and inserted to the 3 utr of the firefly luciferase gene in pcmvluc(v ) validation vector ( origene ) , generating an mrna transcript that encodes both the luciferase ( luc ) and the target gene when expressed in cells . 293 t cells ( atcc ) were co - transfected with the validation vector and the sirnas of interest using lipofectamine 2000 ( thermo fisher scientific ) at 0.1- , 1- , and 10-nm concentrations to assess kd potency . sirna binding to the target gene leads to degradation of the mrna that encode both luc and the target gene , resulting in reduced luciferase expression . luciferase expression was measured 24 hr post - transfection in a functional assay using the promega luciferase assay system ( promega ) , and luciferase signal was detected using a perkinelmer envision plate reader ( perkinelmer ) . for each sirna tested , the efficiency of kd was calculated as percent of luciferase signal compared to cells that were transfected with the validation vector for the target gene alone . the most potent sirna for each target gene ( > 90% luciferase reduction at 1 nm sirna in vitro ) was then formulated as lnps for in vivo application . the sequences of the sirnas that resulted in efficient kd ( 75% ) of their target gene in vivo are provided in table s2 . sirna - lnps were synthesized by mixing together an sirna - containing aqueous phase with a lipid - containing ethanol phase . the aqueous phase contained sirna in 10 mm citrate buffer ( ph 3 ) . the ethanol phase contained ionizable lipid c12 - 200 ( wuxi apptec ) , 1,2-distearoyl - sn - glycero-3-phosphocholine ( dspc , avanti polar lipids ) , cholesterol ( sigma ) , and 1,2-dimyristoyl - sn - glycero-3-phosphoethanolamine - n-[methoxy(polyethylene glycol)-2000 ] ( c14 peg 2000 , avanti ) at a 50:10:38.5:1.5 molar ratio and 5:1 c12 - 200:sirna weight ratio . the aqueous and ethanol phases were mixed together at a 3:1 volume ratio in a microfluidic chip device using syringe pumps as previously described to a final sirna concentration of 1 mg / ml . the resultant sirna - lnps were dialyzed overnight in a 20,000 molecular weight cut - off ( mwco ) cassette against 1x pbs at 4c . on average , sirna - lnps had a mean diameter of approximately 100150 nm , with a polydispersity index between 0.1 and 0.2 as measured by dynamic light scattering ( zetasizer , malvern instruments ) . the sirna encapsulation efficiency ( approximately 60% ) was determined using a modified quant - it ribogreen assay ( invitrogen ) as previously described . this sirna delivery system can target multiple liver cell types , including hepatocytes , monocytes , tissue macrophages , dendritic cells ( dcs ) , and myofibroblasts / pericytes . rna was extracted from liver lobes with trizol ( thermo fisher scientific ) , followed by on - column dnase digestion using rneasy mini kits and rnase free dnase sets ( both from qiagen ) . cdna was generated using the high - capacity cdna reverse transcription kit , and qpcr analysis was performed using pre - designed taqman primer probes ( table s3 ) on the quantstudio 12k flex real - time pcr system ( all from thermo fisher scientific ) to determine the expression levels of sirna target genes and a panel of readout genes . the relative expression of each gene was normalized to mouse or human glyceraldehyde 3-phosphate dehydrogenase ( gapdh ) using the 2 method , and the mean expression of each gene in the control group was set to 100% . 5-m sections were stained with psr using an automated leica system according to standard protocols . anti - alpha - smooth muscle actin ( sma ) ihc was performed with fluorescein isothiocyanate ( fitc)-labeled mouse monoclonal antibody 1a4 , followed by an anti - fitc antibody and periodic acid - schiff ( pas ) counterstain ( abcam ) . anti - iba-1 and anti - col1a1 ihc was performed using rabbit polyclonal antibodies ( cat . # 019 - 19741 , wako , and genetex , cat . the iba-1 positive area was limited to infiltrating macrophages by differentiating isolated single cells ( largely kupffer cells lining sinusoids ) from larger round cells in clusters ( periportal , largely infiltrating macrophages , sometimes filled with mineral ) . de novo interstitial asma was differentiated from endogenous asma in muscular arteries by performing a pas counterstain and then programming the algorithm to distinguish vascular morphology for exclusion from quantification . the human hsc line lx-2 ( emd millipore ) was transfected with sirnas against egr2 , col1a1 , or luc with lipofectamine rnaimax reagent following the manufacturer s protocol . we used the following predesigned sirnas ( listed as sirna i d ) : egr2 : s4540 , s4541 , and s4542 ; col1a1 : s3276 ; luc : am4629 ; and fstl1 : s22032 , s22033 , and s22034 ( thermo fisher scientific ) . rna was isolated on day 2 after transfection using rneasy kits with on - column dnase digestion ( qiagen ) . 293 t cells ( atcc ) were co - transfected with pcmv - egr1 , pcmv - egr2 , or pcmv - egr3 ( origene ) and either silencer select negative control no . 1 sirna ( thermo fisher scientific ) or sirna against egr2 ( axolabs ) . rna was isolated 24 hr after co - transfection using rneasy plus kits ( qiagen ) . statistical significance was assessed by two - tailed , unpaired student s t test for comparison of two groups or by one - way anova , followed by the dunnett s multiple comparisons test for more than two groups . we used an ssmd method to analyze the suitability of the mrna readout genes in our sirna - lnp / ccl4 liver fibrosis platform ( figure s2 ) . the ssmd method was used to calculate the median of differences divided by the standard deviation of the differences between the group treated with oil and the control sirna targeting luciferase ( oil / luc - lnp ) and versus ccl4/luc - lnp . it represents the average fold change penalized by the variability of the fold change across animals . ssmd is a suitable method because it takes the variability between animals into account . for our study , a threshold of < 1.5 was taken as the cut - off value for suitable readout genes . OUTPUT:

fibrotic diseases contribute to 45% of deaths in the industrialized world , and therefore a better understanding of the pathophysiological mechanisms underlying tissue fibrosis is sorely needed . we aimed to identify novel modifiers of tissue fibrosis expressed by myofibroblasts and their progenitors in their disease microenvironment through rna silencing in vivo . we leveraged novel biology , targeting genes upregulated during liver and kidney fibrosis in this cell lineage , and employed small interfering rna ( sirna)-formulated lipid nanoparticles technology to silence these genes in carbon - tetrachloride - induced liver fibrosis in mice . we identified five genes , egr2 , atp1a2 , fkbp10 , fstl1 , and has2 , which modified fibrogenesis based on their silencing , resulting in reduced col1a1 mrna levels and collagen accumulation in the liver . these genes fell into different groups based on the effects of their silencing on a transcriptional mini - array and histological outcomes . silencing of egr2 had the broadest effects in vivo and also reduced fibrogenic gene expression in a human fibroblast cell line . prior to our study , egr2 , atp1a2 , and fkbp10 had not been functionally validated in fibrosis in vivo . thus , our results provide a major advance over the existing knowledge of fibrogenic pathways . our study is the first example of a targeted sirna assay to identify novel fibrosis modifiers in vivo .

PubMed_Summ6588

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: pheochromocytomas are rare catecholamine producing tumors arising from chromaffine cells in the sympatho adrenal system . its prevalence is estimated at 0.1% to 0.6% . they secrete various catecholamines , predominantly norepinephrine , and epinephrine to small extent . these catecholamines are responsible for the manifestations with sustained or paroxysmal symptoms . diagnosis is established by measuring metanephrines in the urine or blood . localization of the tumor is done using computed tomography ( ct ) or magnetic resonance imaging ( mri ) scans . thrombosis of the inferior vena cava ( ivc ) has comparable etiological factors to lower limb deep venous thrombosis . hypercoagulability related to hematological or neoplastic abnormalities , venous stasis secondary to extraluminal pressure from tumors or inflammatory processes , and vessel injury due to trauma have all been implicated as primary mechanism in the pathophysiology of ivc thrombosis . however , its association with pheochromocytoma in indian subjects has not been reported till date . a 48-year - old man was admitted to our hospital with complaints of headache , sweating , anxiety , dizziness , nausea and vomiting . the patient was 164 cm tall and weighed 57 kg . on physical examination , there were no caf au lait spots or neurofibromas . hematological analysis confirmed normocytic anemia with hemoglobin 11.3 gm / dl , a raised erythrocyte sedimentation rate ( esr ) ( 130 mm fall in the first hour ) , while the total and differential leukocyte counts were normal . biochemical parameters such as liver and kidney functions , and serum electrolytes , calcium , phosphorous , alkaline phosphatase and d - dimer were within normal limits . the endocrinological evaluation revealed increased urine catecholamines and urinary vanillyl mandelic acid ( vma ) [ table 1 ] . baseline biochemical parameters of the patient abdominal ct revealed a well defined , heterogenous mass lesion of size 7.6 5.3 4.8 cms with attenuation score of 35 hu at the upper pole of right kidney without any calcifications [ figure 1 ] . there was no involvement of renal vein , hepatic veins and veins of lower limbs demonstrated by doppler ultrasound . magnetic resonance imaging ( mri ) revealed intraluminal thrombus extending proximally up to the confluence of hepatic veins immediately inferior to the right atrium without distal extension to femoral veins bilaterally [ figure 2 ] . an ivc venogram via the right jugular vein demonstrated multiple filling defects indicating occlusion of the ivc inferior to the right atrium [ figure 3 ] . there was simultaneous enlargement of distal part of ivc . computed tomography of the abdomen- showing a well defined , heterogeneously enhancing mass lesion of size 7.6 5.3 4.8 cm at the upper pole of right kidney without any calcifications . the left adrenal gland appeared to be normal t2-weighted axial magnetic resonance imaging demonstrating the mass ( predominantly high signal ) between the inferior vena cava and right kidney ( black arrow ) compressing the overlying inferior vena cava ( white arrow ) ivc venogram showing multiple filling defects indicating occlusion of the inferior vena cava inferior to the right atrium . there is distal enlargement of inferior vena cava a diagnosis of ivc thrombosis with pheochromocytoma was established , and surgical treatment was planned . alpha receptor blocking therapy with prazosin was instituted , followed by blocker , after testing for adequacy of blockade . the patient was treated conservatively with subcutaneous low molecular weight heparin followed by oral warfarin . after 2 weeks , hypertension was well controlled and the remaining symptoms disappeared . with adequate blood pressure control , biopsy of the specimen revealed a typical organoid or zellballen pattern with no cytoplasmatic inclusion , pleomorphism , cytological alterations or necrosis ; and , the mitotic index was low [ figure 4 ] . during the postoperative period , the patient 's blood pressure remained normal . a 24-hour urine specimen collected for metanephrine and vma , revealed levels within normal limits . at present , the patient is asymptomatic , requires no medications , and is employed as an engineer . mri imaging demonstrated resolution of the thrombosis and return of patency of the ivc at 4 months [ figure 5 ] . the typical growth pattern of nests of tumor cells ( zellballen ) surrounded by a discontinuous layer of sustentacular cells and fibrovascular stroma in the biopsy specimen of the patient in the study . blood vessels surrounding tumor nests are composed of round to oval cells t2-weighted axial magnetic resonance imaging comparable in position and image acquisition to figure 2 demonstrating complete resolution of inferior vena cava thrombosis ( white arrow ) after 4-months of oral anticoagulation therapy two aspects render our case unusual : 1 ) the coexistence of pheochromocytoma with ivc thrombosis 2 ) though there are case reports citing the association between malignant pheochromocytoma and ivc thrombus , to our sincere belief ; this is the first such report citing this uncommon association from india . although the lifetime incidence of venous thrombosis is 0.1% , it still remains a rare condition especially in patients below 30 years of age . predisposing factors include alterations in blood flow [ stasis ] , injury to the vascular endothelium and abnormalities in the constitution of blood hypercoagulability ( virchow 's triad ) . endothelial damage is invariably an acquired phenomenon , whereas hypercoagulability may result from both congenital and acquired risk factors ( especially in the peri - operative period ) . the classical presentation of ivc thrombus varies according to the level of the thrombosis with up to 50% of patients presenting with bilateral lower extremity swelling and dilatation of superficial abdominal vessels . whilst some patients remain asymptomatic , lower back pain , nephrotic syndrome , hepatic engorgement , cardiac failure and pulmonary embolus have also been described . tsuji et al . reported a series of 10 patients where 40% were pyrexic at presentation , with an associated elevation in d - dimer levels and inflammatory markers ( white cell count , c - reactive protein ) . our patient had no lower limb , liver or kidney involvement , and this might be ascribed to the partial occlusion of ivc . we could not explain normal d - dimer levels in the backdrop of such a large thrombus in our patient . ct scan with contrast enhanced images and mri scan are used to localize adrenal pheochromocytoma . meta - iodobenzylguanidine ( mibg ) and positron emission tomography ( pet ) scanning ( gallium- dota - toc / noc and dopa - pet perform better than fdg- pet ) are largely reserved for extraadrenal paraganglioma , or very large tumors to rule out metastasis . heterogeneity , high hounsfield density on ct ( > hu ) , marked enhancement with intravenous contrast and delayed contrast washout ( < 60 % at 10 minutes ) , high signal intensity on t2 weighted mri , cystic and hemorrhagic changes point to pheochromocytoma , adrenocortical carcinoma or metastasis . however , pheochromocytoma with lipid degeneration can result in low attenuation scores ( < 10 hu ) and > 60% washout at delayed ct scanning . benign adrenal incidentalomas are characterized by size < 5 cm , sharp margins , smooth contours , lack of demonstrable growth on serial examinations , attenuation scores < 10 hu , and > 60% washout at delayed ct scanning . in our patient , ct scan revealed nonhomogenous mass of hu 35 without any calcification . histologically , pheochromocytomas are capsulated and are composed of round or polygonal epithelioid / chief cells arranged in characteristic compact cell nests ( zellballen ) or trabecular patterns . the chief cells have centrally located nuclei with finely clumped chromatin , and a moderate amount of eosinophilic , granular cytoplasm . tumors of higher grade are characterized by a progressive loss in the relationship between chief cells and sustentacular cells , and a decrease in the number of sustentacular cells . in our patient , typical zellballen pattern was found . presence of markers like chromogranin a ( cga ) , neuron specific enloase , synaptophsyin serve as additional tools to confirm the neuroendocrine nature of the chief cells . the only reliable clue to the presence of a malignant pheochromocytoma is local invasion or distant metastases , which may occur as long as 20 years after resection . benign on pathologic examination , long term follow - up is indicated in all patients to confirm that impression . other markers for malignancy are absent or weak expression of inhibin / activin- beta b subunit , and presence of succinate dehydrogenase b ( sdh b ) subunit is seen . in absence of any invasion , we considered the mass in our patient to be benign . the simultaneous occurrence of pheochromocytoma and ivc thrombosis is reported sporadically . ivc thrombosis in this case could be because of : 1 ) local compression leading to alteration in blood flow and stasis 2 ) sustained hypertension leading to vascular endothelial injury and hypercoagulability , 3 ) association of pheochromocytoma with systemic lupus erythematous and behcet 's disease might explain the triggering of an autoimmune phenomenon leading to a hypercoagulable state , and 4 ) an underlying anatomic abnormality or coagulation disorder . it also could be a chance association between these 2 conditions . in our case , recent advances in the utilization of ultrasound , ct and mri imaging as well as endovascular procedures have resulted in an increase in detection rates of ivc anomalies , as well as an increase in the incidental discovery of such abnormalities during unrelated investigations , therapeutic endovascular or surgical procedures . contrast venography remains the standard for diagnosis of ivc thrombosis with a low false - positive rate , and the advantage of access for immediate treatment if required . however , it is an invasive procedure associated with a 2%-10% incidence of post - procedural deep venous thrombosis ( dvt ) . duplex ultrasound scanning has become an accurate non - invasive method of diagnosing ivc thrombosis and is often the first - line investigative modality . however , duplex usg is operator dependant and can be limited by body habitus or the presence of bowel gas and may occasionally fail to identify any ivc anomaly . ct imaging is a rapid non - invasive method which can accurately diagnose and assess the extent of thrombus as well as delineate any associated abdominal or pelvic abnormality . mri imaging is now replacing ct as the optimal investigative tool avoiding radiation and giving more accurate delineation of thrombus as well as any ivc anomaly . mri is also used to follow - up patients to determine morphological changes in the thrombus following therapy . management of patients with coexisting pheochromocytoma and ivc thrombosis needs operative resection of the adrenal mass and medical / interventional management of ivc thrombosis . the goals of operation include 1 ) removal of the tumor with postoperative normotension , and 2 ) ivc luminal restoration and anticoagulation . minimally invasive techniques are being increasingly used for resection of adrenal tumors and to treat renal artery lesions . our patient was subjected to laparoscopic adrenalectomy after adequate preoperative blood pressure control by blockers , followed by blockers . treatment options in the case of ivc thrombus without anatomical variance include anticoagulation , mechanical thrombectomy , systemic thrombolytic therapy , transcatheter regional thrombolysis , pulse - spray pharmacomechanical thrombolysis and angioplasty . there is no specific literature describing the ideal duration of anticoagulation in these instances ; however , case evidence identifies a trend toward treatment for a minimum of one year with the interplay of hypercoagulability disorders needing to be factored into any decision . surgical reconstruction of the ivc and bypass of an aberrant section are both recognized modalities reserved for the most severe cases and are associated with morbidity and mortality risk . endovascular stent placement in combination with angioplasty is recommended in the cases of residual stenosis and chronic ivc occlusion . in the case of ivc thrombus associated with an aberrant ivc , with no other predisposing factors , treatment involves anti - coagulation . the duration of this treatment is widely debated with no extensive literature to provide an evidence based approach . dean et al . took a view , which is quite similar to that of ours , that a caval anomaly is a permanent risk factor for venous stasis and thrombosis and that anticoagulant treatment should be lifelong . since our patient had no anatomic abnormality or any other predisposing factors , we decided to give the treatment for 4 months only and stopped it then after documenting radiologic luminal restoration . though cases of renal artery stenosis , renal artery aneurysm and inferior vena cava thrombosis have been described , we found the uncommon association with ivc thrombosis in an indian patient . ct or preferably mri imaging are required to delineate ivc anatomy and ascertain proximal extent of the thrombus . although invasive therapeutic modalities exist , long - term and commonly life - long anticoagulation is often required . pheochromocytoma does not seem to have any effect on the outcome of the coexisting ivc thrombosis . OUTPUT:

pheochromocytomas have been described in association with vascular abnormalities like renal artery stenosis . a 48-year - old man was admitted to our hospital with the complaints of headache , sweating , anxiety , dizziness , nausea , vomiting and hypertension . for last several days , he was having a dull aching abdominal pain . abdominal computed tomography ( ct ) revealed the presence of a left adrenal pheochromocytoma . an inferior vena cava ( ivc ) venogram via the right jugular vein demonstrated occlusion of the ivc inferior to the right atrium . surgical removal of pheochromocytoma was done , followed by anticoagulant treatment for ivc thrombosis , initially with subcutaneous low molecular weight heparin , and then with oral warfarin , resulting in restoration of patency . to the best of our knowledge , the occurrence of pheochromocytoma in ivc thrombosis has not been reported so far from india . possible mechanisms of such an involvement are discussed .

PubMed_Summ6589

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: cystic fibrosis ( cf ) is a worldwide disease occurring among virtually all ethnic groups . in caucasians although approximately 1 in 25 are heterozygous carriers , the incidence of clinical disease is approximately 1 in 2500 live births . the condition results from mutations in a single gene of chromosome 7 , which encodes the cf transmembrane conductance regulator ( cftr ) . the cftr protein is a membrane - bound camp - regulated chloride channel thought to regulate other cell membrane ion channels . to date , more than 1000 different mutations have been identified ; however a phenylalanine deletion in amino acid position 508 is present in approximately 66% of patients . early genetic tests demonstrating a molecular defect in the cftr gene confirms the clinical diagnosis of cf , improves quality of life and prolongs survival . recent studies support the theory that cfrd is primarily caused by insulin deficiency due to a loss of beta cells which may occur via a number of mechanisms , including oxidative stress . cftr mutations affect epithelial ion and water transport , primarily in cells in the respiratory , gastrointestinal , hepatobiliary and reproductive tracts , in addition to the sweat glands . the lack of chloride secretion in the pancreatic duct is responsible for obstruction and autodigestion of the pancreas early in embryonic life leading to severe exocrine pancreatic insufficiency in approximately 85% of cf newborns . diagnosis is based on clinical findings and sweat chloride levels greater than 60 meq / l . in iran , thus , the present study aims to assess the characteristic demographic findings of cf patients who attended the children s hospital medical center during a ten - year - period . during a ten - year period ( 1991 - 2000 ) , all patients hospitalized with cf or diagnosed with cf during hospitalization in the children s hospital medical center , tehran , iran were enrolled and related data were extracted from their medical records . sweat chloride tests the diagnosis of cf was established when relevant clinical manifestations were associated with a positive sweat chloride test . clinical manifestations included respiratory signs such as chronic cough or recurrent pneumonia and gi manifestations in the form of chronic diarrhea or fatty diarrhea , failure to gain weight and failure to thrive ( ftt ) . among the 233 patients , 91 ( 39% ) were girls and 142 ( 61% ) were boys . onset of disease was before the first month of life in 12.1% , between 1 - 6 months of age in 75.1% and between 6 - 12 months of age 6.9% of patients . a positive family history of cf or suspected clinical signs was present in 26.6% of patients . barium swallow was performed for 138 patients ; of those , 102 ( 74% ) had gastroesophageal reflux disease . other findings such as nasal polyps ( 6 ) , gallstones ( 1 ) , sinusitis ( 14 ) , cholestasis ( 9 ) and diabetes ( 2 ) were also noted . edema ( 19.4% ) , growth failure in the form of weight below the fifth percentile ( 89.1% ) , anemia ( 69.7% ) and hypoalbuminemia ( 60.5% ) were additionally present . endoscopy was performed in 65 patients and the most frequent finding was esophagitis ( 81.5% ) . in stool samples , fat droplets greater than 100 per hpf were reported in 100% , whereas 62.7% had decreased trypsin activity . among patients with respiratory symptoms , chest radiography was performed in 207 cases and frequent findings were : hyper - aeration with pneumonia ( 35% ) , pneumonia ( 19% ) and hyper - aeration ( 22% ) . death was documented in 27 patients which was attributed to respiratory failure ( 96.3% ) and septicemia ( 3.7% ) ( table 1 ) . * in hospital inpatient mortality currently , due to newer , more appropriate , modern enzymatic and antibiotic therapies in addition to nebulizer treatments , improvements in lifespan and quality of life are seen . recent researches and numerous advancements in the field of gene therapy , which can be the definitive therapy of cf , increased the hope for an extended life . therefore maintenance therapy , with the aim to perform gene - therapy , is of major importance in maintaining growth , preventing respiratory complications and malnutrition . it is important to keep this disease in mind when dealing with patients who present with the vast spectrum of clinical findings of cf , which are to some extent non - specific . thus , children who receive multiple courses of antibiotics for respiratory or gi diseases will need to undergo additional diagnostic tests . the prevalence of cf in european caucasians is 1:2500 and is rare in asia . based on the results of the present study and other reports from various locations in asia ; we have assumed that cf is not rare , as presumed in iran ( table 1 ) . in all studies , the male to female ratio was 1:1.5,the most frequent age of onset of symptoms occurred in the first six months of life ( 78% ) and consanguineous marriages were significant ( 42% ) . this might have been due to the fact that barium swallows were performed only in cases with suspected symptoms , whereas it was performed in all patients mentioned in textbooks . the incidence of ftt in the asian population was almost equal ( 75% - 100% ) . however in developed countries with the use of new nutritional methods such as alternate tpn in the hospital or at home , and nasogastric tube feedings at night , sufficient calories were obtained and growth failure was less commonly reported . death occurred in 13.4% of patients in the present study which was less than actual statistical values because a number of cf patients were not followed . in a study from shiraz ( iran ) , the cf mortality rate was 70% but in another study it was 0% , which probably resulted from the lack of follow up . one of the earliest signs of cf was meconium ileus , which ranged from 8% to 20% in different studies . the authors thank miss maral sayyad and the personnel of the archive of medical documents , endoscopy and gastroenterology departments of children hospital medical center for their assistance . OUTPUT:

background cystic fibrosis ( cf ) is an autosomal recessive disease caused by a cf trans - membrane regulator ( cftr ) defect . its prevalence is 1:2500 in caucasians , 1:15300 among african americans and is rare in southeast asia . the present study aims to review demographic data , clinical manifestations and laboratory findings of iranian children diagnosed with cf who referred to a children s hospital medical center in tehran , iran during a ten - year period . methods in a retrospective study from 1991 - 2000 , all hospitalized patients with documented cf were reviewed . diagnosis was based on clinical findings and sweat chloride levels above 60 meq / l . results a total of 233 patients [ females : 91 ( 39.1% ) , males : 142 ( 60.9% ) ] were enrolled . the onset of symptoms was before the first month of life in 12.1% , between 1 - 6 months of age in 75.1% , and between 6 - 12 months of age in 6.9% of patients . consanguinity of parents was present in 42.5% of patients . respiratory ( 81.5% ) and gastrointestinal ( 73.4% ) symptoms , in addition to growth retardation were the most common presentations eighty - eight percent of patients weighted below the fifth percentile . of the 207 chest radiographs performed , the most frequent finding was hyper - aeration associated with pneumonia . among 138 patients in whom barium swallows were performed , 102 ( 74% ) had gastroesophageal reflux . a total of 27 patients expired , mostly from respiratory failure ( 96.3% ) . conclusion cf is not a rare disease in iran . we suggest early diagnosis and appropriate maintenance therapy for improving morbidity and mortality amongst cf patients .

