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combined resection of the superior vena cava ( svc ) is sometimes required during surgical treatment of mediastinal tumors and lymph node metastasis from lung cancer , and several reconstructive methods of the svc have been described . we herein propose a novel and simple technique for repair of svc wall defects using a left brachiocephalic vein flap . a 33-year - old man was referred to our hospital because of abnormal chest shadow . contrast - enhanced computed tomography ( ct ) revealed a 50-mm - diameter mass in the anterior mediastinum ( fig . 1 ) . invasion of the anterior wall of the svc was suggested because of the unclear border between the tumor and the svc . f - fluorodeoxyglucose uptake on positron emission tomography exhibited a maximum standardized uptake value of 6.5 . from radiographic findings , the mass was suspected to be a malignant tumor such as a thymoma or thymic cancer , although a pathological diagnosis was not established . therefore , we planned extirpation of the tumor via a median sternotomy . figure 1:contrast - enhanced ct showing an anterior mediastinal tumor with suspected invasion of the svc . contrast - enhanced ct showing an anterior mediastinal tumor with suspected invasion of the svc . exploration revealed a solid mass , which infiltrated the anterior wall of the distal portion of the svc from the confluence of the bilateral brachiocephalic veins to just above the azygos junction . the left brachiocephalic vein was transected with stapler 40 mm from the brachiocephalic vein junction . after cross - clamping of the svc at the level above the azygos vein and right brachiocephalic vein , the caudal side of the left brachiocephalic vein was then divided longitudinally , and the pedicled flap of the left brachiocephalic vein was sewn onto the svc defect using 5 - 0 prolene ( ethicon , somerville , nj ) ( fig . contrast - enhanced ct 1 month postoperatively revealed the patency of the reconstructed svc . ( a ) after transection of the distal side of the left brachiocephalic vein with a stapler and extirpation of the tumor with partial resection of the svc , the caudal side of the left brachiocephalic vein was divided longitudinally . ( b ) a pedicled flap was then made from the left brachiocephalic vein and sewn onto the svc defect . ( a ) after transection of the distal side of the left brachiocephalic vein with a stapler and extirpation of the tumor with partial resection of the svc , the caudal side of the left brachiocephalic vein was divided longitudinally . ( b ) a pedicled flap was then made from the left brachiocephalic vein and sewn onto the svc defect . an asymptomatic 57-year - old man was diagnosed with right lung squamous cell carcinoma and referred to our hospital for further evaluation and treatment . contrast - enhanced ct revealed a 45-mm - diameter mass in the lower right lung lobe and a 25-mm - diameter swollen anterior mediastinal lymph node adjoined the anterior side of the svc . the patient had interstitial pneumonia and elected to undergo surgical resection of the tumor instead of chemoradiotherapy . through a posterolateral thoracotomy in the fifth intercostal space the lymph node was excised with the anterior svc wall between the brachiocephalic vein junction and the azygos vein junction . the svc wall defect measured 30 7 mm and was covered with a left brachiocephalic vein , as in case 1 . patency of the reconstructed svc was confirmed on contrast - enhanced ct 1 month postoperatively ( fig . a 33-year - old man was referred to our hospital because of abnormal chest shadow . contrast - enhanced computed tomography ( ct ) revealed a 50-mm - diameter mass in the anterior mediastinum ( fig . 1 ) . invasion of the anterior wall of the svc was suggested because of the unclear border between the tumor and the svc . f - fluorodeoxyglucose uptake on positron emission tomography exhibited a maximum standardized uptake value of 6.5 . from radiographic findings , the mass was suspected to be a malignant tumor such as a thymoma or thymic cancer , although a pathological diagnosis was not established . therefore , we planned extirpation of the tumor via a median sternotomy . figure 1:contrast - enhanced ct showing an anterior mediastinal tumor with suspected invasion of the svc . contrast - enhanced ct showing an anterior mediastinal tumor with suspected invasion of the svc . exploration revealed a solid mass , which infiltrated the anterior wall of the distal portion of the svc from the confluence of the bilateral brachiocephalic veins to just above the azygos junction . the left brachiocephalic vein was transected with stapler 40 mm from the brachiocephalic vein junction . after cross - clamping of the svc at the level above the azygos vein and right brachiocephalic vein , the caudal side of the left brachiocephalic vein was then divided longitudinally , and the pedicled flap of the left brachiocephalic vein was sewn onto the svc defect using 5 - 0 prolene ( ethicon , somerville , nj ) ( fig . contrast - enhanced ct 1 month postoperatively revealed the patency of the reconstructed svc . ( a ) after transection of the distal side of the left brachiocephalic vein with a stapler and extirpation of the tumor with partial resection of the svc , the caudal side of the left brachiocephalic vein was divided longitudinally . ( b ) a pedicled flap was then made from the left brachiocephalic vein and sewn onto the svc defect . ( a ) after transection of the distal side of the left brachiocephalic vein with a stapler and extirpation of the tumor with partial resection of the svc , the caudal side of the left brachiocephalic vein was divided longitudinally . ( b ) a pedicled flap was then made from the left brachiocephalic vein and sewn onto the svc defect . an asymptomatic 57-year - old man was diagnosed with right lung squamous cell carcinoma and referred to our hospital for further evaluation and treatment . contrast - enhanced ct revealed a 45-mm - diameter mass in the lower right lung lobe and a 25-mm - diameter swollen anterior mediastinal lymph node adjoined the anterior side of the svc . the patient had interstitial pneumonia and elected to undergo surgical resection of the tumor instead of chemoradiotherapy . through a posterolateral thoracotomy in the fifth intercostal space , a right middle and lower sleeve lobectomy the lymph node was excised with the anterior svc wall between the brachiocephalic vein junction and the azygos vein junction . the svc wall defect measured 30 7 mm and was covered with a left brachiocephalic vein , as in case 1 . patency of the reconstructed svc was confirmed on contrast - enhanced ct 1 month postoperatively ( fig . the optimal technique for svc reconstruction depends on the extent and location of the neoplastic invasion . when svc infiltration involves > 50% of the circumference of the svc , graft interposition using a ringed polytetrafluoroethylene ( ptfe ) graft is preferred [ 2 , 3 ] . if the svc invasion is < 50% , primary suturing can be applied under partial clamping of the svc . however , primary suturing may cause svc narrowing and early thrombosis , and insufficient surgical margins may result in residual tumor tissue . therefore , if more extensive svc wall resection is required , autologous pericardium is often used to cover the svc defect . ohata et al . recently reported another unique method with which to repair the svc wall defects using an azygos flap . they cut the azygos arch longitudinally on the caudal side to cover the svc wall defect . although their method is useful for reconstruction of the posterior side of the svc near the azygos vein , it seems unsuitable for anterior repair . in contrast , the left brachiocephalic vein flap is useful for repair of the anterior and more distal portions of the svc which is a common site of invasion of mediastinal malignancies . transection of the left brachiocephalic vein may cause temporary left arm swelling , but this usually resolves within 1 week . for example , this method can reduce the risk of infection , which is likely to occur when a vascular prosthesis such as a ptfe graft is used . , a sufficiently long vessel flap can be obtained not only through median sternotomy or hemi - clamshell , but also through lateral thoracotomy by dissecting the left brachiocephalic vein as distal as possible , as in our case 2 . an svc bypass is not always essential when the clamping is performed at the level above the azygos vein , as performed in our cases , because some lateral circulation is preserved and cerebral edema can be reduced . however , a temporary extra - anatomic venous shunt is usually required when clamping is performed below the azygos vein for > 60 min . in conclusion , svc reconstruction using a left brachiocephalic vein flap is a simple and useful method when svc invasion is limited to the anterior wall of the distal portion and involves < 50% of the circumference . this technique can prevent narrowing or early occlusion of the svc , which may occur after primary suturing , and postoperative anticoagulant therapy ( essential for ptfe grafting ) .

interposition with a vascular prosthesis or patch closure using autologous pericardium has been applied for superior vena cava ( svc ) reconstruction during surgery for thoracic malignancies such as thymic epithelial tumors or lymphadenopathy that invade the svc . we herein report a novel and simple method for repair of the svc using a left brachiocephalic vein flap . this procedure is useful to repair the anterior wall of the distal portion of the svc , which is a common site of invasion of thoracic malignancies .

disability is not just a health problem or attribute of individuals , but it reflects difficulties individuals may experience in interaction with society and physical movements . the term disability has many different meanings ; the global burden of disease ( gbd ) however , uses the term disability to refer to loss of health , where health is conceptualized in terms of functioning capacity in a set of health domains such as mobility , cognition , hearing , and vision . for disabled persons and their families situation becomes doubly difficult due to general health problem and unique social stigma attached to various types of disability . disabled people experience various barriers due to restriction of participation and their lives are affected with poor health outcomes , low education , lack of social and economic participation , higher rates of poverty and increased dependency . non - communicable diseases such as diabetes , cardiovascular diseases , mental disorders , cancer , and respiratory illness show increasing trends all over the world . these diseases have profound effects on disability . according to the who estimates 15% of world 's population gbd 2004 data analysis showed that 15.3% of the world population ( approximately 978 million people ) had moderate or severe disability , while around 2.9% population ( 185 million people ) experienced severe disabilities . the millennium development goals ( mdgs ) represent a hard pressing effort to address global poverty . yet there is a striking gap in the current mdgs as persons with disabilities were not considered . the estimated 1 billion people worldwide who live with at least one or more type of disabilities that is , physical , sensory ( blindness / deafness ) , intellectual or mental health impairments , are not mentioned in any of the 8 mdgs or 21 targets or 60 indicators , nor in the millennium declaration . this absence is of particular concern because a growing consensus and awareness among disability advocates , experts , and researchers find that the most pressing issue faced globally by persons with disabilities is lack of equitable access to resources such as education , health care facilities , employment , social participation activities , and not their specific disability . the links between disability and poverty are noteworthy and size of the globally distributed disabled population makes these links of particular concern to all working on issues related to poverty . according to 2001 , census data india had 2.1% disabled population and disability in the movement was observed in 27.8% population . karnataka has a disabled population of 940,643 out of which 661,139 people live in rural areas , while 279,904 people live in urban areas . the literate disabled population was 473,844 , which consisted of 51.40% of the total disabled population . there are many studies available on the prevalence of disabilities in india and mostly focus on the geriatric population . furthermore , there is comparatively less literature available on the quality of life ( qol ) among physically disabled persons . this study attempts to understand the qol and other associated concerns among younger as well as the older population . to assess the qol among physically disabled persons , impact of physical disability on activities of daily living ( adl ) and their awareness regarding laws and / facilities and utility pattern of available benefits in udupi taluk , karnataka there are many studies available on the prevalence of disabilities in india and mostly focus on the geriatric population . furthermore , there is comparatively less literature available on the quality of life ( qol ) among physically disabled persons . this study attempts to understand the qol and other associated concerns among younger as well as the older population . to assess the qol among physically disabled persons , impact of physical disability on activities of daily living ( adl ) and their awareness regarding laws and / facilities and utility pattern of available benefits in udupi taluk , karnataka . a community - based cross - sectional study was conducted in udupi taluk from february to july 2013 . a total of 130 physically disabled persons registered under 16 panchayats in udupi taluk were interviewed . respondents who were 18 years and above and permanently disabled were included in the study , while mentally challenged and severely ill were excluded . list of disabled persons was obtained from each of 16 panchayats . and physically disabled persons were selected with the help of multipurpose rehabilitative workers ( mrw ) and village rehabilitative workers . ( a ) persons having locomotor disability ( b ) loss or absence or inactivity of whole or part of hand or leg or both due to amputation , paralysis , deformity or dysfunction of joints which affected his / her normal ability to move self or objects ( c ) those with physical deformities in the body other than limbs such as , hunch back , deformed spine . dwarfs and persons with stiff neck of permanent nature who generally did not have difficulty in the normal movement of body and limbs were also treated as disabled . the interview schedule was divided into three parts . a structured questionnaire adapted from udai pareek scale was used to assess socioeconomic status of study participants . who bref scale was used to assess qol of the study participants . for assessment of adl , barthel index was used . the interview schedule was translated to the local language for better understanding by the participants . ethical permission to conduct this study written informed consent was obtained from each respondent prior to the interview . who bref scale had 26 questions , which were divided under four main domains namely : physical , psychological , social and environmental . barthel index has 10 main adl which included bowel habits , bladder habits , grooming , toilet use , feeding , dressing , transfer , mobility , stair climbing and bathing . ( a ) persons having locomotor disability ( b ) loss or absence or inactivity of whole or part of hand or leg or both due to amputation , paralysis , deformity or dysfunction of joints which affected his / her normal ability to move self or objects ( c ) those with physical deformities in the body other than limbs such as , hunch back , deformed spine . dwarfs and persons with stiff neck of permanent nature who generally did not have difficulty in the normal movement of body and limbs were also treated as disabled . the interview schedule was divided into three parts . a structured questionnaire adapted from udai pareek scale was used to assess socioeconomic status of study participants . who bref scale was used to assess qol of the study participants . for assessment of adl , barthel index was used . the interview schedule was translated to the local language for better understanding by the participants . ethical permission to conduct this study written informed consent was obtained from each respondent prior to the interview . who bref scale had 26 questions , which were divided under four main domains namely : physical , psychological , social and environmental . barthel index has 10 main adl which included bowel habits , bladder habits , grooming , toilet use , feeding , dressing , transfer , mobility , stair climbing and bathing . majority of the respondents belonged to 2544 years age group . among the total 130 respondents , less than half that is , 46.2% of the respondents were single and reported that disability was main reason for remaining single . majority of the respondents 67.7% were living in nuclear family while remaining 32.3% belonged to joint family . approximately , one - fourth that is , 24.6% respondents were illiterate , while 46.9% of them were found to have primary education . only 18% and 12% respondents were living in mixed and kutcha type of houses , respectively . most of the respondents ( 89.23% ) belonged to low socioeconomic status with score of below 40 , while 10.76% respondents were in middle socioeconomic status group . persons with disability ranging between 40% and 75% were entitled to get 400 rupees every month and with disability above 75% they were entitled to 1000 rupees every month . in this study , we found 60% of men and 59% of women were entitled to 400 rupees every month and 28% of men and nearly 33% of women were entitled to 1000 rupees every month [ table 1 ] . distribution of respondents according to their socio - demographic characteristics ( n=130 ) figure 1 shows that among the study participants 36.15% had congenital disability . the second common cause of disability was found to be postpolio residual paralysis ( pprp ) as it was seen among 26.2% respondents . other two causes of physical disability reported were stroke / paralysis and accidents , in 19.23% and 18.46% respondents , respectively . distribution of respondents according to type of disability ( n = 130 ) among 130 respondents , 17% of the respondents had one or other co - morbidities , hypertension being the most common ( 9.2% ) followed by diabetes ( 3.8% ) and asthma ( 1.5% ) . table 2 shows that activities such as transfer , mobility , and stair climbing showed greater impact of physical disability . among 130 physically disabled persons interviewed , 43.8% respondents required minor help and 13.1% respondents required major help or were unable to transfer . around 4% were immobile , while 10.8% needed wheelchair and 36.9% needed help of a person for walking . only one - fifth that is , 20.8% respondents reported no problem in climbing stairs independently . maximum respondents ( 56.2% ) required help in the form of verbal , physical or carrying aid to climb stairs . approximately , one - fourth of the respondents that is , ( 23.1% ) were unable to climb stairs . distribution of respondents according to adl ( n=130 ) in table 3 overall the qol of the respondents was assessed in different domains like physical , psychological , social and environmental by using who bref scale . overall , qol score was also found low in psychological domain reflecting on negative feelings , bodily image , appearance , spirituality , self - esteem and their thinking . similar finding was reported in a study conducted in bangladesh where similar proportion ( 47.5% ) of respondents were single . when proportions of respondents living in joint family were compared , study done in rural part of an adjacent district had reported higher proportion ( 78.2% ) of respondents living in joint family , whereas in the present study it was observed that 32.3% were living in joint family . the present study revealed that 24% of respondents did not have any formal education . in a similar study done in malaysia reported approximately similar percentage 26.8% of respondents with no formal education . in another study conducted in nigeria on health related qol in pprp survivors socioeconomic status of the respondents in the study was compared with studies conducted in rural community of karnataka where 51% respondents belonged to middle socioeconomic class and 61% of them were from low socioeconomic class . the second cause of disability was found to be pprp as it was found among 26.2% respondents . other causes found were stroke / paralysis and accidents , in 19.2% and 18.5% respondents , respectively . the study conducted in uttar pradesh showed 9.09% of physical disability occurring due to accidents and reported 4.9% to have pprp as cause of physical disability , while 17.07% had physical disability attributed to stroke . co - morbidities observed in this study when compared to a study conducted in uttar pradesh reported higher prevalence of hypertension ( 49% ) , followed by asthma ( 15% ) , and heart problems ( 5% ) . this study showed that 11.5% respondents required help in one of the adl domain , which is less compared with a study conducted in nigeria which reported 28.3% respondents required help in one domain . the reason could be majority being the geriatric population in nigerian study . in the present study , assessment of qol score was done with respect to type of disability . and qol score was found to be low in psychological domain reflecting on negative feelings , bodily image , appearance , spirituality , self - esteem and their thinking . psychological domain score was observed to be low across all types of disabilities . in a similar study carried out in nigeria among physical disabled persons showed high qol scores under all four domains namely physical health , psychological health , social health , and environmental domains . in a study conducted in two provinces namely - chiang mai and nakhon ratchasima of thailand qol activities like transfer , mobility , and stair climbing showed greater impact of physical disability . it was also observed that majority of them are not dependent on others for their daily activities . the qol was found poor among respondents in the psychological domain as compared to other domains . this could be mainly because of their physical appearance , which refrain from the participation in social gatherings and family functions . regarding linking them to social protection schemes , the district authorities have made attempts to link them monthly financial assistance , however efforts need to be directed toward empowering them with knowledge on various social protection schemes and play a facilitative role so that it can be accessed easily without much difficulties .

background : disability is not just a health problem or attribute of individuals , but it reflects the problems individuals experience in their interaction with society and physical movements . disabled persons remain neglected part of society and they also experience various barriers due to restriction of participation.objectives:the aim was to assess the quality of life ( qol ) of physically disabled persons , the impact of physical disability on activities of daily living ( adl ) and to study the awareness about laws and facilities available for disabled persons.materials and methods : a cross - sectional community based study was conducted among 130 physical disabled persons who were selected using convenience sampling technique . the who bref scale was used to assess qol , while assessment of adl was done using barthel index . socio - demographic assessment was done using udai pareek scale . spss version 15.0 was used to analyze data . categorical variables were expressed as frequencies and percentages . as per guidelines physical , psychological , social , and environmental domain scores for who bref scale were calculated.results:among the study participants , 36.2% had a disability from birth that is , congenital . the second common cause of disability was found to be postpolio residual paralysis as it was found among 26.2% respondents . other causes found were stroke / paralysis and accidents , in 19.2% and 18.5% respondents , respectively . activities such as transfer , mobility , and stair climbing showed greater impact of physical disability . it was found that 11.5% respondents required help in one of the adl . qol score was found to be low under the psychological domain reflecting on negative feelings , bodily image , appearance , spirituality , and self - esteem of respondents.conclusion:physical disability had affected social participation as well as marriage of the respondents . however , it was found that very few of them are aware about facilities provided under persons with disability act .

acantholytic dyskeratosis ( ad ) is a histologic pattern characterized by hypergranulosis , acantholysis , suprabasilar clefting , and formation of corps ronds and grains . this can be seen in darier 's disease ( dd ) or dyskeratosis follicularis , transient acantholytic dyskeratosis ( tad ) or grover disease ( gd ) , as well as in isolated lesions , such as warty dyskeratoma ( wd ) , acantholytic dyskeratotic acanthoma , and as an incidental histopathologic finding of isolated ad . dd and tad occur most commonly in seborrheic areas and wd most commonly in the head , neck , trunk , and extremities . we present a case of acantholytic dyskeratosis that is unique based on its genital location and cystic architecture . a 53-year - old woman presented with an otherwise asymptomatic cyst on her left vulva of uncertain duration . there was no known history of generalized skin conditions with similar histology and there were no associated lesions of the vulva or the cervix . the lesion was surgically removed and submitted for routine histologic processing and staining with hemotoxylin and eosin . on microscopic examination , there were fragments of cystic epithelium with areas of hypergranulosis , acantholysis , suprabasilar clefting , and corps ronds , and grains formation [ figures 13 ] . these features were felt to represent isolated dyskeratosis follicularis arising in the context of an infundibular cyst . hematoxylin and eosin 20 medium power view of cystic lesion demonstrating hypergranulosis , acantholysis , and corps ronds formation . h and e 100 medium power view of cyst demonstrating corps ronds , grains , and suprabasal acantholysis . changes of dyskeratosis follicularis are unusual in the genitalia but there have been cases of multiple papular lesions on the genital area reported under various terminology , including papular acantholytic dyskeratosis and acantholytic dermatosis of the vulvocrural fold . in fact , in a review of 28 cases of isolated dyskeratotic acanthoma , none occurred in the genital area . we were able to identify three reports of solitary genital lesions of isolated ad [ table 1 ] . one of the six vulvocrural cases described in the series by cooper exhibited cystic invaginations with multiple follicular connections and histologic features of lora et al . 's report of wd on the mons pubis also histologically showed a similar cup - shaped cystic invaginations involving multiple indundibulae . and of the three vulvar cases of wd reported by duray et al . , at least one appears to show a cystic invagination adjacent to or involving a pilosebaceous unit . however , none of these genital cases of ad demonstrated changes with a truly cystic architecture , as seen in our patient . cases of warty dyskeratoma located on the genital area our patient 's lesion could be considered to represent an unusual presentation of wd . wd commonly presents as a solitary , keratotic papule or nodule on the sun - exposed areas in middle - aged males . histologically , wd displays broad , well - circumscribed invagination of a hyperplastic epidermis with hypergranulosis and papillomatosis , suprabasilar acantholysis , villi formation of the dermal papillae , and presence of dyskeratotic squamous cells ( corps ronds and grains ) . histologic overlap of cystic , nodular , and cup - shaped patterns have been noted in a large clinicopathologic review of wd . the cystic lesions are described as well - circumscribed nodules composed of one or several large infundibular cystic structures filled with masses of keratin material located in the papillary and upper reticular dermis . the cystic structures have a stratified squamous epithelial lining with foci of hypergranulosis and papillomatosis . a focal connection to the epidermis is sometimes observed . although it lacked the typical hyperplastic villous - like proliferations at the periphery seen in other cases of wd , this lesion presented herein otherwise exhibited hypergranulosis , dyskeratosis resulting in iris and target morphologic features of corps ronds , and suprabasilar acanthoysis , all of which are typical of wd . the cystic architecture described by kaddu et al . in other locations is reminiscent of our lesion , suggesting our lesion may lie on a spectrum of infundibular cyst and wd . contiguity with cystic infundibular structures described in the genital cases reported by cooper and lora et al . show a clear - cut histologic connection of these lesions to rudimentary pilosebaceous units or at least were located adjacent to a pilosebaceous unit . in another retrospective study , ck1 and ck10 were expressed in the suprabasal levels of the wd cases , whereas ck5 and ck17 were appreciated in the basal layer . this pattern of expression of cytokeratin markers further supports wd as an adnexal neoplasm with follicular differentiation . the term follicular dyskeratoma has been proposed to acknowledge the follicular infundibular origin of wd . in keeping with this theory , we feel that the infundibular cystic features seen in our patient 's lesion represent a spectrum of changes that can be seen in follicular dyskeratoma . vulvar wd with cystic configuration has never been reported [ based on pubmed search ] , and to the best of our knowledge , our case is the first to describe such a lesion occurring on this site . in addition to the various presentations of ad , the differential diagnosis of acantholysis on the vulva may include pemphigus vulgaris , herpes simplex virus , and hailey these entities are excluded in the absence of positive immunofluorescence in pemphigus , presence of viral changes in herpes , and more prominent acantholysis and less dyskeratosis in hailey acantholytic squamous cell carcinoma ( scc ) is differentiated by the absence of cytologic atypia in wd . interestingly , cystic dd , cystic scc , and keratoacanthoma with associated cystic sebaceous tumors in a muir torre syndrome patient have been reported . although rare and reported to occur at nongenital sites , these entities should be considered as the most important differential diagnoses for cystic wd . topical tazarotenic acid gel was reported to be effective in one patient . in summary , we present a rare case of ad that is unusual in its cystic presentation and genital location . this is thought , by the authors , to be a unique presentation of a follicular adnexal neoplasm , lying on the spectrum of wd or follicular dyskeratoma .

acantholytic dyskeratosis ( ad ) is a histologic pattern seen in darier 's disease or dyskeratosis follicularis , warty dyskeratoma , and transient ad . this pattern is characterized by suprabasilar clefting , acantholysis , and formation of corps ronds and grains . we present a case of ad that is unique based on its genital location and cystic architecture . a 53-year - old woman presented with an otherwise asymptomatic cyst on her left vulva of uncertain duration . on microscopic examination , there were fragments of cystic epithelium with areas of hypergranulosis , acantholysis , corps ronds , and corps grains formation . these features are felt by the authors to be a unique presentation of a follicular adnexal neoplasm .

the food systems and public health conference held april 13 , 2009 , at the airlie center in warrenton , virginia , convened a multidisciplinary group of researchers and practitioners in sustainable agriculture , public health , health care , obesity , economics , food systems , and other relevant fields to discuss opportunities to intervene to promote healthy diets , address health disparities , and promote diversification of agricultural production . presentations and discussion included improving food systems and leveraging the supply chain to promote healthy diets and prevent obesity . to insure that this multidisciplinary group was well prepared , the conference was supported by manuscripts prepared for and distributed to conference participants prior to the meeting . speakers in the session on building a good food toolkit each addressed one of 4 themes : healthy , green , fair , and affordable . these presentations were followed by one on how systems thinking could help to frame the challenges and opportunities for improving the food supply . in this commentary , we apply one of the complex systems frameworks presented in this session to describe the content of the material provided to conference participants . this exercise enabled us to elucidate some of the linkages and differences between food systems that are healthy , green , fair , and affordable . the preconference papers and the dialogue during the conference made clear that the challenge of evolving food systems to create food supplies that are healthy , green , fair , and affordable is complex . systems that are complex , rather than just complicated , have a number of characteristics including nonlinear dynamics , heterogeneity , stochastic behavior , interdependence of variables , and the presence of feedback loops . although the food supply chain is often described in a linear fashion , beginning with production , processing , and distribution and continuing with marketing , retail , and consumption , the specific variables in each of these subsystems interact with each other in a nonlinear fashion , with many interdependencies and both balancing and reinforcing feedback loops . some of this complex behavior is illustrated in the obesity system map developed by the foresight programme in the uk , but this stakeholder - developed concept map lacks many of the variables relevant to food system structures , especially at the production , processing , and distribution end of the supply chain . variables such as the power and influence of large retail chains and large food processors , government agricultural policies , and technological advances all increase further the complexity of the food systems landscape . when tackling a complex problem , the tendency is to oversimplify the problem and the causal linkages or pathways that give rise to outcomes of interest . but for systems where variables have many inputs and outputs , and multiple interacting components create both balancing and reinforcing feedback loops , the outcomes of interest emerge from the system as a whole . outcomes like ( 1 ) ubiquitous and cheap nutrient - poor , calorie - dense food ; ( 2 ) concentration of power in specific parts of the food chain ; or ( 3 ) common agricultural practices that harm the environment may not result from specific , identifiable causal pathways . as a result , an understanding of causal relationships may not be sufficient , possible , or even necessary . examination of individual variables or of pairs of relationships in isolation does not elucidate the behavior of a complex system over time . general planning theory authors , rittel and webber , suggested that the search for a scientific basis for wicked social policy problems is bound to fail because of their nature . tackling a complex problem requires a different approach , one that accepts the problem as complex and seeks solutions appropriate for complex problems . meadows outlined 12 places or levels of intervention for complex problems . at one end of the spectrum leverage points that are relatively easy to change and by themselves generally only have a small impact . at the other end are the goals of the system and the paradigm under which the system operates , leverage points that are often very difficult to change but if changed can have a large impact . these places to intervene arose out of meadows years of experience working with complex systems and out of her frustration for our tendency to seek simple solutions that seem intuitively correct but are often wrong . we recently adapted meadows 12 places to intervene into a 5-level framework ( table 1 ) that can be used to sort qualitative survey data . the 12 levels of meadows framework were collapsed into 5 levels because interrater reliability using all 12 levels was poor . by reducing the framework to 5 levels that were more mutually exclusive the levels of the modified framework were previously used to sort survey data on specific actions needed to address the complex problems of childhood obesity and chronic disease prevention . through sorting these types of data , we have gained insight into the types and distribution of effort needed to address obesity and chronic disease prevention . here we present the application of the intervention level framework to the contents of the background papers provided to participants prior to the food systems and public health conference . the analysts read each of the papers and extracted ideas , statements , or actions that addressed the assigned theme . each analyst compiled these statements into a preliminary list in which similar ideas were consolidated to eliminate redundancy . these statements were then sorted according to the intervention level framework parameters ( see table 1 ) . the 2 analysts for each theme compared and consolidated their sorted preliminary lists to gain consensus . this process resulted in a final sorted list of 353 statements addressing the 4 themes ( healthy : n = 122 ; green : n = 87 ; fair : n = 84 ; affordable : n = 60 ) . intervention level framework corresponds to meadows level 1 ( the power to transcend paradigms ) and level 2 ( the mindset out of which the system arises ) corresponds to meadows level 4 ( organize system structure ) , level 5 ( the rules of the system ) only if the rules affect multiple subsystems , and level 6 ( information flows ) only if the flows occur between multiple subsystems . corresponds to meadows level 7 ( positive feedback ) , level 8 ( negative feedback ) , and level 9 ( length of delays ) . corresponds to meadows level 5 ( the rules of the system ) only if the rules affect a particular subsystem or a specific type of actor , level 6 ( information flows ) only if the flows occur within a specific subsystem , level 10 ( physical structure ) , level 11 ( size of system stabilizers ) , and level 12 ( constants and parameters ) . table 2 illustrates the application of the framework to each of the 4 conference themes . comparison between levels within each theme illustrates how lower levels ( e.g. , structure and structural elements ) can support change at higher levels ( e.g. , goals and paradigm ) . figure 1 shows the emphasis of the content on structural elements of food systems when sorted by intervention level . approximately half of the ideas expressed were at the level of structural elements , with the next largest category being relevant to the system structure . as illustrated in table 2 , there were significant overlaps in ideas relevant to each of the 4 themes . to understand the pattern of these linkages , statements that linked one theme to another examples found include healthy and affordable : decrease the price of healthy food rather than increasing the price of unhealthy food and expand food stamp funds so families can actually purchase healthy food . healthy and green : link health more effectively to the sustainability agenda and organic production to increase food system resilience and also provide food with increased health values . healthy and fair : establish incentives and support for growers to produce healthful products and tackle the inequalities of power that characterize the food system and shape food 's impact on public health . affordable and fair : we need fair and cooperative trading between producers , retailers and consumers and investigate the relationships between crop prices , food prices and food consumption . affordable and green : make sustainably produced food accessible and affordable and subsidize the costs of healthier and more sustainably produced food for food assistance recipients . broaden public discussion around health and agricultural policy to include farmers , environmental groups and other public interest organizations and support local , sustainable , fair agricultural and dairy production practices . the thickness of the arrows is proportional to the number of statements that connect the two themes and the thickness of the lines around the nodes is proportional to the number of statements relevant to that theme . healthy was the dominant theme in this set of preconference papers and healthy was well connected to each of the other 3 themes . less well connected were the themes of green , fair , and affordable to each other . intervention level analysis of the themes healthy , green , fair , and affordable distribution of statements according to the intervention level framework ( n = 353 ) . finally , we further sorted the ideas and actions that were identified at the level of structural elements ( figure 3 ) . these statements were sorted according to their relevance to different parts of the supply chain ( production , processing / distribution , retail , and consumption ) . because there was considerable effort to identify relevant research questions , statements making reference to research ideas relevant to healthy were mostly balanced along the food supply chain , whereas much of the discussion of both green and especially fair was aimed at the production end of the chain . interestingly , no statements on processing , distribution , or research were identified among the structural elements of the affordable theme . thickness of arrows and borders represent the relative number of statements between and within the themes , respectively . prior to the food systems and public health conference , participants were provided with material that considered each of the 4 conference themes . healthy was the dominant theme ( approximately one third of the ideas ) and healthy was clearly well linked to each of the other three themes ( figure 2 ) . the reason for this focus on healthy and the greater detail about linkages between healthy and the other themes are likely a function of the particular authors asked to prepare this premeeting material but may also reflect the progression of ideas in this area to date . supporting the notion that the discussion around healthy is more advanced and comprehensive is the balanced distribution of the structural elements for healthy across all parts of the food supply chain ( figure 3 ) . in contrast , for the theme fair , more than 80% of the statements found in the preconference material were about the production end of the supply chain and none were about research . affordable was the least developed theme , with less than 20% of the statements being relevant to this theme and none were connected to processing , distribution , or research . this seems to be significant because power in the food chain has been concentrated in a smaller numbers of processors and this consolidation has a high potential to affect food prices . the lack of balance of ideas associated with affordable , across the food chain , may reflect the challenge of containing the total content of the background papers to a manageable level . whether or not the preconference material was representative of the broader dialogue taking place regarding food systems and public health remains to be determined . even with this limited sample , the many linkages between the themes suggest considerable terrain for collaboration between and within sectors and movements . the need for collaboration was one of the topics raised during the small group discussions at the conference . our examination of the linkages between themes and the sorting of ideas into levels could facilitate future dialogues on action . analysis of key papers on food systems and public health , supported by an expert panel review , would also help to ensure a thorough understanding of the specific issues and the opportunities for intervention and collaboration . a more detailed analysis could also attempt to identify places where the paradigms , goals , and system structures are not compatible between different themes . for example , passing on the full costs of being green to the consumer will not likely make healthy food more affordable for everyone ( table 2 ) . meadows developed her ideas about places to intervene in complex problems to help us understand the possibilities for changing the structure of systems to produce more of what we want and less of what is undesirable . ( p. 145 ) she notes that it is dangerous to generalize about complex systems , but her years of experience supported her idea that the places to intervene could be described within a rough hierarchy generalized in the language of complex systems . she suggests that her list of places to intervene is an invitation to think more broadly about system change . as illustrated for the 4 conference themes in table 2 , the intervention level framework can help to convert a list of ideas for action into groups of ideas that fit together to support change . in the healthy theme , for example , the belief that a healthy food supply requires consideration of the health impact of agricultural policies naturally gives rise to the goals of maximizing positive health outcomes and minimizing negative health impacts through agricultural policy ( table 2 ) . broad public discussion of healthy agricultural policy and adoption of ecologically sound agricultural practices will require engagement of actors from across the food supply chain and across many sectors including government , the private sector , and the public . building connections across ideas and between actors will support the system in moving toward the goal of maximizing health . many actions within and between different subsystems , such as providing information to support public action or implementing policies that encourage healthy behaviors and healthy agricultural practice , will begin to add up to influence the structure , the goals , and the deepest held beliefs of the system 's actors . consistent with our analyses of survey data on actions needed to address childhood obesity and chronic disease prevention , the largest proportion of the ideas fit into the structural elements level ( figure 1 ) . system structure as a whole was also high on the authors agendas , with an additional 20% of the statements addressing this level of intervention . also consistent with other analyses using this framework is a low number of statements relevant to creating or affecting feedback loops and delays . often ideas for academic research are placed in this category because the description of data collection and its possible uses are core activities of research . evaluation of community - based programs and systems would also support the creation of feedback loops . one author considered the creation of publicly driven feedback loops by calling for public access to information on the use of pesticides and fertilizers . the growing trend toward open access to public and private data encourages the creation of new feedback loops and will shorten delays in the speed of change . in this commentary we have identified many linkages between the themes , including core beliefs , the goals we would like to achieve , and the structures needed to accomplish these goals , but this is far from a comprehensive analysis of the themes healthy , green , fair , and affordable . this preliminary analysis helps to identify areas of greater and lesser emphasis on the part of the authors of the preconference papers and suggests areas that need further effort and additional sources if a comprehensive picture is to be developed . it is evident that to effectively create healthy , green , fair , and affordable food systems action is needed throughout the food chain . systems thinking can support stakeholders in getting a better sense of the big picture , as well as gain insight into the places to intervene to create change within the system . with the intervention level framework , stakeholders can develop a better understanding of how coherent actions among and between subsystems , together with enhanced self - regulating feedback loops and interconnections between subsystems , can create system - wide change that is consistent with goals and paradigms that will help to make our food systems more healthy , green , fair , and affordable .

a food systems and public health conference was convened in april 2009 to consider research supporting food systems that are healthy , green , fair , and affordable . we used a complex systems framework to examine the contents of background material provided to conference participants . application of our intervention - level framework ( paradigm , goals , system structure , feedback and delays , structural elements ) enabled comparison of the conference themes of healthy , green , fair , and affordable . at the level of system structure suggested actions to achieve these goals are fairly compatible , including broad public discussion and implementation of policies and programs that support sustainable food production and distribution . at the level of paradigm and goals , the challenge of making healthy and green food affordable becomes apparent as some actions may be in conflict . systems thinking can provide insight into the challenges and opportunities to act to make the food supply more healthy , green , fair , and affordable .

tubular duplication of esophagus is a rare occurrence and is much less common than cystic duplication of the foregut . esophageal duplication may lie centrally or more usually lie to one side and have been reported to occur twice as commonly on the right as on the left . we report a case of incidental finding on computed tomography of communicating tubular esophageal duplication on the left side of the upper esophagus , in a tuberculosis patient , that was subsequently confirmed on barium test . a 42-year - old man with complaints of dry cough and breathlessness for 15 days was referred to the radiology department for computed tomography of the thorax . his chest x - ray showed cavitation and fibrosis with patchy consolidation in the right upper zone . patient was a diagnosed case of sputum - positive pulmonary tuberculosis and had received the complete course of antitubercular treatment 2 years earlier . on present computed tomography of the thorax ( axial images ) , there were multiple thick - walled cavitary lesions in the posterior segment of right upper lobe with multiple parenchymal nodular opacities indicative of endobronchial spread of infection [ figure 1 ] . in addition to these findings , there was an air - filled tubular structure alongside the esophagus on the left side , beginning at the level of the t2 vertebra and communicating with the normal esophagus at the level of carina [ figure 2 ] . we considered a provisional diagnosis of pulsion diverticula or possibly proximal esophageal duplication as an incidental finding along with the findings of sequelae of post - primary pulmonary tuberculosis . plain ct upper thorax lung window shows multiple cavitary lesions in the right upper lobe . plain ct upper thorax lung window shows air - filled structure on the left side alongside the normal esophagus . barium swallow study [ figure 3 ] was done to rule out diverticulum . on barium study , a contrast - filled tubular structure was seen alongside the normal esophagus on the left side extending from the t2 to the t4 vertebral level and communicating with the esophagus both superiorly and inferiorly . fluoroscopically , swallowing mechanism was normal with normal mucosa and presence of peristalsis in the duplicated segment . gastroesophageal junction was normal . with these definitive findings , diagnosis of incomplete communicating tubular duplication of upper esophagus the duplication of the esophagus is one of two forms : ( 1 ) a cystic form that may or may not communicate with the esophageal lumen or ( 2 ) a tubular form . embryologically , duplications result from a defect in the tubulation ( vacuolization ) of the esophagus , normally occurring in the sixth week of gestation . as the foregut epithelium develops , it elongates , develops a lumen , and undergoes dextrorotations . thus , the majority of esophageal duplications occur distally and on the right . in the present case , in one study , of 44 esophageal duplications only six tubular duplications were identified . in another review of alimentary tract duplications , the present report reveals a case of an incomplete tubular duplication of the upper esophagus . associated anomalies of the thoracic spine ranging from spina bifida and hemivertebra to vertebral fusion defects have been described . in our case however , they become symptomatic when complications such as hemorrhage , rupture , pain , vomiting , displacement of adjacent organs , obstruction , respiratory distress , infection , or perforation occur . tubular duplications are rare and most tubular duplications reported seem to present in late childhood or in adults which indicates their relative asymptomatic nature . because of the asymptomatic nature of this abnormality , the possibility of a greater frequency of its occurrence than clinically apparent has been suggested . computed tomography and magnetic resonance imaging have been used to demonstrate esophageal duplication and vertebral anomalies . endoscopy may reveal the opening in tubular duplications , while cystic duplication may show only esophageal obstruction , due to extraluminal compression . esophageal ultrasound may demonstrate a lesion , or a technetium pertechnetate scan can demonstrate gastric mucosa in the duplication . treatment of this condition must be individualized according to the presenting symptoms and type of lesion . various procedures that have been reported range from excision , enucleation , marsupialization , and internal drainage . cauterization of mucosa , needle aspiration , and division of septum have also been performed . in our patient , further investigations were not advised as the esophageal duplication was an incidental finding , the anatomy of which was well demonstrated on computed tomography and barium swallow test . no treatment for this condition was needed as no symptom due to esophageal duplication was present .

duplications of esophagus are commonly classified into two types , tubular and cystic . tubular duplication of esophagus is a rare occurrence and is much less common than cystic duplication of foregut . most esophageal duplications are located in the lower third of the esophagus . a cervical esophageal duplication is extremely rare . esophageal duplications have been reported twice as commonly on the right as on the left . we report a case of incidental finding identified on computed tomography of communicating tubular esophageal duplication involving the left side of the upper esophagus in a tuberculosis patient that was subsequently confirmed on barium swallow test .

as a country where agriculture is predominant , nepal uses a lot of organophosphate ( op ) pesticides as they are commonly available . op pesticide poisoning is a leading cause of morbidity and premature loss of life in many developing countries , including nepal.1 chronic op - induced neuropsychiatric disorder ( copind ) is a condition characterized by a prolonged exposure to op pesticides ( with or without acute cholinergic episodes ) and the development of various neuropsychiatric symptoms.2 follow - up studies of individuals who were exposed to high levels of the op compound have shown an emergence of certain similar types of neurobehavioral changes , which has been termed together as copind.3 the neurobehavioral changes include anxiety , mood swings , emotional lability , depression , fatigue , irritability , drowsiness , confusion , and lethargy.4 the purpose of this case study is to determine the neuropsychiatric manifestation of prolonged exposure to op compounds . as few cases of this kind have been reported or seen in practice , this report may help others in understanding and diagnosing copind . in an attempted suicide after quarreling with his wife , a 35-year - old male farmer from the plain ( terai ) region of nepal poisoned himself with op pesticide ( malathion ) . he had been using op as a pesticide in his field , as per the advice of an agriculture technician , for over a week at the time of the incident . the unconscious farmer was taken to a nearby hospital in india , near the border , where he suffered from vomiting , salivation , and diarrhea . after being on a mechanical ventilator for 9 days , he was brought to the national medical college and teaching hospital , birgunj , nepal . the patients record showed that his symptoms included deep coma ( glasgow coma scale e1v1m1 ) , hypotension ( 80/56 mmhg ) , tachycardia ( 128/min ) , miosis , and hypersalivations . his plasma cholinesterase value was not tested due to the lack of access to the test . after being brought to the national medical college and teaching hospital , the patient was kept in the intensive care unit under breathing support with a mechanical ventilation and under 24 hours vigilance . his consciousness and respiratory status gradually improved , and he was taken off the mechanical ventilator on the 12th day of his admission . after this time , he developed irritability , restlessness , nonsensical talking , and psychosis . an examination of his mental status revealed uncooperativeness , irritability , abnormal behavior , decreased volume and pitch of speech , increased reaction time , labiality of mood , impaired attention and concentration , and disorientation to time , place , and person . the antipsychotic drug , quetiapine , was started at a low dose of 25 mg once daily , and then was gradually increased over 3 days to 50 mg , which showed dramatic improvements within 2 days . by the 18th day of admission , a decision was made to transfer the patient to the psychiatry inpatient department for further management of his psychiatric manifestation , where he was continued on with the same medications . consistent mood liability , irritability , fatigability , and features of anxiety were observed ; however , features of parkinsonism were seen to be improving . through a detailed history from his spouse , friends , and other family members , major medical , surgical , and psychiatric illness , and substance abuse in addition , the detailed history explored the attempted suicide and saw it as an impulsive act rather than one motivated by depression . an antidepressant , fluoxetine 20 mg , was started once daily and suicidal precaution was explained to family members . upon persistent requests from the family , the patient was discharged with the same medication and advised to return for a 2-week follow - up at the psychiatry outpatient department . gradual improvement in his mood and behavior was seen at this 2-week follow - up , as well as at the 1-month follow - up . gradually quetiapine was stopped , but the patient was advised to continue taking fluoxetine . at the 3-month follow - up , a detailed evaluation revealed that the patient had reached the premorbid level . fluoxetine was continued for another 6 months then gradually tapered out and discontinued . ethical approval from the institutional review committee studies on the long - term effects of high dose op compound exposure are limited by the non - specific nature of these symptoms , and by the low sensitivity and specificity of the neurophysiological scoring system.5 considering our patient , who did not use any precautions while using the op compound for agricultural purposes for just over a week before his attempted suicide , could easily have been exposed to the op compound during that period of time . following this , he then ingested a large amount of the op compound impulsively and developed neuropsychological symptoms after this . a study done by jamal et al6 pointed to a positive link between the long - term low - level exposure to op and the development of chronic neurotoxic and neuropsychological effects . a similar study among agriculture workers who were exposed to op compound showed that they developed neuropsychiatric problems such as anxiety , depression , and problems with memory and concentration.5 in addition , schizophrenia like psychosis , mood labiality , recurrent suicidal ideations , delirium , and aggression have been reported , which was consistent with our study . the mechanisms of the development of these symptoms remain unclear ; however , such symptoms are often seen during the recovery from cholinergic syndrome.3 extra pyramidal symptoms , such as tremor and cogwheel rigidity , were also seen in our patient in the initial phase of treatment and subsided after approximately 2 weeks , which was consistent with findings from another study.5 these extra pyramidal symptoms are thought to be due to the inhibition of acetylcholinesterase in the human extrapyramidal area.7 after 2 weeks of treatment , the patient developed mood swings and suicidal thoughts , which were not present before exposure to op pesticides . a study by davies et al revealed that suicidal thoughts in op victims tend to come on suddenly and abate quickly.4 even though the suicidal thoughts were brief in the absence of major affective disorder , the patient was closely observed and was given antidepressants . a past study have also pointed out the need for hospitalization and close observation in such a type of condition.4 moreover , even if the typical portrayal is of brief impulsive suicidal thoughts , this later may become more persistent suicidal thoughts due to the levels of exposure.4 following recurrent brief suicidal thoughts and mood swings , the patient was started with an antidepressant , which has been found to be effective in the past . a significant proportion of patients diagnosed with copind have found that selective serotonin reuptake inhibitors , especially fluoxetine 20 mg , can be beneficial for treating both suicidal thoughts and mood swings.4 in addition to pharmacological therapy , psychological approaches have also been found to be effective in such cases , although we did not consider it due to the lack of access . cognitive therapy , similar to those used in chronic or degenerative neurological conditions , is the most appropriate , as they essentially involve problem solving and coming to terms with the disability.4 the neuropsychological problems associated with prolonged exposure of op compounds need to be studied using a systematic and methodical approach . there is a need of appropriate assessment and diagnosis in the early stages of exposure , which would assist in formulating appropriate strategies to manage such cases with the available resources . careful monitoring of these disorders not only reduces the treatment costs but also reduces associated morbidity and mortality .

chronic organophosphate ( op)-induced neuropsychiatric disorder is a rare condition following prolonged exposure to op compounds . due to the lack of valid diagnostic tools and criteria , very few cases are seen in clinical practice and are often misdiagnosed . misdiagnosis can lead to inappropriate treatment that may increase the risk of morbidity or suicidality . in this paper , we present the case of a 35-year - old male who needed support in breathing from a mechanical ventilator and developed neuropsychiatric behavioral problems following ingestion of op compounds , which lead to suicidality . the patient was treated by the psychiatric team with antipsychotic and antidepressants and improved following the regular use of medication .

a problem that has frequently emerged as a critical issue in patients with venoarterial ( va ) extracorporeal membranous oxygenation ( ecmo ) is a dilatation of the left heart due to volume overload of the left ventricle . conventionally , a venting cannula is placed in the left atrium via the right upper pulmonary vein or the la auricle with a sternotomy or a lateral thoracotomy . however , these approaches are risky because of significant complications such as bleeding and scarring . the procedure chosen for percutaneous left heart decompression varies from insertion of the la venting cannula to placement of an atrial septal stent . recent reports showed that there was no significant difference between these procedures . here , we describe a successful percutaneous balloon atrial septostomy and an la venting cannula insertion during va ecmo in a patient with severe acute myocarditis . a 38-month - old , 11.7 kg boy he had suffered from intraventricular hemorrhage and intracranial hemorrhage caused by neonatal asphyxia , and he had been kept on antiepileptic medication due to infantile spasm . the patient was transferred to the intensive care unit with very poor hemodynamics and subsequent supraventricular tachycardia ( heart rate > 200/min ) , which did not respond to intravenous amiodarone or adenosine . despite conventional therapy including inotropes , his condition continued to deteriorate with tachycardia . echocardiography revealed a marked decrease of 20% in the ejection fraction , and we therefore decided to support him with va ecmo . arterial cannulation was performed via the right carotid artery with an 8 fr percutaneous arterial cannula ( rmi ; edwards lifesciences , irvine , ca , usa ) , and a 14 fr percutaneous venous cannula ( rmi , edwards lifesciences ) was placed in the right internal jugular vein . ecmo flow was initially 1,300 ml / min and was maintained between 700 to 800 ml / min . after ecmo insertion , the patient s vital signs stabilized and his chest x - ray improved ( fig . however , he began to produce a large amount of frothy , bloody endotracheal secretions and his pulse pressure disappeared twelve hours later . follow - up echocardiography revealed marked left heart distention and a left ventricular ejection fraction lower than 10% . therefore , fourteen hours after ecmo insertion , the patient was taken to the cardiac catheter laboratory for an atrial balloon septostomy and la venting cannula insertion . the procedure was accomplished with a percutaneous approach through the right femoral vein without complications and an 8.5 fr la venting cannula ( mullins sheath ; cook inc . 2 ) . after placement of the la venting cannula , the pulse pressure appeared again , with a 15 mmhg gap between the systolic and diastolic pressure . his follow - up chest x - ray improved ( fig . four days later , we observed recovery of left ventricular function and improvement of the chest x - ray ( fig . follow - up echocardiography showed improved lv systolic function and an ejection fraction of 65% . since its introduction as a major support for severe respiratory distress , ecmo has become a well - established therapy in pediatric patients , particularly those with severe but reversible neonatal respiratory failure , cardiac failure , or cardiorespiratory failure . in particular , va ecmo has been used in pediatric patients with cardiac dysfunction , such as myocarditis , cardiac arrest , and cardiomyopathy . left heart distension during va ecmo may develop , leading to progressive left heart deterioration , pulmonary edema , and impairment of myocardial oxygenation . despite its clinical importance , the management of left heart decompression in a patient with ecmo is rarely discussed . only sporadic case reports and a few articles have shown the efficacy of la decompression on functional recovery of the left heart [ 57 ] . conventionally , la decompression is achieved by insertion of an la venting cannula via sternotomy or thoracotomy . however , sternotomy or thoracotomy themselves are risky and have several complications , such as bleeding and significant scarring . la decompression with a percutaneous cardiac catheterization - based technique including septostomy using a blade or radiofrequency ablation , balloon dilatation , and la venting cannula insertion has been effective [ 2,46,8 ] . several institutions with la vents have identified technical issues related to management of the indwelling catheters , such as kinking , poor flow , movement of the catheter with required patient care , and ongoing concern for thrombosis . therefore , a recent study showed a shift in preference from la vent insertion to balloon dilation alone . however , balloon atrial septostomy alone is not always successful because of varying degrees of atrial septal thickness . we believe that using an la venting cannula after balloon dilation offers several advantages over balloon dilatation alone . first , the placement of an la venting cannula potentially allows for controlled decompression of the left heart by adjusting flow rates on the ecmo circuit or clamping the cannula . third , the size of the cannula can be tailored to each patient , so this procedure can be adjusted for use in smaller patients . for patients with left heart dysfunction causing pulmonary edema during va ecmo , percutaneous balloon atrial septostomy with la venting cannula insertion is a treatment option that carries a low risk of other complications such as bleeding .

patients with venoarterial extracorporeal membrane oxygenation ( ecmo ) frequently suffer from pulmonary edema due to left ventricular dysfunction that accompanies left heart dilatation , which is caused by left atrial hypertension . the problem can be resolved by left atrium ( la ) decompression . we performed a successful percutaneous la decompression with an atrial septostomy and placement of an la venting cannula in a 38-month - old child treated with venoarterial ecmo for acute myocarditis .

a 31-year - old woman visited our outpatient clinic with a small palpable mass on the palmar side of her wrist ; the mass moved concurrently up and down during wrist motion for roughly three years . the movements of mass in the carpal tunnel created momentary pain and snapping during usage of the finger . she complained of numbness on the thumb , index , and middle fingers worsened by usual activities of the hand and wrist , suggesting carpal tunnel syndrome . upon physical examination the direct carpal compression test and phalen test were both positive . a snapping sound and pain around carpal tunnel there was no tenderness on the a1 pulley area of index finger . in nerve conduction studies , median neuropathy at the wrist level computed tomography scanning with gadolinium enhancement showed 11 mm 8 mm 12 mm sized , oval and well demarcated soft tissue mass at wrist level extended into the carpal tunnel ( fig . according to these findings , we suspected either a nodule or ganglion as a space occupying lesion which led to carpal tunnel syndrome . the transverse carpal ligament was divided ; however , there was no mass lesion within carpal tunnel . by exploration of flexor tendons in carpal tunnel and proximal wrist level , we found hypertrophied and anomalous muscle belly of fds of index finger , more distally extended muscle belly than a normal condition ( fig . anomalous muscle belly made compression of median nerve and snapping around carpal tunnel during finger motion . a thirty - nine year old man complained of a catching sensation during wrist motion and a progressive tingling sensation of palmar aspect of right hand for roughly three months . previously , he was treated conservatively in several private clinics for trigger finger or carpal tunnel syndrome ; however , there were no results of the treatment . during physical examination , carpal tunnel syndrome was suspicious because he had paresthesia on median nerve dermatome and positive phalen test , and it was confirmed by nerve conduction studies . plain radiographs were normal , and magnetic resonance imaging ( mri ) showed well defined soft tissue mass attached around flexor tendon sheath from carpal tunnel to mid carpal level ( fig . after release of transverse carpal ligament and exploration of flexor tendons , pale brown colored oval mass was founded between flexor digitorum profundus tendons and moderate synovial hypertrophy of tendon sheath ( fig . a 31-year - old woman visited our outpatient clinic with a small palpable mass on the palmar side of her wrist ; the mass moved concurrently up and down during wrist motion for roughly three years . the movements of mass in the carpal tunnel created momentary pain and snapping during usage of the finger . she complained of numbness on the thumb , index , and middle fingers worsened by usual activities of the hand and wrist , suggesting carpal tunnel syndrome . upon physical examination the direct carpal compression test and phalen test were both positive . a snapping sound and pain around carpal tunnel there was no tenderness on the a1 pulley area of index finger . in nerve conduction studies , median neuropathy at the wrist level computed tomography scanning with gadolinium enhancement showed 11 mm 8 mm 12 mm sized , oval and well demarcated soft tissue mass at wrist level extended into the carpal tunnel ( fig . according to these findings , we suspected either a nodule or ganglion as a space occupying lesion which led to carpal tunnel syndrome . the transverse carpal ligament was divided ; however , there was no mass lesion within carpal tunnel . by exploration of flexor tendons in carpal tunnel and proximal wrist level , we found hypertrophied and anomalous muscle belly of fds of index finger , more distally extended muscle belly than a normal condition ( fig . anomalous muscle belly made compression of median nerve and snapping around carpal tunnel during finger motion . a thirty - nine year old man complained of a catching sensation during wrist motion and a progressive tingling sensation of palmar aspect of right hand for roughly three months . previously , he was treated conservatively in several private clinics for trigger finger or carpal tunnel syndrome ; however , there were no results of the treatment . during physical examination , carpal tunnel syndrome was suspicious because he had paresthesia on median nerve dermatome and positive phalen test , and it was confirmed by nerve conduction studies . plain radiographs were normal , and magnetic resonance imaging ( mri ) showed well defined soft tissue mass attached around flexor tendon sheath from carpal tunnel to mid carpal level ( fig . after release of transverse carpal ligament and exploration of flexor tendons , pale brown colored oval mass was founded between flexor digitorum profundus tendons and moderate synovial hypertrophy of tendon sheath ( fig . trigger finger is one of the most common causes of hand with a painful click during finger motion.1 ) trigger wrist , however , has a low incidence rate in the general population ; therefore , many hand surgeons do not have direct experience dealing with the condition . symptoms such as snapping , catching or triggering at the wrist should be clinically differentiated from trigger finger ; however , it is quite difficult to differentiate because patients often complain of vague pain or discomfort not in the wrist but fingers.23 ) for this reason , trigger wrist might be misdiagnosed as trigger finger ; this can lead to unnecessary surgery and other medical procedures such as a1 pulley release or steroid injection . nodule or mass of flexor tenosynovitis , or benign tumors inside carpal tunnel , often cause median neuropathy . if a patient has long standing ( chronic ) carpal tunnel syndrome without obvious triggering , surgeons probably will perform an early release of carpal tunnel . although the triggering may be solved via this procedure,4 ) the main problem still remains . in order to make a more precise diagnosis , a careful physical examination and review of atypical and uncertain symptoms and signs for trigger fingers are necessary . for example , vague pain on palm , absence of point tenderness on a1 pulley area or difficulties in full flexion of fingers might be clues suggesting a diagnosis of trigger wrist.2 ) if carpal tunnel syndrome is accompanied with trigger finger , triggering should be checked at wrist level.5 ) because patients with trigger wrist also often have carpal tunnel syndrome , if a patient presents with median neuropathy as a main complaint , checking crepitus of intracarpal tunnel might be helpful to find intracarpal mass . if crepitus were felt by light compression over the transverse carpal ligament by examiner 's thumb during finger motion , further evaluation such as mri of ultrasonography is needed to distinguish space occupying lesion of carpal tunnel which can lead to trigger wrist . class a trigger wrist is due to a tumor or nodule occurring on the flexor tendon sheath which enters and exits from the carpal tunnel . class b trigger wrist is due to anomalous muscle belly ( including an abnormal lumbrical muscle or abnormal muscle belly of the fds ) . class c trigger wrist is a combination of class a and b. of the three classes , class a is most prevalent . applying this classificatory system for the cases presented in this paper : case 1 is class b and case 2 is class a. median neuropathy caused by space occupying lesion in carpal tunnel may be candidates of trigger wrist if disease have progressed regardless of treatment.7 ) thus , an accurate diagnosis and carpal tunnel release with excision of triggering mass are necessary to treat trigger wrist.89 ) the clinical differentiation of trigger wrist from trigger finger or carpal tunnel syndrome is difficult when characteristic snapping or triggering around wrist is absent . partly due to this reason , trigger finger is often misdiagnosed ; in addition , trigger wrist is a rare disease with low population prevalence . the diagnosis becomes clearer when the clinical presentation is related to catching , snapping , and locking on wrist level with or without mild to moderate carpal tunnel syndrome rather than triggering of a finger with tenderness over a1 pulley area . ineffective conservative treatments or inappropriate surgical procedures may lead to more advanced disease conditions such as severe tenosynovitis or adhesion of flexor tendons or carpal tunnel syndrome with atrophy of thenar muscles,2 ) which need more extensive explorations or reconstructive surgeries ( i.e. , tendon reconstruction or opponensplasty ) . the accurate examination and proper diagnosis are mandatory to avoided improper and time - wasting treatment for patients with trigger wrist .