PubMed_Summ6590

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: nasal dermal sinus is a very rare congenital anomaly that is frequently associated with inclusion cysts ( dermoid or epidermoid).1 2 3 at the end of the second month of gestation , the nasal and frontal bones are separated by the fonticulus frontalis . in this period , the dura projects into the nasal area through the anterior skull base opening ( foramen cecum ) , and lies in contact with the skin at the tip of the nose . failure during ossification to obliterate this transcranial connection is the embryological pathway to nasal dermal sinus tract development.1 2 3 4 in the present case , combined use of high resolution magnetic resonance imaging and computed tomography ( ct ) clearly demonstrated the detailed anatomical relationship of the dermal sinus associated with a dumbbell - shaped dermoid to the surrounding structures such as the fonticulus frontalis and foramen cecum.3 5 the patient was a boy aged 1 year and 4 months who had had a small pit at his nasion from birth and had developed swelling of the forehead . 1a ) . the sagittal view of a t2-weighted image demonstrated a dumbbell - shaped , mixed intense dermoid at the foramen cecum . the sinus tract was depicted as a strand of isointensity between the dermoid and the nasion . a subcutaneous abscess was noted adjacent to the dermoid , and the subcutaneous swelling of the forehead was demonstrated as hyperintensity ( fig . serial sagittal views of t1-weighted images ( t1wi ) revealed the capsule of the dermoid enhanced with contrast medium ( gadolinium - diethylenetriamine penta - acetic acid [ gd - dtpa ] ) , and that the subcutaneous abscess was in continuity with the dermoid cyst . on axial view of the gd - enhanced t1wi , the subcutaneous abscess was also noted adjacent to the dumbbell - shaped dermoid ( fig . serial sections of the sagittal and coronal ct scans clearly showed an enlarged fonticulus frontalis and foramen cecum remnant and dehiscence of the crista galli ( fig . 1f , g , h ) . three - dimensional ct imaging showed a bony defect at the midline of the junction of the frontal bone and the anterior fossa , with a bifid and bulging crista galli ( fig . ( a ) photograph showing the swelling of the forehead . the black arrow indicates a small pit on the nasion . inset is the magnified view of the pit , which seems to be closed and has no purulent discharge . there is a dumbbell - shaped mixed intense dermoid ( white arrow ) at the junction of the frontal bone and the anterior fossa ( at the foramen cecum ) , and a strand of isointensity ( nasal sinus tract ) between the tumor and the nasion . an abscess in the subcutaneous tissue of the forehead ( black asterisk ) is noted adjacent to the dermoid . the capsule of the dermoid is enhanced with contrast medium ( gd - dtpa ) . the dermoid is dumbbell - shaped ( white arrow indicates the neck of the dumbbell ) . both the dermoid ( white arrow ) and subcutaneous abscess ( black asterisk ) are demonstrated as a hyperintensity . ( f , g , h ) serial sections of the sagittal ( f , h ) and coronal ( g ) computed tomography scan . the enlarged fonticulus frontalis remnant ( white arrow ) , enlarged foramen cecum remnant ( white dotted line ) , and dehiscence of the crista galli ( white arrow heads ) are clearly visible . a bony defect is evident at the midline of the junction of the frontal bone and the anterior fossa with bifid crista galli ( white arrow heads ) . ( j ) schematic drawing demonstrating the anatomical relationship of the dermoid ( d ) , subcutaneous abscess ( a ) , and swelling ( s ) with surrounding structures . the subcutaneous abscess was evacuated through a coronal skin incision on the frontal region , and then the purulent dermoid cyst including the capsule was removed . the part of the dermoid capsule that was tightly adherent to the dura was carefully coagulated . ( a ) intraoperative photograph taken after removal of the dermoid through a coronal skin incision showing the bony defect ( white arrows ) . inset is a three - dimensional computed tomography image shown in the same orientation as ( a ) the white box indicates the extent of the operative field . ( b ) the sinus tract including the pit at the nasion was dissected with a tiny skin incision . the dermoid cyst wall is lined by a keratinizing squamous epithelium ( white asterisk ) . intraluminal keratin ( black asterisk ) and hair shafts ( black arrow ) are also demonstrated . the nasal sinus tract is a ductal structure ( black star ) lined by stratified squamous epithelium . the patient was a boy aged 1 year and 4 months who had had a small pit at his nasion from birth and had developed swelling of the forehead . 1a ) . the sagittal view of a t2-weighted image demonstrated a dumbbell - shaped , mixed intense dermoid at the foramen cecum . the sinus tract was depicted as a strand of isointensity between the dermoid and the nasion . a subcutaneous abscess was noted adjacent to the dermoid , and the subcutaneous swelling of the forehead was demonstrated as hyperintensity ( fig . serial sagittal views of t1-weighted images ( t1wi ) revealed the capsule of the dermoid enhanced with contrast medium ( gadolinium - diethylenetriamine penta - acetic acid [ gd - dtpa ] ) , and that the subcutaneous abscess was in continuity with the dermoid cyst . on axial view of the gd - enhanced t1wi , the subcutaneous abscess was also noted adjacent to the dumbbell - shaped dermoid ( fig . serial sections of the sagittal and coronal ct scans clearly showed an enlarged fonticulus frontalis and foramen cecum remnant and dehiscence of the crista galli ( fig . 1f , g , h ) . three - dimensional ct imaging showed a bony defect at the midline of the junction of the frontal bone and the anterior fossa , with a bifid and bulging crista galli ( fig . ( a ) photograph showing the swelling of the forehead . the black arrow indicates a small pit on the nasion . inset is the magnified view of the pit , which seems to be closed and has no purulent discharge . there is a dumbbell - shaped mixed intense dermoid ( white arrow ) at the junction of the frontal bone and the anterior fossa ( at the foramen cecum ) , and a strand of isointensity ( nasal sinus tract ) between the tumor and the nasion . an abscess in the subcutaneous tissue of the forehead ( black asterisk ) is noted adjacent to the dermoid . the capsule of the dermoid is enhanced with contrast medium ( gd - dtpa ) . the dermoid is dumbbell - shaped ( white arrow indicates the neck of the dumbbell ) . both the dermoid ( white arrow ) and subcutaneous abscess ( black asterisk ) are demonstrated as a hyperintensity . ( f , g , h ) serial sections of the sagittal ( f , h ) and coronal ( g ) computed tomography scan . the enlarged fonticulus frontalis remnant ( white arrow ) , enlarged foramen cecum remnant ( white dotted line ) , and dehiscence of the crista galli ( white arrow heads ) are clearly visible . a bony defect is evident at the midline of the junction of the frontal bone and the anterior fossa with bifid crista galli ( white arrow heads ) . ( j ) schematic drawing demonstrating the anatomical relationship of the dermoid ( d ) , subcutaneous abscess ( a ) , and swelling ( s ) with surrounding structures . the subcutaneous abscess was evacuated through a coronal skin incision on the frontal region , and then the purulent dermoid cyst including the capsule was removed . the part of the dermoid capsule that was tightly adherent to the dura was carefully coagulated . ( a ) intraoperative photograph taken after removal of the dermoid through a coronal skin incision showing the bony defect ( white arrows ) . inset is a three - dimensional computed tomography image shown in the same orientation as ( a ) the white box indicates the extent of the operative field . ( b ) the sinus tract including the pit at the nasion was dissected with a tiny skin incision . the dermoid cyst wall is lined by a keratinizing squamous epithelium ( white asterisk ) . intraluminal keratin ( black asterisk ) and hair shafts ( black arrow ) are also demonstrated . the nasal sinus tract is a ductal structure ( black star ) lined by stratified squamous epithelium . 1j demonstrates the detailed anatomical relationship between the sinus tract with dumbbell - shaped dermoid and the surrounding structures . the body of the dumbbell - shaped dermoid was located in the enlarged fonticulus frontalis and foramen cecum remnant ; the head of the dumbbell was the intracranial extension of the dermoid with bulging dura . a bifid and bulging crista galli was also attributed to the intracranial extension of the dermoid . although bacteriologic examination failed to reveal the causative agents , the microscopically opened sinus tract resulted in the formation of the subcutaneous abscess adjacent to the purulent dermoid . OUTPUT:

nasal dermal sinus is a rare congenital anomaly . we report a case of the dermal sinus associated with a dumbbell - shaped dermoid and demonstrate the detailed anatomy . the patient was a boy aged 1 year and 4 months with a small pit at his nasion from birth and developed swelling of the forehead . the sagittal view of a t2-weighted image demonstrated a dumbbell - shaped , mixed intense dermoid at the foramen cecum . the sinus tract was depicted as a strand of isointensity between the dermoid and the nasion . serial sagittal views of t1-weighted images revealed the capsule of the dermoid enhanced with contrast medium , and that the subcutaneous abscess was in continuity with the dermoid . on diffusion - weighted imaging , both the dermoid and subcutaneous abscess were demonstrated as a hyperintensity . serial sections of the sagittal and coronal computed tomography scans clearly showed an enlarged fonticulus frontalis and foramen cecum remnant and dehiscence of the crista galli . the purulent dermoid cyst including the capsule and the dermal sinus tract were removed completely . we describe our detailed anatomical relationship between the sinus tract with dumbbell - shaped dermoid and the surrounding structures , and emphasize the importance of these anatomy for operation .

PubMed_Summ6591

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: since laparoscopic gastrectomy was introduced by kitano et al . , laparoscopic ( assisted ) distal gastrectomy ( ladg ) has become more commonly performed for early gastric cancer in korea [ 2 - 6 ] . however , there have been several reports on early surgical outcomes of laparoscopic assisted total gastrectomy ( latg ) [ 7 - 10 ] . in these studies , although latg has been shown to be safe and feasible for early gastric cancer , it has not yet been directly compared with the early surgical outcomes of conventional open total gastrectomy ( otg ) . in fact , ladg had not yet become popularized compared with ladg , because of its technical difiiculties and fear of postoperative complications . therefore , the purpose of this study was to evaluate the effectiveness of latg and to introduce techniques from our experiences . we retrospectively reviewed the prospectively collected data on 190 consecutive patients who underwent otg and latg , for gastric cancer between january 2009 and april 2010 at a single institution . all patients in whom the proximal margin too short to perform gastrojejunostomy had total gastrectomy : these patients were included in this study . also , all patients who were preoperatively diagnosed with early gastric cancer were enrolled in this study . after explaining the merits of laparoscopic surgery , the level of difficulty of procedures , and the cost for otg and latg , the decision of otg and latg resided with the patient . a carbon dioxide pneumoperitoneum was created using the umbilical port , and the pressure was maintained between 12 and 15 mmhg . the falciform ligament was fixed to the anterior wall of the peritoneum for retraction of the liver using endo close . if the operating field was not sufficient , an additional 5-mm trocar was inserted into the epigastric area to retract the liver . dissection was begun by dividing the greater omentum ( 4 cm from gastroepiploic arcade ) from the mid - portion of the gastroepiploic arcade to the short gastric vessels . dissection of the lymph nodes around the left gastroepiploic vessels and short gastric vessel was performed . after the dissection of the lymph nodes around the right gastroepiploic area , the infrapyloric area was dissected . in some patients , dissection was advanced to the superior mesenteric vein to include enlarged 14v lymph nodes . lymph nodes around the suprapyloric area ; hepatoduodenal ligament ( along the hepatic artery ) , common hepatic , splenic , celiac , and left gastric arteries ; and right and left paracardial areas were dissected in that order . the duodenum is transected below the duodenal bulb using an endoscopic linear stapler ( endopath ets 60 , ethicon endo - surgery inc . , after clearing the lymph nodes , a 4 - 5 cm midline incision was made from the epigastrictrocar site . a wound protector was applied , and esophagojejunostomy was reconstructed using a circular stapler ( proximate ils , ethicon endo - surgery inc . ; dst series eea , tyco healthcare group lp , north haven , ct , usa ) . clinical data obtained from medical records included patient age , gender , body mass index ( bmi ) , and american society of anesthesiologists ( asa ) score . early surgical outcomes included operation time , postoperative complications , intra - operative blood loss , postoperative change in hematocrit , time to first flatus , day of commencement on soft diet , number of administrations of analgesics , numeric rating scale ( nrs ) , and postoperative hospital stay . pathologic results were analyzed for tumor size , number of retrieved lymph nodes , resection margins , and american joint committee on cancer / international union against cancer staging . to evaluate the intra - operative blood loss , this was based on the observation of the number of surgical sponges used , the amount of fluid in the suction device , and a calculation of the amount of irrigant used during the operation . preoperative hematocrit was checked before undergoing surgery and postoperative hematocrit was checked on postoperative day one at 7:00 am . our postoperative pain control consisted of intravenous patient - controlled analgesia ( fentanyl 2,500 g , ketorolactromethamine 180 mg , ondansetronhcl 16 mg ) . to evaluate the patients ' postoperative pain , we calculated the number of additional doses of analgesics until the patient was discharged from the hospital . also , we applied an nrs for all patients . the nrs was checked on postoperative day ( pod ) 0 at 11:00 pm , pod 1 at 8:00 am , pod 1 at 11:00 pm , pod 2 at 8:00 am , pod 3 at 8:00 am and pod 5 at 8:00 am . patients were discharged if they had no problems eating a soft diet , showed an absence of inflammatory conditions , including leukocytosis , unstable vital sign and abrupt onset abdominal pain , and were generally comfortable . also , we left the final decision about discharge up to the patients . patient data was analyzed by one - way analysis of variance , followed by a post - hoc turkey test and the test . we retrospectively reviewed the prospectively collected data on 190 consecutive patients who underwent otg and latg , for gastric cancer between january 2009 and april 2010 at a single institution . all patients in whom the proximal margin too short to perform gastrojejunostomy had total gastrectomy : these patients were included in this study . also , all patients who were preoperatively diagnosed with early gastric cancer were enrolled in this study . after explaining the merits of laparoscopic surgery , the level of difficulty of procedures , and the cost for otg and latg , the decision of otg and latg resided with the patient . a carbon dioxide pneumoperitoneum was created using the umbilical port , and the pressure was maintained between 12 and 15 mmhg . the falciform ligament was fixed to the anterior wall of the peritoneum for retraction of the liver using endo close . if the operating field was not sufficient , an additional 5-mm trocar was inserted into the epigastric area to retract the liver . dissection was begun by dividing the greater omentum ( 4 cm from gastroepiploic arcade ) from the mid - portion of the gastroepiploic arcade to the short gastric vessels . dissection of the lymph nodes around the left gastroepiploic vessels and short gastric vessel was performed . after the dissection of the lymph nodes around the right gastroepiploic area , the infrapyloric area was dissected . in some patients , dissection was advanced to the superior mesenteric vein to include enlarged 14v lymph nodes . lymph nodes around the suprapyloric area ; hepatoduodenal ligament ( along the hepatic artery ) , common hepatic , splenic , celiac , and left gastric arteries ; and right and left paracardial areas were dissected in that order . the duodenum is transected below the duodenal bulb using an endoscopic linear stapler ( endopath ets 60 , ethicon endo - surgery inc . , after clearing the lymph nodes , a 4 - 5 cm midline incision was made from the epigastrictrocar site . a wound protector was applied , and esophagojejunostomy was reconstructed using a circular stapler ( proximate ils , ethicon endo - surgery inc . ; dst series eea , tyco healthcare group lp , north haven , ct , usa ) . clinical data obtained from medical records included patient age , gender , body mass index ( bmi ) , and american society of anesthesiologists ( asa ) score . early surgical outcomes included operation time , postoperative complications , intra - operative blood loss , postoperative change in hematocrit , time to first flatus , day of commencement on soft diet , number of administrations of analgesics , numeric rating scale ( nrs ) , and postoperative hospital stay . pathologic results were analyzed for tumor size , number of retrieved lymph nodes , resection margins , and american joint committee on cancer / international union against cancer staging . to evaluate the intra - operative blood loss , the attending anesthesiologist recorded the estimated blood loss . this was based on the observation of the number of surgical sponges used , the amount of fluid in the suction device , and a calculation of the amount of irrigant used during the operation . preoperative hematocrit was checked before undergoing surgery and postoperative hematocrit was checked on postoperative day one at 7:00 am . our postoperative pain control consisted of intravenous patient - controlled analgesia ( fentanyl 2,500 g , ketorolactromethamine 180 mg , ondansetronhcl 16 mg ) . to evaluate the patients ' postoperative pain , we calculated the number of additional doses of analgesics until the patient was discharged from the hospital . the nrs was checked on postoperative day ( pod ) 0 at 11:00 pm , pod 1 at 8:00 am , pod 1 at 11:00 pm , pod 2 at 8:00 am , pod 3 at 8:00 am and pod 5 at 8:00 am . patients were discharged if they had no problems eating a soft diet , showed an absence of inflammatory conditions , including leukocytosis , unstable vital sign and abrupt onset abdominal pain , and were generally comfortable . also , we left the final decision about discharge up to the patients . patient data was analyzed by one - way analysis of variance , followed by a post - hoc turkey test and the test . the clinical characteristics of the 190 patients are presented in table 1 . in comparison of patients overall , there was no difference in gender , age , asa score , and bmi between the latg and otg groups . operation time , it took longer to perform for latg than otg ( latg vs. otg ; 150.8 minutes vs. 131.2 minutes ; p < 0.001 ) . there was no significant difference for postoperative complication rate ( latg 12.7% vs. otg 18.9% ; p = 0.291 ) . there were significant differences for the amount of estimated blood loss ( latg 179.7 ml vs. otg 272.7 ml ; p < 0.001 ) and postoperative change in hematocrit ( hct ) ( latg 36.2 vs. otg 34.5 ; p = 0.002 ) . the mean day to first flatus ( p < 0.001 ) and commencement of soft diet ( p = 0.034 ) were checked earlier in the latg group than in otg group . the postoperative hospital stay was significantly shorter in the latg group than in the otg group ( p = 0.045 ) . nrs scores were significantly lower in the latg group than in the otg group at pod 0 at 11:00 am , pod 1 at 8:00 am , pod 1 at 11:00 pm , pod 2 at 8:00 am , pod 3 at 8:00 am , pod 5 at 8:00 am ( p < 0.001 , p = 0.003 , p = 0.005 , p = 0.008 , p = 0.010 , p = 0.004 ) . in pathologic results , there were no significant differences for tumor size , the number of retrieved lymph nodes , resection margins , tumor 's depth and nodal staging ( table 3 ) . in patients who underwent latg , postoperative complications occurred in 8 patients . intra - abdominal abscesses developed in 4 patients . in four of eight patients , extra - luminal bleeding , anastomosis leakage , cholecystitis , and wound complication occurred , respectively . intra - abdominal abscess were managed by pig - tail insertion and administration of antibiotics . extra - luminal bleeding was solved by laparoscopic reoperation for bleeding of suprapancreatic branch around the splenic artery . anastomosis leakage was managed by conservative treatment and upper gastrointestinal series showed closure at postoperative 14 days . the clinical characteristics of the 190 patients are presented in table 1 . in comparison of patients overall , there was no difference in gender , age , asa score , and bmi between the latg and otg groups . operation time , it took longer to perform for latg than otg ( latg vs. otg ; 150.8 minutes vs. 131.2 minutes ; p < 0.001 ) . there was no significant difference for postoperative complication rate ( latg 12.7% vs. otg 18.9% ; p = 0.291 ) . there were significant differences for the amount of estimated blood loss ( latg 179.7 ml vs. otg 272.7 ml ; p < 0.001 ) and postoperative change in hematocrit ( hct ) ( latg 36.2 vs. otg 34.5 ; p = 0.002 ) . the mean day to first flatus ( p < 0.001 ) and commencement of soft diet ( p = 0.034 ) were checked earlier in the latg group than in otg group . the postoperative hospital stay was significantly shorter in the latg group than in the otg group ( p = 0.045 ) . nrs scores were significantly lower in the latg group than in the otg group at pod 0 at 11:00 am , pod 1 at 8:00 am , pod 1 at 11:00 pm , pod 2 at 8:00 am , pod 3 at 8:00 am , pod 5 at 8:00 am ( p < 0.001 , p = 0.003 , p = 0.005 , p = 0.008 , p = 0.010 , p = 0.004 ) . in pathologic results , there were no significant differences for tumor size , the number of retrieved lymph nodes , resection margins , tumor 's depth and nodal staging ( table 3 ) . intra - abdominal abscesses developed in 4 patients . in four of eight patients , extra - luminal bleeding , anastomosis leakage , cholecystitis , and wound complication occurred , respectively . intra - abdominal abscess were managed by pig - tail insertion and administration of antibiotics . extra - luminal bleeding was solved by laparoscopic reoperation for bleeding of suprapancreatic branch around the splenic artery . anastomosis leakage was managed by conservative treatment and upper gastrointestinal series showed closure at postoperative 14 days . many studies have reported that ladg with gastroduodenostomy ( billroth i ) is as safe as that of open gastrectomy and less invasive than open gastrectomy [ 2 - 5 ] . however , latg is not a generally accepted approach among many surgeons due to technical difficulties and high complication rate . up to now , there have been some reports about the technical feasibility and safety compared with conventional open gastrectomy [ 7 - 10 ] . in practical procedures of latg , we often had difficulty in reconstruction of anastomosis due to limited operation field . one of the difficulties was the process of clamping the distal esophagus through small incision . another was the process of inserting and extracting of the straight needle into the purse - string clamp . especially in obese patients , we had difficulties in performing these processes . although it would be difficult to perform these processes in the latg , our results showed the feasibility of latg for postoperative complications as in other previous reports . we speculate that the accumulated experiences of surgeons in laparoscopic gastrectomy will aid us in getting over these difficulties . in our institution , we had experienced 1,100 cases of laparoscopic gastrectomy including ladg with gastroduodenostomy , ladg with roux - en - y reconstruction , latg and total laparoscopic distal gastrectomy with delta - shaped anastomosis by 2008 . from the accumulated experiences of experts , we could learn the method to reconstruct anastomosis easily . in reconstruction as long as we could , we additionally dissected the crus of the diaphragm . to extract the straight needle from the purse - string clamp easily , we rolled up the straight needle in the abdomen ( fig . 2 ) . also , we were able to obtain a shorter operation field by comparing the end of esophageal stump and the location of midline incision . in the present study , we found that the early surgical outcomes were more favorable for patients who underwent latg , as assessed by estimated blood loss , change of postoperative hct , earlier bowel movement , less pain during recovery , and earlier hospital discharge . although there was a report which longer operation time and co2 pneumoperitoneum incur the possibility of several hemodynamic consequences in these patients . we could minimize length of incision and manipulation by performing latg . in comparison to the pathologic results , although the current study could not be confirmed for oncologic results of latg , there were no significant differences of pathologic results between the two groups ( table 3 ) . in the present study , although there was no significance statistically for nodal staging , the proportion of metastatic lymph nodes is higher in latg group than in otg group . we assume that is just part of the reason why the latg group has more advanced gastric cancer in tumor depth . therefore , it will require a large volume and long - term follow up to evaluate the oncologic results of latg . although the baseline characteristics of patients in otg and latg groups were similar , there was the possibility of bias in the study population . also , although the methods of laparoscopic gastrectomy had been decided on by the selected patients , there was , again , the possibility of bias in the study population . therefore , it will require a large , randomized , and prospective study to evaluate the effectiveness of latg . in conclusion , the present study has suggested that latg is not only a feasible procedure for postoperative complications but also contributes to the improvement of early surgical outcomes including bowel movement , pain during recovery , and hospital discharge . OUTPUT:

purposeto evaluate the effectiveness of laparoscopic assisted total gastrectomy ( latg ) , we compared its early surgical outcomes with those of conventional open total gastrectomy ( otg ) in patients who were diagnosed as having early gastric cancer preoperatively.methodswe retrospectively analyzed early surgical outcomes in 190 consecutive patients who underwent total gastrectomy for early gastric cancer between january 2009 to april 2010 . the patients were divided into those who underwent latg and those who underwent otg . their early surgical outcomes were analyzed to evaluate the effectiveness of latg.resultsthere was no significant difference in postoperative complication rates ( p = 0.291 ) . but in the analysis of other early surgical outcomes , we found that latg could improve time to first flatus ( p < 0.001 ) , time to commencement of soft diet ( p = 0.034 ) , administration of analgesics ( p = 0.024 ) , pain score ( numeric rating scale ) , and hospital discharge ( p = 0.045).conclusionalthough latg did n't show better results for postoperative complications than those of otg , latg contributes to the improvement of early surgical outcomes , including bowel movement , pain score and hospital discharge . therefore , we suggest that latg could be a method to improve early surgical outcomes in patients who need total gastrectomy .