trigger wrist is a relatively rare disease compared to trigger finger , which is the most common disorder found in hands . patients with trigger wrist usually complain about the following symptoms : snapping and clicking or triggering around carpal tunnel with or without mild to moderate median neuropathy . there are a total of five cases of trigger wrist : three cases of anomalous muscle belly of flexor digitorum superficialis and two cases of fibroma around flexor tendon sheath within carpal tunnel . this study reports on two of those cases : one with anomalous muscle and the other with fibroma of flexor tendon sheath . accurate examination and proper diagnosis are mandatory to obviate improper and time - wasting treatment for patients with trigger wrist .

conventionally , the evaluation of new analytical systems is conducted on the basis of established protocols related to analytical performance like those published by clsi ( nccls ) , eccls , or other national organizations . sometimes additional exploratory testing is performed in the hope of gaining some insight into the routine behaviour of the system . while the standard protocols produce indispensable information with regard to the quality characteristics , they fail to analyse the system performance under routine conditions . similarly , random obviously , there is no easy way to experimentally test the course of events that lead to an erroneous assay result and to verify its incorrectness under nonstandardized , that is , routine conditions . this situation is caused by the increasingly complex interactions of hardware , software , and chemistry which are found on modern analysis systems . the manual generation of experiments that describe a sample sequence with variable specimens and request patterns is feasible , but it is cumbersome to produce and provides no information on the correctness of the measurements . a better approach can be obtained by developing a software tool which generates appropriate experimental request lists , allowing the testing of a new system under conditions close to the routine in a controlled and systematic manner , and which provides sufficient data reduction for the analysis of the results . we have integrated this functionality in our evaluation software tool windows - based computer - aided evaluation ( wincaev ) [ 3 , 4 ] in such a way , that the generation of simulation experiments , the transfer of requests to the instrument , the on - line data capture , and the result evaluation , can be easily achieved with the available programme functions . the routine simulation ( hereafter referred to as rs ) module allows for the definition and generation of typical test request patterns . a request list that reflects a routine laboratory workload can be simulated by wincaev using appropriately defined parameters . the required input data embraces typical test distributions , sample materials , and sample request profiles . as an alternative to this programme supported simulation , laboratory specific request lists captured electronically from the laboratory information system or directly from the routine analysers are automatically converted by wincaev to a corresponding worklist for the system under evaluation . three main types of rs experiments were designed to allow systematic testing of an analytical system . in this way , different types of routine situations can be modelled and the respective performance situation evaluated . the rs - precision experiment type is used to test for systematic and/or random errors using the imprecision characteristics of the system . the goal is to compare the analyte recovery and precision generated during randomized processing with that produced during batch analysis . a typical request list is shown in table 1 . in repetitions of the same experiment , routine provocations are introduced during the randomized processing to further challenge the system 's performance under various conditions . the type and number of provocations depend on the system under evaluation , but generally include items regularly encountered during operation in a routine laboratory , like calibration and quality control measurements , reagent switchover or exchange , sample short , stat analysis , provocation of various data flags , sample reruns , and so forth . errors related to instrument malfunctions or chemistry problems can be deducted from the experimental data by comparing the batch and random results . the mean , median , cv , relative 68%-median distance ( md68% describes a robust measure of variation ) , and minimum and maximum of the random part are compared with those from the batch part for every analyte measured . random and/or systematic errors will result in significant deviations like elevated cvs and differences of the means . one can expect that the imprecision in a simulated routine run will result in somewhat higher cvs due to more interactions of the analytical system than during a standard batch run . based on experience from various system evaluations , we use the following expected cv in the random part : cvexp , rand = cvexp , ref + cv , where we set cv = 1/2(cvexp , ref ) ; therefore cvexp , rand = 1.5 cvexp , ref ; cvexp , ref is the expected cv in the reference part . usually the routine simulation experiment is performed with many different methods , and the high number of results produced has to be assessed for relevant deviant results . this can easily be done by comparing the cv and the relative 68%-median distance . the system handling of the routine provocations is assessed for correctness , and the analytical results produced during and after provocations are checked for marked deviations which may represent systematic and/or random errors . recently we extended this experiment in order to run the routine simulation precision experiment via a host download procedure ( see below ) so that the real routine request pattern is reflected and a simulation by the wincaev software is not necessary . rs - series 1/2 is used for the comparison of randomized test processing in two runs . fresh human specimens are used as sample materials with request patterns reflecting the evaluation sites typical routine workloads . the sequence of sample processing is identical in both runs and the same samples are used , not placing fresh samples for the second run . random errors can be deducted from the experimental data by comparing the deviation of the second from the first run results . each sample pair is categorized ; a summary shows the number of samples per analyte in each category as well as a total statistic per category for the complete experiment ( see table 2 and figure 1 ) . random errors will result in marked deviations between both run results for one or more samples . rs - method comparison download allows direct comparison of the routine analyser methods ( reference data ) with those of the instrument under evaluation processed in a randomized routine - like fashion . the test results and sampling patterns from the routine laboratory analyser(s ) are electronically captured by wincaev via file import ( host - download ) or simply with a batch upload . using the host - download option , sample identification numbers , requests , and results are exported from the laboratory host in a text format file ( e.g. , comma separated values ( csv ) ) and then imported in wincaev . over the last decade , routine simulation experiments have become an integral part of inhouse and multicentre system evaluations at roche diagnostics . here , we outline some typical areas of use based on practical experience , as well as examples of errors difficult to produce using conventional procedures yet observed using these experiments . rs - precision is an extremely effective means of testing the interaction of software with all other system components under stressed conditions . during a multicentre study of roche / hitachi 917 in the early nineties for example , these experiments yielded cvs of up to 4% for test applications using low - sample volume ( 2 l ) . of the 48 runs performed during this experiment , 83% ( = 40 series ) were found with a cv higher than the expected 2% ; 24 series had a relative 68-median distance of more than 2% . the difference between cv and md68% indicated that several series had clear deviant results . further inhouse investigations revealed that a software malfunction in the sample pipetting process under certain conditions was the root cause for these conspicuous results . after correction of the software and repetition of this experiment , the cv of the cholesterol assay was in all cases below 2% . on roche / hitachi 912 , we found that introduction of stat samples during operation led to intermittent incorrect data flags on stat sample results when a sample material other than serum was selected . investigation showed that if a stat sample was requested by sample disk position only on the analyzer , and the sample type downloaded from the laboratory host is one other than serum or plasma , the sample was correctly measured for the specified biological material but the data flagging was done as if the sample was serum . in this case , an incorrect rerun of the sample was indicated by the generated data flag . with the new generation of roche systems modular analytics from the late nineties , combining multiple analyser modules , an intelligent process manager distributes the sample carriers to the various analyser modules in a way that ensures most efficient operation , and background maintenance features on these systems allow the operator to perform maintenance on one or more modules while continuing routine operation on the other modules . the rs - precision experiment allowed us to check these , among other complex functions , in a systematic manner under numerous simulated routine - like conditions . a typical provocation on such systems is the deactivation and reactivation of a module during routine operation . the goal is to check that the samples with requests for tests on the deactivated module(s ) are handled correctly , and that the reactivated module performs as expected after return to operation . during the modular analytics swa ( serum work area ) evaluation , these provocations revealed sporadic errors after module reactivation like wrong reagent inventory and bottle change - over to standby reagents although current reagents were not empty . also , rs - precision is an effective tool to test the interaction of reagents on a selective access analyser . during the recent multicentre evaluation of cobas 6000 , a new reagent carryover not observed on other roche analysers caused by the reagent probe was found for the creatinine enzymatic assay , when the creatine kinase reagent ( ck ) was pipetted just before the creatinine assay . creatine phosphate of the ck reagent ( vial 2 ) may partly be hydrolysed to creatine which can influence the creatine concentration of the enzymatic creatinine assay , when contaminated by the reagent probe . as shown in table 3 , the cv changes from 0.9% in the batch part to 2.1% in the random part . looking to the single results , the creatinine concentration of sample number 68 is increased and classified as an outlier ( 255 compared to the median of 225 mmol / l , which is increased by more than the fivefold md68 [ 20 mmol / l ] ) . by monitoring the cuvette history data base of the analyser , one could confirm for that sample that the ck reagent was pipetted just before the creatinine assay . consequentially , an extra probe wash cycle was installed on cobas 6000 for this reagent combination in order to avoid carryover . table 3 shows also that the analyser works correctly after a provocation with an expired reagent pack ( example - hcg ) . conventionally used to test for reproducibility of results in two runs with the goal to check for random errors , the rs - series 1/2 experiment can also be easily adopted to address numerous system specific functionalities . for modular systems , this experiment is used to compare consistency between modules for example . on the other hand , during the cobas integra 800 evaluation , it was used to check the analyser 's clot and bubble detection function . samples with clots and bubbles were included in the first run and prior to the second run ; bubbles were removed and those with clots were centrifuged . the results were checked for correct flagging of problematic samples in the first run and analyte recovery compared with the second run . having a practically automated procedure to immediately repeat the workload from one or more routine instruments on the system under evaluation and to directly compare the results , the rs - method comparison download is an invaluable tool . it allows the investigator to assess the new system from an analytical performance as well as from an overall system performance perspective , under real life conditions . a total of 187 method comparisons were processed for 50 analytes in nine laboratories under site - specific routine conditions during the modular analytics evaluation for example . analysis of approximately 27 000 measurements for fresh human specimens gave the final proof that the system was ready for market launch . conducting such routine simulation experiments gives the manufacturer essential information on the overall system performance under real intended - use conditions . this innovative , realistic , and thorough approach to system testing has won the approval of principle investigators during international multicentre evaluations over more than ten years . with the experience gained , we strongly recommend to focus more on routine simulation type experiments during the performance evaluation of a new analytical system , and above all to derive the various quality characteristics like imprecision and method comparison from these results .

the established protocols for evaluating new analytical systems produce indispensable information with regard to quality characteristics , but in general they fail to analyse the system performance under routine - like conditions . we describe a model which allows the testing of a new analytical system under conditions close to the routine in a controlled and systematic manner by using an appropriate software tool . performing routine simulation experiments , either reflecting imprecision or method comparison characteristics , gives the user essential information on the overall system performance under real intended - use conditions .

ventriculo - peritoneal ( vp ) shunting of cerebrospinal fluid ( csf ) is a standard procedure for the management of hydrocephalus . the common complications are infection of the shunt , malfunction due to blockage , disconnection , migration , and shunt failure . other complications reported in the literature include intestinal perforation , csf ascites , inguinal hernia , and intestinal volvulus . extrusion of the peritoneal end of the shunt through mouth is extremely rare and few cases have been reported in the literature.[18 ] we are reporting one such rare case of transoral extrusion of the peritoneal catheter . a 1-year , malnourished male child was admitted in our hospital with chief complaint of protrusion of a white tube from mouth since 6 hours . ventriculo - peritoneal shunt was done for congenital hydrocephalus in some other institution 8 months back . a tube came out from the mouth after a bout of vomiting [ figure 1 ] . on examination there was cerebrospinal fluid ( csf ) coming out from the peritoneal end which increased on pressing the chamber . he was conscious with spontaneous eye opening , had no neurological deficits , and the anterior fontanelle was depressed . the fixation stitch of the proximal end of the catheter was cut by the incision behind the ear and the shunt assembly was cut distal to valve . removal of valve from incision behind ear helps in easy removal of the peritoneal tube and also eliminates risk of enlarging gut opening by a comparatively large diameter valve portion of the catheter . the patient was kept nil orally for 2 days to look for any evidence of gut perforation . the patient was discharged on the 10 postoperative day without any complications . at 1-year follow - up photograph of the patient showing the peritoneal end of ventriculo - peritoneal shunt coming through the mouth ventriculo - peritoneal shunt is the most common operation performed in the treatment of hydrocephalus . complications related to vp shunt are common . malfunction of the shunt after initial placement occurs in approximately 2535% of patients at 1 year , and 7080% of patients require at least one revision at some point in their lives . the incidence of shunt - related abdominal complications has been reported to be from 5% to 47% . bowel perforation is a rare complication of shunt placement , occurring in less than 0.10.7% of cases , out of which nearly half are diagnosed after removal of the catheter . these include the colon , stomach , small bowel , urinary bladder , perforation of the fallopian tube with vaginal discharge . protrusions of the shunt tube through the inguinal canal , perforation of umbilicus , and scrotum have been reported . the majority of cases in the literature had a delayed presentation after surgery , which suggests a chronic inflammatory process rather than a traumatic event . it has been proposed that the tip of the catheter adheres to and then erode the intestinal wall due to continuous friction at the site of contact . another mechanism proposed is the perforation of gut by a chronic irritative process in which the catheter adheres to the serosal surface of the bowel by way of foreign body reaction , related to silicone allergy . the repeated pressure on the fixed point slowly produces an ulcer and eventually a perforation . some authors believe that bowel perforation may be the result of occult shunt infection caused by intraoperative contamination . the predisposing factors for bowel perforation , reported in the literature , are age , male gender , malnutrition , poor general condition , length and type of catheter , previous abdominal operation , infection , and silicone allergy from foreign body reaction . of these factors , age stands out as the main risk factor for bowel perforation and this has been attributed to weaker intestinal musculature and stronger intestinal peristaltic activity in children . stiff , hard tipped , sharp , or spring coiled peritoneal catheters are more likely to perforate . transoral protrusion of vp shunt is rare.[18 ] normally the catheter is propelled distally by peristalsis after perforation of bowel . the catheter has to move against the normal peristalsis and also cross the gastro - oesophageal junction and the oesophagus to come out from the mouth . in a case reported by shridhar et al . , the probable mechanism of bowel perforation was infection , which led to inflammation and adherence of the tube to the proximal gut . odebode reported that probably the perforation was due to a chronic irritative process in which the catheter adheres to the serosal surface of the bowel by way of foreign body reaction related to silicone allergy . infection in the odebode case resulted in shunt rejection due to infected foreign body reaction . low et al . , in their case , postulated that bowel perforation was due to chronic inflammation and infection . the possible mechanism in our case was a chronic irritation by the catheter tip to the serosal surface of the bowel . the forceful episode of vomiting was responsible for antiperistaltic movement of the shunt and shunt came out from the mouth . predisposing factors in our case were age , male gender , mal nourish status , and vomiting . park et al . did laparoscopic exploration for the tube removal , odebode performed laparotomy for tube removal and primary repair of bowel , kothari et al . pulled out the shunt through the incision behind the ear , and murali et al . and low et al . there could be three ways to remove peritoneal catheter in transoral extrusion of vp shunt . a major laparotomy is probably unnecessary as the opening in the bowel is small and seals off spontaneously . pulling the extruded peritoneal end in a retrograde manner can result in increased chances of infection . in this method there is always a theoretical risk of infection as the peritoneal end is exposed to atmosphere and the contaminated gut . this method reduces the chances of infection as there is no contact of the contaminated tube to the peritoneum or the shunt tract . pulling the peritoneal end through mouth is probably the best way of management in such cases as small spontaneous late gut perforation seals off spontaneously and decreases the possibility of infection , morbidity , and hospital stay .

there are several case reports of complications of ventriculo - peritoneal shunt . extrusion of the peritoneal end of the shunt through mouth is extremely rare . there are few case reports . we are reporting one such case . a 1-year male child was admitted with the peritoneal end of ventriculo - peritoneal shunt coming out through mouth since 6 hours after an episode of vomiting . he was conscious and had no neurological deficits . the anterior fontanelle was depressed . there was no infection . the peritoneal end of the shunt was removed through the mouth . shunt revision was performed . the patient was discharged 10 days after the revision without any complications . at 1-year follow - up the patient is doing well . possible mechanisms of bowel perforation are discussed . pulling the peritoneal end through mouth is probably the best way of management as small spontaneous gut perforation seals off spontaneously . it also decreases the possibility of infection , other morbidities , and hospital stay .

a search for the biological factor responsible for energy balance and signal transduction to the hypothalamus was initiated by studies on animal models . in 1994 , a molecular defect in the obese gene ( ob ) , a gene responsible for the obesity phenotype in ob / ob mice was identified using a positive cloning method . ob gene has found on chromosome 6 in mice and on chromosome 7q31.3 in humans and has been shown to encode 4.5 kb - long mrna . the protein encoded by the ob gene has been isolated and named leptin - from the greek " leptos " meaning thin . it has been demonstrated that leptin biological activity strongly depends on its proper interactions with ob - r receptors . ob - r receptor , encoded by db gene has been identified for the first time in a murine vascular plexus using a cloning technique . it is a member of class i cytokine receptors family that , apart from , ob - r consist of gp130 subunit of il-2r , il-3 , il-4 , il-6 , il-7 , lif ( leukemia inhibitory factor ) , g - csf ( granulocytecolony stimulating factor ) , growth hormone , prolactin , and erythropoietin receptors . ob - r expressed in six isoforms , is the product of alternative rna splicing of db gene ( diabetes gen ) . according to its structural differences , the receptor 's isoforms were divided into three classes : long , short and secretory . all ob - r isoforms have a similar , extracellular ligand- binding domain located in n - terminus of the protein . the domain is constituted by 816 amino acids and contains four cysteine residues , wsxws motif ( trp - ser - x - trp - ser ) and a different number of fibronectin iii domains . five isoforms , including the long isoform ob - rb and short ones - ob - ra , ob - rc , ob - rd , and ob - rf , have a transmembrane domain consisting of 34 amino acids . the intracellular domain of the long isoform consists of 303 amino acids at carboxyl terminus , while intracellular domains of short isoforms are shorter and consists of 32 - 40 amino acids . apart from identical extracellular and transmembrane domains , ob - r isoforms ( short and long ) have the same sequence of the first intracellular 29 amino acids . the length of the further intracellular amino acid sequences depends on the alternative mrna splicing . ob - rb isoform contain additional box 2 and socs ( suppressor of cytokine signaling ) motifs . a sixth , secreted ob - re isoform , does not contain intracellular and cytoplasmic domains and is secreted to the bloodstream as a soluble receptor ( figure 1 ) [ 6,8 - 10 ] . cr - cytokine receptor domain , f - iii - type iii fibronectin domains , box 1 , 2 , 3 - constant , intracellular motifs [ according to 7 , 8 ] . a long , fully active isoform of ob - rb is expressed mainly in the hypothalamus , where it takes part in energy homeostasis and in the regulation of secretory organs ' activity . ob - rb is also present in all types of immune cells , involved in innate and adaptive immunity ( figure 2 ) [ 7,9,11 - 14 ] . ob - rb , long isoform of leptin receptor : jak - tyrosine kinases , stat - signal transducer and activator of transcription , socs proteins - cytokine signal transduction inhibitors , p - phosphate residues , cr - cytokine receptor domain , f - iii - type iii fibronectin domains [ according to 7 , 17 ] . lack of a full - length ob - rb receptor is responsible for the development of the early obesity phenotype in db / db mice and in obese rats . in db / db mice , a short ob - ra isoform with limited activity is synthesized . the mice strain is also characterized by cold intolerance and elevated concentration of glucosteroid hormones . moreover , db / db mice phenotype includes a significantly elevated leptin concentration , with no ability to respond to leptin signal . short leptin isoforms that contain box 1 motif are able to bind jak kinases ( janus kinases ) and to activate some signal transduction cascades . however , the effect of short isoform activation differs from that of long isoform activation . a short isoform , ob - ra , is the most common ob - r isoform that can be found in many various cells and tissues , including kidney , lungs , liver , spleen , and macrophages . a soluble isoform of the receptor , ob - re , is probably a result of alternative transcript splicing of db gene or a consequence of transmembrane ob - r receptor destruction . circulating ob - re is able to bind serum leptin and to inhibit signal transduction pathways . on the other hand , the receptor can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors able to transduct the signal into the cell . in normal conditions , only 5 - 25% of all ob - r isoforms are present on the cell surface , whereas the majority of receptors are localized within the cell . after ligand binding , the receptors are internalized into early endosomes via clathrin - coated vesicles . a decrease in ob - rb expression is much higher than changes in ob - ra expression , and short isoform ob - ra is much faster recycled to the cell membrane . relatively weak signal transduction through long ob - rb isoform observed in obese , hyperleptinemic patients is related to delayed receptor expression on the cell surface , which may explain leptin resistance in these patients . the major role in leptin signal transduction through membrane receptors is mediated through jak / stat ( signal transduction and activation of transcription ) pathway . among all ob - r isoforms , only the fulllength isoform ob - rb is able to fully transduce an activation signal into the cell . ob - rb is considered a fully active receptor , because it contains 3 intracellular motifs necessary to activate the jak / stat pathway . the described motifs are the following : box 1 and box 2 that bind jak tyrosine kinase , and box 3 motif that binds stat transcription factor . additionally , in intracellular domain , ob - rb contains four tyrosine residues ( tyr974 , tyr985 , tyr1077 and tyr1138 ) that activate intracellular signal transduction pathways ( figure 2 ) . after ligand binding to the ob - rb receptor , a cytoplasmic tyrosine kinase jak2 binds to box-1 and box-2 motifs . the activated kinase is autophosphorylated and activates specific tyrosine residues ( tyr 985 and tyr1138 ) in the receptor molecule . next , after tyr1138 phosphorylation , stat proteins bind to box-3 motif . stat proteins ( stat1 , stat3 , stat5 , stat6 ) , including the key signal transduction molecule stat3 , are phosphorylated on tyrosine residues by jak2 kinases . the process leads to the dissociation of proteins from the receptor , homo- or heterodimerization and translocation of the proteins to the nucleus . in the nucleus , the described proteins serve as transcription factors activating the expression of a suppressor of cytokine signaling 3 ( socs-3 ) or protein tyrosine phosphatase 1b ( figure 3 ) [ 17,24 - 26 ] . after leptin binding , the ob - rb receptor changes its conformation that leads to jak translocation . jak proteins become activated and start to exert their kinase activity and phosphorylate tyrosine residues of other jak proteins and of ob - rb receptor . tyr1138 phosphorylation allows stat3 protein binding and next , stat proteins become the substrate for jak proteins related to ob - r receptor . stat3 protein phosphorylation leads to dissociation of the protein from the receptor , dimerization and translocation to the nucleus . stat proteins are activated by leptin and depending on the target tissue ; the type of activated protein may differ between various types of target cells . leptin induces socs3 expression by binding to the socs3 sh2 domain with tyr985 or through the inhibition of socs3 dependent jak2 phosphorylation activity . in addition , ptp1b ( protein tyrosine phosphatase 1b ) is another negative leptin signal transduction modulator that regulates signal transduction through dephosphorylation of jak2 . ptpb1 overexpression decreases jak2 phosphorylation and inhibits leptin - induced socs3 and c - fos ( proto - oncogene ) transcription . mapk kinases ( mitogen - activated protein kinase ) , irs1 ( insulin receptor substrate-1 ) , and phosphatidylinositol kinase ( pi3k ) are important pathways responsible for ob - rb receptor activation by leptin in various cells , e.g. , t - cells . the mapk kinase signal transduction pathway is mediated by erk ( estrogen receptor ) and p38 kinases . it has been demonstrated in osteoblasts that leptin , after activation of ob - rb , induces apoptosis through the activation of mapk , erk1/2-dependent activation of cytoplasmic phospholipase a , and subsequent cytochrome c release and activation of caspases 3 and 9 . osmotic stress , heat shock , and cytokines are able to activate another mapk family protein , namely p38 . in mononuclear cells , after binding to ob - rb , leptin increases the level of p38mapk phosphorylation . in lps ( lipopolysaccharide)-stimulated kupffer cells , leptin significantly increases tnf secretion through the activation of p38 and jnk / mapk ( c - jun n - terminal kinase ) , whereas in smooth muscle cells it is able to induce hypertrophy through the activation of p38 mapk . pi3k is believed to constitute an important common element for signal transduction pathways activated by insulin and leptin and its receptor . in the central nervous system , adipose tissue , liver , and pancreas , leptin induces a similar pathway to that activated by insulin , including pi3kdependent activation of pde3b ( phosphodiesterase 3b ) and camp ( cyclic adenosine monophosphate ) reduction . it seems that pi3k / pde3b / camp pathway cooperates with the jak2/stat cascade and is an important element of leptin signal transduction pathways in the hypothalamus . lepr gene ( leptin receptor gene ) mutations are extremely rare in human and animals . a single nucleotide substitution ( g to a ) in exon 6 leads to a deficiency in intracellular and transmembrane domain of the receptor . the mutation caused by premature stop codon insertion at the 3 ' terminus of leprb mrna was found in db / db mice , whereas in zucker rats , the mutation was caused by amino acid substitution ( gln to pro ) at position 269 of the extracellular domain of the receptor . the described mutation resulted in a severe reduction of ob - r expression on the cell surface and limitation in the leptin - receptor binding . obese koletsky rats had a point mutation at 763 position resulting in premature stop codon introduction in the intracellular domain of the receptor that led to a total deficiency in all ob - r isoforms on the cell surface . both zucker and koletsky rats are characterized by morbid obesity , hyperphagia , hyperlipidemia , and numerous hormonal disorders . in humans , a rare mutation caused by a single substitution of g to a in exon 16 was identified . it leads to an abnormal expression of transmembrane and intracellular domains of receptors . as in case of laboratory animals , humans with lepr gene defects it has been demonstrated that the polymorphisms may lead to the impairment of signal transduction from the receptor into the cell through premature ob - ra , instead of ob - rb isoform production , or through a decrease in ob - r expression on the cell surface and limitation in leptin - receptor interactions . lepr gene defects influence the development of hyperphagia , obesity , pubertal development disorders , neuroendocrine system regulation impairment , and diabetes caused by -cell apoptosis in the pancreas . the most commonly seen polymorphism is gln223arg , encoding the extracellular domain of the receptor responsible for leptin binding . glutamine to arginine change may be responsible for an impaired signal transducing capacity of the leptin receptor . a connection between gln223arg polymorphism and breast cancer development and progression has been suggested . genetic interactions between leptin and gln223arg polymorphisms of lepr gene can increase the risk of the development of non - hodgkin lymphoma in obese patients . it also is suggested that the discussed polymorphisms are related to hemodynamic and metabolic disorders found in obese patients . overweight and obesity commonly observed after the management of childhood acute lymphoblastic leukemia also may have to do with the gln223arg polymorphism of lepr gene .

leptin or obesity receptor ( ob - r ) is a member of class i cytokine receptor family . ob - r , expressed in six isoforms , is the product of alternative rna splicing of db gene . according to its structural differences , the receptor 's isoforms are divided into three classes : long , short , and secretory isoforms . a long , fully active isoform of ob - rb is expressed mainly in the hypothalamus , where it takes part in energy homeostasis and in the regulation of secretory organs ' activity . ob - rb is also present on all types of immune cells , involved in innate and adaptive immunity . short leptin isoforms ( ob - ra , ob - rc , ob - rd , and ob - re ) that contain box 1 motif are able to bind jak kinases ( janus kinases ) as well as to activate some other signal transduction cascades . a soluble isoform ( ob - re ) can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors and is able to transduce the signal into the cell . jak / stat pathway plays the major role in leptin signal transduction through membrane receptors . among all ob - r isoforms , only full - length isoform ( ob - rb ) is able to fully transduce activation signal into the cell .

carotid body tumors ( cbt ) are rare chemical receptor tumors which accounts for 0.6% of the head and neck tumors in human . although surgical resection is a reliable therapeutic method for cbt , the procedure is technically challenge for surgeons due to the tumor 's adjacent to great vessels and cranial nerve . we report nine cases of cbt who were treated at our center during 2004 to 2008 with a literature review . from 2004 to 2008 , nine patients were diagnosed as cbt at the department of vascular surgery , xuanwu hospital , capital medical university . among them , five were male , the mean age was 43 years ( range from 26 to 84 years ) . low echo - level chunks were detected in external carotid arteries and internal carotid arteries . seven patients underwent transcranial doppler ( tcd ) sonography before the surgery ( figure 2 ) . in all of these patients , the carotid artery compression test showed that blood flow in cerebral arteries decreased by 60% or more . three patients had ct examination with angiography plus three - dimensional reconstruction , which showed that soft tissues encased the posterior lateral side of the left common carotid artery bulb . all patients had digital subtraction angiography ( dsa ) , which showed abnormal accumulation of contrast medium at the crotch of common carotid artery . four patients were classified as type i , two as type ii and three as type iii . four of them underwent simple carotid body tumor resection , two underwent carotid body tumor resection and ligation of external carotid artery and two had common carotid artery - internal carotid artery artificial vascular reconstruction . no perioperative mortality and stroke occurred . during a mean follow - up of 2.2 years ( 3 months to 6 years ) , the patient who refused surgery died three years after the diagnosis due to complications from bone fracture . the patient with malignant tumor died two years after the surgery due to multiple metastases . cbt is the most frequently diagnosed carotid body disease and is also termed as chemodectoma . it is originated from nervous crest and belongs to nonchromaffin paraganglioma , which is similar to chromaffin suprarenal medulla tumors ( such as chromaffin tumors ) with the same origin in histology . cbt can be found at any age and is frequently seen in those between 50 and 70 years old , which slightly higher prevalence in women than men . bilateral disease is significantly more frequent in familial ( 31.8% of cases ) than in non - familial cbt ( 4.4% ) . the blood supply of cbt is abundant , which is mainly from external carotid artery and branches . blood supplies from internal carotid artery , vertebral artery , ascending pharyngeal artery and superior thyroid artery have also been reported . in addition to external carotid artery , multiple blood supply from internal carotid artery , thyrocervical trunk , vertebral artery and ascending pharyngeal artery were also found in two patients in our case series . color doppler ultrasound , a simple and non - invasive examination , has relatively high specificity and sensitivity for cbt . other diagnostic methods include aspiration - needle biopsy , ct and mri . the accuracy of mri is higher in comparison to that of ct . furthermore , mri is not radioactive , and the diagnostic rate for multiple lesions is particularly important for the patients with family history . shamblin research group classified cbt into type i ( localized type ) , type ii ( partially wrapped type ) and type iii ( wrapped type ) . with the higher shamblin grading , the possibilities for injuries in cranial nerves , fragility of cervical great vessels are higher during or after operations . recent advance in vascular imaging techniques have enabled preoperative grading for tumor size , which can be completely consistent with the shamblin grading during operations . , we have divided the surgery into four types according to shamblin grading and tumor blood supply . simple resection of carotid body tumor is the most ideal operation form , which would not damage the shape and distribution of cervical arteries . thus , it is suitable for shamblin type i / ii cases without abundant blood supply . carotid body tumor resection and reconstructive vascular operation ( including simple vascular anastomosis , internal carotid artery - common carotid artery artificial and autologous reconstructive vascular operation ) are suitable for shamblin type iii cases with enormous tumors and malignant tumors involving important peripheral vessels . in the carotid body tumor resection and ligation of common carotid artery , cerebral ischemia is a relatively common complication and now is only used for emergent treatments . medullary chromaffinoma is always benign and the incidence of malignant tumors is lower than 10% . one case of malignant cbt in our patients had vertebral body metastasis two years after resection and finally died of the disease . hu et al . summarized 967 patients in 36 centers from 1962 to 2001 and reported that radiotherapy can be used as the adjunctive therapy for primary and metastatic foci . the efficacy for local control was equal to that for operations and the incidence of complications was significantly reduced in comparison to that for operations . however , results from prospective studies of radiotherapy for malignant cbt are still unavailable and it is not routinely . color doppler ultrasound , a simple and non - invasive examination , has relatively high specificity and sensitivity for cbt . other diagnostic methods include aspiration - needle biopsy , ct and mri . the accuracy of mri is higher in comparison to that of ct . furthermore , mri is not radioactive , and the diagnostic rate for multiple lesions is particularly important for the patients with family history . shamblin research group classified cbt into type i ( localized type ) , type ii ( partially wrapped type ) and type iii ( wrapped type ) . with the higher shamblin grading , the possibilities for injuries in cranial nerves , fragility of cervical great vessels are higher during or after operations . recent advance in vascular imaging techniques have enabled preoperative grading for tumor size , which can be completely consistent with the shamblin grading during operations . , we have divided the surgery into four types according to shamblin grading and tumor blood supply . simple resection of carotid body tumor is the most ideal operation form , which would not damage the shape and distribution of cervical arteries . thus , it is suitable for shamblin type i / ii cases without abundant blood supply . carotid body tumor resection and reconstructive vascular operation ( including simple vascular anastomosis , internal carotid artery - common carotid artery artificial and autologous reconstructive vascular operation ) are suitable for shamblin type iii cases with enormous tumors and malignant tumors involving important peripheral vessels . in the carotid body tumor resection and ligation of common carotid artery , cerebral ischemia is a relatively common complication and now is only used for emergent treatments . medullary chromaffinoma is always benign and the incidence of malignant tumors is lower than 10% . one case of malignant cbt in our patients had vertebral body metastasis two years after resection and finally died of the disease . hu et al . summarized 967 patients in 36 centers from 1962 to 2001 and reported that radiotherapy can be used as the adjunctive therapy for primary and metastatic foci . the efficacy for local control was equal to that for operations and the incidence of complications was significantly reduced in comparison to that for operations . however , results from prospective studies of radiotherapy for malignant cbt are still unavailable and it is not routinely .

carotid body tumors ( cbt ) are rare chemical receptor tumors . we report nine cases of cbt who were diagnosed at our center during 2004 to 2008 with a literature review . of these nine patients , eight underwent complete resection , one received palliative resection due to the malignant nature of the tumor , and the other one refused surgery . no perioperative mortality and stroke occurred . during a mean follow up of 2.2 years , no deaths related to cbt occurred . surgical treatment for cbt is relatively safe . the surgeon should be careful to maintain the integrity of carotid artery , and prevent cerebral ischemia and cranial nerve injuries in order to improve outcome .

the united states scoliosis research society defines idiopathic scoliosis as a cobb s angle > 10 , which increases the displacement and curvature of spine in the left and right sagittal plane1,2,3 . patients with idiopathic scoliosis have a three - dimensional deformation with lateral curvature and rotation of the vertebral body . the concave surface of the spinal curvature produces forward protrusion and the convex surface of the curvature produces a rearward protrusion in the ribs of the connecting vertebral body . consequently , if the spinal red muscles becomes weak , the white muscle becomes overused and the red muscle becomes weaker because the deep spine muscles are mostly red slow - twitch muscle fibers5 . therefore , stability exercises with isotonic contractions are emphasized rather than simple mobility exercises to correct posture and regain control of white and red muscles in patients with idiopathic scoliosis6 . these exercises provide sensorimotor and kinesthetic stimulation , thereby correcting the abnormal breathing patterns present in patients with scoliosis7 . the us scoliosis research society recommends evaluating cobb s angle in patients with idiopathic scoliosis , which is measured from a standing posture radiograph8 . a detailed intervention with emphasis on active holding to regain stability is needed to improve idiopathic scoliosis with a broad range of deformation9 . therefore , this case study was performed to analyze the effect of the schroth method with emphasis on active holding to regain stability , manage pain , and correct the cobb s angle in patients with idiopathic scoliosis . the subjects were three patients with idiopathic scoliosis and cobb s angle 10. it applied the schroth method individually to subjects during 60 min sessions , three times per week , for 15 weeks . intensity is based on the subject s curve type and the level of passive support . this study excluded subjects who had experienced treatments for idiopathic scoliosis , smokers , patients with asthma , lung disease , central nervous system disease , or a history of spine surgery . consent was obtained from all subjects , and this study was approved by the university of sahmyook university ethics board . it evaluated idiopathic scoliosis by measuring cobb s angle ( intersecting angle between the perpendicular to lines drawn parallel to the superior and inferior endplates of the most tilted vertebrae ) at the coronal plane of the entire spine by x - ray ( ed150l / r-500 - 150 ; shimadzu inc . , , erlangen , germany ) and a computer - aided design program ( cad impact , seoul , korea)8 . a 21-year - old and male with idiopathic scoliosis had low back pain and iliocostal syndrome ( visual analogue scale [ vas ] score : 4 ) , cobb s angle of 20 , and left deviation of the lumbar and right deviation of the hip and pelvis . it applied the schroth method to stabilize the center area between the iliac crest and the twelfth thoracic vertebra . the apex of the lumbar curvature was mobilized in a muscle cylinder position of the right lateral . after applying the schroth method , the vas score decreased to 0 and cobb s angle was 10.8 ( fig . change in cobb s angle in case 1 subject was a 29-year - old female with idiopathic scoliosis had neck pain , headache ( vas score : 8) , cobb s angle of 20.3 and a right deviation of the thoracic and a left deviation of the hip and pelvis . it applied the schroth method with reverse force on the shoulder to stabilize the hip and pelvis . after applying the schroth method , the vas score decreased to 0 and cobb s angle was 4 ( fig . change in cobb s angle in case 2 a 25-year - old female with idiopathic scoliosis had the neck pain and psoas syndrome ( vas score : 8) , cobb s angle of 30.6 , and a right deviation of the lumbar and a left deviation of the thoracic . it applied the schroth method to the center area between the iliac crest and the twelfth thoracic vertebra for stabilization . then , the apex of the lumbar curvature was mobilized on left side by lying in the muscle cylinder position . after applying the schroth method , the vas score decreased to 3 , and cobb s angle was 18.5 ( fig . 3fig . the schroth method was developed based on biomechanical and neurophysiological concepts without compensating for the curve in the spine , which undergoes axial elongation , deflexion , derotation , rotational breathing , and stabilization7 . in addition , a therapist educated in the memory of corrected posture recognizes abnormal during activities of daily living8 , 9 , 12 , 13 . patients with idiopathic scoliosis must consider the of changed appearance after treatment and adjustment of cobb s angle8 . therefore , a detailed intervention is required with emphasis on active holding to gain mobility and stability9 . this case study was performed to analyze the effect of the schroth method on decreasing pain and cobb s angle in patients with idiopathic scoliosis . this case study showed a decrease in pain and cobb s angle in all subjects after applying the schroth method with emphasis on active holding . previous studies have also reported significant decreases in pain and cobb s angle and increased quality of life8,9,10,11 , 13 . thus , the schroth method allows patients to regain normal posture of elongation , de - rotation , and de - flexion of the spine by continuous feedback of visual information8,9,10,11 , 13 . therefore , the schroth method decreases pain and cobb s angle by inhibiting compensation and restoring appearance . therefore , further research may be needed with more subjects to verify the effect of applying the schroth method to treat patients with idiopathic scoliosis .

[ purpose ] the purpose of this study was to examine the effect of the schroth method ( three - dimensional convergence exercise ) of emphasis of active holding on pain and cobb s angle in patients with scoliosis . [ subjects and methods ] it applied the schroth method program of emphasis of active holding individually to three subjects three time per week for 15 weeks . all subject were measured cobb s angle and pain . [ results ] after 15 weeks , pain and cobb s angle decreased compared to values before . [ conclusion ] these results demonstrate the benefit of the schroth exercise program of emphasis of active holding on decreasing pain and cobb s angle in patients with idiopathic scoliosis .

licorice is one of the most commonly used clinical drugs . when glycyrrhizin is administered orally , glycyrrhetinic acid is the major metabolite . glycyrrhetinic acid ( ga ) is an important bioactive substance of licorice with a variety of pharmacological effects , such as anti - inflammatory , antivirus , antiulcer , and adrenal cortical hormone kind function . clinical trials clearly show that glycyrrhetinic acid has a good effect on all types of dermatitis , purulent scar disease , and hair follicle infection and can cure gingivitis , esophagus inflammatory disease . it plays a physiological function in reducing lipemia and antiatherosclerotic and preventing atherosclerosis [ 9 , 10 ] . many enzymes are inhibited by glycyrrhetinic acid in corticosteroids metabolic process , such as 17-hsd , 11-hsd , 5-reductase , and 5-reductase [ 1113 ] . two distinct isozymes of 11-hsd catalyze the interconversion of hormonally active cortisol ( f ) and inactive cortisone ( e ) , which are important human glucocorticoids [ 1416 ] . glucocorticoids have anti - inflammatory , immunosuppressive , antishock , and other pharmacological roles , with clinically important applications . we develop a high performance liquid chromatography method for the simultaneous determination of cortisone and cortisol in rat serum . the pharmacokinetics of cortisone and cortisol in rats after the administration of glycyrrhetinic acid and cortisone were studied . cortisone ( lot no . 0001447641 , purity > 98.0% ) and trifluoroacetic acid ( tfa ) ( lot no . 064k3647 , purity > 98.0% ) were purchased from sigma - aldrich company ( st . cortisol and pirfenidone ( both purity > 98.0% ) were gifts from rockefeller university ( new york , usa ) . purified water was prepared in house with a milli - q water system from millipore ( bedford , ma , usa ) . the drugs were accurately weighed ( 0.0001 g ) , on an analytical balance from mettler toledo ab204-a ( zurich , switzerland ) , to prepare stock solutions of individual compounds at a concentration of 1 mg / ml in methanol . all of the standard solutions were stored in the dark at 277 k for a maximum of one month . working solutions for calibration and controls were prepared from the stock solution by dilution using methanol . the internal standard ( is ) working solution ( 100 g / ml ) was prepared by diluting its stock solution with methanol . calibration curves were prepared using blank serum spiked at concentrations of 50 , 100 , 250 , 500 , 1000 , 2000 , 4000 , and 6000 ng / ml . low , medium , and high quality control ( qc ) samples at concentrations of 100 , 1000 , and 4000 ng / ml were prepared in the same way as the calibration standard . hplc system ( agilent 1100 ) was equipped with quaternary pump , on - line vacuum degasser , autosampler , column compartment , diode array detector , and agilent chem station rev a.10.02 . chromatographic separation was achieved on a 4.6 150 mm , 5 m particle and an agilent zorbax sb - c18 column was kept constant during on the run : a source of temperature of 298 k using a one - step linear gradient . mobile phases a ( acetonitrile ) , b ( 0.1% tfa ) , and c ( water ) ratio changed as follows : 0~12 min , 24~34% a , 40% b , and 36~26% c. the detector operated at 246 nm for cortisone and cortisol . the injection volume was 20.0 l , and the flow rate of mobile phase was 0.9 ml / min . stock solutions of cortisone ( 1 mg / ml ) , cortisol ( 1 mg / ml ) , and is ( 1 mg / ml ) were separately prepared in 25 ml volumetric flasks with methanol and stored at 277 k. working solutions for calibration and controls were prepared from the stock solution by dilution using methanol . the is working solution ( 100 g / ml ) calibration curves were prepared using blank serum spiked at concentrations of 50 , 100 , 250 , 500 , 1000 , 2000 , 4000 , and 6000 ng / ml . low , medium , and high quality control ( qc ) samples at concentrations of 100 , 1000 , and 4000 ng / ml were prepared in the same way as the calibration standard . male sd rats , weighing 300 20 g ( certificate no . 2007 - 0005 ) were purchased from shanghai slac laboratory animal co. , ltd . rats were divided into 2 groups , each group was administered with glycyrrhetinic acid 10 mg / kg or vehicle ( dmso versus water = 1 : 9(v / v ) ) three times at 0 , 12 , and 24 h via intraperitoneal injection . rats were anesthetized by 10% chloral hydrate before intraperitoneal injection of cortisone 20 mg / kg . blood samples 800 l were directly collected into a clean tube from the tail vein at 5 , 10 , 20 , 40 , 60 , 90 , 120 , 150 , 180 , and 240 min . after centrifugation at 5000 rpm for 10 min , serum was separated and stored at 253 k until analysis . a 300 l aliquot of the serum sample was taken in a 10 ml glass test tube , and on that 20 l of is ( 100 g / ml ) was spiked and 150 l of sodium hydroxide solution ( 0.01 mol / l ) was added . to this , 3 ml of extraction solvent ( ethyl acetate ) was added and vortex mixed on a multiple vortexer for 2.0 min , followed by centrifugation at 4000 rpm for 15 min . the supernatant was dried under nitrogen and dissolved in 200 l of mobile phase . a 20 l aliquot of the final supernatant was injected into the hplc system for analysis . the analytical method was validated to demonstrate the selectivity , recovery , accuracy , and precision of measurements . selectivity was established by the lack of interference peaks at the retention time for cortisone , cortisol , and is . recovery of the method was determined at three concentration levels ( 100 , 1000 , and 4000 ng / ml ) by comparing the peak area obtained from the extracted serum samples with the peak area obtained by the direct injection of the corresponding concentration spiked standard solution in the extracted blank serum . qc samples at three concentration levels ( 100 , 1000 , and 4000 ng / ml ) were analyzed to assess the accuracy and precision of the method . intraday accuracy and precision ( n = 6 ) were evaluated by assays of qc samples at different times during the same day . interday accuracy and precision were tested from the results of replicate assays of qc samples over three consecutive days . accuracy of the method was estimated based on relative error ( re ) and precision was estimated by the relative standard deviation ( rsd ) . the significance of differences was assessed by unpaired t - test and one - way analysis of variance . in our study , the resolution of cortisone , cortisol , and their internal standard was satisfactory . the retention time of cortisone , cortisol , and internal standard was 10.1 min , 9.3 min , and 7.6 min , respectively . the regression equation of cortisone was y1 = 0.1991x1 + 0.0041 ( r = 0.9998 ) and its lower limit of quantitation ( lloq ) was 0.05 mg / l ( n = 6 ; rsd = 3.70% ) ; the regression equation of cortisol was y2 = 0.2262x2 0.0033 ( r = 0.9999 ) and its lloq was 0.05 mg / l ( n = 6 ; rsd = 5.22% ) . the extractive recoveries for cortisone were ( 82.00 0.64)% , ( 79.68 2.04)% , and ( 81.21 0.98)% , respectively at different serum standard concentrations of 0.1 , 1.0 , and 4.0 mg / l ; the extractive recoveries for cortisol at the same concentration levels were ( 78.18 1.63)% , ( 79.71 1.02)% , and ( 81.47 1.18)% , respectively . the intra- and interday precision ( rsd ) of cortisone was 4.53% , 2.34% , and 3.29% and 4.87% , 2.76% , and 3.79% at different serum standard concentrations of 0.1 , 1.0 , and 4.0 mg / l ; the intra- and inter - day precision ( rsd ) of cortisol at the same concentration levels were 4.97% , 3.74% , and 2.67% and 4.95% , 3.56% , and 2.36% . to investigate the pharmacokinetic parameters , we applied compartmental model . the mean concentration - time curves of cortisone in two groups were presented at figure 2 and the pharmacokinetic parameters were presented at table 1 . the mean concentration - time curves of cortisol in two groups were presented in figure 3 and the pharmacokinetic parameters were presented in table 2 . we studied the pharmacokinetic characteristics of e and f in rats combined using ga and e and then fitting their pharmacokinetic parameters . a two - compartment model was found meeting concentration - time curves of cortisone and cortisol in group e and e + ga . t1/2 , cl / f , auc(0t ) , auc(0 ) , and cmax of cortisone and cortisol were affected by glycyrrhetinic acid . the t1/2 of cortisone in group e + ga is 43% more as much as group e. auc increased by 110% , and cmax by 50% , almost to 3.516 auc of cortisol in group e + ga increased almost 25% , cmax increased by 30% , to 0.815 although t1/2 of both extended , no significant differences were found . because individual differences exist in animal test , and the sample size is too small to achieve requirement of test power ( power = 1 ) , as the result differences in parent population can not be found out . ga is an inhibitor of 11-hsd that catalyzes conversion between e and f , so the change of pharmacokinetic characteristics of e and f may be the result of affect of ga [ 16 , 18 ] . two isoforms of 11-hsd have been cloned [ 19 , 20 ] , with type i ( 11-hsd1 ) as a primary reductase that converts e to f , and type ii ( 11-hsd2 ) as a unidirectional oxidase that converts f back to e. the effects of ga on both enzymes have been reported . our previous research demonstrated that ga significantly increased endogenous corticosterone level and further increased its level when administrated in combination with ga . in human subjects , liquorice has also been found to inhibit 11-dehydrogenase , as measured by a rise in the plasma half - life of f . in our study , we clearly demonstrated that ga increased the auc of e after combinatory administration , indicating that ga inhibited 11-hsd1 , which is a primary reductase located in the liver and metabolizes e into f. however , we also witnessed the rise of f level , suggesting that ga may inhibit the further metabolism of f. as we all know that ga can increase effective blood concentration and t1/2 of glucocorticoids , when combined using that it can increase the effect of anti - inflammatory , antiallergic action , antistress response , and so on . it also can inhibit the hypothalamic - pituitary - adrenal - acceptor systems , decreasing and relieving some reverse effect , withdrawal symptom , and dependency , so it is often used as replacement drugs when reduce or withdraw cortical hormone [ 23 , 24 ] . the result found at present study indicated that the pharmacokinetic characteristics of e and its metabolite can be changed by combined preparation of ga and e. it has significant clinical value . the wide use of ga can greatly increase compliance , but the administrate dose of ga should be noticed when using ga combined with e or acted as the alternative medicines . although radioimmunity is used to detect glucocorticoids usually for its high sensitivity ; the result would be much higher than the actual concentration [ 18 , 19 ] . because target molecule , glucocorticoids , would cross - react with their isomers or metabolites . previous research had proved the result that conducted by elisa and ria assay it would have the same problem . in this work , we employed an hplc - dad assay to detect e and f concentrations in serum . compared to the methods mentioned above , the specificity of hplc - dad is much higher , so the result is much more reliable .

the purpose of this paper is to study pharmacokinetics of cortisone ( e ) and its metabolite cortisol ( f ) in rats after administration of glycyrrhetinic acid ( ga ) and cortisone . healthy male sd rats were randomized to be given 20 mg / kg e or e combined with 10 mg / kg ga . blood samples were collected at 5 , 10 , 20 , 40 , 60 , 90 , 120 , 150 , 180 , and 240 min after administration . the serum concentrations of e and f were determined by hlpc and pharmacokinetic parameters were calculated using dasver2.0 software . the parameters of auc(0t ) , auc(0 ) , and cmax for e in the group of e + ga were significantly higher than those in the group of e ( p < 0.01 ) ; the half - time ( t1/2 ) was extended compared to e ( p < 0.05 ) and cl / f was dropped obviously ( p < 0.01 ) . the rise in auc(0t ) , auc(0 ) , and cmax for cortisol in the group of e + ga was significantly compared to the group of e ( p < 0.01 ) . cl / f was lower than e ( p < 0.01 ) and the half - time ( t1/2 ) was slightly extended . in this study , we find that ga restrains the metabolism of e and f and thus increases auc , t1/2 , and cmax of e and f , which may be related to its inhibition effect on 11-hydroxysteroid dehydrogenase ( 11-hsd ) .

several factors can influence the degree of polymerization of resin cements , namely , porcelain shade and thickness4 , light - curing unit ( lcu ) and curing time12 . dual - cured resin luting agents are usually chosen based on the best combination of mechanical and physical properties when the efficacy of light activation is doubtful . light activation of dual - cured resin - based materials is necessary to maximize strength and rigidity of composites2 . also , maximum bond strength of dual - cured cements is achieved only when light activation is properly done3,8,17 . it is important to understand the light activation process of dual - cured resin cements because of the differences existing between light activation methods20 , including energy density , spectral distribution16 of the light emitted by the lcu and the polymerization process itself18 . it has been advocated that low irradiation output of lcus may be compensated by increasing the irradiation time , without affecting the conversion degree for composites , in such a way that different lcus can have the same energy density ( [ mw / cm ] x t ) . the concept of energy density is based on the theory that polymerization of light - activated composite resins depends on the total energy delivered to it7,14,21 . this study tested the following null hypotheses : ( 1 ) different lcus ( hal , led and pac ) have similar effects on the microhardness of a dual - cured resin cement when equivalent energy dose is applied , and ( 2 ) different energy doses do not significantly reduce knoop hardness . feldspathic ceramic material ( duceram plus ; ducera dental gmbh&co.kg , rosbach , germany ; vita shade dentin a3 ) was condensed into a metallic mold to produce a cylindrical specimen that was fired in ceramic furnace . one disc - shaped specimen ( 2.0 mm thick x 8.0 mm in diameter ) was obtained and submitted to finishing and glaze firing . a resin cement ( enforce with fluoride ; dentsply , ind . ltda , petrpolis , rj , brazil ) was mixed according to the manufacturer 's instructions and in compliance with iso 4049 standard10 , and inserted into a black painted nylon mold with a central hole ( 5.0 mm in diameter x 1.0 mm thick ) . the chemically activated group ( control , n=10 ) was mixed in a dark room with a red light filter to avoid light initiator sensitization . when the dual activation was used , the resin cement was light - irradiated by two modes : direct light - activation ( dla ) or irradiation through ceramic ( ltc ) . in this latter mode , a ceramic disc was interposed between the tip of lcu and the polyester film ( 25-m thick ) placed onto the resin cement and irradiation was performed using one of the 3 energy doses ( table 1 ) lcu= light - curing unit ; hal= tungsten halogen light ; led= light - emitting diode and pac= xenon plasma - arc ; cact= chemical activation only ; dla= direct light - activation ; i= irradiance or energy density of the lcu , used for specific energy dose . i/2= approximately half full potential irradiance of the lcu ; t= irradiation time ; s= turn - on sequences needed to achieve irradiation time . = for pac , there was a 3-s delay among " turn - on " sequences . three lcus were used : hal - tungsten halogen ( xl 2500 ; 3m / espe , st paul , mn , usa ; mean irradiance of 589 mw / cm ) ; led - light - emitting diode ( ultrablue is , d.m.c . equipamentos ltda , so carlos , sp , brazil ; mean irradiance of 614 mw / cm ) ; and pac - xenon plasma arc ( apollo 95e , dmd medical diagnostic systems , westlake village , ca , usa ; mean irradiance of 1,656 mw / cm ) . the lcus were connected to a voltage stabilizer and supported by an apparatus to allow positioning the tip of lcu at 90 to material surface . a hand - held radiometer ( hilux , dental curing light meter , benbionglu dental inc . times were adjusted according to the irradiance of each lcu to reach the desired energy doses , according to the equation : where : " p " is the potency of lcu ( mw ) , " a " is the area of the output light guide for the lcu ( cm ) and " t " is the irradiation time ( s ) . the irradiance data given for each hand - held radiometer ( mw / cm ) were used for p / a . " d " is the resulting energy dose in mj / cm ( j.cm ) . three energy doses were applied through the ceramic sample ( table 1 ) , based on an equivalence condition to the 600 mw / cm irradiance obtained with halogen lamps for 40 s. in order to decrease the irradiance to approximately half of the original values , the tips of the lcu light guides were kept at a distance of 7.7 mm ( hal ) , 4.8 mm ( led ) and 4.75 mm ( pac ) from material surface . for each lcu , one group was prepared with dla ( no interposed ceramic ) for the hardness test using optimal light activation conditions . the irradiation time was set as specified in the manufacturers ' instructions ( hal=40 s , led=40 s and pac=3 s ) . one group was prepared in a light - proof environment to obtain the chemically - polymerized hardness profile . combination of lcus and test conditions resulted in 13 groups ( n=10 ) ( table 2 ) . lcu= light - curing unit ; hal= tungsten halogen light ; led= light - emitting diode and pac= xenon plasma - arc ; dla= direct light - activation ; different uppercase letters in rows represent statistically significant differences ( p<0.05 ) among light irradiation modes for each lcu . different lowercase letters in columns represent statistically significant differences ( p<0.05 ) among the lcus for each light activation mode . means are significantly higher than control ( chemical activation only ) [ 44.7 ( 3.8 ) ] . specimens were stored in a culture oven under dry storage and dark conditions at 37c for approximately 24 h. after storage , specimens were fixed in a previously prepared acrylic mold , using sticky wax to improve fixation and fill gaps , avoiding misfit . resin cement discs were sectioned longitudinally and cement surface was finished and polished with abrasive papers in a decreasing sequence of abrasiveness ( # 180 , # 320 , # 400 , # 600 and # 1200 grit ) . a universal indenter tester ( hmv2 , shimadzu , tokyo , japan ) was set at the automatic mode with 50 g of force for 15 s. indentation measurements were made manually at 40x magnification across the section of the resin cement specimens . knoop hardness number ( khn , kg / mm ) was calculated based on the indentation measurement obtained by a single operator . three indentations were made on each specimen at 1-mm distance from each other , at 100-m depth from the irradiated surface . overall changes in khn at 100-m depth were evaluated by two - way anova and holm - sidak method as a post - hoc test . one - way anova and holm - sidak test were performed for comparison of all groups versus chemical - activation mode ( control ) . khn means at 100-m depth showed a statistically significant interaction between lcus and activation methods ( p=0.02 ) . when direct light activation was performed , hal showed significantly higher khn means than led and pac ( p<0.05 ) . no significant differences were found between led and pac ( table 2 ) . for ix2 t and i/2x2 t energy doses , led and hal showed significantly higher khn means than pac ( p<0.05 ) , but hal and led groups were statistically similar . khn means obtained with led were similar to those obtained with hal for all energy doses ( ltc mode ) . hal setting at 48 jcm showed significantly higher khn means than the other modes of indirect irradiation ( p<0.05 ) . differences were not found among the activation modes with pac . when the experimental groups were compared to the chemically - activated control group , dla with hal and pac led to significantly higher khn means ( p<0.05 ) . pac showed similar hardness to that of the control group for other energy doses through ceramic . only led set at i/2x2 t showed significantly higher khn means ( p<0.05 ) than the control ( figure 1 ) the first null hypothesis was rejected because hardness was significantly affected by the type of lcu , depending on the light - activation modes . thus , in addition to the energy dose7,21 the efficiency of the irradiation mode was dependent on the type of lcu . the different output wavelengths , spectral irradiance , light power , as well as differences in the efficiency of the optical delivery system , including the light - guide tips , can affect hardness7,14 . hal and pac had similar effects on hardness when used in the ix2 t mode . however , when these lcu were used in the dla mode , hal performed better than pac . in addition , the hal 48 jcm dose was statistically superior to the control and to other energy doses , while similar to the dla mode . thus , when irradiation was performed with hal , the highest hardness values were obtained with ltc mode when the highest energy dose was applied . the hardness was dependent on the energy dose used when the halogen lcu was employed . in general , energy dose is well correlated with a polymerization profile for each composite.23 however , when composites and lcus are compared , the energy dose concept should be treated with caution4 . the led lcu used in this study provided an adequate hardness with energy doses of ix2 t and i/2x2 t , which were , respectively , superior and similar to dla ( no interposed ceramic ) and higher than the control . although the energy dose of ix2 t ( 48 jcm ) was twice as that of i/2x2 t ( 24 jcm ) , khn means were similar . this similarity can be due to the exposure time , almost 3 times greater than the irradiation time for pac under the same conditions . it may be of particular importance in some clinical conditions , such as light curing in proximal areas of inlays , where the placement of the lcu light - guide at a certain distance may be a hindrance to irradiation . the led dose of ix2 t showed significantly higher khn means than dla . in a previous study15 , led lights provided greater curing depths with a3 shade , while halogen lights had greater curing depths with c4 shade . since the ceramic used was shade a3 , perhaps this fact contributed to the observed differences . certainly , one of the most important factors to consider is that the final irradiation time was twice as that of dla . the emission of wavelengths ( around 469 nm ) in specific excitation peak is related with composite scraping depth that is an iso measuring method14 . according to other studies , furthermore , as shown by hofmann9 , the degree of polymerization with a shorter wavelength - specific band for lcu can be compensated with higher exposure times . probably for these reasons , halogen light , in direct use , can better fulfill the requirements as a photoinitiator of resin cement due to its broad spectral irradiance . manufacturers should provide a graph indicating the minimum acceptable exposure for each product for specified curing lamps15 , since some photoinitiators used have specific irradiance requirements.5 the understanding of light attenuation effect of ceramics is also important and should be considered for the choice of cement and activation mode . it has been found that the increase of the exposure time may overcome the effect of less specific wavelength for composite resin11 . if some change to the useful wavelength occurred due to the ceramic , then the change could be compensated with longer exposures times used for hal and led lcus . shorter irradiation times have been advocated for pac lcus5 , but these reduced light - activation time and interrupted activations sequences could change the kinetics of polymerization with pac . only dla with 3-s irradiation provided higher khn means at 100 m depth than that of the control group . although pac devices used in direct activation have shown satisfactory results in light - activation of thin composite layers3,17 , pac techniques require a significant increase in the irradiation time when applied to indirect polymerization19 . the delay between light emission , features inherent to light , such as spectrum , energy absorbance and attenuation , and features inherent to the ceramic may have negatively affected the polymerization kinetics . despite the five situations that differ from the chemical - activation mode , doses with longer times ( i/2x2 t and ix2 t ) for hal and led showed advantages compared to other conditions ( except for led i/2x2 t ) . in those situations , when khn means were similar to the control , the results should be carefully interpreted based on microhardness methodology . some resin cements have shown low hardness at first time post - polymerization with a decrease of strength against immediate loads6 . light - activation is always desired for improvement of mechanical properties of resin cements immediately after cementation2,12 . like hardness22 , adhesion can be significantly improved1 when an effective lcu is used since bond strength is dependent on the irradiance level applied through ceramic13 . additionally the use of lcus with high output irradiances is preferable instead of increasing the exposure time to compensate low output irradiances . within the limitations of this study , it may be concluded that : 1 . hal and led lcus had similar performance , according to khn means of resin cement when irradiation through ceramic was used ; 2 . the chemical - activation mode was similar to the light / chemical - activation mode of the several protocols proposed in the study , representing a satisfactory chemical reaction profile of the tested resin cement ; 3 . only hal showed a relationship between hardness increase and increase of energy dose ; 4 .