PubMed_Summ6592

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: nearest neighbor approaches were developed to predict the folding stabilities of nucleic acid secondary structures ( 1 ) . these parameter sets utilize empirical rules , generally derived from optical melting experimental data , as the basis of the predictions . for rna , rules exist for predicting both free energy and enthalpy change of watson crick helices , gu pairs and loops ( 25 ) . parameters for dna have also been assembled for predicting watson crick pair free energy and enthalpy change and free energy changes of loops ( 6,7 ) . these parameter sets are the basis of computer programs that predict low free energy secondary structures . such programs include mfold / unafold ( 8,9 ) , the vienna rna package ( 10 ) , rna structure ( 2 ) , rnasoft ( 11 ) and sfold ( 12 ) . additional approaches that use statistical learning of parameters for rna folding have also used the rules from the nearest neighbor methods and derived new parameter values ( 13,14 ) . nearest neighbor parameter sets include both a set of rules , called either equations or features , for predicting stability and a set of parameter values used by the equations ( 14 ) . for rna , separate rules exist for predicting stabilities of helices , hairpin loops , small internal loops , large internal loops , bulge loops , multibranch loops , exterior loops and pseudoknots . given the number of rules and constraints on the length of journal publications , it is difficult to assemble all the parameters in one publication and provide meaningful tutorials for using the parameters . this is a barrier to software development for novel algorithms that could take advantage of the parameters . for example , many software packages that use rna parameters still implement the set of parameters assembled in 1999 ( 4 ) , in spite of the fact the rna parameters were updated in 2004 ( 2 ) based on experimental results . the nearest neighbor database ( nndb ) is a web - based tool for assembling and archiving complete nearest neighbor sets , including rules and values . currently , the 1999 and 2004 sets of rna folding parameters are provided ( 25 ) . the nndb is built using a set of static html , specifically xhtml 1.0 transitional pages with a page hierarchy shown in figure 1 . text is encoded in unicode ( utf-8 ) to facilitate display of equations in pages with diverse browsers running on diverse operating systems . the top - level page provides access to a help page , available parameter sets and a page of references to rna optical melting experiments . additionally , links provide downloading of the whole database in either zip or gzipped tar format . the help page introduces the purpose of the database and defines basic terms , including the set of structural features defined by secondary structures . for example , figure 2 , from the help page , shows an rna secondary structure that illustrates the loop features covered by nearest neighbor parameter sets . the basic equations for utilizing the parameters to extrapolate folding free energy changes to temperatures other than 37c and to predict melting temperatures are also provided . this figure illustrates the page hierarchy by following the linked pages down through the 1999 parameters and down to the hairpin loop pages . note that there are five example calculations for hairpin loops to illustrate the separate sequence - dependent rules that are used depending on the specific loop . figure 2.an rna secondary structure illustrating the types of features included in nearest neighbor parameter sets . internal loops have nucleotides not in canonical pairs on each of two strands , but bulge loops have nucleotides not in canonical pairs on only one strand . formally , a pseudoknot occurs when there are at least two pairs , with indices i paired to j and i paired to j , that satisfy the condition i < i < j < j. the pseudoknot helix is often considered to be composed of the fewest pairs that need to be removed to relieve the pseudoknot ( 19 ) . in this structure , this figure illustrates the page hierarchy by following the linked pages down through the 1999 parameters and down to the hairpin loop pages . note that there are five example calculations for hairpin loops to illustrate the separate sequence - dependent rules that are used depending on the specific loop . an rna secondary structure illustrating the types of features included in nearest neighbor parameter sets . internal loops have nucleotides not in canonical pairs on each of two strands , but bulge loops have nucleotides not in canonical pairs on only one strand . formally , a pseudoknot occurs when there are at least two pairs , with indices i paired to j and i paired to j , that satisfy the condition i < i < j < j. the pseudoknot helix is often considered to be composed of the fewest pairs that need to be removed to relieve the pseudoknot ( 19 ) . in this structure , the tan nucleotides are in pairs that could be removed to relieve the pseudoknot . for each set of parameters , for example , the 1999 rna rules predict only folding free energy changes ( 4 ) , but the 2004 rules can be used to predict both folding free energy and enthalpy changes ( 2,5 ) . for each structural feature , a page defines the basic equations and provides links to parameter values ( in plain text and html ) , references and tutorial pages ( e.g. figure 3 ) . the number of tutorials varies from feature to feature ; the set of tutorials is designed to cover each type of rule that can be encountered in practice . crick helix parameters are covered with two tutorials , one for self - complementary and one for non - self - complementary strands . these two tutorials also demonstrate the difference in the calculation when there are terminal au base pairs , which receive a free energy and enthalpy change penalty ( 3 ) , because the self - complementary duplex example has two terminal au pairs and the non - self - complementary case has no terminal au pairs . this tutorial demonstrates the prediction of folding free energy change for a hairpin loop of six unpaired nucleotides using the 2004 parameters ( 2,3 ) . an example tutorial from the database . this tutorial demonstrates the prediction of folding free energy change for a hairpin loop of six unpaired nucleotides using the 2004 parameters ( 2,3 ) . individual pages above the level of value tables have top banner , a left navigation bar that allows the user to navigate back up the hierarchy to any level above and a bottom bar with the date of last editing . for pages edited after the database has gone online , previous versions of the page are available using this bottom content bar . to facilitate indexing by search engines , all pages have a descriptive title , including the set of parameters to which it belongs ( if applicable ) . the first release of the nndb contains the rna folding rules assembled in 1999 and 2004 ( 25 ) . these rules represent the most recent set of parameters and a prior set that is widely used in software packages . because folding rules are derived to work as a set , the two versions of rules and values should not be mixed and the website hierarchy reinforces this . it is anticipated , for example , that additional pages will be written to include nearest neighbors for dna folding ( 6,7 ) and for predicting rna pseudoknot stabilities ( 1518 ) . additionally , the values derived from the re - estimation of the values of the 1999 parameter set using the set of known rna secondary structures will also be included ( 14 ) . the nndb is designed to provide a convenient location for assembling parameter sets for predicting the stability of nucleic acid secondary structures . it is modular in design , which facilitates its future expansion to contain additional parameter sets . furthermore , the web format makes it feasible to provide extensive tutorials for utilizing the parameters , which is generally not possible in print . the creation of the nndb was supported by united states national institutes of health grants gm076485 to d.h.m . and gm22939 to d.h.t . funding for open access charge : united states national institutes of health . OUTPUT:

the nearest neighbor database ( nndb , http://rna.urmc.rochester.edu/nndb ) is a web - based resource for disseminating parameter sets for predicting nucleic acid secondary structure stabilities . for each set of parameters , the database includes the set of rules with descriptive text , sequence - dependent parameters in plain text and html , literature references to experiments and usage tutorials . the initial release covers parameters for predicting rna folding free energy and enthalpy changes .

PubMed_Summ6593

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: mucocele of the appendix ( collection of mucus within the appendiceal lumen ) is a rare lesion , found in only 0.2% to 0.3% of 43,000 appendectomies reviewed . currently , the assessment of pelvic masses relies heavily on usg as the primary diagnostic tool . in such cases , clinical findings and other investigative modalities are warranted to aid the diagnostic process . in spite of extensive preoperative investigations , the diagnosis may still remain elusive and may only be made at the time of surgery . some regard this lesion as benign , a result of obstruction of the proximal lumen by fibrosis ; others believe it to be a neoplasm of the appendix . is the method of choice in the management of simple mucocele and for cystadenoma with an intact base . several studies ( mostly case reports ) on laparoscopic resection of mucocele have been reported . a 60-year - old female presented with pain in lower part of abdomen and palpable tender lump in the right ileac fossa . ultrasound of the abdomen reports a cystic mass of size 12 15 cm with thin internal septations in the right adnexa . the pneumoperitoneum was created with veress needle using carbon dioxide and the pressure was kept at 11 mmhg . a 0 telescope was introduced through the umbilical port for the complete examination of the abdomen . diagnostic laparoscopy revealed approximately 14 15 cm large bluish mucocele of the appendix with omental adhesions . two 5-mm ports were placed in the supra pubic area below the pubic hair line as the working port . the mucocele of the appendix was isolated after separating the mesoappendix from it with the help of bipolar cautery . following this , mucocele of the appendix [ figure 1 ] was retrieved out in a plastic bag through the umbilical port . hemostasis was obtained and a suction drain left in situ which was removed when non - productive . cut section showed appendix was filled with mucin - like material [ figure 2 ] . she was started orally after 4 hours of operation and solid food on the next day . appendicular lump from the distal portion of appendix after removal the appendicular lump filled with mucinus material mucocele of the appendix is a descriptive term for an appendix distended by mucus , secondary to mucinous cystadenoma ( 63% ) , mucosal hyperplasia ( 25% ) , mucinous cystadenocarcinoma ( 11% ) , and retention cyst . clinical presentation may include right lower quadrant pain , change in bowel habits , per rectal bleeding , or a palpable mass . approximately 23 - 50% of patients are asymptomatic , with the lesions being discovered incidentally during surgery , radiological evaluations , or endoscopic procedures . the preoperative clinical diagnosis of appendiceal mucoceles can therefore be difficult because of this lack of clinical symptomotology . the initial detection of the lesion may be facilitated by radiological , sonographic , or endoscopic means . on barium enema , the lesion may be seen as a sharply outlined sub - mucosal or extrinsic mass indenting the cecum and laterally displacing it . purely cystic lesions with anechoic fluid , hypoechoic masses with fine internal echoes as well as complex hyperechoic masses can be seen depending on the contents . ct of the abdomen usually shows a cystic well - encapslated mass sometimes with mural calcification , in the expected location of the appendix . it may be causing extrinsic pressure on the cecal wall without any surrounding inflammatory reaction . colonoscopic findings include the volcano sign , the appendiceal orifice seen in the center of a firm mound covered by normal mucosa or a yellowish , lipoma - like submucosal mass . in our case , usg was unable to provide a preoperative diagnosis . in our case , the decision for excision of the appendiceal mucocele was made as a result of diagnostic laparoscopy and a need to rule out malignancy . therefore mucocele of the appendix can mimic an adnexal mass and prove to be a diagnostic challenge . in a woman presenting with right iliac fossa mass and with clinical features not indicative of gynecological pathology , an appendiceal origin should be considered in the differential diagnosis . surgery is the treatment of choice and should be done early as tumor can not be ruled out as the causative factor for the mucocele . pre - operative diagnosis is important to avoid unintended rupture and the development of pseudomyxoma peritonei during surgery . however , laparoscopic dissection , grasping of the appendix specimen , pneumoperitoneum , or transport of the specimen through the abdominal wall might contribute to peritoneal dissemination of a tumor , if present . these setbacks can be avoided by taking precautions like using bowel holding graspers ( non - traumatic ) to handle the mucocele and using a non - permeable bag to deliver the specimen out of the port . mucocele of the appendix can mimic an adnexal mass and prove to be a diagnostic challenge . laparoscopic resection of mucocele of the appendix is feasible in spite of the danger of malignancy , provided necessary precautions are taken . OUTPUT:

mucocele of the appendix is an aseptic dilatation secondary to obstruction . the preoperative clinical diagnosis of appendiceal mucoceles can therefore be difficult because of this lack of clinical symptomotology . surgical excision is the treatment of choice in benign mucocele . we report a case presenting to the surgeons where initial clinical findings and investigations suggested a cyst in the right adnexa . diagnostic laparoscopy revealed mucocele of the appendix and laparoscopic appendicectomy was done .

PubMed_Summ6594

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: postpartum psychiatric disorders , described as lactational psychoses by hippocrates in the 4 century bc , have long been of interest to the medical community . pregnancy and postpartum period are widely considered periods of increased vulnerability to psychiatric disorders . after more than 50 years and four revisions , postpartum disorders were incorporated into the diagnostic and statistical manual of mental disorders , fourth edition text revision ( dsm - iv - tr ) . although diagnostic guidelines in dsm - iv tr have been restricted to the first 4 weeks after delivery , most clinicians and researchers regard the postpartum period as 6 months or even 1 year after childbirth . in the international classification of diseases-10 edition ( icd-10 ) , the postpartum disorders are grouped under behavioral syndromes associated with physiological disturbances and physical factors as mental and behavioral disorders associated with the puerperium , not elsewhere classified ( f53.053.9 ) . in icd 10 , the duration criteria in contrast to dsm - iv - tr is 6 weeks . further , in dsm-5 , the specifier with postpartum onset has been replaced by with peripartum onset . this specifier is used if the onset of mood symptoms occurs during pregnancy or within the 4 weeks following delivery . however , postpartum psychiatric disorders may manifest weeks beyond the 1 month or 6 weeks after delivery . hence , the utility of dsm specifiers and icd special code in the classification of puerperal disorders is limited . in addition , very little is known about whether the assessment or screening can be done on the days immediately after birth . the traditional view that there are three postpartum psychiatric disorders such as postpartum blues , depression , and puerperal psychosis is an oversimplification . childbirth presents many challenges to the mother such as trauma , sleep deprivation , breastfeeding , and adjustments in relationships and is a major life transition and developmental process . these include the blues , which occur in the 1 day after birth and which is very common , ranging from 50% to 75% , and self - limiting . the most severe form of mental disorder associated with postpartum period is postpartum psychosis , observed in 12/1000 child - bearing women occurring as early as 23 days after childbirth . the mild to moderate depression recent studies suggest that postpartum anxiety disorders are underemphasized and are more common than depression . the case series of obsessions of infanticide are many . also , posttraumatic stress disorders ( ptsds ) and newer entities such as the morbid preoccupations regarding the childbirth and the disorders of the mother maternal morbidity and mortality are not the only reasons why effective action is necessary to deal with postpartum illnesses , but the impact it has on the family and the child and the subsequent bonding . maternal psychiatric disorders during pregnancy and the postpartum period are also associated with numerous adverse outcomes for the offspring , including maladaptive fetal growth and development , poor cognitive development and behavior during childhood and adolescence , and negative nutritional and health effects . hence , our primary objective was to assess the proportion and types of psychiatric morbidity and correlates in postpartum women in a tertiary care hospital as per dsm - iv tr . our secondary objective was to study the relationship between the psychiatric morbidity and specific sociodemographic and clinical variable correlates in postpartum women ( within 4 weeks ) in a tertiary care hospital . after obtaining the approval from the institutional ethics committee , the study was conducted in a tertiary care hospital attached to a medical college at mysore , india , during june december 2011 . the subjects were explained in their language about the purpose of the study and that their identity will not be revealed in the published material . then , written consent was taken on the consent form before recruiting them . the study sample consisted of women getting admitted for delivery in the department of obstetrics and gynecology of the study venue . all consenting consecutive patients who are in the postpartum period ( < 4 weeks as per dsm iv tr ) were considered for the study . women with mental retardation , organic mental disorders , and severe comorbid medical disorders were excluded from the study . the sociodemographic data were obtained on a semistructured proforma consisting of items relating to patients ' age , social , educational , cultural background , education , and occupation of the spouse . then , clinical data were obtained on a similar semistructured proforma comprising items related to patients ' family history of psychiatric illness , history of psychiatric illness , clinical details of delivery , sex of fetus , current episode including onset , duration , and timing of illness , and parity and state of physical health of infant . following this , the mini international neuropsychiatric inventory ( mini ) , a short , structured diagnostic interview designed to diagnose dsm - iv and icd-10 psychiatric disorders for multicenter clinical trials and epidemiology studies as well as the first step in outcome tracking in nonresearch clinical settings was administered . in our study , an additional question about obsession of child harm was included while assessing the obsessive compulsive disorder ( ocd ) . in the end , the patients were rated on the global assessment of functioning ( gaf ) . it was usually the 3 postpartum day in case of a normal delivery and the 7 or 8 day in case of a delivery by episiotomy or cesarean section . the sample size was calculated at 95% confidence interval and 20% relative precision considering the prevalence of postpartum depression as 23.7% . the sample size was calculated using n master software ( developed by department of biostatistics , christian medical college , vellore ) . the statistical analysis of the data has been done using the statistical package for social sciences ( spss ) windows version 15 ( ibm corporation , new york , usa ) . for frequencies , test of significance was done using independent t - test and chi - square test . the study venue provides tertiary care and is a referral center for the district of mysore and the four neighboring districts . the age range varied from 18 to 35 years with a mean age of 23 4.8 years . table 1 shows the sociodemographic picture of the study population . socio - demographic profile of the 152 patients , 146 ( 96.1% ) had received antenatal care as against only 6 ( 3.9% ) who did not ; similar numbers followed in the number of pregnancies planned and unplanned . majority delivered normally 93 ( 64.2% ) and at term - 148 ( 97.4% ) . only 4 ( 2.6% ) delivered preterm . fifty - five ( 36.2% ) had undergone episiotomy and only 4 ( 2.6% ) underwent cesarean section . clinical profile of study population the psychiatric morbidity was seen in 67 ( 44% ) of the study subjects as shown in graph 1 . depressive disorder not otherwise specified ( nos ) , obsessive harm to the child , panic disorder , and social phobia were the different disorders identified . there were no cases of mania , bipolar disorder , psychosis , ptsd , or substance use disorder diagnosed across the sample . graph 2 and table 3 represent the different psychiatric disorders seen in the study population . pie chart showing psychiatric morbidity pie chart of different psychiatric disorders psychiatric morbidity in study population psychiatric illness detected in the study population was studied for association with education , education of spouse , religion , type of family , occupation , occupation of spouse , antenatal care , consanguinity , order of child , number of dead children before this delivery , number of abortions before this delivery , term of delivery , mode of delivery , planning of pregnancy , and congenital anomalies . statistically significant association was seen to be present between psychiatric illness and number of previous stillbirths and dead children before this delivery ( p = 0.045 ) . association between psychiatric illness and number of children dead ( stillbirths and neonatal deaths ) prior to the present delivery this is a cross - sectional hospital - based study in which we assessed the proportion of psychiatric morbidity of postnatal women attending the department of obstetrics and gynecology of the hospital . we found that the psychiatric morbidity was as high as 44% , found in 67 of 152 study subjects . the disorders were diagnosed using mini , the diagnostic schedule based on dsm - iv tr . the overall psychiatric morbidity found in our study is comparable with that quoted as 33.4% in an epidemiological study . however , that study gave the prevalence rates of postnatal blues , postpartum depression , and psychosis . the tools used in the study included general health questionnaire , hamilton depression rating scale , and edinburgh depression rating scale . they assessed the psychopathology on day 3 of delivery as well as after 3 weeks . of 478 subjects , 129 ( 27% ) had postnatal blues , 28 ( 5.86% ) had postpartum depression and 3 ( 0.63% ) had postpartum psychosis . a higher rate reported in our study might be due to the different assessment tools used in our study and difference in the sample size . a majority of the studies have only looked into depression in postpartum period and report a prevalence rate ranging from 10% to 18% . those earlier studies that have reported psychiatric morbidity in general , have followed the same traditional view of assessing the three frequently reported disorders , mentioned earlier . one of them has studied 100 consecutive postpartum women who are known cases of psychiatric syndromes , according to icd-9 . interestingly , it infers that 67 patients had schizophrenic psychosis , which was the most common disorder . this was followed by postpartum blues ( 14 ) , manic excitement ( 6 ) , depressive psychosis ( 5 ) , hysteria ( 4 ) , hysterical psychosis ( 3 ) , and psychogenic paranoid psychosis ( 1 ) . however , the recent studies have thrown light on the other postpartum psychiatric syndromes . different studies across europe report a frequency of ptsd to be 0.18% although no indian data are available , and it is said to be the fourth most common postpartum disorder . further , many studies observe that other puerperium - related anxiety disorders such as maternity neurosis , phobia , and panic disorder are underemphasized . even , obsession of child harm is not an uncommon phenomenon , found to be comorbid to postpartum depression in some cases . in our study , though we did not come across any ptsd , there were cases of panic disorder ( 2% ) and social phobia ( 6% ) . we have also reported two subjects who had obsessions of child harm and in one subject , it was comorbid to social phobia . the most common psychiatric disorder in our study population was depression , seen in 41 subjects ( 27% ) . among them , 9 had social phobia comorbid to depression and one had obsession of child harm . the diagnosis of nos category of depression was used , due to the fact that the majority of the patients seen were in the 1 week of postpartum period and had onset of mood symptoms following delivery , whereas the mini specifies that the depressive disorder to be present for a duration of 2 weeks . both indian and western literature quotes that postpartum depression is prevalent in the range of 1015% . an indian study done with a similar methodology as ours quotes the rate of postpartum depression to be 23% . it reports that 16% of those delivering by normal delivery had depression as compared to 20% by cesarean method , though the difference was not statistically significant . our study reports a slightly higher rate of depression probably due to early assessment during the 1 week of delivery wherein some cases of blues might be identified that recover spontaneously after 2 weeks and are not picked up by mini as separate entity . obsessions of child harm ( 10% ) , panic disorder without agoraphobia ( 2% ) , and social phobia ( 6% ) were the other disorders identified in our study . hysteria ( conversion and dissociative reactions according to icd-9 ) was seen in 7% of all psychiatric morbidity among 100 consecutive postpartum subjects in an indian study though other anxiety disorders were not reported . in another study , social phobia was seen in 10% , simple phobia in 12% , panic disorder with or without agoraphobia in 4% , and ocd in 7% . however , most of them were present antepartum . further , all cases of social phobia and one case of ocd were antepartum . the number of dead children before the present delivery was the only risk factor contributing for the development of psychiatric morbidity in our study . among those who had one or more previous deaths , 16 of 19 had developed psychiatric problems , thus significantly differing from those who had no previous fetal deaths ( p = 0.045 ) . a review states that perinatal loss is a significant psychological trauma to parents both immediately as well as in the long term , and there is a tendency to focus exclusively on affective symptomatology in such cases . women with multiple losses were more likely to be diagnosed with major depression or ptsd than women with one pregnancy loss . another study reports that a history of previous loss by miscarriage and stillbirth is associated with depression during the current pregnancy . however , there is no significant difference in the psychopathology during current pregnancy associated with the type of loss in the past ( miscarriage vs. stillbirth ) . it also infers that the depression persists beyond the current pregnancy even though it resulted in a healthy baby . this is a cross - sectional , hospital - based study and we could analyze the data of all 152 subjects who participated in the study . some of the studies in this area are longitudinal , involving assessments during different stages of pregnancy and postpartum . although prospective studies are ideal to study psychopathology in such disorders , there will be attrition due to patients losing for follow - ups . the aim of our study was to assess the proportion and types of psychiatric morbidity and correlates in postpartum women in a tertiary care hospital . the study was based on the thinking that there is a need for the assessment and care of psychiatric morbidity in a tertiary care maternity centre , as the indian data in this area are not exhaustive . we have used mini to evaluate a variety of psychiatric comorbidities unlike the earlier studies focusing on postpartum blue , depression , and psychosis based on unstructured interviews and psychopathology rating scales . we did not administer any psychopathology rating scales as we did not compare psychopathology prospectively . the study reveals that psychiatric comorbidity is very common in the postpartum period and can be detected as early as 1 week after delivery . the overall psychiatric morbidity was 44% and the most common disorder was depression , seen in 26% women . the number of dead children ( stillborn and neonatal death ) before the present delivery is a risk factor for psychiatric morbidity during the current pregnancy . social phobia identified as a common association , though antepartum , is a new finding and needs further replication . it needs a larger sample with a prospective assessment to generalize the findings of our study . OUTPUT:

background : a range of psychological disorders occur in women in the postpartum period apart from the traditional blues , postpartum depression and psychosis . these include obsession of infanticide , ptsd , morbid preoccupations regarding child birth and disorders of mother - infant relationships , though they are under emphasized.methods:it is a cross - sectional study conducted in the tertiary maternity care hospital . a total of 152 study subjects were interviewed on mini ( mini international neuropsychiatric inventory ) and gaf ( global assessment of functioning ) within 2 weeks after delivery.results:the psychiatric morbidity was seen in 67 ( 44% ) of the study subjects . about 26% of subjects had depressive disorder nos . obsessive harm to the child , panic disorder , social phobia were the other disorders identified . there were no cases of mania , bipolar disorder , psychosis , post traumatic stress disorder or substance use disorder diagnosed across the sample . the global assessment of functioning ( gaf ) score averaged 87.8 . statistically significant association was seen to be present between psychiatric illness and number of previous still births and dead children before this delivery ( p = 0.045).conclusions : the study reveals that psychiatric co - morbidity is very common in the postpartum period and can be detected as early as first week after delivery . social phobia identified as a common association is a new finding and needs further replication . it needs a larger sample with a prospective assessment to generalize the findings of our study .

PubMed_Summ6595

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: microdissection , genetic , and inhibitor experiments have been used to define the parts of the spindle that are required for cleavage furrow induction . chromosomes have been shown to be dispensable for cytokinesis ( rappaport , 1996 ; zhang and nicklas , 1996 ; bucciarelli et al . , 2003 ; dekens et al . , 2003 ) . likewise , centrosomes can be ablated or genetically disrupted without preventing cytokinesis ( khodjakov and rieder , 2001 ; megraw et al . , 2001 ) . though chromosomes and centrosomes are dispensable , they may influence the process when they are present ( piel et al . , 2001 ) . in addition to chromosomes and centrosomes , the spindle contains a large array of microtubules . microtubule depolymerization during metaphase or very early anaphase prevents cleavage furrow formation , indicating that microtubules are essential ( hamaguchi , 1975 ) . however , furrow formation can occur if the mitotic spindle is depolymerized later in anaphase , but before ingression has begun ( hamaguchi , 1975 ) . thus , mitotic spindle microtubules are required to induce furrow formation , but they are not , per se , required for ingression . further insight into the mechanism of cleavage furrow induction has come from experiments in which cells , usually embryos , are physically manipulated and their potential to cleave assessed . these perturbations include alteration of the position of the spindle with respect to the cell cortex , cell shape deformation , and removal of parts of the spindle . for example , the classic torus experiment in which two spindles in a common cytoplasm induce an additional furrow indicates that opposing asters are sufficient to induce a furrow ( rappaport , 1961 ) . additionally , repositioning of the spindle during anaphase results in multiple cleavage furrows whose positions are dictated by the spindle ( rappaport , 1985 ) . results of numerous experiments of this type have led to the astral stimulation model ( fig . this concept assumes that astral microtubules provide a cleavage stimulus , which , for example , could be a factor that is transported along astral microtubules . this model proposes that because the equatorial cortex is influenced by astral microtubules from two poles , the strength of this stimulus would be highest at the cell equator . with some assumptions concerning the nature of the signal , its mode of delivery , and the distribution of microtubules , computer modeling indicates that a cleavage stimulus could reach a maximum at the equatorial region ( devore et al . , 1989 ; , asserts that astral rays ( i.e. , microtubules ) cause a reduction of cortical contractility in a density - dependent manner . according to this model , the density of astral rays is higher near the poles than at the equator , assuming spherically symmetric asters in spherical cells . this would cause the polar regions to be less contractile than the equator , and this difference in contractility would induce equatorial furrowing ( fig . 1 b ; wolpert , 1960 ) . quantitative modeling confirmed that this model could , in principle , allow furrow formation , but indicated that a positive feedback loop during contractility would be required to allow complete ingression ( white and borisy , 1983 ; yoshigaki , 1999 ) . these two models come to opposite conclusions regarding the role of astral microtubules because they differ in their underlying assumptions about the distribution of microtubules , their lengths , and the way in which they interact with the cell cortex . in addition , it is now apparent that activities exist that bundle microtubules from opposing asters and generate a structure that is called the central spindle ( also known as the spindle midzone ) . the evolutionarily conserved centralspindlin complex containing a kinesin - like protein mklp1 and a rho family gap , hscyk-4/mgcracgap ( mishima et al . , centralspindlin is directly involved in central spindle assembly because it localizes to the central spindle and has microtubule - bundling activity ( mishima et al . , another important factor in central spindle assembly is the microtubule - binding protein prc1 ( mollinari et al . , 2002 ) . because there is evidence that antiparallel microtubule bundles can regulate furrowing ( see below ) , some of the micromanipulation experiments that have led to the astral stimulation and relaxation models may need to be reinterpreted . indeed , observations in drosophila provide compelling evidence that astral microtubules may not be critical for furrow formation and that the central spindle is necessary and sufficient to induce furrow formation ( fig in particular , cells deficient in the kinesin - like protein pavarotti ( the orthologue of hs mklp1/ce zen-4 ) fail to form a central spindle , have rather normal appearing astral microtubules , and do not form cleavage furrows ( adams et al . conversely , asterless mutants , which lack most astral microtubules but retain a central spindle , are still capable of forming cleavage furrows ( bonaccorsi et al . , 1998 ) . these data fit neither the astral stimulation nor the astral relaxation model , and suggest that the central spindle is responsible for furrow induction . additional evidence supports the notion that the central spindle is involved in furrow formation . in cultured rat cells , if a small perforation is created adjacent to the central spindle , furrow formation occurs on the side of the perforation adjacent to the central spindle and not at the cortical site where furrow formation would have occurred in an unmanipulated cell ( cao and wang , 1996 ) . furthermore , grasshopper spermatocytes have been manipulated to simultaneously remove centrosomes and chromosomes , and the remaining microtubules self - organize into bundles that resemble the central spindle and appear to induce furrow formation ( alsop and zhang , 2003 ) . these results , combined with the fact that many key regulators of mitotic events localize to the central spindle , have lead to the proposal that central spindle microtubules ( or more generally , antiparallel microtubule bundles ) are a principle regulator of furrow formation . however , there is also compelling evidence that the central spindle is dispensable for cleavage furrow formation . in caenorhabditis elegans embryos , cleavage furrows form and constrict , but they fail to complete cytokinesis ( powers et al . , 1998 ; raich et al . , 1998 ; jantsch - plunger et al . , 2000 ) . the dramatically different requirement for the central spindle in furrow formation in drosophila and c. elegans could result from differences in cell size in these systems . indeed , some variation has been reported in the localization of critical factors that regulate cytokinesis . for example , in drosophila , in addition to the central spindle localized pool of pavarotti , there is also a cortically localized pool that is not detected in other organisms ( sellitto and kuriyama , 1988 ; adams et al . , 1998 ; powers et al . conversely , in mammalian cells , ect2 ( a gef for rhoa ) is readily detected in association with both the cell cortex and the spindle , but its orthologue in drosophila is primarily associated with the cell cortex ( prokopenko et al . , 1999 ; however , recent results suggest that neither cell size nor lack of conservation underlies the variable degree to which the central spindle controls furrow formation , and indicate that this process is controlled by two parallel pathways . in c. elegans embryos , the central spindle is not generally essential for furrow formation . however , if the extent of spindle elongation during anaphase is reduced by one of several genetic perturbations , the central spindle becomes essential ( dechant and glotzer , 2003 ) . in addition , although furrow formation can occur in the absence of the central spindle , initiation of cytokinesis is slightly delayed under these circumstances . thus , perhaps different cell types use both astral microtubules and the central spindle for furrow formation , albeit to varying degrees . indeed , there is evidence for plasticity in the induction of cleavage furrows in mammalian cells . microsurgical experiments indicate that the central spindle has furrow - inducing activity , yet cells depleted for key central spindle components , such as mklp1 or prc1 , still form furrows ( cao and wang , 1996 ; matuliene and kuriyama , 2002 ; mollinari et al . , given that both the central spindle and astral microtubules can contribute to induction of cleavage furrows , at least under some circumstances , proteins that localize to these structures are potential clues to the mechanism of furrow induction . , these factors could regulate furrow formation in two ways : they could be positive inducers of furrow formation , or they could inhibit a negative regulator of furrow formation . there are several factors that concentrate on the central spindle that have been suggested to be inducers of cleavage furrow formation . one candidate is the abi complex consisting of aurora b , incenp , and survivin / bir-1 ( adams et al . , 2000 ; , 2001 ; bolton et al . , 2002 ; cheeseman et al . , 2002 ; honda et al . , 2003 ; romano et al . , this complex contains a fourth protein , csc-1 ( romano et al . , 2003 ) . in mammalian cells , incenp first localizes to chromosomes during prometaphase , then it concentrates on centromeres during metaphase , and then , upon anaphase onset , it localizes to both the central spindle and , interestingly , the overlying cell cortex ( cooke et al . , 1987 ) . both astral microtubules and the central spindle contribute to cortical localization of aurora b ( murata - hori and wang , 2002 ) , presumably due to interactions with incenp and survivin , whose sole function appears to be to activate and localize aurora b. interestingly , aurora b localizes to the central spindle in cells that lack chromosomes ( bucciarelli et al . , 2003 ) , indicating that these subcellular targeting events are independent . the cortical localization of the abi complex precedes the early stages of cytokinesis ( eckley et al . , 1997 ) . although this localization of the abi complex suggests that it may direct cleavage furrow formation , cells deficient in aurora b ( due to mutation , rnai - mediated depletion , or chemical inhibition ) are competent to form cleavage furrows ( schumacher et al . , 1998 ; fraser et al . , 1999 ; kaitna et al . , 2000 ; hauf et al . , a second potential activator of cleavage furrow formation that could link the central spindle to cleavage furrow formation is the rhogef , pebble . pebble was recently shown to associate with drosophila centralspindlin ( somers and saint , 2003 ) . pebble ( hs ect2/ce let-21 ) is essential for furrow formation , presumably because it is the critical activator of rhoa in cytokinesis ( prokopenko et al . two - hybrid analysis indicates that the nh2 terminus of pebble binds to the nh2-terminal region of the fly orthologue of cyk-4 , racgap50c . concentration of centralspindlin in the spindle midzone could thereby recruit pebble and induce the local activation of rhoa , followed by actin polymerization and cleavage furrow formation . if this were the case , then cells defective in central spindle formation would also be expected to be defective in furrow formation . although coupling of these two processes is observed in drosophila , this is not the case in c. elegans embryos or in mammalian cells . moreover , overexpression of the nh2-terminal domain of the pebble orthologue , ect2 , causes a late defect in cytokinesis ( tatsumoto et al . , 1999 ) , not the early defect expected if the association of pebble with centralspindlin was essential for spatial regulation of pebble function . thus , although pebble is critical for furrow formation , its association with the central spindle does not appear to be critical in all species . the association of pebble with centralspindlin might promote the continued ingression of the cleavage furrow by maintaining rhoa in an active state . it will certainly be interesting to understand the interplay between the rhogap and the rhogef in this unusual protein complex . an alternative way to regulate furrow formation is through local inhibition of a negative regulator . experiments in mammalian cells and c. elegans embryos suggest that during cytokinesis , microtubules inhibit the contractility of the cell cortex . when microtubules are induced to be unusually short by prolonged activation of the katanin microtubule - severing complex , similarly , mammalian cells forced to exit mitosis in the absence of microtubules undergo vigorous unorganized contractions ( canman et al . , 2000 ) . given that there is compelling evidence that microtubules control furrow formation , it is conceivable that modulation of their distribution or properties could control furrow formation . in principle , bundling of microtubules to form the central spindle could quantitatively and/or qualitatively regulate the inhibitory effects of microtubules . thus , a second mechanism by which the central spindle could promote furrow formation is by inhibiting this negative regulation . experimental evidence that furrow positioning may result from local relief from microtubule - dependent inhibition of furrow formation . ( a ) stabilization of the microtubule - severing complex katanin leads to microtubule shortening and ectopic furrowing . ( b ) either central spindle assembly or spindle elongation are sufficient to induce furrow formation , but when both pathways are inhibited , no furrow formation occurs . ( c ) in mammalian cells , a subset of the microtubules in the vicinity of the furrow are less dynamic ( purple ) than elsewhere in the cell . spindle elongation and central spindle assembly act together to create a local minimum of microtubule density at a position in the cell equator equidistant from the two spindle poles ( dechant and glotzer , 2003 ) . importantly , these two processes also act in parallel to promote furrow formation ( fig . these observations are consistent with a model in which the position of the cleavage furrow in the equatorial region is determined by a site where the inhibitory effect of microtubules reaches a local minimum ( fig . central spindle assembly may not only affect the spatial organization of microtubules it could also alter the capacity of microtubules to inhibit contractility by changing the properties of the microtubules . for example , inhibition of cortical contractility could rely on the dynamics of microtubules or microtubule - associated proteins . binding of factors to the ends of the microtubules could alter their properties or dynamics . indeed , early work in mammalian cells indicated that midzone microtubules are more stable than elsewhere in the cell ( saxton and mcintosh , 1987 ) , and more recent observations confirm and extend these findings . in particular , before furrow ingression , a subset of microtubules in the vicinity of the presumptive furrow are significantly more stable than microtubules near the cell poles ( fig . it is not yet known if the stabilization of microtubules in the equatorial region is mediated by the centralspindlin complex , but this seems likely because it is present there , and overexpression of the kinesin subunit of centralspindlin ( mklp1/pavarotti ) induces hyperstabilization of microtubules ( minestrini et al . , 2002 ) . thus , binding of centralspindlin to microtubules could induce central spindle assembly and simultaneously prevent the microtubule - dependent inhibition of furrow formation . the rhoa exchange factor , dm pebble ( hs ect2 , ce let-21 ) is one of the most upstream molecules in this pathway and is a candidate for regulation by microtubules . however , little is known about how this critical exchange factor is regulated , except that its activity requires phosphorylation ( tatsumoto et al . , 1999 ) . additionally , although rhoa and some of its effectors concentrate at the cleavage furrow , there is no direct evidence for local differences in rhoa activity early in cytokinesis . recently , a fret - based approach to observe active rhoa during cytokinesis was reported . these probes did not reveal detectable amounts of active rhoa during early cytokinesis , but active rhoa did appear late in cytokinesis ( yoshizaki et al . , 2003 ) . because rhoa activity is required for the initial stages of furrow formation , it is possible that low levels of active rhoa drive furrow formation , and these levels of rhoa were below the detection limit of these probes . second generation probes specific for active forms of rhoa and other molecules essential for cytokinesis may provide further insight into this important question . however , given that there are several precedents for local activation of gtpase signaling complexes , a reasonable working model is that a local increase in rhoa signaling induces furrow formation . if so , furrow positioning could simply be explained if astral microtubules inhibit rhoa activation , thereby inhibiting furrow formation at ectopic sites , and central spindle assembly and spindle elongation conspire to provide local relief from these inhibitory effects and allow rhoa activation at the equatorial region . interestingly , microtubule depolymerization in interphase cells causes activation of rhoa - gtp ( ren et al . , 1999 ) , implying that microtubules can , directly or indirectly , inhibit rhoa . moreover , a particular rhogef , gef - h1 , is inhibited by microtubule - mediated sequestration ( krendel et al . , 2002 ) , illustrating one such mechanism . further analysis of the biochemical events that occur during furrow initiation is absolutely essential , with particular attention paid to how these events might be regulated by microtubules . at this juncture , furrow positioning does not appear to be solely due to induction by astral microtubules or the central spindle , but rather , both components contribute . cleavage furrow induction through local relief from the inhibitory effects of microtubules is an appealing model because it explains how two pathways , spindle elongation and central spindle assembly , could control furrow formation through a common molecular mechanism . in addition , it accounts for the fact that the central spindle has a positive ( though nonessential ) role in furrow formation . it also has predictive value in that local depolymerization of microtubules should induce cleavage furrows . in particular , it is tempting to speculate that the signals discussed here are important for patterning of the cortex in response to a local inhomogeneity in the distribution of microtubules . subsequent reactions may be required to refine this positional information and to amplify the signal that directs assembly of the contractile ring . alternatively , contractile ring assembly might be a cooperative process that is self - refining and amplifying . OUTPUT:

to complete the cell cycle , the cleavage furrow draws the plasma membrane toward the cell center , pinching the cytoplasm into two lobes that are subsequently separated into two cells . the position of the cleavage furrow is induced by the mitotic spindle during early anaphase . although the mechanism of cleavage furrow positioning is not understood at a molecular level , recent results suggest that it might be mediated by local relief from the inhibitory effects of microtubules .