the purpose of this study was to evaluate the knoop hardness of a dual - cured resin - based luting cement irradiated with different light sources as well energy density through a ceramic sample . three light - curing unit ( lcus ) were tested : tungsten halogen light ( hal ) , light - emitting diode ( led ) and xenon plasma - arc ( pac ) lamp . disc - shaped specimens were fabricated from a resin - based cement ( enforce ) . three energy doses were used by modifying the irradiance ( i ) of each lcu and the irradiation time ( t ) : 24 jcm-2 ( i/2x2 t ) , 24 jcm-2 ( ixt ) and 48 jcm-2 ( ix2 t ) . energy doses were applied through a 2.0-mm - thick ceramic sample ( duceram plus ) . three groups underwent direct irradiation over the resin cement with the different lcus and a chemically - activated group served as a control . thirteen groups were tested ( n=10 ) . knoop hardness number ( khn ) means were obtained from cross - sectional areas . two - way anova and the holm - sidak method were used for statistical comparisons of activation mode and energy doses ( =5% ) . application of 48 j.cm-2 energy dose through the ceramic using led ( 50.52.8 ) and hal ( 50.93.7 ) produced significantly higher khn means ( p<0.05 ) than the control ( 44.73.8 ) . led showed statistically similar performance to hal . only hal showed a relationship between the increase of lcu energy dose and hardness increase .

amnestic mci was defined by petersen et al in the context of a natural observation study , which demonstrated a rate of conversion to ad that was well above the incidence of agematched populations . the original amnestic mci criteria are as follows : memory complaint , preferably corroborated by an informant . a more recent subclassification of mci has been proposed by petersen on the basis of findings from cognitive testing in larger number of subjects : amnestic or single memory mci . the first two groups ( single memory mci and multiple domain [ including memory ] mci ) seem to share the same risk of conversion to ad , whereas the third group ( single non - memory - domain mci ) may be a prodrome to the nonad dementias . for the purpose of rcts , operational criteria with specific inclusion / exclusion criteria have been specified . the criteria for the study completed by the alzheimer disease cooperative study comparing donepezil with tocopherol and placebo are listed in table ii ; this study will be referred to in this monograph as the memory impairment study ( mis ) . although not fully analyzed and published , entry criteria for the twin studies ( with and without mag _ netic resonance imaging [ mri ] ) comparing galantamine and placebo are available and are summarized in table iii . the investigation into the delay to diagnosis of ad with exelon ( rivastigmine ) ( inddex ) study is not yet completed , but the entry criteria of this 4-year rct comparing rivastigmine with placebo have been published . these are listed in table iv for purposes of comparison between the mis , the galantamine studies , and the inddex study the fact that most patients with amnestic mci convert to ad led to the hypothesis that they were suffering from a reduction in cholinergic activity , which is the basis for the so - called cholinergic hypothesis of ad , at least in terms of its mainline symptomatic therapy . on the other hand , observations made by dekosky et al of increased choline acetyltransferase activity in the superior frontal cortex and hippocampus of subjects with mci compared with controls and with subjects with mild ad suggested that a cholinergic deficit in amnestic mci may not be as prominent as was initially postulated . the safety and efficacy of the acetylcholinesterase inhibitors ( acheis ) donepezil , galantamine , and rivastigmine have been studied extensively versus placebo in amnestic mci . to date , results are available from a short - term ( 6-month ) symptomatlc study with donepezil and long - term studies with galantamine and donepezil etiological approaches to ad include anti - inflammatory drugs and it was logical to test cyclooxygenase-2 ( cox-2 ) selective inhibitors , such as refecoxib . unfortunately , there have only been negative results reported from such studies and so these agents will not be discussed further in this monograph . non - transmitter - specific drugs , such as piracetam , have also been tested , with negative results and will not be discussed further . there has been much interest in the short - term benefit of drugs in amnestic mci , with particular attention to cognitive outcomes . a 6-month study comparing donepezil with placebo was performed using parallel groups , with the alzheimer 's disease assessment scale - cognitive component ( adas - cog ) and a clinical global impression of change modified for mci ( cgic - mci ) as primary outcomes ; secondary outcomes included the new york university ( nyu ) paragraph test , digit span backwards test , symbol digit modalities test , and a patient global assessment ( pga ) . the possibility of delaying conversion from amnestic mci to ad has attracted a lot of interest since it offers good face validity designs have included parallel groups with conversion to ad as a primary end point . this conversion has been defined operationally in different ways , ranging from , a clinical opinion to a change in the clinical dementia rating ( cdr ) scale global score from 0.5 to 1 . conversion committees were asked to monitor conversions taking place in the different rcts and to analyze the key factors leading to conversion . this information will be very useful to design future rcts and also for practicing clinicians who want reassurance in the very early diagnosis of ad , when adl changes are minimal . secondary outcomes in these studies include a number of cognitive , adl , and global outcomes . the 6-month donepezil rct has shown a statistically significant but small improvement in adas - cog , driven by the adas - cog immediate word recall test . in the fully evaluable population , scores on the nyu paragraph immediate and delayed recall tests as well as the digit span backwards test were significantly better in the donepezil group . the cgic measured by the clinician failed to detect a difference , but the self - rated impression of change from the subjects ( pga ) showed a highly statistically significant difference between donepezil and placebo . side effects were predominantly gastrointestinal ( diarrhea , nausea , and vomiting ) and nocturnal ( abnormal dreams ) at a higher frequency than patients with ad at a similar dose of 10 mg at bedtime . the 2-year galantamine studies showed no difference in the primary analysis of conversion from amnestic mci to ad . analysis of secondary outcomes is under way , but it is apparent that a reduced rate of whole - brain atrophy has been found in patients treated with galantamine . baseline demographics of the 3-year mis have been reported and are listed in table v. an annual conversion rate of the order of 13% was reached with this amnestic mci population , which most investigators would consider as prodromal ad . results of the primary analysis of mis have been presented at the 9th international conference on alzheimer 's disease and related disorders : there was no difference in the primary analysis of conversion from amnestic mci to ad after 3 years . analysis of secondary outcomes is under way , and it is already apparent that there is a statistically significant delay of conversion between subjects treated with donepezil and placebo at 6 , 12 , and 18 months into the study , with the conversion curves overlapping at 24 , 30 , and 36 months . patients carrying the apolipoprotein e4 ( apoe-4 ) mutation were at a much higher risk of converting to ad and had a statistically significant protective effect from conversion on treatment with donepezil from month 6 until month 36 . tolerability of achei in long - term amnestic mci appears to be similar to patients with ad in terms of a predominance of gastrointestinal transient side effects . their incidence and severity are slightly higher than in ad and lead to a higher rate of discontinuation , particularly in the first year of treatment . although not all the data are in and not all subanalyses on the available data have been performed , it is apparent that the achei class does not delay the conversion from amnestic mci to ad beyond 18 months . this suggests that the acheis have a symptomatic and potentially clinically significant effect , but one that is transient . this is congruent with the ad2000 study , which demonstrated a sustained benefit of donepezil on cognition using the mini - mental - state examination ( mmse ) and an adl measure over 2 years . in terms of safety , the gastrointestinal side effects of acheis appear to be more prominent in mci than in ad , and lower doses may be preferred in both rcts and clinical practice . earlier diagnosis of ad has been facilitated by research on amnestic mci more patients presenting because of memory complaints will get a full assessment , seeking reversible causes , concomitant disorders , and risk factors , all of which are amenable to treatment . acheis will be one option for treatment , most likely at lower doses than are usual in ad . this option should not be recommended at this stage of our knowledge , but should not be denied for people who ask for it . it is premature to recommend that subjects with amnestic mci be screened for apoe-4 genotype and only those with the apoe-4 mutation be treated , but genotype ing must be done at entry into rcts for mci because of its strong effect on conversion rate ; in other words , we must stratify for apoe-4 alleles between treatment arms . it is still early days in the analysis of what has been achieved with acheis and noncholinergic drugs in amnestic mci already , rct protocols are being created for other classes of drugs with ( i ) potential cognitive effects demonstrable in short - term 6-month studies ; and ( ii ) potential effects delaying conversion to ad over 3 years . placebo - controlled studies are not an issue in amnestic mci , in contrast to mild - to - moderate ad . the prodromal stage of ad may be the most promising stage to test the efficacy and safety of diseasemodifying drugs , when the neurons are still salvageable .

amnestic mild cognitive impairment ( mci ) can be considered as a state with a high risk of developing alzheimer 's disease within 5 years , or as a prodromal stage of this condition . randomized clinical trials comparing the acetylcholinesterase inhibitor donepezil with placebo have shown some symptomatic benefit on ( i ) cognition in one short - term ( 6-month ) study ; and ( ii)conversion to dementia in one long - term ( 3-year ) study , but not for the full duration of the study , except in subjects with the apolipoprotein e4 ( apoe-4 ) mutation , in whoom the benefit was sustained throughout the 3 years . results from studies on galantamine are still being analyzed ; and a rivastigmine study will close in the fall of 2004 . it is premature to recommend that acetylcholinesterase inhibitors be used systematically in amnestic mci . however , important lessons have been learned from studies in this prodromal stage of ad , allowing the testing of hypotheses for disease modification .

the double duct sign is a simultaneous dilatation of both the pancreatic duct ( pd ) and the common bile duct ( cbd ) and is usually a result of narrowing of terminal parts of both the ducts due to various causes including encasement of the cbd and main pd by a pancreatic head tumour , ampullary carcinoma , pancreatitis and periampullary stenosis . we report a 54-year - old male who came with abdominal pain and was found to have an unusual etiology of double duct sign . a 54-year - old man presented to us with right upper abdominal pain of 4 months duration . the pain was episodic , severe and used to last around h and occurred in relation to meals . there was no associated vomiting , jaundice , fever , loss of weight or appetite . he had a history of chronic alcohol abuse as well as oral opium ingestion for last 25 years . he used to daily consume oral powdered form of opium husk ( vernacular bhukki ) . blood tests revealed a serum bilirubin of 1.0 mg / dl ( normal , 0.2 - 1.4 mg / dl ) , aspartate aminotransferase of 47 u / l ( normal 1 - 35 u / l ) , alanine aminotransferase of 41 u / l ( normal , 1 - 35 u / l ) and alkaline phosphatase 156 u / l ( normal , 20 - 128 u / l ) . abdominal ultrasound revealed a dilated anechoic cbd with mild central intra - hepatic biliary radical dilatation and dilated pd . contrast enhanced computed tomography of the abdomen showed a double duct sign with cbd dilated until lower end and a dilated pd [ figure 1 ] . endoscopic ultrasound ( eus ) using a linear echoendoscope ( gf - uct 180 linear echoendoscope , olympus corp , tokyo ) revealed simultaneous dilatation of the cbd and pd ( double duct sign ) with anechoic lumens of both the ducts . the ampullary region revealed a prominent hypoechoic layer suggestive of muscular hypertrophy [ figure 3 ] . a diagnosis of opium - induced sphincter of oddi dysfunction ( sod ) was made , and patient underwent biliary sphincterotomy with improvement in his symptoms and normalization of his liver enzymes . post sphincterotomy spy glass cholangioscopy ( boston scientific corp , natick , mass ) was also done for evaluation of the bile duct mucosa at the terminal end and it revealed normal mucosa [ figure 4 ] . he was referred for de - addiction and was asymptomatic after 3 months follow - up . abdominal computed tomography showing dilated common bile duct ( arrow ) side viewing endoscopy revealing a bulky papilla endoscopic ultrasound showing dilated common bile duct and pancreatic duct with hypoechoic prominence at lower end ( arrow ) spy glass done for evaluation of common bile duct . sphincter of oddi dysfunction is a benign , non - calculous obstruction at the major duodenal papilla that can produce variable clinical symptoms including pancreaticobiliary pain , cholestasis , and/or pancreatitis . opiates produce multiple pharmacologic effects in the gastrointestinal tract with constipation being the most common . constant prolonged use of this drug might be responsible for the contraction and permanent dysfunction of the sphincter of oddi and sod due to chronic opium use is now recognized as a distinct clinical entity . clinical features of this entity are variable and may consist of anorexia , weight loss , constipation and abdominal tenderness . the endoscopic visualization of the second part of the duodenum may reveal a prominent papilla , but even ulcerative and tumourous changes are common in opium related sod and therefore it is important to carefully exclude the malignancy . eus is an important investigation for excluding the malignancy as even small lesions in the ampullary area can be detected by a carefully performed eus . eus can also help in the detection of hypertrophy of the muscular sphincter of oddi as was seen in the index case . the response to biliary sphincterotomy in such cases is excellent as was in the present case . the case is reported because opium abuse is an uncommon cause of sod and the history of opium abuse must be sought in patients with unexplained biliary dilatation or dual duct dilatation and residing in areas where opium abuse is common . furthermore , eus provides an excellent modality to rule out small malignant lesions resulting in double duct sign .

double duct sign where there is a simultaneous dilatation of both the common bile duct ( cbd ) and pancreatic duct is usually associated with sinister causes like malignancies of pancreatic head or ampulla . occasionally , benign causes like chronic pancreatitis or sphincter of oddi dysfunction ( sod ) may cause double duct sign . chronic opium abuse is a rare cause of the double duct sign , and endoscopic ultrasound ( eus ) findings of this rare entity have been occasionally reported . we report about a 54-year - old male with a history of chronic alcohol and opioid abuse evaluated for episodes of abdominal pain and found to have opioid - related sod and improved with biliary sphincterotomy . eus was done to rule out malignancy and revealed hypoechoic prominence around terminal cbd suggestive of hypertrophied muscle .

they are usually small , quite round and noncompressive3 ) . magnetic resonance imaging ( mri ) cranial mri showed a left - sided choroidal fissure cyst measuring 45 mm ( fig . the cyst was hemorrhagic and showed fluid - fluid level on t2-weighted and susceptibility weighted images . she was followed conservatively . during this period she occasionally suffered headache , but her neurological examination remained normal . follow - up mri showed that the size of the cyst had increased gradually , eventually becoming 108 mm , while other imaging features had not changed ( fig . six months after the latest mri scan , the patient was admitted to our emergency department with severe headache . mri and computed tomography ( ct ) showed an intracystic hematoma , 2525 mm in size , with surrounding edema and slight mass effect ( fig . the choroidal fissure is the narrow cleft between the fornix and thalamus along which the choroid plexus is attached . the edges of the thalamus and fornix bordering this choroidal fissure have small ridges , called the teniae , along which the tela choroidea , the membrane in which the choroid plexus arises , is attached . the choroidal fissure is formed at approximately 8 weeks of embryonic development when the vascular piamater that forms the epithelial roof of the third ventricle invaginates into the medial wall of the cerebral hemisphere . no nervous tissue develops between the ependyma and piamater along this invagination that forms the choroidal fissure , thus creating the thinnest site in the wall of the lateral ventricle . the choroidal arteries , which supply the choroid plexus enter the ventricles through the choroidal fissure . the veins coursing in the walls of the ventricles exit the ventricles bypassing through the margin of the choroidal fissure in the subependymal location to reach the internal cerebral , basal , or great veins4 ) . developmental errors may occur at the time of formation of primitive choroid plexus anywhere along the choroid fissure , thus forming a cyst5 ) . however , the etiology is stil controversial . sherman et al.5 ) reviewed the mri studies of choroidal fissure cysts and reported 26 cases , mostly adults , with neurological symptoms such as complex migraine , seizure , gait disturbance , tremor , vertigo , hearing loss , paresthesia , hemiparesis and visual scotomata . clinical follow - up without development of symptoms referable to the cyst average 17.8 months . they reported that the cysts could not explain the patients ' signs or symptoms5 ) . de jong et al.3 ) reported 6 patients with a csf - containing cyst at the level of choroidal fissure with neurological symptoms such as headache , narcolepsy and hyperactivity disorder . all patients were followed with mri which demonstrated total absence of progression of the lesions . tubbs et al.6 ) reported progression of choroidal fissure cysts which were treated with fenestration and possible ventriculo - peritoneal shunting . baka and sanders1 ) reported a case of spontaneous hemorrhagic choroid plexus cyst in lateral ventricle . it was thought that the cyst was incidental and was not related to the patient 's symptoms . differentiation between neuroepithelial and arachnoid csf - containing cysts at the level of choroidal fissure can only be made by histopathological examination3 ) . differentiation of benign choroidal fissure cysts from other cysts ( cystic neoplasms or infectious cysts ) is important because of the need for active treatment in the latter group . cystic neoplasms or infectious cysts were excluded in our case because of the absence of a solid component , contrast enhancement , perilesional edema or mass effect . dermoid cyst could also be considered in the differential diagnosis ; however , in our case t1 hyperintensity represented hemorrhage and did not correspond to lipid content , since on fat - saturated t2 weighted images , nondependant part of the lesion was bright , not following the signal of fat . the presence of hemorrhage could be explained by the close relationship of the lesion with the choroid plexus of the temporal horn or the presence of heterotopic choroid plexus within the cyst . in cases of choroidal fissure cysts , at least 2 years of clinical and radiological follow - up is recommended , while surgery is indicated only in accompanying life - threatening conditions such as massive hemorrhage . this case report is intended to emphasize that they may rarely present with intracystic hemorrhage , enlargement of the cyst and increasing symptomatology .

choroidal fissure cysts are often incidentally discovered . they are usually asymptomatic . the authors report a case of growing and hemorrhagic choroidal fissure cyst which was treated surgically . a 22-year - old female presented with headache . cranial mri showed a left - sided choroidal fissure cyst . follow - up mri showed that the size of the cyst had increased gradually . twenty months later , the patient was admitted to our emergency department with severe headache . mri and ct showed an intracystic hematoma . although such cysts usually have a benign course without symptoms and progression , they may rarely present with intracystic hemorrhage , enlargement of the cyst and increasing symptomatology .

a 54-year - old african - american male with an unremarkable past medical and family history presented with a gradually worsening and painful swelling of his right middle finger , which severely impaired the use of his hand over several months . on physical examination , a mass was palpated on the proximal phalanx without evidence of fixation to the overlying skin . x - ray showed an erosive destructive lesion involving the third metacarpophalangeal joint with adjacent soft tissue swelling and abnormalities of the phalangeal bones adjacent to the joints ( fig . 1b ) and the contiguous cartilage revealed glandular structures , as seen in mucinous adenocarcinoma , suggestive of gastrointestinal or pulmonary origin . non - contrast - enhanced ct scans of the chest , abdomen , and pelvis presented an 8.6 5 cm dense mass in the ascending colon . colonoscopy confirmed a large ulcerating obstructing tumor in the ascending colon , and the biopsy result was consistent with infiltrating adenocarcinoma . a pet scan showed multiple areas of uptake in the right colon ( suv 8.1 ) , the dome of the liver ( suv 6.3 ) , portocaval and para - aortic lymph nodes ( suv 6.1 ) , and in several bones [ right first rib , right side of the sternal manubrium and left posterior tenth rib ( suv 3.7 ) ] . the carcinoembryonic antigen level was elevated at 72.9 ng / ml ( normal 03 ng / ml ) . 1c ; h&e stain ) invading through the muscularis propria into the pericolonic adipose tissue , but not perforating the peritoneal surface . nine of 24 analyzed lymph nodes contained tumor cells , consistent with the ajcc stage of pt3/n2/m1 ( 6th edition of ajcc cancer staging handbook ) . kras mutation analysis was positive for a g13d mutation in codon 13 of the kras gene . chemotherapy with capecitabine 1000 mg / m on days 1 to 14 , oxaliplatin 130 mg / m on day 1 , and bevacizumab 7.5 mg / kg on day 1 of a 21-day cycle was initiated , as was treatment with zoledronic acid every 28 days . partial remission with resolution of the liver and lymph node lesions was achieved after six cycles . four months later , an fdg - pet scan revealed increased activity in the sternal manubrium extending into the right first rib ( suv 5.2 ) , corresponding to mixed blastic and lytic changes of an exophytic lesion seen on the ct scan ( fig . in the abdomen , new focally increased activity was found in the right lobe of the liver ( suv 4.1 ) and in a right para - aortic lymph node ( suv 4.2 ) . chemotherapy with capecitabine at 1,000 mg / m on days 1 to 14 , irinotecan at 225/m on day 1 , and bevacizumab at 7.5 mg / kg on day 1 of a 21-day cycle was started . zoledronic acid was continued throughout the treatment . although the patient initially responded well to this regimen and hepatic abnormalities were no longer detectable after three cycles , a repeat pet / ct scan after six cycles showed that the painless sternal metastasis had grown in size . liver involvement continued to remain undetectable , but increased activity was also noted in celiac and peripancreatic lymph nodes . the initial regimen with capecitabine , oxaliplatin , and bevacizumab x - ray revealed an expansile , partly calcified mass involving the distal right ulna ( fig . 2c , twenty - three months after initial presentation , no solid organ or lymph node metastases were detectable , while the patient 's osseous involvement remained unresponsive to systemic treatment . palliative radiation was administered to the bone lesions and efforts were made to enroll the patient onto a clinical trial . they are found in approximately 10% of all crc patients in only 5.5% of the patients at the time of initial diagnosis and generally occur in the setting of synchronous metastatic disease at other organ sites . they develop predominantly in the vertebral column , pelvic or hip bones , and the long bones . radiographically , they are usually osteolytic , but an osteoblastic or a mixed osteoblastic - osteolytic appearance with periosteal reactions and calcification of the adjacent soft tissue ( pseudosarcomatous appearance ) is also seen . metastases to the hands or fingers so - called acrometastases from the greek akros , meaning extreme are very rare , their incidence having been reported to be as low as 0.0070.2% [ 7 , 8 ] ; even after taking into account metastases from primary sites other than the colon . a recent review of the english language medical literature published reported lung , kidney , and breast cancers as the most common origins for phalangeal metastases ( 44 , 12 , and 10% , respectively ) . colon cancer , while ranking low ( 6% ) as the primary tumor site , was found to be the most frequent site of origin among all gastrointestinal tumors . men are more likely than women to develop finger metastases , and the average age at the time of tumor detection is reported to be 58 years . interestingly , the right hand appears to be more susceptible to phalangeal metastases , with the middle finger being most frequently affected , followed by the thumb ( 28 vs. 21% of all cases analyzed ) . among the bones of the hand , the distal phalanges are the most likely metastatic locations , followed in frequency by the metacarpal bones . partial or ray amputation appears to be the most frequently reported treatment method for acrometastases , although alternatives encompass systemic therapy and radiation , which in the palliative setting can sometimes achieve disease control and alleviation of bony pain . in addition , bisphosphonates were shown to prevent skeletal - related events in patients with bone metastases from solid tumors ; more recently , the human monoclonal antibody denosumab was introduced as a new option to reduce skeletal morbidity in patients with solid tumors that have metastasized to bone . in summary , this case illustrates a highly unusual manifestation of metastatic crc involving the fingers . accurate diagnosis and effective treatment in a timely manner are essential to ensure that patients regain full use of their hands and maintain their independence . while we were able to achieve resolution of the extra - osseous metastases with systemic treatment , the skeletal metastases were refractory to the agents used .

the propensity of colon cancer to metastasize to bones is very low compared to prostate , breast or lung cancer . the reason for this is not yet understood , although an explanation for the osteotropism of certain primaries has been offered by the seed and soil concept , suggesting that the bone microenvironment provides a favorable soil for metastasis and proliferation of some tumor cells ( seeds ) [ 1 ] . here , we report an unusual case of colon cancer with metastasis to the finger at initial presentation , and exophytic sclerotic lesions to other bones . the incidence of metastases to fingers / toes ( acrometastases ) is reported to be only 0.1% , even after including involvement of primary sites other than the colon . the etiology and characteristics of acrometastases are reviewed in this case report .

prolidase ( pr ) is a cytosolic enzyme , which hydrolyzes the peptide bonding of imidodipeptides and imidotripeptides , which include proline or hydroxyproline in the carboxyl terminal position [ 13 ] . this enzyme is present in many tissues in animals and humans and plays an important role in collagen metabolism . proline and hydroxyproline are formed when collagen is degraded . while proline takes part in collagen synthesis again , hydroxyproline is excreted in urine . the conjunctiva and the underlying tenon cover the sclera and contain elastin - rich connective tissue . conjunctival fibroblast activity and wound healing are of great importance in pterygium and trabeculectomy operations . detection of prolidase enzyme in conjunctival tissue would create a novel field of debate on the diseases and the operations concerning this tissue , as prolidase enzyme is a rate - limiting enzyme in collagen metabolism . to the best of our knowledge , there are no published studies on the presence of prolidase enzyme activity in the conjunctiva . therefore , we aimed to investigate the presence of this enzyme activity in conjunctival tissue and its relationship with pterygium , which is a disease of collagen tissue irregularity in the conjunctiva . prolidase enzyme activity was measured in serum and conjunctival tissues of 23 eyes of 23 pterygium patients , who had undergone an operation in our clinic between 2013 and 2015 . the control group was composed of 25 patients with similar age and sex distribution , who did not have pterygium , and conjunctival tissues obtained from 25 eyes of 25 patients and their serum samples were used . approval for the study was granted by the local ethics committee and informed consent was obtained from all patients . afterwards , glycine - proline was used as substrate and the revealed proline was stained with ninhydrin in an acid environment and measurement was made at 515 nm . all analyses were carried out using the statistical package for social sciences version 13 ( spss , inc , chicago , il . ) . , glycine - proline was used as substrate and the revealed proline was stained with ninhydrin in an acid environment and measurement was made at 515 nm . all analyses were carried out using the statistical package for social sciences version 13 ( spss , inc , chicago , il . ) . statistically , there were no significant differences between age and sex distribution ( table 1 ) . prolidase activity could not be measured in healthy conjunctiva or in pterygium tissues ( table 2 and figure 1 ) . mean serum prolidase level of the control and pterygium groups was 967.46353.64 and 858.29301.83 , respectively ( figure 2 ) . this enzyme is accepted as the rate - limiting enzyme in collagen metabolism , as 90% of proline used in collagen production is provided from the proline included in the cycle . the reason for the absence of a difference between serum prolidase levels may be pterygium not being a systemic disease . prolidase enzyme activity has been demonstrated in various tissues , such as serum , plasma , erythrocytes , leukocytes , amniotic fluid , intestinal mucosa , kidneys , liver , brain , heart , uterus , and the thymus . proline is excreted with urine because it is not included in the cycle in prolidase deficiency . skin ulcers , mental retardation , specific facial characteristics , skeletal anomalies , splenomegaly , hematological disorders , and chronic infections are seen in these patients . elevated serum prolidase activity has been associated with oxidative stress and increased collagen formation - degradation . serum prolidase activity has been found to increase in diabetic nephropathy , metabolic syndrome , behcet s disease , and chronic hepatitis , whereas it has been found to decrease in keratoconus , systemic sclerosis , joint hypermobility syndrome , and myeloproliferative syndromes [ 1117 ] . in some studies , serum prolidase activity has been shown to alter in fibrotic diseases and some cancers [ 1821 ] . a statistically significant elevation has been demonstrated in tissue prolidase activity in nasal polyps , chronic wounds , and keloid tissue . pterygium is a chronic proliferative lesion of the conjunctiva , characterized by inflammation and angiogenesis . however , angiogenesis plays an important role in the formation of fibrovascular tissue , especially in recurrent pterygium . significant prolidase activity was not detected in normal and pterygium conjunctival tissues in our study . a low level of prolidase taking part in collagen metabolism is an expected condition because these tissues are not collagen - rich . mitomycin - c , which is used postoperatively , prevents scarring by hindering fibroblast proliferation and migration . while there is no prolidase activity in conjunctiva , there may be fibroblast - derived prolidase activity during scar formation after trabeculectomy . although the conjunctiva is not collagen - rich , pterygium , which is a pathology of this tissue , is characterized by connective tissue irregularity . a study reported that prolidase activity was increased 4-fold in keloid tissue that accompanies connective tissue irregularity . although the pathology in pterygium is different , irregularity and hypertrophy are also present in this disease . therefore , we suggest that prolidase activity could increase in pterygium tissue ; however , prolidase activity could not be detected in pterygium tissue . this result suggests that there is no difference in collagen production and destruction in pterygium tissue . elastin material increases and connective tissue irregularity develops as a result of elastodysplasia and elastodystrophy . our results indicate that the main problem in the pathogenesis of pterygium is related to abnormality in elastin , and collagen is not included in this process .

backgroundthe aim of this study was to determine prolidase activity in conjunctival tissue and its relationship with pterygium.material/methodsprolidase activity was measured in 23 pterygium and 25 healthy conjunctival tissues and the 2 groups were compared.resultsprolidase enzyme activity could not be measured in either the healthy conjunctival or in pterygium tissues . the mean serum prolidase levels of the control and pterygium groups were 967.46353.64 and 858.29301.83 , respectively . statistically , there was no significant difference between the groups with regard to serum prolidase levels ( p>0.05).conclusionsin conclusion , absence of prolidase activity in pterygium tissue indicates that there is no collagen turnover in this tissue . we may explain this finding with the elastin - rich structure of the conjunctiva .

laboratory error remains a serious problem , with specimen mix - up errors constituting one of the most serious preanalytic errors . in an attempt to detect specimen mix - up errors , it is common practice for laboratories to use delta check algorithms . delta checks compare the current test result with a previous result for the same test obtained over a short period of time ( within 96 hours ) from the same patient . if the change in the value of the analyte exceeds an expected physiological range , the result is flagged as a possible error . different delta check algorithms employ various equations including absolute differences in analyte levels , percentage changes , and rate changes ( see the results section ) . the calculation of these values is generally automated within analyzer software or laboratory information systems . a variety of delta check algorithms have been described;[246 ] however brief perusal of the references to this paper will show that much of the work on delta checks was performed several decades ago . modern technologies such as bar - coding and automated specimen processing have undoubtedly decreased the incidence of specimen mix - up errors but the potential effect of this on the positive and negative predictive values of delta checks has not been explored . in order to determine these positive and negative predictive values two pieces of information are necessary . first we must know the sensitivity and specificity of the various delta checks for detecting specimen mix - ups . second , we need to know the expected incidence of specimen mix - ups in the population studied . the sensitivity of delta checks could be estimated in part from data on the follow - up of positive delta checks . however the determination of the specificity of delta checks is much more difficult with little information available . the reason for this , of course , is that other mechanisms to detect these mix - up errors are lacking and so there is no practical mechanism to detect false - negative delta checks . the only viable method to estimate the specificity of delta checks is to employ a modeling approach which intentionally introduces errors into a database of repeat measurements and then tests the ability of delta checks to detect these errors . in this paper we follow this modeling approach by first obtaining a data set of repeated measurements of actual patient results and then using a simple computer program to introduce mix - up errors into this dataset ( by switching pairs of second results ) . because these introduced errors are known , we can then apply delta check equations to determine both sensitivity and specificity for each equation and each analyte . finally , using literature values for the range of actual specimen mix - up errors following ethics approval by the university of calgary conjoint health research ethics board , data were obtained from the laboratory information system ( lis ) of calgary laboratory services . calgary laboratory services is the sole provider of laboratory services to the 1.4 million residents of calgary , alberta , canada and the surrounding area , performing approximately 15.8 million chemistry tests per year . we queried the lis for patient test results for potassium , sodium , chloride , bicarbonate , and creatinine , performed within the previous 12 months on hospitalized patients where two measurements of the same analyte were available within a 96-hour period . test results were then anonymized by removing all identifying information . between 8135 and 8432 pairs of test results these results were entered into an excel database along with the time interval between the two tests . a stochastic dynamic model was then written in visual basic which ran as a macro within the spreadsheet . this program simulated specimen mix - up errors by switching a subset of the pairs of second results . this resulting error rate could be changed by the operator and was set at 1% for the subsequent modeling , a number chosen so as to be higher than any reasonable estimate of real specimen mix - up errors already existing in the patient data . the data were then run through a series of delta check algorithms in order to attempt to detect the errors that had been introduced . the results of each algorithm were presented in truth table format to calculate sensitivity and specificity . because errors were introduced at random , we were concerned that certain iterations of the model may have introduced simulated mix - up errors that were more or less amenable to detection by certain delta checks . therefore , each iteration of the model was run 10 times and the mean values and ranges were reported . a copy of the visual basic program ( without patient data ) is available by emailing the corresponding author . following ethics approval by the university of calgary conjoint health research ethics board , data were obtained from the laboratory information system ( lis ) of calgary laboratory services . calgary laboratory services is the sole provider of laboratory services to the 1.4 million residents of calgary , alberta , canada and the surrounding area , performing approximately 15.8 million chemistry tests per year . we queried the lis for patient test results for potassium , sodium , chloride , bicarbonate , and creatinine , performed within the previous 12 months on hospitalized patients where two measurements of the same analyte were available within a 96-hour period . these results were entered into an excel database along with the time interval between the two tests . a stochastic dynamic model was then written in visual basic which ran as a macro within the spreadsheet . this program simulated specimen mix - up errors by switching a subset of the pairs of second results . this resulting error rate could be changed by the operator and was set at 1% for the subsequent modeling , a number chosen so as to be higher than any reasonable estimate of real specimen mix - up errors already existing in the patient data . the data were then run through a series of delta check algorithms in order to attempt to detect the errors that had been introduced . the results of each algorithm were presented in truth table format to calculate sensitivity and specificity . because errors were introduced at random , we were concerned that certain iterations of the model may have introduced simulated mix - up errors that were more or less amenable to detection by certain delta checks . therefore , each iteration of the model was run 10 times and the mean values and ranges were reported . a copy of the visual basic program ( without patient data ) is available by emailing the corresponding author . six combinations of delta check equations and cut - off values were obtained from the published literature and tested with our model . the specificities of individual delta checks ranged from 50% to 99% , with most equations giving results above 90% . the exception to this was creatinine , in which the best performing delta check had a sensitivity of 82.8% . comparison of the sensitivity and specificity of four delta check equations ( two with two different cut offs ) as table 1 also shows , the optimal delta check equations tended to be different for each analyte . no delta check equation provided both the best sensitivity and specificity for an individual analyte . the positive and negative predictive values of delta checks may be of greater practical interest than sensitivities and specificities . positive and negative predictive values are contingent upon the prevalence of the condition in the population ( here the rate of specimen mix - ups ) . we do not know the true rate of mix - up errors in modern laboratories but the rate is thought to be less than 1 in 1000 . table 2 shows that as the rate of mix - ups drops below 1 in 1000 the associated positive predictive value of even the best performing delta check becomes negligible . a positive predictive value of 58% with a 1% specimen mix - up rate is comparable to the positive predictive value of 50% estimated in an older study also using a 1% mix - up rate . example positive predictive values and negative predictive values of the highest sensitivity ( 82.8% ) and highest specificity ( 99.4% ) delta checks delta checks are commonly used in a laboratory setting to detect specimen mix - up errors . this makes it important to determine the most effective delta check equations for detecting these important errors . in this paper , we used a stochastic dynamic modeling approach to provide estimates of delta check sensitivities and specificities for five common analytes . an obvious weakness in our approach was that we tested only single analytes and did not use delta checks from multiple analytes in combination . the number of possible combinations of equations and cut - off values is very large in a multivariate approach and therefore it would not be practical to test all possible combinations . however , preliminary analyses showed that combinations of delta checks showed only marginal increases above the sensitivity of creatinine alone . additionally , it should be noted that our analysis refers only to the ability of delta checks to detect specimen mix - up errors and not the ability to detect other preanalytical or analytical errors . we also ran the model with variations in cut - off levels for each analyte . examination of the resulting receiver operator curves showed that the literature cut - off values we used in the model were close to the optimum cut - off values for each analyte . the finding of superior sensitivities for creatinine compared to the other analytes examined could be explained by the fact that electrolytes are actively regulated within a narrow physiologic range but creatinine , as a metabolic by - product dependent on both muscle mass and renal function , would be expected to show greater interindividual variation . similarly , the tight homeostatic control of electrolytes within an individual could explain the high specificities observed when specimen mix - up errors occur . based on plausible specimen mix - up rates obtained from the published literature , our model suggests that the positive predictive values of delta checks are currently very low . as modern techniques such as specimen bar - coding further reduce the rate of mix - up errors , the very low positive predictive values estimated by our model must be weighed against the effort involved in investigating false - positive delta checks to determine if this quality assurance strategy warrants ongoing use by clinical laboratories our model suggests that delta checks have widely varying sensitivities depending on the particular equation and analyte examined . in all cases the positive predictive values are anticipated to be very low and will decrease as modern technologies further reduce the incidence of specimen mix - up errors .

introduction : delta checks use two specimen test results taken in succession in order to detect test result changes greater than expected physiological variation . one of the most common and serious errors detected by delta checks is specimen mix - up errors . the positive and negative predictive values of delta checks for detecting specimen mix - up errors , however , are largely unknown.materials and methods : we addressed this question by first constructing a stochastic dynamic model using repeat test values for five analytes from approximately 8000 inpatients in calgary , alberta , canada . the analytes examined were sodium , potassium , chloride , bicarbonate , and creatinine . the model simulated specimen mix - up errors by randomly switching a set number of pairs of second test results . sensitivities and specificities were then calculated for each analyte for six combinations of delta check equations and cut - off values from the published literature.results:delta check specificities obtained from this model ranged from 50% to 99% ; however the sensitivities were generally below 20% with the exception of creatinine for which the best performing delta check had a sensitivity of 82.8% . within a plausible incidence range of specimen mix - ups the positive predictive values of even the best performing delta check equation and analyte became negligible.conclusion:this finding casts doubt on the ongoing clinical utility of delta checks in the setting of low rates of specimen mix - ups .

visual phenomena related to hyperglycemia are not uncommon . these symptoms can vary from mild blurry vision to homonymous hemianopia without eeg findings or even prominent electroclinical occipital seizures . prompt recognition of occipital seizures as a manifestation of nonketotic hyperglycemia is essential as it is easily reversible . although hyperglycemia typically causes focal motor seizures , occipital seizures have also been associated with hyperglycemia . our case highlights the key features of hyperglycemia - induced occipital lobe seizures and illustrates the need for clinical vigilance since the presenting symptoms may be nonspecific or mistaken for migraine , temporal arteritis , or ischemia . prominent features of this case include elevated glycated hemoglobin ( hba1c ) , electrographic seizures , and reversible subcortical t2 hypointensity with leptomeningeal enhancement . we report the case of a 66-year - old man with subacute onset of visual symptoms and discuss his hospital course , diagnosis , treatment , and follow - up . we review the literature for similar case reports and present the diagnostic modalities utilized in those cases along with the treatment protocols implemented . a 66-year - old right - handed man with history of non - insulin - dependent diabetes mellitus type ii , hypertension , and hyperlipidemia was transferred to our institution from another hospital for fluctuating alteration of mental status , hyponatremia ( na level of 126 meq / l ) , and visual disturbances , with finger stick blood glucose level of 400 mg / dl for further work - up . prior to arrival , he had 1 week of intermittent confusion with apraxia ( not knowing what to do with his toothbrush , difficulty getting dressed ) . he reported visual hallucinations consisting of mathematical figures in his peripheral vision and people in his home . he did not have a history of seizures or migraines , nor did he have any known risk factors for epilepsy . on examination , he had a right homonymous hemianopia and deficits in attention , praxis , and calculations . during examination , he also had 4 episodes characterized by a head turn to the right , unresponsiveness , and right - beating nystagmus . laboratory abnormalities included a blood glucose level of 359 mg / dl , an hba1c level of 13.4% , and a sodium level of 129 meq / l . magnetic resonance imaging of the brain showed subcortical t2 hypointensity within the left occipital lobe ( fig . 1 ) . these findings raised radiological concern for subacute infarction or infectious etiology such as encephalitis or paraneoplastic syndrome , but lumbar puncture revealed a normal opening pressure , while csf analysis showed normal protein and cell counts and was notable only for elevated glucose . an initial 22-minute scalp eeg recording captured 7 seizures , each lasting 12 min , and characterized electrographically by left occipital polyspikes at a frequency of 2025 hz with spread to the right occipital region within about 3 s followed by diffuse bilateral involvement before abruptly terminating . some of the seizures evolved to approximately 2-hz spike - and - wave discharges with left occipitoparietal predominance . seizures stopped within 1 h following administration of phenytoin , lorazepam , insulin , and aggressive fluid hydration . follow - up mri 2 months later showed resolution of subcortical t2 hypointensity and leptomeningeal enhancement . a 66-year - old right - handed man with history of non - insulin - dependent diabetes mellitus type ii , hypertension , and hyperlipidemia was transferred to our institution from another hospital for fluctuating alteration of mental status , hyponatremia ( na level of 126 meq / l ) , and visual disturbances , with finger stick blood glucose level of 400 mg / dl for further work - up . prior to arrival , he had 1 week of intermittent confusion with apraxia ( not knowing what to do with his toothbrush , difficulty getting dressed ) . he reported visual hallucinations consisting of mathematical figures in his peripheral vision and people in his home . he did not have a history of seizures or migraines , nor did he have any known risk factors for epilepsy . on examination , he had a right homonymous hemianopia and deficits in attention , praxis , and calculations . during examination , he also had 4 episodes characterized by a head turn to the right , unresponsiveness , and right - beating nystagmus . laboratory abnormalities included a blood glucose level of 359 mg / dl , an hba1c level of 13.4% , and a sodium level of 129 meq / l . magnetic resonance imaging of the brain showed subcortical t2 hypointensity within the left occipital lobe ( fig . 1 ) . these findings raised radiological concern for subacute infarction or infectious etiology such as encephalitis or paraneoplastic syndrome , but lumbar puncture revealed a normal opening pressure , while csf analysis showed normal protein and cell counts and was notable only for elevated glucose . an initial 22-minute scalp eeg recording captured 7 seizures , each lasting 12 min , and characterized electrographically by left occipital polyspikes at a frequency of 2025 hz with spread to the right occipital region within about 3 s followed by diffuse bilateral involvement before abruptly terminating . some of the seizures evolved to approximately 2-hz spike - and - wave discharges with left occipitoparietal predominance . seizures stopped within 1 h following administration of phenytoin , lorazepam , insulin , and aggressive fluid hydration . follow - up mri 2 months later showed resolution of subcortical t2 hypointensity and leptomeningeal enhancement . nonketotic hyperglycemia ( nkh ) as a cause of focal seizures is well - described . in some cases , this was initially described by maccario and colleagues in 1965 and later by others , , . the most commonly encountered seizure types in nkh are focal motor seizures and epilepsia partialis continua . however , occipital lobe seizures have been reported in the setting of hyperglycemia . in the majority of cases , the seizures occurred in the setting of only moderate hyperglycemia and in the absence of significant hyperosmolality . thus , this may be more related to long - standing hyperglycemia ( as reflected by the elevated hba1c ) than to the degree of hyperglycemia in the acute setting . several of these cases have demonstrated subcortical t2 hypointensity in the involved occipital lobe , , , , , , . in spite of the increasing recognition of this entity , this may lead to a compensatory increase in metabolism of gaba to succinic acid and subsequent depletion of gaba which results in neuronal hyperexcitability , . however , this explanation does not fully account for the evidence that seizures may occur with hyperglycemia in the absence of significant hyperosmolality . symptoms related to occipital seizures may not cause severe impairments , thus delaying diagnosis and treatment , but seizures must be promptly recognized as they are easily treatable . symptoms may include visual phenomena such as colored circles or letters or other well - formed visual hallucinations , headache , confusion , blurry vision , or homonymous hemianopia . migraine with aura , temporal arteritis , and posterior reversible encephalopathy syndrome ( pres ) are some of the other diagnoses often under consideration . a high index of clinical suspicion may be needed to recognize acute symptomatic occipital seizures in the setting of hyperglycemia . while eeg is the gold standard for diagnosing seizures , subtle mri findings may suggest the diagnosis . magnetic resonance imaging may show reversible diffusion abnormalities , flair and t2 hyperintensities in the cortical gray matter , and/or hypointensities in the subcortical white matter . subcortical hypointensity is becoming increasingly recognized in relation to nonketotic hyperglycemia and has been attributed to transient free radical accumulation during excitotoxic damage from seizures , . fludeoxyglucose - positron emission tomography(fdg - pet ) performed in a patient with hyperglycemia - related right occipital seizures and right occipital subcortical t2 hypointensity showed associated right occipital cortical hypermetabolism . magnetic resonance spectroscopy performed in a similar patient showed a moderate decrement in naa and lipid spikes , suggesting a component of laminar necrosis in the pathology despite the transient abnormalities on t2-weighted mri . subcortical t2 hypointensity is rare but has also been described as an unusual manifestation of ischemia , multiple sclerosis , leptomeningeal metastasis , and meningitis or meningoencephalitis . leptomeningeal enhancement has also been reported with hyperglycemia - associated seizures though it may be less common . these findings can raise concern for subacute infarct , encephalitis , malignancy , or a paraneoplastic process . these were excluded in our case by csf studies and the resolution of these findings on the follow - up mri . aggressive fluid management and glycemic control should be the focus of therapy . while anticonvulsants are certainly warranted in the acute setting of status epilepticus , it is unclear whether long - term aed therapy is needed as the seizures are provoked by a reversible process . our patient was treated with phenytoin and recovered completely , but phenytoin may not be the optimal aed choice given concerns that phenytoin may worsen hyperglycemia . gamma - aminobutyric acid(gaba)-enhancing medications are suggested as strategic alternatives , though not well studied in this condition . we report a case of multiple electroclinical occipital seizures in the setting of hyperglycemia and elevated hba1c with focal leptomeningeal enhancement and subcortical t2 hypointensity on mri . occipital lobe seizures should be considered in the differential diagnosis when patients with hyperglycemia present with visual changes , and occipital t2 hypointensity should raise suspicion for hyperglycemia - associated seizures .

introductionoccipital lobe seizures are a recognized manifestation of diabetic nonketotic hyperglycemia , though not as common as focal motor seizures . occipital lobe white matter t2 hypointensity may suggest this diagnosis.methodswe present a case of a 66-year - old man with hyperglycemia - related occipital lobe seizures who presented with confusion , intermittent visual hallucinations , and homonymous hemianopia.resultsmagnetic resonance imaging showed subcortical t2 hypointensity within the left occipital lobe with adjacent leptomeningeal enhancement . these findings were transient with disappearance in a follow - up mri . the eeg captured frequent seizures originating in the left occipital region . hba1c level was 13.4% on presentation , and finger stick blood glucose level was 400 mg / dl.conclusionhyperglycemia should be considered in the etiology of differential diagnosis of patients with visual abnormalities suspicious for seizures , especially when the mri shows focal subcortical t2 hypointensity with or without leptomeningeal enhancement .

gitelman 's syndrome ( gs ) is an autosomal recessive tubular disorder characterized by hypokalemic alkalosis , hypomagnesemia , and hypocalciuria . hypopituitarism can have varied etiologies including tumor in hypothalamo - pituitary region or its treatment , inflammatory , genetic , trauma , and hemorrhage , and can result in a host of hormonal and electrolyte abnormalities . both these disorders can cause significant morbidity and a combination of both can be potentially devastating . a few case reports are emerging which show a combination of inherited tubular disorders with pituitary abnormalities on imaging , but with normal hormonal profile . we report the first case of a post - menopausal lady who had a combination of gitelman 's syndrome with multiple pituitary hormone deficiencies ( mphd ) and was treated successfully by replacement of hormones and electrolytes . a 57-year - old lady , a known case of hypothyroidism for 7 years on levothyroxine replacement , presented with complaints of generalized weakness , postural giddiness , and intermittent episodes of spontaneous carpopedal spasms for past 9 months and was bedridden for past 1 month . she used to consume approximately 250 ml of milk products per day and had sunlight exposure for 10 minutes per week . there was no history of diuretic use , protracted vomiting or diarrhea , polydipsia , or polyuria . she was noted to have hypotension on several occasions over the past 9 months for which she was treated with intravenous fluids . she has three children ( last child birth 21 years back ) and there was no history of lactation failure . she attained menopause at the age of 47 years , prior to which her periods were regular . clinically , she was obese ( bmi 34.13 kg / m ) , and had supine hypotension ( bp 70/50 mmhg ) , pallor , bilateral non - pitting edema , acanthosis nigricans , and skin tags . trousseaus and chvosteks 's signs were positive . there was no goiter , deep tendon jerks were normal , and rest of the examination was normal . investigations revealed anemia ( hb 10.3 gm% ) , hyponatremia , hypokalemia , hypomagnesemia , hypocalcemia , hypophosphatemia , hypochloremia , and metabolic alkalosis [ table 1 ] . her serum 25-hydroxy vitamin d3level was 11.89 ng / ml and intact parathyroid hormone ( pth ) was 249 pg / ml ( 10.065.0 ) . urinary spot sodium ( 180 meq / l ) , potassium ( 13 meq / l ) , and chloride ( 161 24-hour urinary calcium [ 127 mg ( normal < 200 mg ) ] , phosphorus [ 412 mg ( normal < 1200 mg ) ] , and copper [ 8.3 g / d ( normal < 60 g / d ) ] excretion were normal . plasma renin activity 4.4 ng / ml / h ( 0.13.1 ) and plasma aldosterone 38.1 ng / dl ( 316 ) levels were high . plasma glucose levels ( ogtt ) , and renal and liver function tests were normal . qualitative test for urinary amino acids , hiv and antinuclear antibody ( ana ) serologies were negative . biochemical parameters pre- and postpresentation ( at 6-month follow - up ) thyroid profile at baseline was suggestive of hypothyroidism [ low t4 , thyroid stimulating hormone ( tsh ) 9.06 u / l ] , whereas it was normal at presentation . there was hypocortisolism ( random plasma cortisol : 164 nmol / l and peak cortisol during insulin - induced hypoglycemia : 453.2 nmol / l ) , relatively normal adrenocorticotropic hormone ( acth ) 11.6 pg / ml ( 7.263.3 ) , and low gonadotropins [ luteinizing hormone ( lh ) 1.36 miu / ml , follicle stimulating hormone ( fsh ) 4.00 miu / ml ] . serum prolactin [ 5.8 ng/ ml ( 525 ) ] and serum insulin - like growth factor 1 ( igf-1 ) [ 156 ng / ml ( 66310 ) ] were low normal . peak growth hormone level after iih was 5.6 ng / ml . anti - thyroid peroxide antibody levels were normal . mri sella showed loss of posterior pituitary bright spot [ figure 1 ] ; however , anterior pituitary was normal . in view of the above , a diagnosis of gitelman 's syndrome with mphd was made . she was treated with levothyroxine , hydrocortisone , and supplementation with vitamin d , sodium , potassium , magnesium , calcium , and chloride . she showed global improvement in symptoms , her carpopedal spasms resolved , blood pressure normalized , and biochemical parameters improved which are enumerated in table 1 . bartter 's and gitelman 's syndrome are two ends of a spectrum of inherited renal tubulopathies that are characterized by renal salt wasting , hypokalemic metabolic alkalosis , hyperreninemic - hyperaldosteronism with normal blood pressure , and hyperplasia of juxtaglomerular apparatus . gitelman 's syndrome ( gs ) , in addition , also exhibits hypomagnesemia and hypocalciuria . bartter 's syndrome is the more severe of two and presents in antenatal period or early childhood , whereas gitelman 's syndrome presents later in life and adult cases have also been described . our patient presented with nonspecific features of generalized weakness that can be explained on the basis of severe dyselectrolytemia and hypopituitarism . postural giddiness can be a manifestation of gitelman 's syndrome per se or that of hypotension that our patient had . loss of fluid and electrolytes leads to activation of renin angiotensin aldosterone system ( ras ) resulting in hyperaldosteronism on one hand and renal release of vasodilator prostaglandins ( pge2 and prostacyclins ) on the other . hence , blood pressure remains normal despite hyperaldosteronism as prostaglandin - induced vasodilatation counters the hypertensive effects of overactive ras . association of conn 's syndrome that results in hyporeninemic - hyperaldosteronism has also been recently reported with gs . our patient , however , had hyperreninemic - hyperaldosteronism and normal adrenals on mri , hence such an association is ruled out . hypokalemic metabolic alkalosis occurs due to hyperreninemic - hyperaldosteronism leading to increased potassium and hydrogen ion secretion in the collecting tubules . magnesium wasting in distal convoluted tubules as a result of inhibition of its uptake in the presence of hypokalemia and metabolic alkalosis leads to hypomagnesemia in gitelman 's syndrome , as was seen in our case . hypochloridemia with increased urinary chlorine excretion is also a feature of bartter 's syndrome and an overlap of both the conditions can not be denied in our case . hypocalcemia in our patient is thought to have occurred due to poor oral intake of milk products ; vitamin d deficiency , and possibly reduction in 1-hydroxylase activity . an overlap with bartter 's syndrome is seen in many patients and this could also possibly have worsened hypocalcemia . hypophosphatemia in our patient can be explained by poor oral intake , hypovitaminosis d , and secondary hyperparathyroidism . panhypopituitarism , on the other hand , refers to total or partial loss of pituitary hormone secretion as a result of pituitary or hypothalamic dysfunction resulting in loss of anterior pituitary hormones with or without loss of antidiuretic hormone . our patient had low lh , fsh levels despite having attained menopause ; acth was relatively normal in spite of low cortisol and stimulated cortisol level was suggestive of compensated adrenal insufficiency . her tsh value was mildly elevated despite low total t4 that is seen in subclinical hypothyroidism , but can also occur in secondary hypothyroidism . due to the presence of above combination of hormonal profile and abnormality in pituitary on imaging , a diagnosis of pituitary failure was made . diuretic use and protracted vomiting or diarrhea as a possible cause of hyokalemia was were excluded by history taking . secondary causes for tubulopathy were excluded including fanconi 's syndrome , renal tubular acidosis , systemic lupus erythematosus , wilson 's disease , and hiv . in the light of above , we diagnosed our patient to be suffering from gitelman 's syndrome though she had some overlapping features of bartter 's syndrome as well . both these syndromes are autosomal recessive disorders caused by an inactivating mutation of the thiazide - sensitive sodium - chloride cotransporter in the loop of henle and distal renal tubule , namely slc12a3 and clcnkb genes , encoding the chloride channel . mphd can be due to tumor or its treatment in the hypothalamo - pituitary region , which was ruled out by history and imaging . autoimmune etiology is another important factor ; however , surrogate antibodies ( anti - tpo and ana ) were negative in our patient to rule out autoimmune disrorder . also , there was no history of lactation failure to suggest sheehan 's syndrome as a possible cause . barring these , inherited causes can give rise to mphd which could be a causative factor in our patient . the tubular defect in bartter 's or gitelman 's syndrome can not be corrected and lifelong magnesium and potassium supplementation is required , whereas treatment of mphd is replacement of deficient hormones , as was done in our patient . the combination of nonsteroidal anti - inflammatory drugs ( nsaids ) to reduce renal pg synthesis and a potassium - sparing diuretic to raise the plasma potassium concentration toward normal partially reverses the metabolic alkalosis and corrects the hypomagnesemia . to conclude , gitelman 's syndrome is an often overlooked cause of hypokalemia and hypomagnesemia in adults . hence , a clinician should be alert to such a possibility as the outcome can be rewarding . it remains to be seen , however , whether association of gitelman 's syndrome with pituitary abnormalities with or without mphd is just a chance association or there is a common genetic link .