PubMed_Summ6596

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: bacterial adherence is an essential step in all infections which involves surface interactions between specific receptors on the mammalian cell membrane and ligands on the bacterial surface . tissue specificity of infection is determined significantly by the presence or absence of specific receptors on mammalian cells . the ability of uropathogenic escherichia coli ( upec ) to adhere to host uroepithelia is an important stage in the successful colonization of the urinary tract and pathogenesis of urinary tract infection ( uti ) . the principal adherence organelle of upec is p fimbriae , which mediates gal(1 - 4)gal - specific binding via the adhesin molecule papg . the three molecular variants ( i to iii ) of the adhesin are coded by the adhesin gene papg of which there are three known alleles . these variants exhibit different receptor binding specificities . naturally , papg alleles occurin four combinations , that is , class plus iii , class iii only , class ii plus iii , and class ii only [ 2 , 5 ] . according to the receptor specificity of the papg adhesin , p - fimbriated uropathogenic e. coli is clinically divided into two subtypes : papg allele ii strains associated with pyelonephritis and bacteremia , and papg allele iii strains associated with cystitis but have been found in pyelonephritis and bacteremia [ 2 , 57 ] . the most common extraintestinal e. coli infection in healthy women is utis [ 8 , 9 ] which develop in an ascending manner , with e. coli gaining access to the bladder via the urethra , and the initial colonization of the vaginal mucosa is considered a critical step toward infection [ 1012 ] . acute cystitis is extremely common among reproductive - age women , whereas acute pyelonephritis , while much less common , is associated with high per - episode costs and morbidity and is more common in pregnant women than in nonpregnant women . as vaginal colonization by upec is a possible previous step to urinary tract infection , this work was designed to see if there is any difference in papg alleles ' distribution ( especially papg allele ii ) among e. coli vaginal isolates from pregnant and nonpregnant women and also to evaluate the possible ability of papg allele ii isolates to cause pyelonephritis by genotypic analyses of e. coli phylogenetic groups and extraintestinal pathogenic e. coli virulence factors ( expec vfs ) . this study included 122 e. coli isolates ( 61 vaginal and 61 fecal isolates ) . vaginal isolates ( 23 from pregnant and 38 from nonpregnant women ) were recovered as significant growth from high vaginal swabs collected by gynecologists from pregnant and nonpregnant women ( aged 1845 years ) clinically diagnosed as having symptomatic genital tract infection , without investigating the exact cause of infection ( women with vaginal discomfort , causes of which had not been clarified by gynecological examination ) . the swabs were streaked immediately after collection on eosine methylene blue agar ( emb ) ( himedia ) and blood agar plates . the plates were incubated at 37c for 2448 hours at ambient air . fecal isolates ( included for comparison ) were recovered from healthy volunteers ( pregnant ( 30 isolates ) and nonpregnant ( 31 isolates ) women , aged 1845 years ) . the specimens were processed according to plos et al . by dilution streaking the fecal material onto emb . after incubation , from each plate the last three colonies ( with the appropriate color and morphology , that is , characteristics of e. coli ) at the end of the streak area were selected and subcultured onto emb plate again , incubated , subcultured again onto tryptic soy agar plates ( tsa ) ( himedia ) , and then kept in the refrigerator for further work . all this study - included isolates were collected over a 2-year period from may 2008 to june 2010 at obstetrics and gynecology clinics in al - kut / wasit province / iraq , and were identified by conventional biochemical tests [ 16 , 17 ] . all isolates were screened for the presence of the three papg alleles ( i , ii , and iii ) by a multiplex pcr assay using specific primers ( table 1 ) . for template dna extraction , each isolate was subcultured onto tsa plates for 24 h at 37c . from the agar plate , bacterial suspensions were run for 10 min at 94c in a dna thermocycler ( multigene , labnet international , inc . , usa ) , and cell debris was removed by centrifugation ( 12,000 rpm for 1 min ) . pcr amplification reactions were performed in a volume of 25 l containing 12.5 l of kapataq 2x ready mix ( kapa biosystems , usa ) , 20 pmol concentrations of each primer , and 5 l of dna template . the cycling parameters [ 19 , 20 ] were as follows : an initial denaturation at 94c for 5 min ; followed by 26 cycles of 94c for 1 min , 60c for 2 min , and 72c for 3 min ; and with a final extension at 72c for 20 min . the amplified pcr products were subjected to electrophoresis at a 2% agarose gel in 0.5x tbe buffer . phylogenetic classification of e. coli isolates was determined using triplex pcr - based phylotyping described by clermont et al . . briefly , genomic dna of bacterial strains was amplified by triplex pcr using primers targeted to three markers , chua , yjaa , and tspe4.c2 . the phylogenetic grouping was made on the basis of the presence of specific pcr - amplified fragments as follows : group b2 ( chua+ , yjaa+ , tspe.c2 ) , group d ( chua , yjaa+ , tspe.c2 ) , group b1 ( chua , yjaa , tspec2 + ) , and group a ( chua , yjaa , tspe.c2 ) ( table 2 ) . multiplex pcr was used to detect five genes encoding virulence determinants usually associated with extraintestinal pathogenic e. coli strains ( expec vfs ) : neuc ( k1 capsule antigen ) , hly ( alpha - hemolysin ) , papc ( type p pili ) , sfa / foc ( type s pili and type 1c fimbriae ) , fimh ( type 1 pili ) , and iucc ( aerobactin ) [ 2 , 7 ] . virulence factor genes were amplified with the primers described in table 3 , in a total volume of 50 l containing 25 l of kapataq 2x ready mix ( kapa biosystems , usa ) , 20 pmol concentrations of each primer except hly ( 30 pmol ) , and 5 l of dna template . the reaction conditions were as follows : initial denaturation at 94c for 4 min followed by 25 cycles of denaturation at 94c for 30 s , annealing at 63c for 30 s , and extension at 68c for 3 min , followed by a final 10 min extension period at 72c . the amplification products were separated by electrophoresis in a 2% agarose gel containing ethidium bromide . a 100-bp dna ladder ( kappa universal ) was used in each gel as a molecular size marker . sixty - one vaginal e. coli isolates from pregnant and nonpregnant women were surveyed for papg alleles as predisposing factor to pyelonephritis . papg allele ii was the most prevalent allele among both vaginal ( 32.7% ) and fecal ( 3.2% ) isolates , whereas other alleles were found only among vaginal isolates ( 1.6% for alleles ii + iii ) . also 90% ( 9/10 ) and 78.5% ( 11/14 ) of papg pregnant and nonpregnant women 's vaginal isolates were papg allele ii , respectively ( table 4 ) . papg isolates were further genotyped for e. coli phylogenetic groups and expec vfs ' genes ( table 5 ) . papg vaginal isolates clustered in groups b2 ( 78.2% ) and d ( 21.7% ) , whereas all of the fecal isolates clustered in group d. except for sfa / foc , for all the studied vfs ' genes ( table 5 ) , papg vaginal isolates did not differ significantly in comparison with papg fecal isolates . also pregnant and nonpregnant women 's vaginal isolates did not differ significantly from each other for the possession of all the studied vfs ' genes . the vast majority of papg allele ii vaginal isolates were clustered in group b2 ( 81.8% ) and much less in group d ( 18.1% ) ( table 6 ) , whereas all of the fecal isolates clustered in group d. also , most of them were positive for fimh ( 100% ) , papc ( 100% ) , iucc ( 90.9% ) , and hly ( 72.7% ) , and about half of them were positive for sfa / foc ( 45.4% ) ( table 6 ) . in addition , the mean of vfs ' gene possession was 3.5 ( range from 2 to 5 ) . here in this work , the vast majority of papg allele ii vaginal isolates clustered in group b2 and much less in group d , and most of them were positive for fimh , papc , iucc , and hly , and about half of them were positive for sfa / foc ( table 6 ) . previous studies demonstrated that vaginal e. coli share common virulence factor profiles , phylogenetic groups , and serotypes with e. coli strains from urinary and neonatal ( blood and csf ) origins [ 11 , 20 ] as the vagina favors colonization by strains that possess features different from those of fecal flora strains , therefore , the vagina can be considered as an anatomical barrier that selects for strains with a greater capacity to cause disease . this high prevalence of phylogenetic group b2 and expec vfs among this work 's isolates indicates their pathogenic potential as expec ( especially pyelonephritic e. coli ) since most of upec strains belong to phylogenetic group b2 and , to a lesser extent , group d . in addition upec strains harbor numerous vfs , such as adhesins ( p fimbriae , type 1 fimbriae , s and f1c fimbriae , and afimbrial adhesin ) , toxins ( hemolysin and cytotoxic necrotizing factor ) , siderophores ( the aerobactin system ) , and polysaccharide coatings ( group ii capsules ) [ 7 , 27 , 28 ] . in comparison with cystitis and fecal isolates , pyelonephritic e. coli had a much greater prevalence of phylogenetic group b2 , uti - associated o antigens , and individual vfs , plus higher aggregate vf scores . papgii and papc are suggested to be associated with pyelonephritis and that papg allele ii is one of the significant predictors of this infection [ 2 , 29 ] . all papg allele ii isolates in this work were positive for both papc and fimh and about half of them were positive for papc , fimh , and sfa / foc . this is consistent with others who demonstrated that type 1 , p , s , f1c , and dr fimbriae are all known to bind to different sites within the human kidney and that p and type 1 fimbriae appeared to act in synergy to promote colonization of kidney . this possession of multiple fimbrial types contributes to the pathogen 's overall success during renal colonization . pregnant women 's isolates did not differ significantly from those of nonpregnant in possession of papg allele ii ( 39.1% versus 28.9% ) , whereas both ( 32.7% ) differed significantly ( p 0.05 ) in comparison with fecal isolates ( 3.2% ) ( table 4 ) . also papg allele ii isolates did not differ significantly from each other regarding the phylogenetic groups and expec vfs ' genotypes ' distribution ( tables 5 and 6 ) this indicates that both pregnant and nonpregnant women have the same chance to get pyelonephritis in accordance with this work 's proposal , although , previous studies found that acute pyelonephritis is more common in pregnant than in nonpregnant women [ 11 , 31 ] which means that physiological differences seem to be the critical determinants of predisposition to this infection due to stasis of urine and bacteriuria in the urinary tract caused by relative obstruction . the vaginal ecosystem and especially lactobacillus , as well as intestinal populations of e. coli , coitus and the physiological and anatomical conditions of the urinary tract also play a major role in the pathogenesis of urinary tract infections . the possible role of vaginal colonization by such isolates as predisposing factor to pyelonephritis can not be excluded and required further in vitro and in vivo analyses , as it previously had been found that vaginal colonization by e. coli represents an intermediate stage in extraintestinal e. coli pathogenesis and women often suffer from an enhanced susceptibility to recurrent urinary and genital tract infections in association with uropathogenic e. coli strains . so , it can be concluded that vaginal colonization by papg allele ii e. coli is possibly one of the predisposing factors of both pregnant and nonpregnant women to pyelonephritis , but its potential is modified by other factors especially host factors . OUTPUT:

vaginal ( 61 ) and fecal ( 61 ) escherichia coli isolates from pregnant and nonpregnant women ( 1845 years old ) were surveyed for papg alleles by pcr technique . papg allele ii was the most prevalent among both vaginal ( 32.7% ) and fecal ( 3.2% ) isolates , whereas other alleles were found only among vaginal isolates ( 1.6% for alleles i and iii and 3.2% for alleles ii + iii ) . papg+ pregnant women 's isolates did not differ significantly from those of nonpregnant in possession of papg allele ii ( 90% versus 73.3% ) , whereas both ( 32.7% ) differed significantly ( p 0.05 ) in comparison with fecal isolates ( 3.2% ) . the vast majority of papg allele ii+ vaginal isolates were clustered in group b2 ( 81.8% ) and much less in group d ( 18.1% ) . also , most of them were positive for fimh ( 100% ) , papc ( 100% ) , iucc ( 90.9% ) , and hly ( 72.7% ) , and about half of them were positive for sfa / foc ( 45.4% ) . in addition , the mean of vfs ' gene possession was 3.5 ( range from 2 to 5 ) . it can be concluded that vaginal colonization by papg allele ii+ e. coli is possibly one of the predisposing factors of both pregnant and nonpregnant women to pyelonephritis , but its potential may be modified by other factors especially host factors .

PubMed_Summ6597

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the incidence of stbi has been reported at 200 cases per 100,000 people worldwide . according to the world health organization 's study on the global burden of disease in 2010 , trauma remains as a public health problem and generates a significant burden on healthcare systems in latin american countries . in colombia in particular , the global burden of injuries is bigger in economically active , male population between 12 and 45 years of age . in 2013 , for example , about 26,000 deaths resulted from trauma , and most were associated with interpersonal violence ; of these injuries , a large percentage were associated with both closed and penetrating tbi . the objective of this study was to evaluate the outcomes of patients with stbi treated with a strategy of early cranial decompression ( ecd ) as a damage control procedure ( dc ) . this study was undertaken over a period of 4 years in a university hospital in colombia with limited neuromonitoring resources in the intensive care unit ( icu ) . the hospital at which this study was conducted , neiva university hospital ( nuh ) , is a 504-bed , level i trauma center and tertiary referral hospital in southern colombia . nuh admits approximately 2000 adult trauma patients per year and has 30 adult icu beds . the hospital is the primary trauma center for 3.2 million inhabitants living in an area extending over 60,000 square miles . its radius of care extends far into the amazonian region , where the most intense fighting between rebel groups , cocaine traffickers , and government forces has taken place for over 40 years . in this setting , tbi is exceptionally common , but few resources have been devoted to neurologic care in the hospital . nuh has one computed tomography ( ct ) and one magnetic resonance imaging machine and did not have continuous access to advance neuro - monitoring . thus , this is an appropriate location to study the effects of a dc procedure that may be implemented in a timely manner without the extensive use of already limited resources . this is a descriptive observational study of head trauma patients , who were managed with ecd as a dc approach in nuh between february 2009 and february 2013 . approval from the nuh , quality improvement office and the institutional review board of nuh was obtained prior to conducting this study . the patient outcomes were evaluated according to the glasgow outcome scale ( gos ) at 12 months postinjury . based on the gos score , a dichotomous variable divided into ( gos 4 or 5 ) , and unfavorable ( gos 13 ) groups was created . patients were evaluated using the gos in both the outpatient clinic and by phone interview . classic scale scoring was used ( 1 = dead , 2 = vegetative state , 3 = severe disability , 4 = moderate disability , and 5 = good recovery ) . additional criteria include age 18 years old , severe head trauma ( glasgow coma score 8 on arrival or head abbreviated injury scale 3 ) and icd-10 diagnostic codes of s-00 to s-09 or t-00 to t-14 . all of the patients included in the study were operated in less than 12 h post - trauma . we excluded patients with severe extracranial traumatic injuries , patients who do not receive a decompressive craniectomy , and patients operated after 12 h posttrauma . early decompression included a > 12 cm by 12 cm hemispheric craniectomy either with or without dural closure . surgical criteria for the procedure included : obliteration of the basal cisterns , midline shift of > 0.5 cm , acute subdural hematoma wider than 1 cm , epidural hematomas of > 30 cc in volume , or intracerebral hemorrhage of > 50 cc in volume [ figure 1 ] . tbi : traumatic brain injury , er : emergency room , eb : excess of base , asdh : acute subdural hematoma , edh : epidural hematoma , ich : intracranial hemorrhage , mdls : midline shift , cd : cranial decompression , icu : intensive care unit , sbp : sistolic blood pressure , hobe : head of the bed elevation , ab : antibiotic postoperative care includes sedation for at least 5 days with midazolam and fentanyl , 7.5% hypertonic saline in boluses every 6 h for 48 h and control ct at 24 h after surgery . antibiotic and anti - convulsive prophylaxis was used in penetrating injuries [ figure 1 ] . documentary review of medical records by data recording was performed using an intake form that included epidemiological , clinical , surgical , and outcomes data . the analysis of clinical , demographic , and imaging variables was performed for patients who had tbi and were operated with an ecd . variables such as glasgow coma scale at the emergency room , type of trauma , the severity of injuries , ct scan findings including the presence of hematoma , midline shift , and the compression of the basal cisterns were included . the results obtained in the study were analyzed by a statistical r software , version 2.15.2 , r foundation , free software foundation ( boston ma ) , usa . measures of central tendency and dispersion for continuous variables were calculated including frequencies and proportions for categorical variables . the student 's t - test was used to compare continuous variables , and pearson chi - square test was used for categorical variables this is a descriptive observational study of head trauma patients , who were managed with ecd as a dc approach in nuh between february 2009 and february 2013 . approval from the nuh , quality improvement office and the institutional review board of nuh was obtained prior to conducting this study . the patient outcomes were evaluated according to the glasgow outcome scale ( gos ) at 12 months postinjury . based on the gos score , a dichotomous variable divided into ( gos 4 or 5 ) , and unfavorable ( gos 13 ) groups was created . patients were evaluated using the gos in both the outpatient clinic and by phone interview . classic scale scoring was used ( 1 = dead , 2 = vegetative state , 3 = severe disability , 4 = moderate disability , and 5 = good recovery ) . additional criteria include age 18 years old , severe head trauma ( glasgow coma score 8 on arrival or head abbreviated injury scale 3 ) and icd-10 diagnostic codes of s-00 to s-09 or t-00 to t-14 . all of the patients included in the study were operated in less than 12 h post - trauma . we excluded patients with severe extracranial traumatic injuries , patients who do not receive a decompressive craniectomy , and patients operated after 12 h posttrauma . early decompression included a > 12 cm by 12 cm hemispheric craniectomy either with or without dural closure . surgical criteria for the procedure included : obliteration of the basal cisterns , midline shift of > 0.5 cm , acute subdural hematoma wider than 1 cm , epidural hematomas of > 30 cc in volume , or intracerebral hemorrhage of > 50 cc in volume [ figure 1 ] . tbi : traumatic brain injury , er : emergency room , eb : excess of base , asdh : acute subdural hematoma , edh : epidural hematoma , ich : intracranial hemorrhage , mdls : midline shift , cd : cranial decompression , icu : intensive care unit , sbp : sistolic blood pressure , hobe : head of the bed elevation , ab : antibiotic postoperative care includes sedation for at least 5 days with midazolam and fentanyl , 7.5% hypertonic saline in boluses every 6 h for 48 h and control ct at 24 h after surgery . antibiotic and anti - convulsive prophylaxis was used in penetrating injuries [ figure 1 ] . documentary review of medical records by data recording was performed using an intake form that included epidemiological , clinical , surgical , and outcomes data . the analysis of clinical , demographic , and imaging variables was performed for patients who had tbi and were operated with an ecd . variables such as glasgow coma scale at the emergency room , type of trauma , the severity of injuries , ct scan findings including the presence of hematoma , midline shift , and the compression of the basal cisterns were included . the results obtained in the study were analyzed by a statistical r software , version 2.15.2 , r foundation , free software foundation ( boston ma ) , usa . measures of central tendency and dispersion for continuous variables were calculated including frequencies and proportions for categorical variables . the student 's t - test was used to compare continuous variables , and pearson chi - square test was used for categorical variables at nuh , 156 patients were admitted with a diagnosis of stbi between february 2009 and february 2013 , but only 106 were managed under ecd with all the inclusion criteria [ table 1 ] . at 12 months postsurgery , a favorable clinical outcome ( gos 45 ) was found in 70 patients ( 66.1% ) , while an unfavorable clinical outcome ( gos 13 ) was found in 36 patients ( 33.9% ) ( p = 0.0001 ) . of the 36 patients with an unfavorable outcome , mortality ( gos = 1 ) was observed in 27 , with an overall rate of 25.4% . 70.1% ( 20 ) of the patients who die , were patients admitted for penetrating brain injury . the clinical and demographic characteristics of both groups are described in [ table 2 ] . clinical characteristics of patients with stbi admitted to nuh clinical and demographic characteristics of patients with stbi the factors that were associated with an unfavorable neurologic outcome were the following injury severity score ( iss ) > 35.62 ( 95% confidence interval [ ci ] , 35.645.8 ) , subdural hematoma at the first ct , closed basal cisterns , and unreactive pupils upon emergency room arrival . in [ table 3 ] , significant findings were analyzed for both groups . the average length of stay in the icu for the patients with a favorable gos ( 45 ) was 12.96 2.67 days while the group with an unfavorable gos ( 13 ) spent an average of 26.71 5.35 days in the icu ( p = 0.0002 ) . the average total hospital stay for the favorable group was 26.60 5.78 days while the unfavorable group spent 48.07 12.92 days ( p = 0.0001 ) . clinical and radiologic findings of patients with stbi postoperative care of all the patients was performed in the icu and included sedation with midazolam and fentanyl for a mean of 5 days and 7.5% hypertonic saline boluses every 6 h for 48 h. ct imaging was performed at 2472 h. brain swelling was present in 100% of the cases at both time points . cranioplasty was performed in most of the cases with autologous bone in a mean period between 1 and 3 months after the initial decompression . the world health organization predicts that traffic accidents will be the third leading cause of illness and injuries worldwide by 2020 , and this is one of the most common causes of tbi . in our study , we observed a population of 106 patients with stbi managed with ecd , where 84.9% were male , and the mean age was 36 years , representing the population that is at a major risk for trauma in low and middle - income countries . the management of tbi with ecd has been the subject of many studies in recent years , but often these studies do not provide enough scientific evidence for the procedure . these studies , though , utilize small sample sizes of patients , or use a time definition for ecd as > 12 h posttrauma , which disregards the importance of early intervention in regards to the ecd procedure and treatment for stbi . in addition , the results of these studies show high variability in patient age , type of surgery , and time to initiation of edc surgery . despite this , in many parts of the world ecd surgery as dc therapy has begun to play a critical role as management for neurotrauma . ecd has been cataloged as an important option to improve survival and reduce disability associated with tbi . this trend has been confirmed in our study where we found that of the 106 patients with stbi receiving ecd , 79 ( 74.6% ) survived and of those 79 surviving patients , 88.6% had a favorable neurological outcome ( gos 45 ) at 12 months after injury . we do not compare results with patients operated after 12 h in our center or with patients without surgical management in order to avoid bias into the final analysis . in addition , this sample has a homogeneous postoperative care as they were managed inside the specifically described algorithm . we do not include the other variables of the postoperative care , as part of the analytical model for the outcome , and maybe this is a limitation for this study . several studies of ecd have been conducted in centers where there is the availability of continuous medical monitoring in the neurological icu . in our hospital , continuous neuromonitoring in the icu is not an option ; however , the results obtained using edc as dc therapy reflected a better neurological outcome in patients with severe head injury . recent studies using the same technique have shown mixed results , including studies in centers of similar resources . in our study , patients who underwent ecd as dc therapy , an unfavorable neurological outcome was associated with closed trauma , an iss > 16 , obliterated basal cisterns , subdural hematoma as the predominant finding on ct , and nonreactive pupils upon admission . many of these factors have also been described in other studies that recommend ecd as a dc therapy for stbi , but our study findings need to be highlighted in a context of few resources for neuromonitoring and an aggressive surgical care as an option due to this resource limitation . the only available study of ecd in low resources environment includes the analysis of 10 patients in a teaching hospital in africa . at present , the management of patients with stbi should be aggressive from the moment they arrive at the emergency department ; different management protocols can be used help increase survival and reduce hospital time for these patients . in our study , hospital stay was significantly shorter for the group of patients with a favorable neurological outcome at 12 months from injury . twelve months outcome of patients with stbi managed with ecd in a neuromonitoring limited resource university hospital in colombia shows an important survival rate with favorable clinical outcome measure with gos . authors are supported by the nih - fic grant # r21tw009332 awarded to meditech foundation ( col ) and the university of pittsburgh ( usa ) . authors are supported by the nih - fic grant # r21tw009332 awarded to meditech foundation ( col ) and the university of pittsburgh ( usa ) . OUTPUT:

introduction : severe traumatic brain injury ( stbi ) is a disease that generates significant mortality and disability in latin america , and specifically in colombia . the purpose of this study was to evaluate the 12-month clinical outcome in patients with stbi managed with an early cranial decompression ( ecd ) as the main procedure for damage control ( dc ) therapy , performed in a university hospital in colombia over a 4-year period.materials and methods : a database of 106 patients who received the ecd procedure , and were managed according to the strategy for dc in neurotrauma , was analyzed . variables were evaluated , and the patient outcome was determined according to the glasgow outcome score ( gos ) at 12 months postinjury . this was used to generate a dichotomous variable with favorable ( gos of 4 or 5 ) or unfavorable ( gos of 13 ) outcomes ; analysis of variance was performed with the chi - square , wilcoxon mann whitney and fisher tests.results:an overall survival rate of 74.6% was observed for the procedure , at 12 months postsurgery , a favorable clinical outcome ( gos 45 ) was found in 70 patients ( 66.1% ) , unfavorable outcomes in patients were associated with the following factors : closed trauma , an injury severity score > 16 , obliterated basal cisterns , subdural hematoma as the main injury seen on the admission computed tomography , and nonreactive pupils observed in the emergency department.conclusion:twelve months outcome of patients with stbi managed with ecd in a neuromonitoring limited resource university hospital in colombia shows an important survival rate with favorable clinical outcome measure with gos .