gitelman 's syndrome is an inherited tubulopathy affecting thiazide - sensitive sodium chloride cotransporter , which manifests with hypokalemic alkalosis , hypomagnesemia , and hypocalciuria . recently few cases have been described having an association of gitelman 's syndrome with pituitary abnormalities on imaging , though with normal hormonal status . we describe the first case of an adult patient having gitelman 's syndrome and hypopituitarism with abnormal pituitary imaging . she presented to us with hypotension , hypokalemia , hypomagnesemia with alkalosis , hypothyroidism , hypocortisolism , and hypogonadism . she was treated with replacement of electrolytes and hormones , to which she showed an excellent response .

rhinosporidiosis is a granulomatous disease caused by rhinosporidium seeberi ( earlier described as a fungus , now reclassified in its own class mesomycetozoea ) . the disease is more prevalent in sri lanka and india due to the widespread custom of bathing in pond water.1 the disease may involve ear , nose , throat and eye . in the eye , the conjunctiva , lacrimal passage and sclera may be affected.2 we present a rare manifestation of ocular rhinosporidiosis presenting as an intracorneal mass . a healthy 22 year - old male patient reported to the cornea clinic of our institute with a history of gradual dimness of vision in the left eye over the previous 6 months . he had a history of ocular trauma in left eye inflicted while swimming in a pond . subsequently he was examined by a local ophthalmologist who removed a vegetative foreign body partially embedded in the superficial stroma near the limbus at the 9 o'clock position of left cornea at the slit lamp under topical anesthesia . presenting vision in left eye . slit lamp examination of involved eye revealed a large intracorneal mass with lobulated edges . many small greyish white dots were noted along the edges of the lesion [ figure 1 ] . posterior segment evaluation of the left eye ( by b - scan ultrasonography ) and the right eye ( by slit lamp biomicroscopy ) was normal . anterior segment ocular coherence tomography ( visante oct , software version 3.0.0.139 ; carl zeiss meditech , jena , germany ) scan in left eye confirmed the intracorneal nature of the mass ( vertical length 0.68 mm and horizontal length 6.52 mm ) sparing the deeper part corneal stroma and descemet 's membrane [ figure 2 ] . deep anterior lamellar keratoplasty was performed under peribulbar anesthesia with sedation , layer - by - layer dissection of the stromal layers was performed until exposure of descemet 's membrane . a 9.0-mm donor lenticule whose dm - endothelial layers had been stripped off was sutured to the recipient bed with 16 interrupted 10:0 monofilament nylon sutures . he was discharged with standard postoperative regimen of topical moxifloxacin ( 0.5% ) four times a day and prednisolole acetate ( 1% ) six times a day with gradual tapering . the patient was seen the following day and the graft was clear with good graft - host apposition . slit lamp photograph of intracorneal mass anterior segment optical coherence tomography image showing an intracorneal lesion the intracorneal mass was fixed in 10% formol - saline , processed for paraffin embedding and subsequent staining of 4 - 5-m sections with the hematoxylin and eosin ( h and e ) stain . the slide showed many sporangias of varying sizes containing spores . some empty sporangias were documented . his postoperative period was uneventful with clear graft , good graft - host apposition and bcva of 20/60 with -1.25 120 1 year postoperatively . rhinosporidiosis is prevalent in india and sri lanka due to common practice of bathing in river and pond water . involvement other than eye and ear had been reported in africa.3 trophocyte of r seeberi gives rise to mature sporangium which are seen as white punctuate dots through submucosa . from mature sporangium , endospores ( the infective unit ) are released and they usually produce the classic lesion of rhinosporidiosis upon entry through a breach in the epithelium on the mucosal surface of the body . in the current case , we assumed that the endospores found a portal into the corneal stroma when the left eye was injured while swimming in pond water resulting in intracorneal foreign body . ocular rhinosporidiosis might be a rare differential diagnosis of intracorneal mass lesion as presented in this case report .

a healthy 22-year - old male presented to institutional cornea clinic with an intracorneal mass overlying the pupil with lobulated edges having many tiny greyish white dots . the patient had a history of trauma while swimming in a pond with subsequent removal of intracorneal foreign body in the left eye approximately a year prior to presentation . anterior segment optical coherence tomography ( oct ) confirmed that an intracorneal mass sparing deep stroma and descemet 's membrane . a deep anterior lamellar keratoplasty ( dalk ) was performed in left eye and the mass was sent for histology examination . histology evaluation was suggestive of rhinosporidiosis . the patient achieved 20/60 bcva with -1.25 120 1 year postoperatively without any evidence of recurrence at the graft - host interface . this unique presentation ( as an intracorneal mass ) of ocular rhinosporidiosis emphasizes that clinicians from our region of the world must consider rhinosporidiosis in the differential diagnosis especially with a history of penetrating injury while swimming in pond or river water .

pancreatic oxidative stress occurs during an early stage of pancreatitis.1 - 3 scavenger therapy for reactive oxygen species ( ros ) showed some success in experimental pancreatitis models , including cerulein pancreatitis.4,5 in human acute pancreatitis , the increased levels of lipid peroxide in the bile or pancreatic tissue and subnormal levels of antioxidant vitamins in the blood were reported.6 cerulein is an analogue of cholecystokinin ( cck ) and causes the maximum pancreatic secretion of amylase and lipase,7,8 cytoplasmic vacuolization , death of acinar cells , edema formation , and infiltration of inflammatory cells into the pancreas,9,10 which are observed in human pancreatitis . the mechanism of action of cerulein is suggested to involve production of large amounts of ros , activation of oxidant - sensitive transcription factor nuclear factor-b ( nf-b ) and induction of cytokine expression in pancreas.11,12 nicotinamide adenine dinucleotide phosphate ( nadph ) oxidase components have been detected in pancreatic acinar ar42j cells.13 ar42j cells are derived from a transplantable tumor of a rat exocrine pancreas and are tumorigenic in nude mice and maintain many characteristics of normal pancreatic acinar cells.14 cerulein - induced nf-b activation and interleukin ( il)-6 expression were inhibited by treatment with the antioxidant rebamipide , diphenylene iodonium ( nonspecific inhibitor for nadph oxidase ) , or by transfection with antisense oligodeoxynucleotides for nadph oxidase subunits p22phox and p47phox in pancreatic acinar ar42j cells . therefore , nadph oxidase has been considered as a main source of ros during development of pancreatitis induced by cerulein . both nf-b and janus kinase / signal transducer and activator of transcription ( jak / stat ) are activated in response to ros in pancreas.11,15 although there are reports indicating the involvement of nf-b in the pathogenesis of pancreatitis and pancreatic cancer , only limited data are available on the role of jak / stat in the pathogenesis of these diseases . it has been reported that inhibition of jak1/stat1 improves the severity of cerulein - stimulated pancreatic injury by inhibiting nf-b activation , indicating that activation of jak1/stat1 is an early event in pancreatic injury.16 since jak / stat mediates cell proliferation and malignant transformation17 as well as inflammatory signaling18,19 in pancreas , we focus our discussion on the possible role of jak / stat in the pathogenesis of pancreatitis and pancreatic cancer in this review . the jak family kinases consist of four members jak1 , jak2 , jak3 , and tyrosine kinase 2 ( tyk2 ) in mammals , whereas there are seven stat family members such as stat1 , stat2 , stat3 , stat4 , stat5a , stat5b , and stat6 . the binding of a cytokine to its receptor induces conformational changes of the receptor , which subsequently results in the activation of the associated jaks . phosphorylation of stats leads to their dimerization and translocation into the nucleus , in which they bind specific dna sequences to activate gene transcription . stat1 , stat2 , stat3 , stat5 , and stat6 are widely distributed in various tissues , whereas stat4 is restricted mainly to thymus , spleen , testis , myeloid cells , and monocytes.20 in pancreatic tissue and acinar cells , jak1 , jak2 , tyk2 , stat1 , stat2 , stat3 , stat5 , and stat6 are expressed . however , expression of stat4 is detected in pancreatic tissue but not in isolated pancreatic acinar cells.21 in pancreatic acinar ar42j cells , tumor necrosis factor- ( tnf- ) stimulates the activation of stat1 , stat3 , and stat422 and stat3 and suppressor of cytokine signaling 3 ( socs3 ) which are all signaling pathways involved in tissue inflammation.23 tnf- and tnf- receptors ( tnfr1 and tnfr2 ) have been shown to be expressed in normal rat pancreatic acinar cells and cerulein upregulated the expression of tnf- receptors24 and activated jak2/stat3 and il-1 in pancreatic acinar cells.25 together these studies suggest that stat3 activation by cerulein is mediated by tnf- signaling in pancreas ( fig . although various hormones such as growth hormone and prolactin have been reported to activate the jak / stat pathway,26 there have been little studies on the involvement of jak / stat on cck signaling . a cck analogue cerulein triggers phosphorylation of jak1 , stat1 , and stat3 proteins and induce inflammatory cytokines such as tnf- , il-1 , and il-6 in pancreas.27 cck receptors are a group of g - protein coupled receptors ( gpcrs ) which bind two subtypes of cck , cck1 , and cck2 . cck2 receptor ( cck2r ) upon binding of cck activated the jak2/stat3 pathway in pancreatic acini in transgenic mice expressing cck2r.17 the mechanism of jak2 activation involves gq proteins and requires the npxxy motif , located at the end of the seventh transmembrane domain of cck2r . this motif , which is critical for gq - dependent signaling pathways , is also required for stat3 activation by cck2r . thus , jak / stat signaling is involved in the proliferative effect of cck2r , which contributes to the increase in the growth of pancreas and pancreatic tumor development . the stat family of transcription factors is known to be activated by various cytokines and growth factors and may be activated by oxidative stress . in epithelial cells and fibroblasts , activation of stat3 and stat1 in response to h2o2 occurs within minutes.15 ros act as upstream signaling molecules for jak2 activation in smooth muscle cells.28 the mechanism of h2o2 activation of stat proteins involves activation of the jak2 and tyk2 kinases . stats are phosphorylated in response to h2o2 subsequent to the phosphorylation of jak2 and tyk2 kinases.15 the possible mechanism for activation of jak2 by h2o2 is inactivation of protein tyrosine phosphatases ( ptps ) . using ptp inhibitors vanadate and pervanadate results in stat activation.29,30 in human pancreatic cancer mia paca-2 and panc-1 cells , nadph oxidase 4 ( nox4 ) , which produces ros , mediates the sustained phosphorylation of jak2.31 nox4 inhibits ptp , leading to enhanced and sustained phosphorylation of jak2 and suppresses apoptosis of pancreatic cancer cells . these studies demonstrate that ros mediate activation of jak / stat and inhibit apoptotic cell death of pancreatic cancer cells . we previously reported that activation of jak2/stat3 results in edematous and inflammatory changes in the pancreas and increased serum levels of il-1 in rats with experimental pancreatitis.19 the maximal lung injury after cerulein - induced acute pancreatitis occurs in stat4- or stat6-deficient mice.32 in pancreatic acinar cells stimulated with tnf- , the activation of jak2/stat3 mediated the development of pancreatic injury.22 inhibition of jak / stat as well as nf-b improved the severity of pancreatitis.27 since ros mediates induction of inflammatory cytokines and nadph oxidase produces ros in pancreas , inhibition of nadph oxidase may be beneficial for the prevention and the treatment of pancreatitis by suppressing jak2/stat3 and mitogen activated protein kinases ( mapks ) and expression of tgf-1 in pancreatic acinar cells.25 lipopolysaccaride ( lps ) , tnf- , and cerulein are potent mediators of stat3 and socs3 expression as well as the induction of il-6 and il-1 in pancreas.23,33 targeting mapks , nf-b , and stat3 pathways by dexamethasone treatment downregulated the expression of chemokines during the course of acute pancreatitis , resulting in decreased severity of the disease in the rats with bile duct ligation.34 administration of cerulein and lps induced an increase in serum amylase and il-6 levels , severe acute pancreatitis , pancreatitis - associated lung injury , and phosphorylation of stat3 in the pancreas . blocking il-6 suppresses stat3 activation in the pancreas and consequently attenuated the severity of pancreatitis by promoting pancreatic acinar cell apoptosis.35 pancreatitis - associated ascitic fluid ( paaf ) which is known to contribute to the progression of acute pancreatitis activated the expression of monocyte chemoattractant protein-1 ( mcp-1 ) and induced the phosphorylation of p38-mapk , degradation of ib , and increases in nuclear level of p65 , and stat3 activity in rat pancreatic acinar cells.36 it was suggested from this study that acinar cells are activated by paaf to produce mcp-1 , mediated mainly by the activation of nf-b and stat3 pathways . in early acute pancreatitis in the rat , oxidant - mediated activation of mapk , nf-b , and stat3 triggers the expression of chemokines in acini but not in non - acinar cells in the pancreas.37 cyclooxygenase-2 ( cox-2)-derived bioactive lipids including prostaglandin e2 are potent inflammatory mediators that promote tumor growth and metastasis by stimulating cell proliferation , invasion and angiogenesis.38 in cox-2 deficient mice , deletion of cox-2 gene prevented the histologic and inflammatory changes associated with pancreatitis compared with the wild - type littermates , indicating that cox-2 is an important regulator of the severity of acute pancreatitis.38 in the rats treated with a jak / stat inhibitor , ag490 , the expression of cox-2 , il-1 , and il-6 induced by cerulein was inhibited by the suppression of stat activation.27 therefore , stat may play an important regulatory role in the expression of inflammatory cytokine il-6 and cox-2 in cerulein - treated pancreatic acini . jak2/stat3 pathway is activated by the cck2r in pancreatic tumor cells and contributes to cell proliferation.17 targeted expression of cck2r , a gpcr , in mouse pancreatic acinar tissue led to the activation of jak2 and stat3.16 the activation of jak2/stat3 increased growth of the pancreas and resulted in the development of preneoplastic lesions , which is similar to those found in human pancreatic cancers . deregulation of jak2/stat3 pathway by cck2r represents an early step in pancreatic carcinogenesis , contributing to cell proliferation and pancreatic tumor development.17 recent studies indicate that stat3 controls the development of the earliest premalignant pancreatic lesions , acinar - to - ductal metaplasia and pancreatic intraepithelial neoplasia ( panin).39 stat3 directly regulates vascular endothelial growth factor expression and hence angiogenesis , growth , and metastasis of human pancreatic cancer fg and panc-1 cells.40 on malignant transformation , activated stat3 promotes cellular proliferation by acceleration of g1/s - phase progression and thereby contributes to the malignant phenotype of human pancreatic cancer capan-1 cells.41 the deregulation of jak2/stat3 pathway by cck2r represents an early step contributing to cell proliferation and pancreatic tumor development.17 the transcription factor pancreatic and duodenal homeobox factor 1 ( pdx-1 ) is expressed in pancreatic progenitor cells . in exocrine pancreas , pdx-1 is down - regulated during late development , while re - up - regulation of pdx-1 has been reported in pancreatic cancer and pancreatitis . the pancreas of pdx-1 expressing transgenic mouse was markedly small with the replacement of acinar cells by duct - like structures ( acinar cell - ductal metaplasia ) , accompanied by activated stat3 . these results provide a mechanism of pancreatic metaplasia by which persistent pdx-1 expression induces acinar - to - ductal transition through stat3 activation.42 inactivation of il-6 transsignaling or stat3 inhibits panin progression and reduces the development of pancreatic ductal adenocarcinoma ( pdac ) . aberrant activation of stat3 through homozygous deletion of socs3 in the pancreas accelerates panin progression and pdac development.43 thus , inflammatory mediator stat3 is a critical component of spontaneous and pancreatitis - accelerated pdac precursor formation and contributes to cell proliferation , metaplasia - associated inflammation , and matrix metalloproteinase 7 ( mmp7 ) expression during neoplastic development . it was also shown that stat3 signaling enforces mmp7 expression in pdac cells and that mmp7 deletion limits tumor size and metastasis in mice . these studies suggest that stat3 and mmp7 are important mediators for pdac initiation and progression.44 in cultured human pancreatic cancer su 86.86 cells , cox-2 was induced by treatment with tumor - promoting phorbol esters45 and in cox-2-positive pancreatic cancer bxpc-3 cells , cox-2 inhibitor reduced angiogenesis and growth.46 recently , a novel pathway in which cox-2 activates stat3 by inducing il-6 expression has been suggested in non - small cell lung cancer cells.47 together , these studies provide a rationale for the development of stat3 , il-6 , cox-2 , and mmp7 targeted therapy for the treatment of pancreatic cancer . in addition to nf-b , ros activates jak / stat pathway , which regulates inflammatory gene expression , cell proliferation , and transformation in pancreas . thus , the activation of nf-b and jak / stat seems to be the molecular mechanisms underlying the pathogenesis of pancreatitis and pancreatic cancer . inhibition of either jak / stat or nf-b may alleviate inflammation and carcinogenesis of pancreatic tissues . therefore , jak / stat may serve as the potential therapeutic targets in the development of new drugs in the treatment of pancreatitis and/or pancreatic cancer .

in the pathogenesis of pancreatitis , oxidative stress is involved in the activation of the janus kinase / signal transducer and activator of transcription ( jak / stat ) pathway and cytokine expression . high serum levels of cholecystokinin ( cck ) have been reported in patients with acute pancreatitis , and treatment with cerulein , a cck analogue , induces acute pancreatitis in a rodent model . recent studies have shown that cerulein - activated nicotinamide adenine dinucleotide phosphate oxidase elicits reactive oxygen species , which trigger the phosphorylation of the jak1 , stat1 , and stat3 proteins and induce the production of inflammatory cytokines , such as tumor necrosis factor- , interleukin ( il)-1 , and il-6 , in pancreatic acinar cells . the jak / stat pathway also stimulates cell proliferation and malignant transformation and inhibits apoptosis in the pancreas . this review discusses the possible role of the jak / stat pathway in the pathogenesis of pancreatitis and pancreatic cancer in response to oxidative stress .

during the outbreak period , ptwrc housed 6001,000 wild animals ( 70 species of mammals , birds , and reptiles ) . the center is divided into 3 main sections that cover 37 ha . birds were kept in sections s11 , s12 , and s2 , and the cats were in all sections ( figure ) . the information on bird deaths at ptwrc was systematically recorded by wildaid staff members who were at the centre at the time of the outbreak . in june 2004 , a complete investigation was conducted at ptwrc , and semistructured interviews of key informants were used to identify deaths of domestic poultry in the surrounding villages . every bird death between december 15 , 2003 , through january 15 , 2004 , was defined as a suspected case of hpaiv ( h5n1 ) . for s1 , the cumulative mortality rate could not be estimated because the exact bird population was not known and the birds were difficult to observe in that section ( the semicaptive waterfowl population is able to mix with the wild population and disperse to breed ) . for s2 , map of the 3 main sections of the phnom tamao wildlife rescue centre , cambodia , during outbreak of highly pathogenic avian influenza virus ( h5n1 ) , december 15 , 2003january 13 , 2004 . s1 , aviary section in which cumulative mortality rate could not be estimated because exact bird population was not known and birds were difficult to observe ; s2 , aviary section in which captive bird population was exactly known and number of dead birds was precisely recorded ; np , species not present in s1 or s2 . only sample that was negative for highly pathogenic avian influenza virus ( h5n1 ) ; all other birds sampled were positive . the first case , in a crested serpent eagle ( spilornis cheela ) , was reported on december 15 , 2003 , in s2 ( figure ) . on december 19 , the outbreak had reached every section and continued until january 12 ; a total of 86 birds , representing 8 taxonomic orders and 12 families , died ( table 1 ) . of 7 cat species , cats from 5 species were reported sick ( 16/39 total cats ) ( table 2 ) . in s2 , of the 29 wild bird species kept in s2 at the beginning of the outbreak , no birds from 12 species showed signs of disease ( table 1 ) . the only mammals present in the aviaries in s2 , slow lorises ( nycticebus sp . ) , did not become ill . none of the 27 animal keepers , who were 2050 years of age , were reported to have gotten sick . * all serum samples were positive ( date of collection : march 4 , 2004 ) . most of the birds died within a few hours without showing any clinical signs of infection . a few birds died 12 days after onset of clinical signs ( anorexia , extreme lethargy , occasional dark green diarrhea , respiratory distress , and neurologic abnormalities ) . the cats were sick for 57 days and exhibited anorexia and lethargy but no respiratory illness . laboratory investigations of the organs from 8 birds sampled in december 2003 were performed ( table 1 ) . for those birds , pcr ( rt - pcr ) , according to the procedure described by lanciotti et al . all birds sampled , except a parakeet , were positive for influenza subtype h5n1 by rt - pcr ( 3 ) ( table 1 ) . molecular characterizations of hemagglutinin ( h)5 and neuraminidase ( n)1 were performed from the influenza virus ( h5n1 ) strains from ptwrc as previously described ( 4 ) . amino acid sequences were identical in the coding region to the sequence of isolates obtained from poultry cases in cambodia ( ill poultry from a flock with high mortality rates ) and similar ( > 96.5% ) to hpaiv ( h5n1 ) strain h5 sequences from vietnam and thailand in 2004 ( data not shown ) . all belonged to the h5 clade 1 ( 4 ) . amino acid sequences from n1 from cambodia were very close to each other ( > 97.12% identity ) and to 2004 vietnamese and thai n1 sequences ( > 96% ) ( data not shown ) . the ha and na sequences of the isolates were deposited in genbank ( accession nos . retrospective investigation of the villages surrounding the ptwrc and phnom penh showed that chickens from 2 flocks in which deaths had been reported in mid - december had been provided to the ptwrc , either for the restaurants or for the captive animal feeding . furthermore , at the time of the outbreak , many wild crows were found dead in the forest surrounding the ptwrc . the 4 cat serum samples , each from a different species , were positive for hpaiv ( h5n1 ) with serum neutralization test ( 5 ) ; titers ranged from 10 to 40 ( table 2 ) . none of the affected cats died . the sources of introduction of hpaiv ( h5n1 ) within the ptwrc were probably multiple : virus - infected chicken bought to feed the carnivorous species , infected live chickens brought to restaurants near s2 ( i.e. , the first place where deaths were detected ) , and contact between infected wild and captive birds . the introduction through infected chickens is supported by the absence of an outbreak at the ptwrc after the feeding of chickens to carnivorous species was discontinued ; however , deaths in domestic poultry continued in the area . in addition , almost all carnivorous bird species in s2 died ( 93% of falconiformes and 92% of strigiformes ) as did most species usually fed chicken meat in captivity ( herons , storks , crows , great hornbill , pelican ) . diet was also the origin of the outbreak among tigers and leopards in thailand ( 6,7 ) . the dispersion of the disease between ptwrd sections was probably due to poor biosecurity measures . the clinical outcome of wild birds with suspected hpaiv ( h5n1 ) infection at ptwrc ranged from severe illness and death to complete absence of clinical signs , as described ( 8) . several species from the orders ciconiiformes , galliformes , passeriformes , gruiformes , coraciiformes , and pelecaniformes were affected during the outbreak . this observation is consistent with data published earlier , except for coraciiformes represented by 1 bird in our study ( 9 ) . only the carnivorous species ( corvus macrorynchos ) among the 5 species of passeriformes in the aviaries showed clinical signs and later this outbreak confirms that falconiformes and strigiformes are sensitive to hpaiv ( h5n1 ) infection and disease ( 1012 ) and shows that numerous species of these orders can be affected by hpaiv ( h5n1 ) ( table 1 ) . psittaciformes and columbiformes were not visibly affected by the outbreak although they were kept in large numbers in s2 , where large numbers of deaths occurred . as non water - bird species , they do not belong to groups in which avian influenza is commonly reported ( 13 ) . anseriformes , represented in ptwrc by only 4 birds ( anas poecilorhyncha ) , did not show any clinical signs . heterogeneity in the susceptibility of wild ducks to hpaiv ( h5n1 ) , including asymptomatic infection , has been demonstrated ( 14 ) ; this species also belongs to the group of wild ducks found asymptomatically infected with hpaiv ( h5n1 ) in the people s republic of china during the winter of 2005 ( 15 ) . the serologic evidence of influenza virus ( h5n1 ) infection in 4 species of wild cats is in agreement with previous infection in thailand ( 6,7 ) . the report of illness in the asiatic golden cat ( catopuma temminckii ) and the clouded leopard ( neofelis nebulosa ) broadens the host range of the virus among mammals . this report confirms the great variability of wild bird and mammal responses to hpaiv ( h5n1 ) infection . it also confirms the broadening range of susceptible species that may be specific to this clade 1 virus .

from december 2003 through january 2004 , the phnom tamao wildlife rescue centre , cambodia , was affected by the highly pathogenic influenza virus ( h5n1 ) . birds from 26 species died . influenza virus subtype h5n1 was detected in 6 of 7 species tested . cats from 5 of 7 species were probably infected ; none died .