PubMed_Summ6598

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: supported nanoparticles are used on a tremendously large scale for catalytic reactions . due to the inherent inhomogeneity of these , often industrial , materials , the basic understanding of their exact atomic structure and relation to their functionality can become very complex . one route to overcome this problem is by design of so - called bottom - up experiments in which well - defined nanoparticles are subjected to controlled environments . such studies can be performed by depositing nanoparticles in ultrahigh vacuum on perfect single crystal substrates , after which their structure is characterized under different thermodynamic conditions and gas environments . in this way , for example , oxidation reduction - induced reversible shape changes in nanoparticles have been discovered . solid oxide fuel cells ( sofcs ) are devices used for energy conversion and are considered as an important future green technology . their function is largely dependent on catalytic processes taking place at their interfaces . two important chemical reactions between the surrounding gas atmosphere and the solid play a decisive role . at the cathode , oxygen is dissociated , and the ions enter the electrolyte . fuel is being oxidized at the anode side , for which the required oxygen reaches the interface through the solid electrolyte . both the cathode and the anode consist of complex materials having a large surface area , such as polycrystalline oxides ( cathode ) or nickel nanoparticles ( anode ) . usually , ni is grown on the electrolyte by wet - chemical methods . here we investigate ni nanoparticles ( nps ) deposited on a polished yttria - stabilized zirconia ( ysz ) substrate as sofc model anode by surface sensitive x - ray diffraction methods . ysz with 9.5 mol % y2o3 content is a widely used sofc electrolyte material because of its high oxygen ion conductivity . nickel films grown on mgo(100 ) have been found to show several preferential orientations , forming a complex epitaxial system and of which the core is stable toward high temperature oxidation . this raises the question how smaller particles in the size regime from 310 nm , as typically encountered on the anodes of sofcs behave when in contact with a solid electrolyte . their sintering behavior in different atmospheres is particularly important for catalytic activity and long - term stability . here we show the results of such a study , whereby the ni nps are first annealed and finally oxidized . we find that ni nanoparticles grow with two very distinct orientations on ysz(111 ) , in contrast to mgo(100 ) . the nio formed during oxidation grows epitaxially with repect to the ni nanoparticles . from the measured particle heights and widths , the energy of adhesion , which is an important quantity with respect to the nanoparticles sintering stability , is determined . the experiments presented in the following were performed at the mpi beamline of the ngstrm - quelle karlsruhe ( anka ) using an x - ray energy of 10 kev . x - ray data consist of x - ray reflectivity , extensive reciprocal space mapping , and crystal truncation rod ( ctr ) data . in addition , ex situ atomic force microscopy ( afm ) measurements were performed in air once the synchrotron experiments had finished . polished single crystals of 9.5 mol % yttria - doped zirconia with orientation were used as substrate having a surface diameter of 10 mm . prior to the ni deposition , the substrates were annealed at 673 k in 10 pa o2 for 120 min , a procedure which was found to result in smooth and well - defined surface structures . the ni nps were grown with a substrate temperature of 623 k at a growth rate of 0.2 nm / min resulting in a nominal 3 nm of deposited material . here , we present results from two such growth runs with different samples , named sample i and sample ii hereafter . for sample i , only the as - prepared nps were structurally characterized , and after the in situ synchrotron experiment , the sample was investigated by atomic force microscopy ( afm ) in air . in a second experiment on sample ii , the ni nps were further treated , and extensive x - ray characterization was carried out . the as - prepared ni nps were first annealed at 973 k for 75 min , then exposed to 10 pa of methane at 573 k for 30 min and finally oxidized at 10 pa of o2 at 573 k for 35 min . after each of these steps , extensive x - ray data were taken , which allow us to determine changes in the orientation , size , and composition of the nps . because the methane exposure did not result in any notable structural changes , these data are not included in the present report . in addition , at each of the sample preparation steps , the ysz surface structure was investigated by measuring several ctrs with a nonzero in - plane momentum transfer . these data do not indicate any considerable changes after ni evaporation and after the oxygen treatment . because these ctrs probe the 3d atomic structure of the ysz(111 ) surface , which is partly covered by the nps , we conclude that each of these processing steps does not result in any significant atomic relaxations of the substrate . afm images were taken ex situ after the first growth run of nickel nanoparticles on ysz(111 ) without further treatments ( sample i ) . particles are clearly observed , and typical heights of 3 nm can be derived . just after growth , with the sample still in the uhv chamber , x - ray reflectivity ( xrr ) measurements were taken ( see figure 2 together with the xrr curves from sample ii described more extensively in this paper ) . the curves of the as - prepared states in both experiments are very similar . analysis of the xrr data is performed by fitting the electron density profile along the surface normal . here we use a so - called slab model , based on the fully dynamical parratt formalism . by comparison of the value obtained for the ni nps to that of a closed bulk ni layer , their coverage can be estimated . at the same time , the average height of the ni nps can be obtained from the xrr measurement . this information is contained mostly in the period of the oscillations of the reflectivity . the result from sample i gives an average height of 3.6 nm , in good agreement with afm performed on the same sample when considering that due to tip convolution effects those values will be systematically lower . in contrast to the height determination procedure described in the section nanoparticle shape and adhesion energy , xrr gives a value averaged over all np orientations . ( left ) afm phase contrast image of the ysz(111 ) surface after nickel evaporation ( sample i ) . ( middle ) height profile from the topographic data along the line as indicated ( left ) . x - ray reflectivity vs the momentum transfer along the surface normal qz(= 4 sin( ) / , with half the scattering angle and the wavelength ) measured after nickel evaporation . shown are the measurements ( symbols ) and fits ( solid lines ) for sample i as - prepared ( gray ) and sample ii as - prepared ( black ) , annealed ( blue ) and oxidized ( red ) nps , whereby the curves are scaled for clarity . the oscillations are a clear indication for the presence of the nps . from fitting an electron density profile to the data , the thickness and coverage of the nps are determined and these results are listed in table 1 . due to coexistence of ni and nio , it is not possible to reliably determine a coverage and merely the total apparent thickness is determined . once the crystalline ni nps were grown , the positions of their bragg peaks with respect to those of the underlying substrate were used to determine their orientation . in the following , several notations will be used interchangeably , depending on the particular frame that is referred to . due to conventions in surface diffraction , use is made of the ysz(111 ) surface unit cell to construct the reciprocal basis vectors of the substrate frame . the direct space axes of this nonprimitive hexagonal cell are a = b = 0.361 nm and c = 0.921 nm . the cell parameters of the conventional cubic lattices of both materials are ani = 0.354 nm and aysz = 0.541 nm . in the remainder of this article , subscripts of ( h , k , l ) coordinates are used to indicate with respect to which basis they are defined : ysz for the ysz(111 ) surface unit cell and ni - bul for the conventional fcc ni lattice and ni-111 for the ni(111 ) hexagonal surface unit cell . table 2 lists different ( h , k , l ) values in the different frames . by mapping out reciprocal space in selected areas , we have found two preferred np orientations and at least one other not yet reported for the epitaxial growth of ni nps . the first major one corresponds to the ni ( 111)-direction parallel to the substrate surface normal . the in - plane directions of the ni lattice were found to align with the substrate surface unit cell directions . this orientational relationship ( or ) is described by yszni111 and [ 110]ysz[110]ni111 and will be denoted or1 in the remainder of this paper . the ( 1,0,l)ni111 bragg peaks are found in a plane ( h,0,l ) at h= 1.44 ( see figure 3 ) , indicating that the ni is completely relaxed and adopts its bulk lattice parameter because this value corresponds exactly to the ratio between the bulk lattice parameters aysz / ani . two peaks , which belong to -oriented particles as described above , at h = 1.44 but at different l - values are seen , corresponding to the ni - bul ( 11 1 ) and ni - bul ( 002 ) reflections . these ni peaks indicate that the ni atoms follow an abc - type stacking along the substrate surface normal . if there were only one unique stacking sequence of the ni atoms , only one of these peaks would be visible , because the 3-fold symmetry axis of the fcc ni along its body diagonal would be preserved . instead , the observation of both peaks indicates that the ni atoms have two different stackings , which results in an apparent 6-fold symmetry axis around the stacking direction , which was also evident from scanning the sample around the surface normal whereby diffraction peaks separated by 60 appeared ( not shown ) . this diffraction feature indicates that the ni nps possess an internal twin structure , that different nps possess different stacking sequences starting from the substrate , or a combination of both of these . from the peak widths along the l direction , it is concluded that internal twinning does not occur frequently because this effect would lead to additional broadening and would result in lower apparent np heights , as explained in more detail in the section nanoparticle shape and adhesion energy . the substrate bragg peak at ( 1,0,2 ) and the corresponding ctr along the l - direction . the ( 1 , 0 , 1)ni111 and ( 1 , 0 , 2)ni111 bragg peaks from ( 111)-orientated ni nps . at ( 1.25 , 0 , 2.53 ) a peak belonging to ( 100)-oriented ni nps and at ( 1.66 , 0 , 1.86 ) a peak orignating from internal twinning as described in the text . the peak at ( 1.02,0,3.28 ) , which is labeled as ( 0 , 0 , 3)ni tilt , originates from the tilted nps as described in the text . table 2 gives an overview of the ( h , k , l ) coordinates expressed in different frames . the hk projection ( inset ) shows the substrate ( black ) and ni ( blue ) reciprocal lattice vectors . another strong ni - bul ( 111 ) peak is observed at ( 1,0,3.28 ) , which originates from np which are 41.33 tilted with respect to the ( 111)-oriented particles . this or2 is described by yszni111r41.33 and [ 120]ysz[120]ni111 , where r indicates a rotation . the full 3d information is confirmed by the observation of a ( 2,2,0)ni bul reflection , belonging to or2 and which is rotated by 34.4 from the substrate surface plane . the angular position of this reflection is obtained by rotating the ( 0,2 , 2)ni bul of or1 , which makes an angle of 30 with the plane of the rsm shown in figure 3 , around the [ 120]ysz direction by 41.33. the atomic - scale arrangement , schematically depicted as a side view along the rotation axis , is shown in figure 4 . the orientation can be understood from a so - called coherent tilt strain - relieving mechanism , which is rather common in thin film heteroepitaxy . for fcc metals , this epitaxial relationship originates from the diffusion of dislocations along ( 111 ) slip planes . the resulting edge dislocations line up laterally at the hetero interface , thereby reducing the strain and tilting the metal lattice . the energetics of this mechanism competes with other types of strain relaxation and can be kinetically hindered by dislocation movement . therefore , depending on the growth technique in combination with temperature , which determines the supersaturation and surface diffusion , different orientations are expected . nanoparticles as investigated here , would actually form the very early growth stage of textured polycrystalline thin films . the np nickel lattice is tilted such that the projection of ( 111 ) planes fits much better to the substrate atomic distance of 0.314 nm along this direction and therefore accommodates strain . the particular arrangement originates from an interfacial strain driven slip mechanism , which is common in fcc metals . by the diffusion of dislocations along the ( 111 ) slip planes toward the interface , the projected d - spacings have a better match with the substrate thereby relieving strain . as a consequence , figure 3 also shows much weaker peaks at ( 1.25,0,2.53 ) and ( 1.66,0,1.86 ) , which are ascribed to ( 100)-oriented nps and from internal twinning around the ni 111-direction pointing toward a side facet , respectively . because these orientations represent only a fraction of all the nps , as judged from the much weaker diffracted bragg intensities , these are left out of further consideration . the or1 found here has been reported before for a variety of different growth methods of ni on ysz(111 ) , like pulsed laser deposition and mbe . because this or results from a simple cube - on - cube stacking and most likely is energetically favorable , it has also been found for the ni - ysz(100 ) interface grown by directional solidification . these studies also report on other ors , but not on the or2 found by our x - ray diffraction study . interestingly , from the geometrical analysis of coincident lattice points , sasaki et al . find that the best match would be formed by yszni bulk and yszni bulk , an or that has experimentally never been verified , also not in this study . this point illustrates that ni - ysz lattice - matching alone is not enough to describe the different ors and that other energy terms such as chemical bonding and dislocation formation and their kinetic interplay during growth play a potentially more important role . moreover , it has been shown previously that the ysz(111 ) possesses a surface morphology with 2d monolayer high islands , which is expected to play a role in the np binding . the average size of the nps can be determined from the widths of their corresponding bragg peaks , under the assumption that the line broadening can be mostly attributed to their finite size and that nonuniform strain plays a minor role . the experimentally observed diffraction peaks are further broadened by the instrument resolution , which in the case here is anisotropic due to the synchrotron radiation characteristics in combination with the beamline focusing optics . from the single - crystal substrate bragg peaks the in- and out - of - plane instrument resolution is determined . because our sample coordinate system is chosen such that the hk - plane lies horizontal and the l - direction is vertical , the instrument resolution can be described by ( h , k,l ) = ( 0.025,0.060 ) , expressed in dimensionless reciprocal lattice units . all the experimentally determined diffraction peaks were well described by gaussians , so that the peak breadths are corrected for the instrumental resolution by = exp2res2 . the average height of the nps is given by the following reciprocal relationship:1where c = 0.890 nm is the direct lattice parameter of the ysz(111 ) surface unit cell and l the peak width ( fwhm ) along the l - direction corrected for the instrument resolution . a similar expression holds for the determination of the average widths ( w ) , for which the peak profile along the h - direction must be considered together with the fact that the h - direction makes an angle of 30 with the real space atomic layers within the hexagonal surface unit cell . the np heights and widths have been determined after each of the treatments , and the resulting values are presented in table 3 . the errors that are listed are calculated from the spread in values obtained from several bragg peaks at different positions in reciprocal space . in a next step , the average sizes are used together with wulff s construction to deduce the nps equilibrium shape when in contact with a foreign substrate . the underlying principle is that the nps are faceted and that those facets with the lowest surface energy will have the largest surface area . this aspect is now combined with the geometrical constraint that the nickel nps are supported by the ysz substrate . it is important to note that the description of the nps shape used in the following is valid for isolated particles ( i.e. , in the absence of particle particle interaction ) . from the afm measurement , shown in figure 1 , it can be concluded that coalescence may have set in for certain particles / areas but probably not for all . a more detailed analysis is hampered by the inherent lateral resolution of the used afm . nevertheless , the sample used for this study is probably not far off a model system with completely isolated nps . for fcc metals like ni , the wulff shape ( i.e. , without support ) is given by a polyhedron with predominantly ( 111)-oriented hexagonal facets together with smaller square ( 100 ) facets . this basic shape is taken as a starting point to construct the shape when in contact with a substrate . using the dimensions and orientation with respect to the substrate , the wulff shape has to be cut at particular positions . for the ( 111)-oriented particles , the wulff shape is shown in the upper part of figure 5a ) . the width of 8 nm and height of 5 nm , as determined previously , require a truncation of the wulff - shape , as shown in the lower part of figure 5a ) . the resulting shape of the ( 111)-oriented nps is then given by a large ( 111)-oriented top facet , six ( 111)-oriented side facets and three ( 100)-oriented side facets . the shape of the tilted nps is determined by rotating the wulff - shape by 41.3 in order to comply with the experimentally determined orientation . then this tilted particle is truncated at the experimentally determined height , see figure 5b ) . ( a ) wulff shape for the unsupported ( 111)-oriented np ( top ) and when supported by the ysz substrate ( bottom ) . the different treatments did not significantly change the nps shapes , although the heights and widths did change , as described in the text and seen in table 3 . the energy of adhesion for relatively round supported nps ( i.e. , which are not very flat and at least half as high as the wulff - constructed free particle ) is given by2with h the height of the np and h * the height of the buried part . it seems a reasonable approximation to relate the experimentally determined heights and widths to the geometric lengths of eq 2 as w = h + h*. taking a value of 111 = 1.89 jm , this gives wadh = 1.4 jm for the ( 111)-oriented ni nps after annealing . ( note : these surface - energy values were checked and recalculated with density functional theory ( dft ) using the latest perdew burke enzerhof ( pbe ) potential , which does not suffer too much from overbinding . ) because the error bar on the widths is relatively large , the criterion for using eq 2 might not hold anymore and they could actually be much flatter , in which case the following relation holds:3 this relation gives , together with 100 = 2.2 j / m ( see parenthetical note above ) , wadh = 2.1 j / m . the adhesion energy value obtained from eq 2 is somehwat smaller than typical values obtained for other materials systems , such as ptrh - al2o3 and pd al2o3 . the value obtained using eq 3 is much closer to those values and is in very good agreement with the value obtained for much larger ( w = 200 nm , h = 150 nm ) ni particles . for the tilted nps , a higher h / w ratio is observed , pointing to a reduced adhesion energy . the occurrence of two distinct np growth directions can be related to a difference in interfacial binding which either could originate from a lateral chemical inhomogeneity of the ysz substrate or a kinetically trapped state . also a size dependence can not be ruled out which is difficult to investigate due to the inherent size distribution of the nps after growth via thermal deposition . at a temperature of 573 k , the nps were exposed to molecular oxygen at a pressure of 10 pa for approximately 35 min , after which the oxygen was pumped off again . figure 6 shows a reciprocal space map after oxidation from the same plane as that shown in figure 3 . clearly observable are two new bragg peaks along the l - direction at h = 1.24 , which originate from nio . from the position of these two peaks with respect to the nearby bragg peaks of the ni -oriented nps the average heights and widths of the -oriented and tilted nps after oxidation are listed in table 3 . additionally , the temporal evolution during oxidation of some structural parameters were followed as well , see figure 7 . the integrated bragg peak intensity , which is proportional to the amount of pure metal , is seen in the decay below half of its initial value , which means that about 65% of the ni contained by the -oriented nps transforms into nio . at the same time , the average height of the -oriented nps changes only by approximately 0.2 nm , which is equal to the estimated error , see table 3 . nevertheless , the data do indicate a trend , whereby the average height of the pure metal ( core ) is reduced . the particular bragg reflection that was followed during oxidation gives an average height somewhat smaller than the value obtained from other bragg reflections and therefore is not identical to the values listed in table 3 . the position of the bragg peak along l can be used to determine changes in the uniform strain of the nps ni ( 111)-planes along the substrate surface normal . by comparing its shift from its initial value , which relates to d0 , the relative strain state d / d0 is calculated . it is seen in figure 7 that as oxidation proceeds , the lattice expands along the surface normal and levels off after an approximately 0.5% increase , a value very close to that found during thin ni film oxidation . we argue that this can be attributed to oxygen incorporation into the ni lattice . from the trend in the intensity curve , it is concluded that the oxidation process had not yet finished , although the lattice did not expand anymore , which indicates that the oxygen dissolution has reached a final state . l plane after oxidation at 573 k and 10 pa of molecular oxygen for 35 min . kinetics of the 111-oriented ni np evolution during oxidation . shown are the average height ( top ) , relative 111 bragg peak intensity ( middle ) and relative strain d / d0 ( bottom ) as a function of oxidation time . in order to rationalize the obtained results , we postulate the following oxidation mechanism . one important ingredient is that small nps oxidize relatively faster than large ones ; their so - called burn - up time is even lower than expected from the oxidation rate of planar surfaces , because the geometry of the electric field around these often more - rounded particles is predicted to accelerate the oxidation process . larger nps will first form an oxide skin around them , and eventually , they also burn up completely , but with a much lower rate . schematically , an intermediate state of this scenario is depicted in figure 8a , which represents the situation after the oxidation step presented here . given a certain particle size distribution , the resulting bragg peak shape figure 8 shows the results for such a calculation , using a hypothetical gaussian width distribution , around an average of 8 nm and a standard deviation of ann = 3 nm . gaussian - shaped diffraction peaks corresponding to each of the np size represented in the distribution are used in the calculation . a cutoff value around 5.5 nm is used , below which the nickel nps are completely oxidized . from the resulting ni and nio therefore , the width of a nio np , which has formed from a metal ni particle , is larger by a factor of 1.19 , which reflects the ratio of their lattice parameters . metal ni . in this particular numerical example , the average ni np width before oxidation is 8 nm , whereas after oxidation , both ni and nio widths are 9 nm . although this numerical simulation certainly does not include all the details of the oxidation process , it does show how the average np sizes can in principle be affected by a preferential oxidation of small particles and how this can lead to average np widths that are larger after oxidation . the simulation presented here does not differentiate between partially and completely oxidized particles , although the experimental results point toward such a situation . this is mostly seen in the large anisotropy between the oxidation of the nps top 111 facet and the average widths . both xrr and high - angle bragg peaks indicate that upon oxidation , the average height of the metal ni nps is slightly reduced , at most by 0.2 nm . it has been observed that during the oxidation of a ni(111 ) single - crystal surface under identical conditions as used in this work , a nio skin of approximately 2 nm forms after approximately 14 h. therefore , it seems reasonable to assume that for the oxidation time investigated here , at most , only one single outermost layer of ni atoms , which constitute the top facets , form an ultrathin nickel oxide . the oxidation process at the other facets , like 100 , seems to proceed much faster and even leads to complete oxidation of nickel nps . ( a ) small nps oxidize comparatively faster and burn up completely , whereas at the same time , an oxide skin has formed on larger nps and the core is still metallic . the evolution of the diffraction peaks is simulated using np width distributions during this partial oxidation process . ( b ) np width distributions before and after oxidation : initial metallic ni nps ( black line ) with an average of 8 nm and a spread of = 3 nm . after oxidation , the width distribution of the metallic core of the partially oxidized particles has become asymmetric and peaks at around 9 nm ( filled white ) . the width distribution of the oxidized metallic ni ( red ) is shifted due to the lattice expansion and is used to calculate the expected nio bragg peaks , see text for more explanation . ( c ) bragg peaks calculated as weighted averages using the gaussian width distributions . shown are the initial ni peak ( black ) , the final ni peak ( red ) , and the newly formed nio peak ( filled red ) . from the diffraction lines , average widths of 8 , 9 , and 9 nm for the initial ni , final ni , and nio particles are found , respectively . the oxidation behavior of the nps belonging to or2 has not been followed in situ , but the overall changes in height and width , as listed in table 3 , are very similar to those of or1 . the intensity loss on the metal ni bragg peaks is about 50% , very similar to that of the peaks belonging to or1 . we therefore conclude that the fact that the particles belonging to or1 have different facets exposed to the gas phase leads to minor changes in oxidation behavior and the stability of the particles is not much different . nickel nps were grown in uhv by pvd using an electron beam evaporator with a nominal average height of approximately 4 nm at substrate temperatures of 623 k. x - ray diffraction revealed that two distinct np orientations form ; there is no random orientational growth which would give rise to powderlike diffraction patterns . the np orientations are or1 : ni ( 111 ) planes parallel to the surface whereby the in - plane directions are also aligned ( niysz and ni[1 10]ysz[1 10 ] ) and or2 : ni 111 planes tilted by 41.33 from the substrate normal in the plane spanned by ysz and ysz[1 10 ] . the average heights and widths of the nps were determined from the x - ray diffraction line breadths . the relatively well - defined height is furthermore extracted from x - ray reflectivity and afm in a separate growth run , which all give systematically comparable values . the average heights and width of nps in both ors increase by approximately 25% , indicating that the particles exhibited already equilibrium shape at the growth temperature . from the height - to - width ( h - to - w ) ratio , together with the ni ( 111 ) and ( 100 ) surface energies , the adhesion energy is determined . depending on the np shape being more round or flat , two different relations hold . because the nps average aspect ratio h / w is close to , either of the relationships might give representative values . this is even more likely when taking into acount the appreciable size distribution , which is more broad in w than in h. the more rounded nps will then have an adhesion energy of 1.4 j / m and the flatter ones 2.2 j / m . this adhesion energy calculation does not hold for the tilted nps forming or2 because of their asymmetric shape . when exposing the nps to methane at a pressure of 10 pa and a temperature of 573 k for 30 min , no changes are observed . a possible adsorption of the hydrocarbons on the nps is thus concluded not to affect the structure of the nps . the most distinct changes are caused by an oxygen treatment at 10 pa and 573 k for 35 min . the intensity of the or1 bragg reflections , which is a measure for the total amount of metal , decreases to less than half its initial value . after the oxidation step , nio bragg reflections are detected , and from their positions in reciprocal space , it is deduced that nio has grown epitaxially , in a cube - on - cube fashion , on the nps from or1 or in contact with the ysz ( 111 ) surface . at the same time , the average height has changed by 0.2 0.3 nm and the average width + 1 3 nm . the average size of the nio is approximately equal to that of the remaining pure metal particles . these results can be rationalized by considering a preferential oxidation mechanism in combination with an anisotropic size distribution , whereby the spread in h is much narrower than that in w. it has been predicted that small , more rounded , nps will oxidize at an enhanced rate compared to larger ones . on the basis of these and our experimental results , we postulate that ni nps smaller than approximately 5.5 nm have burnt up completely and that larger ones have a nio skin formed around them . a simulation , using a hypothetical gaussian width distribution , shows that indeed this scenario can explain the experimentally observed average widths before and after oxidation . this description does not include all the details of the oxidation process , such as exact oxidation rate and nio thickness on the different facets , and even assumes that part of the larger nps does not oxidize at all , which is not very realistic . nevertheless , it shows numerically the effect one important aspect of the mechanism , namely , size - dependence , can have on the final average size . the size - dependent oxidation behavior might also be related to the kink seen after approximately 3 min in the time - dependent intensity reduction of the 111 bragg peak of figure 7 . the average size of the nio particles and/or skin is of the same order of magnitude as the remaining pure ni metal ( cores ) because of two effects : ( 1 ) due to the lattice expansion after oxidation ( i.e. , nio has larger lattice constants than ni ) , a completely oxidized np will be larger than the original one . this effect shifts the average oxidized np size to higher values , thereby compensating for the fact that the smaller metal particles have prefentially oxidized . ( 2 ) the oxide skin on the top facet is formed by a completely structurally correlated nio lattice . therefore , the in - plane nio size will be comparable to the underying metal particle . from ni(111 ) single - crystal oxidation studies , it was found that an approximately 2 nm oxide forms after 14 h at conditions similar to the ones here . extrapolating to the oxidation time used here , it would be expected to have oxidized only a monolayer from the 111 facets , which is about 0.2 nm thin . this value corresponds very well to the reduction in the average height of the ( 111)-oriented nps upon oxidation and would imply that the oxidation proceeds mostly along the ( 100 ) facets . the results obtained here can be discussed in relation to real sofcs , in particular with respect to the so - called redox cycling ( i.e. , the oxidation reduction process of ni ) . during sofc operation , the anode is continuously supplied with fuel , the amount of which is burnt depends on the availability of oxygen . instabilities around the ideal ratio of fuel and oxygen levels can lead to the formation of nio , which is known to lower the sofc performance and lifetime by stress development , lowering of the metal triple phase boundary density , and mechanical failure . our results may add another cause to sofc anode failure , namely , that during the time when there exists a surplus of oxygen , probably the smallest ni nps will completely oxidize and , depending on the reducing properties of the fuel , might not revert to pure metal anymore . after many cycles of such a process , the sofc might gradually loose its efficiency because the smallest particles are most likely to be the most reactive and therefore relatively more important for the functionality . moreover , such a preferential oxidation process , whereby the particle size distribution shifts toward larger values , might result in the sofc operation to drift away from complete reaction leaving unburnt fuel and increasing oxygen levels thereby oxidizing ever more ni . x - ray diffraction revealed two distinct orientations of ni nanoparticles grown in uhv by mbe : -oriented particles and ones with their planes tilted by 41.33 from the surface normal . a combination of diffraction line width analysis , x - ray reflectivity , and afm delivered information on the average np height and width . these sizes were used to determine the energy of adhesion to be in the range of 1.42.2 jm , whereby particles that have a more round shape are more weakly bound than those that have a flatter geometry . annealing the nps in uhv to 923 k led to the observation of sintering : most significantly , their average height increased and the data also indicate an increase in average width . this sinterering process does not lead to a significant shape change from just after growth . exposure to methane at 10 pa at a temperature of 573 k did not show any structural changes . however , oxidation at 10 pa of o2 at the same temperature led to the formation of expitaxial nio on the -oriented particles . an oxidation mechanism is postulated , which is based on a preferentially faster burn up rate for small particles and the formation of an oxide skin around larger ones . such a preferential oxidation mechanism which shifts the np size distribution toward higher values might be one factor responsible for the long - term degradation of sofcs . OUTPUT:

nickel nanoparticles supported by the yttria - stabilized zirconia ( 111 ) surface show several preferential epitaxial relationships , as revealed by in situ x - ray diffraction . the two main nanoparticle orientations are found to have their [ 111 ] direction parallel to the substrate surface normal and 41.3 degrees tilted from this direction . the former orientation is described by a cube - on - cube stacking at the oxide metal interface and the latter by a so - called coherent tilt strain - relieving mechanism , which is hitherto unreported for nanoparticles in literature . a modified wulff construction used for the 111-oriented particles results in a value of the adhesion energy ranging from 1.4 to 2.2 jm2 , whereby the lower end corresponds to more rounded particles and the upper to relatively flat geometries . upon oxidation at 103 pa of molecular oxygen and 673 k , a nio shell forms epitaxially on the [ 111]-oriented particles . only a monolayer of metallic nickel of the top ( 111 ) facets oxidizes , whereas the side facets seem to react more severely . an apparent size increase of the remaining metallic ni core is discussed in relation to a size - dependent oxidation mechanism , whereby smaller nanoparticles react at a faster rate . we argue that such a preferential oxidation mechanism , which inactivates the smallest and most reactive metal nanoparticles , might play a role for the long - term degradation of solid oxide fuel cells .

PubMed_Summ6599

***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: Output: Example: ***TASK*** the task is to summarize an input biomedical literature in six sentences ***INPUT*** the input is a biomedical literature ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences ***DOCUMENTATION*** ***EXAMPLES*** Input: mast cells ( mcs ) belong to the innate - compartment of the immune system and are widely known for their role in allergic reactions via their binding to ige receptor ( alvarez - errico et al . , 2009 ) . mcs are a common cellular component of both connective and mucosal tissues ( kitamura and ito , 2005 ) . beside this , mcs contain a wide range of biologically active molecules , including biogenic amines , heparin or heparan sulfate proteoglycans , neutral proteases , and neuropeptides . in addition , upon stimulation , they also produce and eject a large number of factors ( wilhelm et al . , 2000 ) . taking these characteristics together , it is clear that even a small number of such potent unicellular glands have a significant effect on different physiological processes . in addition to the very well known and described mechanism of mc activation and posterior degranulation throughout ige receptor , several other alternative but not redundant mechanisms of mc activation have been described ( mousli et al . , 1994 ; bradding , 2005 ; kim et al . , , 2005 ; vasiadi et al . , 2006 ; narita et al . , 2007 ; zaitsu et al . , 2007 ; jensen et al . , 2010 ; jing et al . , 2011 ; walter et al . , we will discuss in this review the current bibliography evidences about the effect of female sex hormones on mc functionality . female sex steroid hormones act primarily via their receptors : estrogen via estrogen receptor er or er , progesterone via progesterone receptor pr - a or pr - b ( carey et al . , 2007 ) . steroid receptors are best described as nuclear receptors acting as transcription factors on gene expression . however , in the past decade abundant evidences accumulated showing addition binding sides localized at the plasma membrane ( levin , 2011 ) , whose activation is more often involved in the rapid effects of steroids occurring within seconds to minutes ( watson et al . , 1999 ; watson and gametchu , 2003 ) . in this regard , it has been shown that classical er at the membrane but not in the nucleus mediates 17 - estradiol ( e2 ) - induced rapid signaling to kinase activation ( levin , 2011 ) . similarly , extra - nuclear pr induces activation of erk / mapk kinases , which lead to cell surviving as well as cells migration ( levin , 2011 ) . we and other authors have demonstrated the expression of , estradiol and progesterone receptors in human , mouse , and rat mcs ( theoharides et al . , 1993 ;( 2007 ) have shown mrna expression of er but not er in human and mouse mcs . alongside the authorshave also shown that e2 rapidly stimulated mc degranulation which could be blocked by tamoxifen , a tissue specific er antagonist , clearly indicating that estradiol - induced mc degranulation throughout one of its receptors . bone marrow - derived mcs ( bmmcs ) isolated from er knockout animals did not degranulate in response to e2 treatment confirming that the e2 effect on mcs is more likely mediated by the er ( zaitsu et al . , 2007 ) . due to the rapid onset of e2 effect on mc activationthe authors concluded that e2 in this context does not function through the classical ( genomic ) mechanisms , which require enhanced mrna and protein synthesis over 2 h or longer period and proposed that the effect is mediated by a membrane - associated ( non - genomic ) form of er ( zaitsu et al . we were additionally able to show that the human mast cell line ( hmc - 1 ) treated in vitro with physiological concentration of e2 and p4 significantly increased the synthesis of - tryptase , which is a serine proteinase abundantly produced by mcs , and is a marker of mc maturation . beside , e2 and p4 treatment induced degranulation of hmc - 1 in vitro ( jensen et al . , 2010 ) . supporting the idea of female sex hormones having an effect on mc function , kirmaz et al . ( 2004 ) have demonstrated that allergen skin prick tests ( spt ) , a very sensitive and specific tests to detect allergic sensitization in atopic patients , is altered in women upon hormonal changes during the menstrual cycle . in addition to female sex hormone receptor expression , mcs have been also shown to express androgen receptor ( chen et al . , 2010 ) . however , testosterone treatment had no effect on mc degranulation ( chen et al . , 2010 ) . the idea that female sex hormones , e2 and p4 , may affect mc functionality and therefore have an influence on the symptoms of mc - associated disorders has long been suggested . asthma and other allergic diseases of the airway are up to three times more common in women than in men during the early to middle adulthood and remains so through the reproductive years ( de marco et al . , 2002 ; mannino et al . , 2002 ; schatz and camargo , 2003 ) . a number of clinical and epidemiological studies suggested that female sex hormones are accountable for these differences . beside this , postmenopausal women taken hormone replacement therapy had higher risk of new onset of asthma ( barr et al . , 2004 ) . furthermore , 3040 % of women who had asthma , experience a worsening of their symptoms during the perimenstrual phase of the menstrual cycle ( perimenstrual asthma ) being the time point when e2 and p4 concentrations are changing rapidly ( vrieze et al . , 2003 ) . in this context , it is of great importance to mention that the prevalence and morbidity of asthma and other allergic diseases have increased dramatically during the last 30 years , particularly in developing countries ( burr et al . , 2006 ) . ( 2007 ) have nicely demonstrated that this may be related to the increase of low concentrations of environmental like - estrogen compounds . these estrogen - like compounds , called xenoestrogens , are present in the environmental pollutants mainly in water and food . they are able not only to activate mcs but enhance mc degranulation upon allergen cross - linking of ige which may explain the above described increment of allergic diseases in the last years in developing countries ( narita et al . , 2007 ) . in an animal model of allergic disease , the role of female sex hormone was tested . female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice ( reviewed in carey et al . , 2007 ) . levels of ige are much higher in allergic female mice compared to their syngeneic male ( corteling and trifilieff , 2004 ) . female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals ( ligeiro de oliveira et al . however , estrogen replacement in the ovariectomized animals re - established airway inflammation levels of intact females ( ligeiro de oliveira et al . , 2004 ) . treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease ( ligeiro de oliveira et al . , 2004 ) . thus , the direct effect of these hormones on disease development is hereby demonstrated . beyond the well - documented effects of estradiol and progesterone on mc function in mc - associated diseases , for instance , estradiol was showed to be a potent inducer of ovarian mc degranulation , which seems to be a necessary factor during the process of oocyte ovulation ( jaiswal and krishna , 1996 ; tamura and kogo , 1999 ) . the presence of mcs in the uterus has been already described in many species including human ( drudy et al . , 1991 ) , mouse ( padilla et al . ,1990 ) , rat ( aydin et al . , 1998 ) , hamster ( harvey , 1964 ) as well as goat ( karaca et al . , 2008 ) . besides , the number of mcs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on mc recruitment to the uterus ( aydin et al . , 1998 ) . ovariectomized mice , in which estradiol and progesterone are almost absent , have less number of uterine mcs compared to control , non - ovariectomized animals ( jensen et al . , 2010 ) . hormonal replacement , estradiol alone or in combination with progesterone , restored the number of uterine mcs after ovariectomization , which was comparable to the levels observed in control mice ( jensen et al . , 2010 ) . hormonal replacement additionally induced an augmentation in the levels of mc - related proteases expression in the uterus as well as boosted mc degranulation ( jensen et al . , 2010 ) . this is of particular importance because upon degranulation , mcs release several molecules ( histamine , proteases , metalloproteinases , pro - angiogenic factors ) , all very well known to account for the process of embryo implantation . mast cells , the so - called unicellular glands , once solely known as effectors cells of the innate immune system only activated by ige cross - linking to the ige receptor upon allergen stimulation are now known to be much more plastic and susceptible to be activated by several factors including female sex hormones , estradiol and progesterone . strong data in the last years reinforced the idea that these hormones are crucial component of mc behavior not only in physiological conditions but also in several mc pathological situations . deciphering the mechanisms by which female sex hormones activate mcs and under which conditions these happens , alongside with explanation why female sex hormones have these effects is of crucial interest for a better understanding of the physiology of these cells . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest . Output: female sex hormones have long been suspected to have an effect on mast cell ( mc ) behavior . this assumption is based on the expression of hormone receptors in mcs as well as on the fact that many mc - related pathophysiological alterations have a different prevalence in females than in males . further , serum ige levels are much higher in allergic female mice compared to male mice . ovariectomized rats developed less airway inflammation compared to sham controls . following estrogen replacement ovariectomized rats re - established airway inflammation levels found in intact females . in humans , a much higher asthma prevalence was found in women at reproductive age as compared to men . serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma . around 3040 % of women who have asthma experienced worsening of their symptoms during the perimenstrual phase , the so - called perimenstrual asthma . postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma . beside , estrus cycle dependent changes on female sex hormones are related to changes on mc number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine mc maturation and degranulation . we will discuss here the currently available information concerning the role of these female sex hormones on mc behavior . INPUT: the existence of different crystalline forms ( polymorphs , hydrates , and solvates ) represents one of the most challenging phenomena in solid - state chemistry and related sciences , since we are still not able to predict the number of practically relevant forms and the conditions under which these can be grown or exist . the existence of different solid - state forms of a compound is important as these usually show different physical properties , for example , solubility , density , hardness , melting point , etc . this is true for pharmaceuticals ( the majority of the active ingredients are used in a crystalline form(2 ) ) , because the solid - state form can profoundly influence the manufacturing process , the long - term stability , and the performance of drug products , and for many other materials used in the chemical industry ( plant protection substances , dyes , explosives , etc . ) . the present study deals with the solid - state of -resorcylic acid ( 2,4-dihydroxybenzoic acid , ra , figure 1 ) , a small organic molecule exhibiting molecular flexibility and the ability to form different hydrogen bonding motifs . the compound is used as a starting material for the production of dyestuffs , pharmaceuticals , cosmetic preparations , and fine organic chemicals . the cambridge structural database ( csd)(5 ) contains entries for three ra solid - state forms , namely two anhydrates ( zzzeeu:(6)p1 , z = 2 and zzzeeu01 to zzzeeu04:(7)p21/n , z = 1 , measured at 90 , 100 , 110 , and 150 k ) , and a hemihydrate ( qivtuk:(8)p1 , z = 1 ) . for the triclinic anhydrate , only the lattice dimensions have been reported , and the volume of zzzeeu corresponds to a monohydrate rather than an anhydrous form(9 ) but not to the new monohydrate described in this work . for the monoclinic polymorph ( form ii hereafter ) , the temperature range has been extended very recently down to 20 k.(10 ) furthermore , different hydrate stoichiometries , ranging from 0.5 to 3 mol water per mol of acid can be found in literature reports , but only the crystal structure of the hemihydrate has been determined . a recent study comparing six isomeric dihydroxybenzoic acids failed to crystallize new polymorphs by melt crystallization and sublimation experiments.(12 ) joint experimental and computational studies have shown that there is no cooperative hydrogen atom disorder in the cooh and o - oh groups in form ii at temperatures up to 150 k. however , ra was neither subjected to a systematic solution crystallization screen nor to a comprehensive solid - state characterization program , and also theoretical predictions of possible crystal structures have not been reported so far . global ( conf_p1 ) and second lowest conformational minima ( conf_p2 ) of -resorcylic acid ( ra ) . the intramolecular degrees of freedom ( dihedral angles ) that were optimized within the crystal energy minimizations are indicated with arrows : 1 : c6c1c7o2 , 2 : c3c2o3h , 3 : c5c4o4h and 4 : c1c7o1h . therefore , our investigation aimed at an efficient screening program , using an experimental and computational(16 ) approach to complement and validate the results and comprehensively characterize all ra solid - state forms at ambient conditions . the experimental screen was based on manual solution crystallizations of the compound in a variety of solvents and crystallization conditions , sublimation and moisture sorption experiments . the thermodynamic and kinetic stability of the solid - state forms were ascertained by hot - stage microscopy , differential scanning calorimetry , thermogravimetic analysis , and solvent - mediated transformation studies . vibrational spectroscopy ( mid infrared and raman ) and x - ray diffractometry ( powder and single crystal ) were employed to determine the structural features of the phases . however , as neither high - throughput methodologies or other widely applied screening strategies(19 ) guarantee all possible forms will be found , we supported and complemented our manual screen with computational crystal structure prediction ( csp ) . by contrasting the thermodynamically feasible crystal structures with the experimentally observed ones , we discuss the factors that control crystallization and polymorphism of ra . ra was purchased from fluka ( form ii ) . for the solvent screens , a set of 25 solvents was chosen ( supporting information , section 1.1 ) , which were all of analytical quality . crystallization conditions included solvent evaporation , fast and slow cooling crystallization , precipitation with a miscible antisolvent , vapor diffusion , and solvent - mediated transformation . in total , more than 150 manual crystallization experiments were performed ( conditions and crystallization outcomes are provided in the supporting information , tables s1s5 ) . we have named the polymorphs according to the kofler notation using roman numerals in the order of the melting points ( i.e. , the highest melting is named form i ) and flagged the thermodynamically stable form at room temperature with the symbol . form ii was either prepared by slow crystallization from numerous solvents , including n - butanol , n - propanol , i - propanol , acetonitrile , ethyl methyl ketone , ethyl acetate , or by solvent - mediated transformation of any ra form , using water - free solvents that did not form a solvate . form i could be obtained from solvent crystallization , but it predominantly grew concomitantly with form ii. the easiest way to produce form i was heating any ra form above the transition temperature of the polymorphic transition ii i ( 150170 c ) . however , decomposition , although slow compared to the polymorphic transformation , starts at ca . other methods included sublimation experiments in the same temperature range or the desolvation of the hemihydrate ( hh ) , dimethyl formamide hemisolvate ( sdmf - i ) , dimethyl sulfoxide hemisolvate ( sdmso ) , or dioxane hemisolvate ( sdx ) at temperatures above 60 c . the two hydrates could be prepared by crystallization from a hot , saturated water solution , with the resulting solid form depending on the cooling rate . fast crystallization to the final temperature of 0 c ( in ice ) led to the monohydrate ( mh ) , whereas slow cooling ( test tube wrapped in aluminum foil ) produced the hemihydrate ( hh ) . the dioxane hemisolvate ( sdx ) , dimethyl formamide 0.75-solvate ( sdmf - ii ) , and the dimethylsulfoxide hemisolvate ( sdmso ) were prepared from ii by solvent - mediated transformation experiments in the respective solvent , the acetic acid monosolvate ( saa ) by fast crystallization ( cooling a hot saturated solution in acetic acid to ca . 8 c ) . finally , the dimethyl formamide hemisolvate ( sdmf - i ) was obtained as an intermediate desolvation product of the sdmf - ii solvate . every crystallization or solvent - assisted grinding experiment with pyridine resulted in the formation of the pyridinium salt.(22 ) for hot - stage thermomicroscopic ( htm ) investigations a reichert thermovar polarization microscope equipped with a kofler hot stage ( reichert , a ) was used . photographs were taken with a digital camera ( olympus colorview iiiu digital camera , d ) . dsc was performed with a dsc 7 ( perkin - elmer , norwalk , ct , usa ) using the pyris 2.0 software . approximately 13 0.0005 mg sample ( um3 ultramicrobalance , mettler , ch ) was weighed into al - pans ( 25 l ) . dry nitrogen was used as the purge gas ( purge : 20 ml min ) . the instrument was calibrated for temperature with pure benzophenone ( mp 48.0 c ) and caffeine ( mp 236.2 c ) , and the energy calibration was performed with pure indium ( purity 99.999% , mp 156.6 c , heat of fusion 28.45 j g ) . tga was carried out with a tga7 system ( perkin - elmer , usa ) using the pyris 2.0 software . two - point calibration of the temperature was performed with ferromagnetic materials ( alumel and ni , curie - point standards , perkin - elmer ) . heating rates ranging from 10 to 20 k min were applied , and dry nitrogen was used as a purge gas ( sample purge : 20 ml min , balance purge : 40 ml min ) . the stated error limits of thermochemical data are calculated as confidence intervals at a 95% level . isothermal ( 25 0.1 c ) moisture sorption isotherms were acquired using a sps-11 moisture sorption analyzer ( projekt messtechnik , d ) . the samples were gently ground prior to measurement to exclude the influence of particle size and surface area . sorption and desorption cycles covered the 1090% rh range in 10% steps and the 010% range in 5% steps . the equilibrium condition for each step was set to a mass constancy of 0.001% over 35 min . spectra were recorded with a bruker ( bruker optic gmbh , d ) ifs 25 spectrometer connected to a bruker ir microscope i ( 15-cassegrain - objective , spectral range 4000 to 600 cm , resolution 4 cm , 64 scans per spectrum ) . the samples ( rolled on a znse disk or fused between two znse windows ) were measured in transmission mode . spectra were recorded with a bruker rfs 100 raman - spectrometer ( bruker analytische messtechnik gmbh , d ) , equipped with a nd : yag laser ( 1064 nm ) as the excitation source and a liquid - nitrogen - cooled , high sensitivity ge - detector . the spectra ( 128 scans per spectrum ) were recorded in aluminum sample holders with a laser power of 200 mw and a resolution of 2 cm . experiments were performed on an oxford diffraction gemini r ultra ( 4-circle kappa - goniometer , 135 mm ruby ccd detector , mok radiation , monocapillary collimator ) with an oxford cryosystems 700 series cryostream plus low temperature attachment . the single crystal structures of hh , sdmso , and the pyridinium salt were solved by direct methods using the program package wingx(23 ) ( sir2004(24 ) and shelxl97(25 ) ) . all hydrogen atoms bonded to carbon atoms were generated by a riding model on idealized geometries with uiso(h ) = 1.2 ueq(c ) . the polar hydrogens were identified from the difference map and refined isotropically , with the exception of h9 in sdmso , where the position was refined with a constrained oh bond distance . for further details , pxrd was used to determine the structure of form i. the sample was loaded in a rotating 1.0 mm borosilicate glass capillary and mounted on a bruker axs d8 powder x - ray diffractometer equipped with primary monochromator ( cuk1 , l = 1.54056 ) and lynxeye position sensitive detector . data was collected at room temperature using a variable count time scheme ( supporting information , table s6 ) . the diffraction pattern indexed to a monoclinic unit cell ( omitting an impurity peak at 20.8 2 arising from a suspected decomposition product ) and the space group was determined to be p21/a based on a statistical assessment of systematic absences,(26 ) as implemented in the dash structure solution package.(27 ) the data were background subtracted and truncated to 50.5 2 for pawley fitting(28 ) ( pawley = 15.91 ) . simulated annealing was used to optimize the form i model against the diffraction data set ( 115 reflections ) in direct space . the internal coordinate ( z - matrix ) description was derived from the hf/6 - 31g(d , p ) gas phase global conformational minimum ( conf_p1 ) , with oh distances normalized to 0.9 and ch distances to 0.95 . the structure was solved using 200 simulated annealing runs of 2.5 10 moves per run as implemented in dash , allowing 7 degrees of freedom ( 6 external and 1 internal ) . 4.66 ( profile / pawley ) and was used as the starting point for a rigid body rietveld refinement(29 ) in topas v4.1.(30 ) the rigid body description was derived from the z - matrix used in the simulated annealing runs and the final refinement included a total of 61 parameters ( 40 profile , 4 cell , 1 scale , 1 uiso , 9 preferred orientation , 3 position , and 3 rotation ) yielding a final rwp = 5.53 ( figure 2 ) . powder x - ray diffraction pattern and rietveld fit ( rigid body ) of ra form i at 25 c . we considered all eight planar hf/6 - 31g(d , p ) conformational minima produced by varying the torsion angles 1 3 ( figure 1 ) in the csp searches for anhydrate crystal structures , using a three - stage methodology.(31 ) first , z = 1 and z = 2 crystal structures were generated using crystalpredictor(32 ) in 25 common space groups for organic molecules . the molecules were held rigid and the lattice energy was evaluated by an exp-6 potential with atomic charges derived using the chelpg scheme(33 ) and minimized . all crystallographically distinct low energy crystal structures were used as starting points for optimizing the intermolecular lattice energy ( uinter ) , with an improved model for the intermolecular forces . this was calculated using the fitexp-6 potential parameters and the distributed multipoles(37 ) derived from the pbe0/aug - cc - pvtz charge density using gdma2.(38 ) finally the 28 most stable structures were refined with crystaloptimizer(39 ) to allow small changes in conformation ( torsion angles 1 4 in figure 1 ) by minimizing the lattice energy , elatt = uinter + eintra , where eintra is the conformational energy penalty ( with respect to the global conformational minimum ) paid to improve the intermolecular interactions . the conformational energy penalty was computed at the pbe0/6 - 31g(d , p ) level . all isolated - molecule wave function calculations were performed using gaussian03(40 ) and intermolecular lattice energies by dmacrys.(41 ) more details of the conformational analysis , model testing , and search procedure and results are given in supporting information . the solvent screening program resulted in a new ra polymorph ( form i ) , a new monohydrate ( mh ) , and five new solvates , namely acetic acid ( saa ) , dioxane ( sdx ) , dmso ( sdmso ) , and two dmf solvates ( sdmf - i and sdmf - ii ) . the previously described anhydrous form ( form ii)(7 ) and the hemihydrate ( hh)(8 ) could be reproduced . the relationships between the ra solid state forms ( figure 3 ) and their structures are described in experimental section 3.1 , and their relationship to the computed possible structures are described in section 3.2 . transition pathways of the ra forms at different temperatures and relative humidities ( rh ) ; mh : monohydrate , hh : hemihydrate , i : form i , ii : form ii , saa : acetic acid monosolvate , sdmf - ii ( 0.75 ) and sdmf - i ( hemi ) : dimethyl formamide solvates , sdmso : dimethyl sulfoxide hemisolvate and sdx : dioxane hemisolvate , t : heating , * : removing from the mother liquor , mechanical treatment , for example , grinding form ii occurs in solvent crystallization / evaporation experiments as long needles , whereas form i occurs as a polycrystalline powder comprising multilayered plates . htm and dsc experiments revealed that form ii transforms to form i upon heating at temperatures above 150 c . optically this transformation can be recognized by a darkening of the form ii needles due to cleavage and the formation of small aggregates of form i ( figure 4 ) . tga experiments and further thermomicroscopic investigations ( silicon oil embedding ) showed that no desolvation process is involved in this process , confirming that the reaction is a single component ( polymorphic ) transition . the weak endotherm in the dsc curve ( figure 4 ) at an experimental transition temperature ( ttrs , exp ) of 159.8 0.5 c corresponds to the solidsolid transformation ii i with a transition enthalpy of trsh = 2.1 0.1 kj mol . from the fact that the transition is endothermic , it can be concluded that the two polymorphs are enantiotropically related ( heat of transition rule ) . this implies that the melting point of form ii is lower than that of form i , which melts at 231 c with decomposition ( second endotherm in dsc curve of figure 4 , overlapping with a broader endotherm , indicating the decomposition process ) . form ii is thus the thermodynamically stable polymorph at room temperature ( rt ) and form i represents the high temperature form , which nevertheless shows a high kinetic stability at rt . a reversible transformation i ii was only observed if the sample was mechanically treated ( e.g. , grinding at room temperature ) . the fact that form ii is thermodynamically stable at 20 c was also confirmed with solvent - mediated transformation experiments . the energy - temperature diagram of the two polymorphs derived from the thermoanalytical data is provided in supporting information ( figure s2 ) . hot - stage microscopy photographs of the ra form ii to form i transformation , along with the dsc curve that shows the transformation ( ii i ) , melting ( mp ) , and decomposition ( dec . ) of form i ( heating rate : 10 k min ) . the hh forms transparent blocklike crystals ( figure 5 ) , which are stable when removed from the aqueous mother liquor . single crystals of hh turn opaque when heated above 70 c , while the original shape of the crystals is more or less maintained ( pseudomorphosis ) . in silicon oil preparations , the release of bubbles accompanies the darkening of the crystals and confirms the desolvation process ( see figure s1 , supporting information ) . the mass loss of 5.55% ( tga , figure 6 ) is consistent with the theoretical water content of a hemihydrate ( 5.52% ) . the second hydrate ( monohydrate , mh ) crystallizes as needles and was found to be very unstable at ambient conditions . tga shows ( figure 6 ) that the dehydration of mh occurs below 60 c resulting in form ii. a transformation of mh to hh can only be observed in a water slurry . the measured mass loss ( figure 6 ) of ca . 9.5% corresponds to 0.9 mol water per acid molecule , which is slightly lower than expected for a monohydrate ( theory : 10.47% ) due to some loss of water during the preparation of the unstable mh . photomicrographs ( dry preparation ) showing the dehydration process of ra hh to form i in a htm experiment ( heating rate ca . all five solvates form transparent , thin , needle- or plate - like crystals losing their transparency within hours when removed from the mother liquor . upon heating ( figure 6 ) , desolvation of saa occurs in one step between about 40 and 60 c resulting in needle - shaped form ii crystals . sdmf - ii shows two desolvation steps under heating . the first desolvation process ( figure 6 , mass loss ca . 50 and 70 c and corresponds to the transformation of the 0.75-solvate ( sdmf - ii ) to the hemisolvate ( sdmf - i ) , which then desolvates at ca . 90 c to form i. sdmso shows a peritectic melting / decomposition at 90 c . upon further holding the temperature , long plates ( form i ) slowly crystallize from the melt ( observed in htm , not visible in shown dsc curve ) . it was not possible to clearly determine the stoichiometric solvent content from tga experiments , as the desolvation and decomposition process overlaps . however , the course of the first step of the curve shows that the desolvation process decelerates before the fast decomposition process starts at about 150 c , indicating that the majority of the solvent is released . we can extrapolate the end of the first step to about 80% , suggesting that sdmso is a hemisolvate ( theoretical mass loss : 20.2% ) sdx shows an inhomogeneous melting process consisting of the following events : peritectic melting / decomposition , evaporation of the solvent ( dsc : endotherm at ca . 85 c ) , and the crystallization of form i ( exotherm above 110 c ) . dsc ( black ) and tga ( red ) curves of ra hydrates and solvates ( pin - holed dsc capsules and a heating rate of 10 k min was used for all thermograms ) . forms i , ii , and hh were subjected to a gravimetric moisture sorption study at 25 c ( figure 7 ) . the anhydrous phases absorb water and transform only to hh even at the highest rh value ( 90% ) . the moisture sorption cycle of form i was completed within 48 h , whereas only ca . hh dehydrates only under rather dry conditions ( 5% rh and below ) demonstrating its high stability . under these conditions , the profile of the moisture sorptiondesorption isotherm ( sharp steps , strong hysteresis between sorption and desorption ) is a very clear indication that hh is a stoichiometric hydrate.(44 ) from the huge hysteresis , we can deduce that the anhydrates and hh can be handled and stored as stable phases provided extremely low or high moisture conditions are avoided . moisture sorption isotherm of ra performed at 25 c showing a moisture sorption cycle of anhydrous ra to hh and a desorption cycle of hh to a polymorphic mixture of forms i and ii . the ft - ir spectra ( figure 8) allow an unambiguous identification of all forms , as variations were found in numerous regions , for example , (oh ) , (carh ) , (c = o ) , and (coh ) vibrations . the most striking difference in the ir spectra of the two polymorphs concerns the (oh ) vibration of the p - oh group . in form ii a sharp band occurs at 3373 cm , whereas in form i the band is broader and shifted to higher wavenumber ( 3432 cm ) implying weaker and more complex hydrogen bonding . saa exhibits additional bands in the range of 970880 cm due to the out of plane oho hydrogen deformations(45 ) ( most intensive band : 920 cm ) . the two dmf solvates showed two distinct vibrations at 1107 and 10941095 cm , whereas all other phases exhibit only one or three bands in this region . on the basis of the (c = o ) vibrations , the dmf solvates can be discriminated , with sdmf - ii at 1666 cm and sdmf - i at 1652 cm . the (s = o ) vibrations(46 ) in sdmso occur at 1002 cm ( strong band ) . finally , the symmetric stretch vibrations of the ether group in sdx can be found at 865 cm . ft - ir spectra of ra polymorphs ( i , ii ) , hydrates ( hh , mh ) , and solvates ( saa , sdmf - ii , sdmf - i , sdmso , and sdx ) . ft - raman spectroscopy ( figure 9 ) also allows the identification of the different ra solid - state forms . the presence of the solvent molecules ( acetic acid , dmf , dmso , and dioxane ) can be clearly seen in the spectral range around 2900 cm ( stretching vibrations of the aliphatic ch3 and ch2 groups , only present in the solvent molecules ) . moreover , the lattice phonon vibrations below 150 cm differ markedly , indicating that the crystal structures of the ra solid - state forms are different and also that the solvates are not obviously isostructural as frequently observed if compounds form a series of such adducts . ft - raman spectra of ra polymorphs ( i , ii ) , hydrates ( hh , mh ) , and solvates ( saa , sdmf - ii , sdmf - i , sdmso , and sdx ) . the clear differences in pxrd patterns from each phase studied are consistent with the very distinct structures for all ra solid - state forms ( supporting information , figure s3 and table s6 ) . temperature- and humidity - controlled powder x - ray diffraction studies of the dehydration process ( supporting information , figures s4 and s5 ) confirmed the results presented in sections 3.1.2 and 3.1.5 . form i crystallizes in the monoclinic space group p21/a ( z = 1 ) and form ii in p21/n ( z = 1 ) , both adopting a conformation similar to conf_p1 ( figure 1 ) . the two polymorphs form inversion related r22(8 ) dimers and furthermore share the same 1d arrangement ( supramolecular construct(49 ) ) of inversion related dimeric units ( figure 10a , c ) however , they differ in the way the 1d constructs are linked to neighboring units , the o4ho3 hydrogen bonds , and consequently in the packing . in form ii , the o4ho3 interaction exhibits n glide symmetry ( figure 10b ) , leading to puckered hydrogen - bonded sheets ( figure 10a ) and to a dihedral angle between the 1d constructs ( benzene rings ) of 31. in form i , where 21 symmetry is present a dihedral angle between the benzene rings of 82 is observed . hirshfeld dnorm surface(50 ) plots ( figure 10e , f ) clearly indicate that the p - oh proton forms only one h - bond in form ii , but that the assumed p - oh conformation in form i corresponds to two hydrogen bonds . the p - oh proton can form a hydrogen bond to either the o- or p - oh oxygen , without otherwise changing the structure . the difference in shape and larger volume of the surface around the p - oh in form i in contrast to form ii is consistent with possible disorder of the p - oh proton between the two positions , which due to the weak scattering contribution of hydrogen could not be verified based on the fit to the pxrd data alone but would be consistent with the broad ir band . it appears that there is an unusual freedom in the position of the p - oh proton in the form i structure and so there will be ambiguities in the proton position . crystal packing of form ii ( a , b ) and form i ( c , d ) viewed along the a - axis ( a ) , direction ( b ) , c - axis ( c ) , and b - axis ( d ) . black dotted lines indicate the hydrogen bonds . for clarity only selected symmetry symbols are shown . hirshfeld surfaces for forms ii ( e ) and i ( f ) were generated using the program crystal explorer v. 2.1,(52 ) with ch and oh distances normalized to neutron values , dnorm is mapped on the surfaces over the range 0.48 to 0.78 . this function highlights contact distances relative to the sum of van der waals radii , with closest contracts shown in red . the circles in ( e , f ) highlight the p - oh group and hirshfeld surface around it , hh crystallizes in the triclinic space group p1 with two molecules of ra ( similar to conf_p1 and conf_p2 ) and one water molecule in the asymmetric unit , in agreement with the stoichiometry determined by tga . the structure comprises columns of r22(8 ) dimers , formed by symmetrically equivalent , inversion related ra molecules ( homodimers ) . each dimeric unit is directly linked to the adjacent alternate dimers with an o4ho4 hydrogen bond and indirectly via a water molecule bridge , that forms two hydrogen bonds ( o4howater and owaterho4 ) , leading to sheets . in addition to connecting the acid dimers , water forms the only strong hydrogen bond between the parallel stacked sheets , leading to a 3d network structure ( figure 11 ) . the dehydration of hh involves a structural collapse , as despite the water interactions the o4ho4 hydrogen bonds also break due to the conformational change , which is around 180 in the torsion angle for the p - oh proton in every second molecule . the units differ from the 1d construct present in the polymorphs in the location of the inversion center ( figure 11a ) . crystal packing of hh : ( a ) ( 046 ) plane shown , ( b ) viewed along the a - axis showing the parallel sheets . hydrogen bonds are denoted with dotted lines , and for clarity the water protons were omitted . two acid molecules and one dmso molecule are present in the asymmetric unit of sdmso , which crystallizes in the orthorhombic space group p212121 . the two symmetry inequivalent molecules adopt a conformation similar to conf_p1 and form r22(8 ) heterodimers . strong hydrogen bonds are only present within the alternating heterodimer - dmso bands ( figure 12 ) and not in between the layers or stacking of the bands , which implies that the solvent could escape easily compared with hh and could explain why sdmso is not a long - living solvate . the solvate and the desolvation product , form i , both contain similar 1d stacks of acids , along a in sdmso ( perpendicular distance : 3.024 , centroid distance : 6.398 ) and c in form i ( perpendicular distance : 3.489 , centroid distance : 5.198 ) . this implies that on losing the solvent a rearrangement of the acid stacks with respect to adjacent stacks is necessary . on the other hand , crystal packing of sdmso : ( a ) corrugated heterodimer dmso bands , view along the b - axis , ( b ) viewed along a - axis . the pyridinium cation interacts with ra carboxylate via an ionic nho hydrogen bond ( supporting information , figure s5 ) . the crystal energy landscape showed that only the two most stable conformations , differing in the position of the p - oh proton , could generate crystal structures within the likely energy range of polymorphism . the lowest energy crystal structures had the lowest energy conformation ( conf_p1 , figure 1 ) , there were a few with the alternative p - oh conformation ( conf_p2 ) , but the majority of hypothetical structures contained both conformations , conf_p1 and conf_p2 , in a 1:1 ratio producing z = 2 structures . the lack of any crystal structures varying the conformation of the intramolecular h - bond , involving the o - oh proton and c = o oxygen , is consistent with the experimental cocrystals , solvates , including hydrates and modifications.(7 ) experimentally , only conformations closely related to conf_p1 and conf_p2 , or a mix of the two , were observed , with the largest deviation of up to 10 in the position of the p - oh proton from planarity . all low - energy structures ( figure 13 ) form one intra- and two intermolecular hydrogen bonds . the majority of computed crystal structures exhibit the experimentally observed r22(8 ) acid dimer ( d ) , but there are also acid catemer ( c ) , coohoh chain ( ch ) , and the combination of d and ch structures . the two experimental anhydrates were found to correspond to the lowest - energy structures within the two lowest energy groups of structures , with form i being the global minimum . however , there is a low energy catemeric structure that is very competitive in energy with the known forms , and various other high density structures which also appear thermodynamically feasible . lattice energy landscape for the ra anhydrates ( elatt = uinter + eintra ) after relaxation of the conformation within the crystal structure , classified by the hydrogen - bonding motif . all structures with the same hydrogen bonding motif ( symbol ) within an ellipse are closely related . the reproduction of form ii was excellent , given the neglect of thermal effects in our model , with an optimal root - mean square overlay of all non - hydrogen atoms in a 15 molecule coordination cluster ( rmsd15)(56 ) of 0.16 . in contrast , the reproduction of form i was poor with an rmsd15 of ca . 1 , and it was wrongly predicted to be denser and more stable than form ii. the estimated helmholtz free energies(57 ) derived from the elastic constants(58 ) and k = 0 phonons(59 ) calculated in rigid - body harmonic approximation ( table s11 , supporting information ) for the two polymorphs bring forms i and ii to within 0.2 kj mol in energy . hence , the static lattice energy model ( figure 13 ) is certainly overestimating the energy differences between the two polymorphs . since proton disorder is suggested by the ir spectrum and the hirshfeld dnorm plot ( section 3.1.3 and 3.1.4 ) , we computationally generated three alternative ordered versions of form i differing only in the proton conformations which were kept fixed ( supporting information , section 2.3 ) . this resulted in structures that were slightly less dense , and in similar or better agreement with the experimental structure than the global minimum on the crystal energy landscape . hence , proton disorder in form i would result in a less dense structure , and some of the destabilization(60 ) may be counteracted by configurational entropy . the calculations also showed that there was no barrier in this crystal structure to the proton moving by 30 from the lowest energy planar conformation . unfortunately , we were not able to grow single crystals suitable for structure determination for all solid - state forms . from the ir and raman spectra , it could be assumed that in all phases the ra molecules are dimerized , as the symmetric (c = o ) band appeared in the region 16751625 cm . furthermore , information about the hydrogen bonding of the p - oh group in the two anhydrates could be derived from the ir spectra . the shift of (oh ) in form ii to lower wavenumbers indicates a stronger intermolecular oho hydrogen bond compared to form i. the broadening in the form i spectrum was attributed to the undetermined p - oh proton position between adjacent o- and p - oh groups ( see section 3.1.4 ) . on the basis of the experimental as well as theoretical results , we could not rule out the p - oh proton showing static or dynamic disorder . static proton disorder has been shown to be possible by lattice energy minimization calculations which also show that there is no barrier to changing the proton position within the form i crystal structure , so it could also be dynamically disordered . further insight into the disorder could be obtained from periodic ab initio calculations,(62 ) but the possibilities of experimental verification are very limited without neutron diffraction data . the ra solid - state forms differ considerably in their relative stability . at ambient conditions only the two anhydrates and hh are stable . mh and all five solvates survive only for a short time after harvesting from the mother liquor . the formation of such unstable solvent adducts is common in organic molecules ; however , these are easily overlooked , especially when the product is dried prior to analysis or when the analysis is not performed immediately after the removal from the mother liquor.(44 ) in contrast to the metastable solvates , hh , in which water plays a structural role , is a very stable phase , as dehydration occurs only at temperatures higher than 60 c or under the driest conditions ( below 10% rh , 25 c ) . the extreme hysteresis between the sorption and desorption process of hh attests to the high kinetic barrier of the hydration and dehydration processes with respect to vapor pressure . hh ) exhibit a desolvation temperature above 60 c in the dsc / tga experiments and revert to the metastable form i. the monosolvates ( saa and mh ) desolvate below 60 c to the thermodynamically most stable form ii. therefore , it is obvious that the desolvation temperature is critical for the formation of a specific polymorph . even though a large number of experiments were performed , we can not guarantee that all possible ra forms were found , as the range of variables in crystallization experiments that could influence the outcome is very large . the anhydrate crystal energy landscape showed that the two known forms are the most likely polymorphs . the alternative dimerbased structures ( figure 13 ) are sufficiently similar to the known polymorphs suggesting that they could readily transform to form i or ii in the unlikely event that they were distinct at the nucleation stage . however , the lattice energy landscape suggests that other polymorphs could exist , which do not have the carboxylic acid dimer motif , but form exclusively cooh catemers or chains . a csd(5 ) analysis of o - oh benzoic acid derivatives(63 ) showed that the r22(8 ) carboxylic acid dimer motif is the predominant hydrogen bonding motif , as seen in all four structurally characterized ra phases . the relative stability of the catemeric structures on the crystal energy landscape may be overestimated by the computational model . we can not exclude the possibility that the formation of the dimer motif is kinetically favored in all the crystallization conditions we have explored , hence ruling out the formation of catemers during our screening experiments . -resorcylic acid represents another organic molecule exhibiting a complex solid - state behavior , that is , polymorphism , salt , and solvate ( hydrate ) formation . the experimental search has resulted in seven new solid - state forms ( anhydrate , monohydrate , and five solvates ) , in addition to the previously known , and structurally characterized anhydrate ii and hemihydrate hh.(8 ) we found no evidence for a triclinic polymorph ( zzzeeu(6 ) ) or a hydrate showing a water / acid stoichiometry greater than 1:1.(64 ) before we can answer the question how exhaustive should a polymorph screen be ? , perhaps we must add a supplementary question , namely , how exhaustive does your knowledge of physical form diversity need to be ? ; that is , do we need to confirm that the most thermodynamically favorable form at 25 c is already known or do we want to identify all accessible solid forms , perhaps to select a metastable form that has superior properties ? it is worth considering these alongside any limitations in terms of available material , stability , time , etc . when designing a comprehensive screening strategy . however , recognizing that it is impractical to sample all possible nucleation and growth conditions for a given molecule , we can conclude that as a minimum , a polymorph screen should include sufficient diversity to at least find the thermodynamically most stable polymorph ( non solvated ) and hydrate form(s ) as well as those thermodynamically unstable forms that show sufficient kinetic stability at ambient conditions ( termed metastable forms ) to enable them to be isolated and identified . furthermore , a polymorph screen should identify all crystallization products , including intermediates in the crystallization process , for example , solvates , amorphous form , etc . and characterize transformation pathways in order to find alternative , or perhaps only , routes to obtain a specific form . therefore , a robust screening approach requires the combination of a variety of experimental approaches(67 ) including crystallization from solution ( evaporation , cooling , slurry conversions ) , sublimation , crystallization from the melt , thermal and moisture dependent studies and desolvation methods . the statement by maria kuhnert - brandstaetter,(68 ) probably every substance is potentially polymorphous . the only question is , whether it is possible to adjust the external conditions in such a way that polymorphism can be realized or not , reflects the problem that there are numerous additional strategies , at ambient and nonambient conditions , which might be adequate for the nucleation and growth of further solid - state forms . it is practically not feasible to cover the whole range of techniques that have been shown to produce new polymorphs for certain systems,(21 ) particularly using all kinds of templates , additives , seeds , or impurities that might generate new forms or stabilize metastable phases . the instability of many solvates of -resorcylic acid , the possibility of considerable variation in the p - oh position in form i , and the computed thermodynamically feasible anhydrates mean that we can not exclude the discovery of other solid - state forms . therefore , our results for -resorcylic acid emphasize the problems of determining the complete set of solid - state forms when there is evidence of disorder or short - lived intermediate crystallization products whose lifetime is very dependent on conditions . thus , the consistency between the experimental and computational techniques used in this study adds confidence that the practically most important -resorcylic acid solid - state forms at ambient conditions have been characterized , showing the value of calculating the crystal energy landscape as part of the screening process . 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a combined experimental and computational study was undertaken to establish the solid - state forms of -resorcylic acid ( 2,4-dihydroxybenzoic acid ) . the experimental search resulted in nine crystalline forms : two concomitantly crystallizing polymorphs , five novel solvates ( with acetic acid , dimethyl sulfoxide , 1,4-dioxane , and two with n , n - dimethyl formamide ) , in addition to the known hemihydrate and a new monohydrate . form ii , the thermodynamically stable polymorph at room temperature , was found to be the dominant crystallization product . a new , enantiotropically related polymorph ( form i ) was obtained by desolvation of certain solvates , sublimation experiments , and via a thermally induced solidsolid transformation of form ii above 150 c . to establish their structural features , interconversions , and relative stability , all solid - state forms were characterized with thermal , spectroscopic , x - ray crystallographic methods , and moisture - sorption analysis . the hemihydrate is very stable , while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates . complementary computational work confirmed that the two experimentally observed -resorcylic acid forms i and ii are the most probable polymorphs and supported the experimental evidence for form i being disordered in the p - oh proton position . these consistent outcomes suggest that the most practically important features of -resorcylic acid crystallization under ambient conditions have been established ; however , it appears impractical to guarantee that no additional metastable solid - state form could be found .