percutaneous closure of patent ductus arteriosus ( pda ) has evolved with development of various surgical and nonsurgical methods . although surgical ligation of pda is a safe procedure with negligible mortality , it is associated with discomfort , morbidity , longer hospital stay and thoracotomy scar.1 the percutaneous closure of pda with ivalon plug was first reported by porstman et al . , in 1967.2 since then , a variety of devices has been developed for percutaneous closure of pda . at present almost all the cardiovascular centers prefer use of amplatzer duct occluder ( ado ) as the safe and effective technique.345678 we herein report the immediate , short , mid - term and long - term results of percutaneous closure of pda with ado from a single centre . between may 2005 and january 2013 , 260 consecutive patients with significant pda were considered for percutaneous closure with ado . the 17 infant patients excluded because of weight < 4.5 kg and severe heart failure after clinical and echocardiographic evaluation . therefore , 243 patients underwent percutaneous closure of pda . the age at the time of procedure raged from 3 month to 38 years ( median : 2 - 5 years ) and the weight ranged from 4.5 kg to 85 kg ( median : 10 kg ) . all patients were reviewed for their information from physical examination , electrocardiogram ( ecg ) , chest radiography and echocardiography before the procedure . after obtaining informed consent from adult patients or child 's parents , right and left heart catheterisation descending aortogram in right anterior oblique or lateral views was performed to measure of pda size . standard technical delivery of the device over a guide wire through the defect and the implantation of device was performed under fluoroscopic guidance , as previously described.49 prophylactic antibiotic with 30 mg / kg cefazoline ( maximum 1 g ) was administered intravenously at 30 minute before the beginning of the procedure and two subsequent doses 8 hour apart . heparin ( 100 unit / kg / dose maximum 5,000 unit ) was administered intravenously after femoral artery access and prior to the procedure . a right anteroposterior or lateral descending aortogram was done to locate pda and obtain the size at the narrowest part , the aortic ampulla and the centre of pda [ figure 1 ] . descending aortogram in the lateral position showing medium sized pda ( patent ductus arteriosus ) the device was chosen to be at least 12 mm larger than the narrowest diameter of the pda . a repeat descending aortogram was done before and after release of device to check for residual shunt and aortic obstruction [ figure 2 ] . ( a ) descending aortogram in lateral position before release of the device showing trivial mesh leak shunt and appropriate device position ( b ) shows release of the device in lateral view ( c ) descending aortogram in lateral position immediately after release of the device showing complete closure of pda and no aortic obstruction all the patients were discharged 1 day after the procedure . all the patients had complete transthoracic echocardiographic studies at 24 hour , 1 , 6 and 12 months and annually thereafter . special attention was paid to residual shunt , left pulmonary stenosis and descending aorta obstruction . endocarditis prophylaxis was discontinued at 6 month follow - up if pda was completely occluded . follow - up of the patients including physical examination and echocardiography were performed at 1 day , 1 , 6 , 12 months and annually thereafter . special attention was paid to residual shunt , left pulmonary artery stenosis and aortic obstruction or any complication . the patients were recommended to take antibiotic endocarditis prophylaxis at least for 6 month or residual shunt was completely disappeared . the patients characteristic and procedure - related data are show in table 1 . the demographic and procedure - related data during the 8.5 year study , a total 260 patients were scheduled to undergo percutaneous closure of pda . seventeen infant patients were excluded from percutaneous closure because of sever congestive heart failure and body weight less than 4.5 kg . of these , 169 ( 69.5% ) were female and 74 ( 30.5% ) were male . median age and weight at the time of the procedure were 2.5 year ( range : 3 months-38 years ) and 10 kg ( range : 4.5 - 85 kg ) . of the total number of patients , 22.6% ( n = 55 ) were infants , 56.8% ( n = 138 ) children and 20.6% ( 50 ) adolescents or adults . the mean sd follow - up was 53.9 25.7 months ( range : 14.5102 month ) . percutaneous closure of pda was performed successfully for 239 of 243 patients ( 98.3% ) . five patients experienced device embolisation immediately in patients and during night in two patients . for three patients , devices were retrieved percutaneously and then a second larger device was successfully implanted . for the other two patients , surgical retrieved and then surgical ligation was performed . one unrelated procedure death occurred 5 days after procedure because of severe aspiration pneumonia during bottle feeding . the patient was a 7-month - old girl with large pda and sub - systemic pulmonary hypertension , congestive heart failure and failure to thrive . immediately after release of the device , descending aortogram showed residual shunt including foaming through the wire mesh of the device in 171 patients ( 70.4% , small residual shunt in 32 patients ( 13% ) and moderate residual shunt in 3 patient ( 1.2% ) patients . on color flow doppler , all trivial and small residual shunting were disappeared at ( the time of discharge , 1 day after pda closure ) and only three moderate shunt continued . at 1-month follow - up , a moderate residual shunt remained at 6 months , 12 months and during follow - up . the patient did not experience worsened aortic obstruction during follow - up . in one child on the next day of the procedure , mild left pulmonary ( lpa ) stenosis with 20 mmhg gradient was observed on transthoracic echocardiographic examination . one the control echocardiography performed 1 month later , pressure gradient across lpa increased from 20 mmhg to 60 mmhg . no other major complications such as late migration of the device , haemolysis , nickel allergy or bacterial endocarditis were detected during follow - up . minor complications related to the procedure such as femoral artery thrombosis ( nine patients ) or blood loss with the need for blood transfusion ( two patients ) , only occurred in infant age - group . heparin ( intravenous continues effusion ) was used successfully in six patients with femoral thrombosis . streptokinase intravenous infusion ( loading does 10,000 iu / kg over 1 hour followed by 10,000 iu / kg for 6 hours ) produced a complete and successful turn of pulse in two patients with mild and asymptomatic groin haematoma . pda is one of the most common congenital heart disease , and various devices are available to close of pda percutaneously.5101112 the ado ( aga medical corporation , golden valley , minnosota ) is one of the commonly used devices.345678911 in 1998 , masure et al . , reported the first clinical trial of percutaneously closure of pda using amplatzer duct occluder . the immediate success rate was 96%.9 in our study , six ( 2.4% ) major complications ( device embolisation in four patient , moderate lpa obstruction in one patient and moderate residual shunt in one other patient ) were noted among 243 patients with pda . one the most significant complication of percutaneously closure of pda is device embolisation.241314151617 the reported rate of the major complication with ado was 2.3% in a multi - centre registry.18 we believe selection of the device with appropriate size is of utmost important . the important concern with most devices is the irretrievability during implantation resulting in the need for catheter or surgical removal of displaced device . a major advantage of ado is that is can be easily retracted in to delivery sheath and re - deployed several time before final release . this greatly reduced the chance of displacement , risk for surgical or percutaneously retrieval of embolisation device and the cost obviating the introduction of a new device.1920 bilkis et al . , described on a large series of 209 patients with a pda closed with ado . complications detected in six cases ( 3 % , ) .15 three experienced device embolisation that required surgery . an infant patient of 5 kg developed mild aortic obstruction after implantation a large device and two other patients needed blood transfusion because of significant blood loss . in several studies , the reported incidence of distal embolisation of ado varies between 0 - 2%.151821 in current study , device embolisation rate was 2% ( n = 5 ) . another common complication of percutaneously amplatzer pda closure is left pulmonary artery ( lpa ) obstruction.3512131819212223 the reported rate of lpa stenosis varies , between 0 - 12%.121624 contrary to pda closure in infants and children , lpa stenosis is not a problem in adult patients . in current study , in one patient , ( 0.4% ) after the deployment of the ado , device was observed to protrude into proximal of lpa , resulting in a pressure gradient of 20 mmhg on doppler echocardiography . the pressure gradient in lpa increased from 20 mmhg to 60 mmhg at 1 month after procedure . several studies reported aortic obstruction after the percutaneous amplatzer pda closure.13151819 in our study , one patient had protrusion of the device in to the descending aorta resulting in a pressure gradient 18 mmhg on doppler echocardiography . on doppler color echocardiography at 6 months and 12 months after procedure obstruction of descending aorta was evaluated . although the device was detected to protrude into descending aorta , pressure gradient decreased from 18 mmhg to 12 mmhg . we speculate that this type of mild aortic obstruction is expected to improve gradually with subsequent growth of the child . other complications such as infective endocarditis , haemolysis , and nickel hypersensitivity after device implantation are rare.13 the complications such as haemolysis infective endocarditis , nickel allergy were not encountered in our series . late complications were more rarely described and only late device embolisation were reported.25 at follow - up ( 8.5 years ) , we have recognised no late complications such as device migration , aortic obstruction , lpa stenosis , haemolysis or recanalisation . based on our findings with the use of the ado , it suggests that this occluder is a promising device for percutaneous closure of pda . device closure was successful in all patients including infants , children , adolescent and adult with pda . percutaneous closure of pda using ado , regardless of patient 's age at the time of the procedure is associated with high efficacy and a low complication rate . although some complications such as device embolisation , left pulmonary artery or aortic obstruction may occur in some patients , we believe that risk of attempting percutaneous closure of pda with ado is overall very low , therefore it should be considered as a primary choice for treating a pda in all age - groups including infants , children and adults .

background : percutaneous closure of patent ductus arteriosus ( pda ) with amplatzer duct occluder ( ado ) has become increasingly popular in many cardiovascular centres . this study analysed the long - term results of percutaneous closure of pda with ado in a single centre.materials and methods : between may 2004 and january 2013 , 243 patients with median age of 2.5 years ( range = 30 months to 38 years ) and median weight of 10 kg ( range 4.580.5 kg ) underwent percutaneous closure of pda using the ado . the devices were implanted under fluoroscopic guidance . patients were followed - up for any complications.results:the mean diameter of narrow part of pda was 6.4 2.2 mm . the mean diameter of devices was 7.8 2.3 mm . the devices were successfully implanted in 239 ( 98.3% ) cases . at immediate , 1 day , 1 , 6 , 12 months and late follow - up , the complete occlusion rate was 33% ( 79 case ) , 97.1% ( 236 case ) , 97.5% ( 237 case ) , 98.3% ( 238 case ) , 98.3% ( 238 case ) and 98.3% ( 238 case ) , respectively . residual shunt remained in one case at late follow - up . the device embolisation occurred in five patients . the devices were successful retrieved in three patient and second larger devices were inserted . two other devices were surgically retrieved and pdas were ligated . moderate left pulmonary artery stenosis ( lpa ) in one child and mild lpa stenosis in one infant were detected . mild aortic obstruction occurred in one infant.conclusions:long-term follow - up of patients indicate that percutaneous closure of pda using ado is a safe and effective procedure . however , some complications , including device embolisation , left pulmonary stenosis and aortic obstruction may be observed in some cases .

conditions such as puberty , pregnancy and menopause have a significant effect on the oral health of women.1 pregnancy is a period of both joy and anxiety in a woman s life and is characterized by various physiological changes in her body brought about by the circulating female sex hormones.2 a number of oral changes are inevitable during pregnancy . immunological , dietary and behavioral factors associated with pregnancy are believed to be contributing factors . pregnant women are particularly susceptible to gingival and periodontal diseases.3 - 5 in addition , they may not experience symptoms until advanced disease stages and therefore unknowingly increase perinatal risk . associated risks include premature birth , low birth weight babies , pre - eclampsia , ulcerations of the gingival tissue , pregnancy granuloma , and tooth erosion . these risks increase in women who smoke , experience nutritional deficiencies or have less frequent visits to the dentist.6 - 8 in recent years , research linking periodontitis to the risk for adverse birth outcomes has resulted in increased interest in the topic of oral health during pregnancy . increased attention has been focused on maternal periodontitis and preterm and low birth weight.9 - 11 several studies have confirmed the association after adjusting for confounding factors . practices such as exposure to radiation,12 intake of certain drugs like tetracycline chlorampenical , aspirin , etc.13,14 and practices like smoking and alcoholism have adverse pregnancy outcome or birth defects . aspirin and diffusional have both been associated with prolonged gestation and labor , anemia , increased bleeding potential and premature closure of the ductus arteriosus of the heart and thus not recommended for pregnant women , even ibuprofen , ketoprofen , and naproxen are contraindicated in the third trimester of pregnancy . the period in which dental treatment should be taken is also of considerable interest to pregnant woman . the achievement of optimal oral health in pregnant women has its own benefits , however in the past it has been hampered by myths surrounding the safety of dental care during pregnancy . many women fail to understand the importance of oral care in pregnancy while others experience barriers to care . most of the mothers are very keen about proper growth and development of their children . any educational program can have a lasting impact on pregnant women to improve their oral health . the available data indicate , moderate to poor knowledge related to oral health and adverse pregnancy outcomes , poor dental attendance and oral health related practices.15 - 19 hence , the present study aims at assessing the knowledge , attitude and practices of pregnant women of bagalkot district . the present study was a cross sectional survey conducted among the pregnant women of bagalkot district . ethical clearance was obtained from institutional ethical committee of pmnm dental college and hospital bagalkot . the subjects were selected from two tertiary care centers , four primary health centers and 12 private nursing homes of bagalkot district over a period of 2 months . the demographic data including socioeconomic status ( ses ) and oral hygiene practices were recorded from each of the pregnant woman . based on the pilot study results , with 31% prevalence of knowledge , 5% permissible error and 95% confidence interval , sample size was estimated to be 332 . the questions were based on knowledge and practices related to pregnancy and oral health , gingival conditions , oral hygiene , utilization of dental health services , habits and use of medications . few of the questions had multiple options based on the positive response for both knowledge and practices . the questionnaire was distributed to pregnant women and asked to complete in front of the investigator . for those who were illiterate each positive response to knowledge and practices was scored as 1 and negative response as zero . the total scores including suboptions were summed up and divided by total number of subjects to obtain the mean value for both knowledge and practices respectively , and percentage is obtained accordingly . the majority ( 152 or 45.8% ) of the participants were in the age group of 20 - 24 years and around 37% were between 25 and 30 years . nearly half of the participants ( 46.7% ) belonged to the urban area , and 24.1% were from semi urban and 29.1% belonged to the rural area . ses showed that the majority of the respondents ( 53.9% ) belonged to upper lower class and 30.4% to upper middle class ( table 1 ) . the mean knowledge level was around 1.36 ( 27.17 % ) ( table 2 ) most of the respondents ( 78.7% ) were not aware that gum diseases are common during pregnancy ( graph 1 ) . most of the respondents ( 84.3% ) were not aware that the first and third trimesters are not so suitable for dental treatment . more than half of the subjects ( 60.16% ) were aware that the intake of certain drugs can affect child s development . proportion of respondents to knowledge and practices . the mean level of practice was 8.9 ( 55% ) ( table 3 ) . nearly one third of study population ( 38.46% ) had perceived signs of dental disease during pregnancy . slightly more than one - third of the subjects ( 42.9% ) had consulted their obstetrician and gynecologist for dental problems , about 40.1% to their dentist and 16.6% had ignored . less than one third of the population ( 27.8% ) had experienced bleeding gums during pregnancy . a small proportion ( 18.6% ) did not brush when they experienced bleeding , 23.9% cleaned using finger , 16.4% used the soft brush and 41.1% consulted the dentist . less than half of respondents ( 44.4% ) were hesitant to brush when they experienced bleeding . more than half of them brush twice daily , 11.2% made use of dental floss , 22.8% used mouth wash and 31% consulted dentist at frequent intervals ( graph 2 ) . around 30.5% , had analgesics for dental pain without prescription of a dentist . there is no significant difference in the knowledge and practices of pregnant women when adjusted for place of residence and socioeconomic class ( tables 4 and 5 ) . there was a partial positive correlation ( r = 0.307 p < 0.05 ) between knowledge and practices ( graph 3 ) . the majority ( 152 or 45.8% ) of the participants were in the age group of 20 - 24 years and around 37% were between 25 and 30 years . nearly half of the participants ( 46.7% ) belonged to the urban area , and 24.1% were from semi urban and 29.1% belonged to the rural area . ses showed that the majority of the respondents ( 53.9% ) belonged to upper lower class and 30.4% to upper middle class ( table 1 ) . the mean knowledge level was around 1.36 ( 27.17 % ) ( table 2 ) most of the respondents ( 78.7% ) were not aware that gum diseases are common during pregnancy ( graph 1 ) . most of the respondents ( 84.3% ) were not aware that the first and third trimesters are not so suitable for dental treatment . more than half of the subjects ( 60.16% ) were aware that the intake of certain drugs can affect child s development . nearly one third of study population ( 38.46% ) had perceived signs of dental disease during pregnancy . slightly more than one - third of the subjects ( 42.9% ) had consulted their obstetrician and gynecologist for dental problems , about 40.1% to their dentist and 16.6% had ignored . less than one third of the population ( 27.8% ) had experienced bleeding gums during pregnancy . a small proportion ( 18.6% ) did not brush when they experienced bleeding , 23.9% cleaned using finger , 16.4% used the soft brush and 41.1% consulted the dentist . less than half of respondents ( 44.4% ) were hesitant to brush when they experienced bleeding . more than half of them brush twice daily , 11.2% made use of dental floss , 22.8% used mouth wash and 31% consulted dentist at frequent intervals ( graph 2 ) . around 30.5% , had analgesics for dental pain without prescription of a dentist . there is no significant difference in the knowledge and practices of pregnant women when adjusted for place of residence and socioeconomic class ( tables 4 and 5 ) . there was a partial positive correlation ( r = 0.307 p < 0.05 ) between knowledge and practices ( graph 3 ) . establishing a healthy oral environment is the most important objective in planning dental care for the pregnant patient . pregnancy is a potential risk condition where many pregnant women yield to dentist advice to safe guard the proper development of their babies . in the present study , majority of the pregnant women were in the age group of 20 - 24 years . education status revealed that 45% of them had high school education and 27% were illiterate . for the majority of them the source of antenatal care was private nursing homes , 25% received care in tertiary care centers . the present study findings have clearly shown that the knowledge of pregnant women about association of oral health and adverse pregnancy outcome was poor . similar results were reported in the study by habashneh et al.20 where knowledge was poor among homogeneous population of relatively high socioeconomic standing . few of the earlier studies have reported that the ses and ethnic background have an impact on the knowledge and practices22,23 and positively influencing the dental seeking behavior but not so in the present study . although the differences were not significant , further studies to assess the precise role of ses and place of residence should be conducted . in the present study , majority of respondents were unaware of gingivitis , safe period for dental treatment and hazards of exposure to high dose of radiation during pregnancy . it is also advisable for pregnant woman to seek dental care during second trimester , as most of the tissues are in the formative period in the first trimester and because of risk of postural hypotension and positional discomfort , in the third trimester dental treatment should be avoided . poor knowledge in the present study can also be attributed for patient being interviewed at varying length of pregnancy . evaluation at the third trimester would have better estimated the knowledge and practices . in the present study despite perceived dental problems , majority of them did not receive any dental treatment during pregnancy . almost a quarter ( 23.5% ) of the women believed that they had periodontal problem while 46.3% reported of having carious teeth . in the study of hashim19 more than 44% reported to the dentist having dental pain , and about 40% women felt that their oral health was poor . about 94% of the women were brushing their teeth at least once a day . more than half of the women ( 58.3% ) visited the dentist during their most recent pregnancy , mostly for dental pain . 96% brushed their teeth at least twice a day and nine out of ten were regular users of the dental - care system.15 however , the data were collected by telephonic survey . the significant increase in dental attendance was attributed to provision of special care to pregnant women . in the study by hullah , majority reported good oral hygiene habits such as brushing their teeth twice a day ( 73.7% ) and using mouthwash ( 51%).17 in the present study , 57.9% said that they were brushing once daily and 36% twice daily . in the present study , nearly 40% of subjects said that they reported to dentists when experience any dental problems and only 17% consulted dentist for treatment . the findings suggest that patients should be encouraged to schedule elective dental treatment during the second trimester but seek prompt care for acute dental problems . less than half of respondents said that they consulted their gynecologist or obstetrician for oral health problems . the findings suggest the need of adequate training of gynecologist or obstetrician for oral diseases during pregnancy and patients should also be encouraged to visit dentist . the number of pregnant women who reported to dentists was relatively less as compared to the study of prams that is 34.7%.24 in the study by honkala,18 nearly half of the women had visited a dentist during pregnancy , mostly for dental pain . . reports of dental care use during pregnancy in other parts of the world also showed similar figures ranging from 27% to 61%.18 - 23 relatively high dental attendance rate of 55% was reported in the study of bamanikar et al . which can be attributed to high response rate when compared to other studies.22 there is serious concern about the dental care seeking behavior of pregnant women in the present study . relatively poor attendance in the present study can be attributed to lack of availability of dental service , fear and misconception associated with dental treatment , perceptions of not having any oral health problems or long waiting time at the clinic etc . the data related to source of payment and dental insurance which significantly influence the dental attendance rate in most of the reported studies has not been assessed , because the mode of payment is predominantly fee for service in india . there are no data to compare the knowledge regarding the use of medication , exposure to radiation and the safe period for dental treatment among pregnant women , which were significantly low in the present study . as these practices have significant adverse post natal effect , further studies should give due attention . one of the limitations of the study was the convenience sampling technique , and hence generalizibity of the present study results should be done with caution . the overall results suggest that knowledge and practices of pregnant women need to be greatly improved . all necessary measures should be taken for maintenance of oral hygiene and to avoid complications with the use of drugs and exposure to radiation . pregnancy is a unique risk condition in terms of poor oral health related practices and its adverse effect on developing fetus . illicit use of medicines and exposure to high dose of radiation , especially in the first trimester further increases the risk . providing oral health education in clinics and advocating affordable oral health services for all pregnant women should be considered . nurses , nurse practitioners , and nurse - midwives should include an assessment of maternal dentition and referral for dental problems as part of their prenatal practice . public policies that support comprehensive dental services for vulnerable women of childbearing age should be expanded .

background : cumulative evidence in the dental literature strongly supports the fact that poor oral hygiene practices and inadequate attention toward oral health during pregnancy have an impact on developing the fetus and significant adverse postnatal effects . available literature suggests that the research is deficit in assessing knowledge and practices related to exposure to radiation , use of medication and safe period for dental treatment during pregnancy . assessing the knowledge and practices among pregnant women could be a valuable tool for policy makers to improve the oral health . to assess knowledge and practices of pregnant woman regarding oral health.materials and methods : this study was a cross sectional survey . a total of 332 samples were selected by convenience sampling technique . a questionnaire containing 14 close - ended questions related to knowledge and practices pertaining to oral health during pregnancy along with sociodemographic data were used for collecting baseline information.results:the overall level of knowledge and practice was 27.17% and 55% , respectively . majority of respondents ( 89.10% ) were not aware that gum diseases are common during pregnancy . most of them ( 73.07% ) were not aware of safe period for undergoing dental treatment during pregnancy . only 19.87% were aware that exposure to high dose of radiation was hazardous to their babies . around 18.6% did not brush when they experienced bleeding , 35.25% cleaned their teeth using finger.conclusion:the overall results suggest that knowledge and practices of pregnant women need to be greatly improved . all necessary measures should be taken for maintenance of oral hygiene and to avoid complications with the use of drugs and exposure to radiation .

b6 mice carrying myd88 and tlr mutations were backcrossed 10 - 12 times to nod / ltj males and intercrossed to produce ko and heterozygous animals . gf animals were re - derived from nod / ltj females impregnated by nod.myd88ko males and kept gf at taconic farms , germantown , ny , the university of chicago and washington university ( st . asf was introduced to gf nod.myd88ko mice by adding cecal contents from donor mice to sterile drinking water . wild - type gf mice were colonized with microbiota from spf nod.myd88ko animals by co - housing gf nod females and newborn progeny with spf myd88.ko females . damage to the islets was scored in a blinded fashion , and graded as follows : 0 no visible infiltration ; i periinsulitis ; ii - insulitis with < 50% and iii with > 50% islet infiltration ( supplemental fig . at least 100 islets in each group of 5 to 12 animals were scored . in microbiota transfer experiments 20 sections per pancreas cut at 40m intervals ( 10 islets / section ) were examined and scored ( combining grades ii and iii ) . 610 splenocytes alone , or 210 lymph node cells mixed with 410 irradiated splenocytes from b6.nod-(d17mit21-d17mit10)/ltj ( b6.g7 ) mice , per well of 96-well plates pretreated with anti - ifn- antibodies were incubated overnight with listed peptides . lymphocytes were stained with antibodies against cd4 and cd8 to calculate the frequency of peptide - specific cells per 10 cd4 or cd8 t cells . 16s rrna gene sequences were edited and assembled into consensus sequences using phred and phrap , aided by xplorseq23 , and bases with a phrap quality score of < 20 were trimmed . sequences were aligned using the nast online alignment tool ( http://greengenes.lbl.gov/cgi-bin/nph-index.cgi ) , and checked for chimeras using the online greengenes server ( http://greengenes.lbl.gov/cgi-bin/nph-bel3_interface.cgi ) with a window size of 300 and using the nast - aligned sequences31 . b6 mice carrying myd88 and tlr mutations were backcrossed 10 - 12 times to nod / ltj males and intercrossed to produce ko and heterozygous animals . gf animals were re - derived from nod / ltj females impregnated by nod.myd88ko males and kept gf at taconic farms , germantown , ny , the university of chicago and washington university ( st . asf was introduced to gf nod.myd88ko mice by adding cecal contents from donor mice to sterile drinking water . wild - type gf mice were colonized with microbiota from spf nod.myd88ko animals by co - housing gf nod females and newborn progeny with spf myd88.ko females . damage to the islets was scored in a blinded fashion , and graded as follows : 0 no visible infiltration ; i periinsulitis ; ii - insulitis with < 50% and iii at least 100 islets in each group of 5 to 12 animals were scored . in microbiota transfer experiments 20 sections per pancreas cut at 40m intervals ( 10 islets / section ) were examined and scored ( combining grades ii and iii ) . 610 splenocytes alone , or 210 lymph node cells mixed with 410 irradiated splenocytes from b6.nod-(d17mit21-d17mit10)/ltj ( b6.g7 ) mice , per well of 96-well plates pretreated with anti - ifn- antibodies were incubated overnight with listed peptides . lymphocytes were stained with antibodies against cd4 and cd8 to calculate the frequency of peptide - specific cells per 10 cd4 or cd8 t cells . 16s rrna gene sequences were edited and assembled into consensus sequences using phred and phrap , aided by xplorseq23 , and bases with a phrap quality score of < 20 were trimmed . sequences were aligned using the nast online alignment tool ( http://greengenes.lbl.gov/cgi-bin/nph-index.cgi ) , and checked for chimeras using the online greengenes server ( http://greengenes.lbl.gov/cgi-bin/nph-bel3_interface.cgi ) with a window size of 300 and using the nast - aligned sequences31 .

type 1 diabetes ( t1d ) is a debilitating autoimmune disease that results from t cell - mediated destruction of insulin - producing cells . its incidence has increased during the past several decades in developed countries 1 , 2 , suggesting that changes in the environment ( including human microbial environment ) may influence disease pathogenesis . the incidence of spontaneous t1d in non - obese diabetic ( nod ) mice can be affected by the microbial environment in the animal housing facility3 or by exposure to microbial stimuli , such as injection with mycobacteria or various microbial products 4,5 . here we show that specific - pathogen free ( spf ) nod mice lacking myd88 protein ( an adaptor for multiple innate immune receptors that recognize microbial stimuli ) do not develop t1d . the effect is dependent on commensal microbes as germ - free ( gf ) myd88-negative nod mice develop robust diabetes , whereas colonization of these gf nod.myd88-negative mice with a defined microbial consortium ( representing bacterial phyla normally present in human gut ) attenuates t1d . we also find that myd88-deficiency changes the composition of the distal gut microbiota , and that exposure to the microbiota of spf nod.myd88-negative donors attenuates t1d in gf nod recipients . together , these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying t1d predisposition .

accessory spleens result from the failure in the fifth week of foetal life of groups of mesodermal cells in the dorsal mesogastrum . they are relatively common , with an autopsy study involving 3000 patients identifying 364 accessory spleens , of which 61 were found in the pancreatic tail . whilst the pancreatic tail and the splenic hilum are the most common sites , accessory spleens can be found in the stomach , jejunum , mesentery as well as the ovaries and testis . despite being common , accessory spleens themselves have no clinical consequence unless a patient suffers from a disease like idiopathic thrombocytopaenic purpura . however , as they are commonly mistaken for tumours , patients undergo needless operations for removing the lesion . consequently , it is important to accurately differentiate an accessory spleen from other pancreatic lesions requiring more aggressive treatment . a 76-year - old male presented to his general practitioner with nausea , weight loss and change in bowel habit . a recent colonoscopy was unremarkable , a computed tomography ( ct ) abdomen and pelvis showed a homogenously enhancing 13-mm lesion in the tail of the pancreas , with the reported differentials including neuroendocrine tumour or a pancreatic adenocarcinoma . a subsequent magnetic resonance imaging ( mri ) illustrated the lesion enhancing homogenously in the portal venous post - contrast phase suggesting a solid neoplastic lesion , likely to be primary ( fig . 1 ) . pathology revealed a splenunculus with no evidence of malignancy ( fig . 2 ) . figure 1:mri : small round lesion in the pancreatic tail measuring 11 cm , enhancing homogenously in the portal venous post - contrast phase suggesting a solid neoplastic lesion . the differential includes primary pancreatic lesion such as a small mucinous cystic pancreatic tumour or an islet cell tumour figure 2:histology of the lesion showing the normal pancreas on the left with the accessory spleen on the right mri : small round lesion in the pancreatic tail measuring 11 cm , enhancing homogenously in the portal venous post - contrast phase suggesting a solid neoplastic lesion . the differential includes primary pancreatic lesion such as a small mucinous cystic pancreatic tumour or an islet cell tumour histology of the lesion showing the normal pancreas on the left with the accessory spleen on the right pancreatic cancer was the fifth leading cause of cancer - related deaths in australia in 2010 . surgery offers the only chance of cure ; however , most patients have unresectable disease at the time of presentation . in potentially resectable disease , the high false - negative biopsy rate of 20% and the potential complications arising from the biopsy generally discourage most surgeons from pre - operative tissue biopsy . because of this mri , ct , ultrasound scan ( uss ) and scintigraphy are all used for this purpose . ultrasound usually shows an accessory spleen as a round , mildly echogenic mass with homogenous texture and posterior enhancement . importantly , doppler uss has a sensitivity of 90% when a vascular hilum entering the lesion is identified . also , inhomogenous enhancement due to the differing flow rates between the red and white pulp of the accessory spleen may indicate splenic tissue . during the other phases , triple - phase ct is usually performed to differentiate pancreatic lesions , and the attenuation of accessory spleens in the pancreas is usually identical to that of the spleen in all three phases . generally , this means that the splenic tissue will be brighter than the normal surrounding pancreatic tissue . in comparison , most pancreatic tumours ( including islet cell tumours ) are brighter on the arterial phase , and lower on the venous phase . pancreatic tumours share signal characteristics with that of the spleen , which makes differentiation difficult . despite this , the fact that the signal intensity ( si ) of accessory spleens is usually identical to that of the spleen can lead to the diagnosis . in rare instances , the si is different due to differing amounts of the red and white pulp in the accessory spleen . another differentiation can be found with the fact that tumours usually contain areas of haemorrhage and necrosis , which is readily demonstrated with mri . scintigraphy using tc-99 m heat - damaged red blood cells ( hdrbcs ) is a highly specific medium used to detect accessory spleen tissue . the technique uses autologous hdrbcs which are converted into rigid spherocytes , injected and then sequestered in the spleen , as well as any functioning accessory splenic tissue . despite this , the sensitivity is poorer than other modalities as it requires a certain amount of functioning splenic tissue . endoscopic ultrasound ( eus ) with fine needle aspirate ( fna ) is increasingly used to characterize both solid and cystic lesions in the pancreas and obtain specimens for pathological diagnosis . there is minimal literature on pre - operative diagnosis of intrapancreatic accessory spleens ( ipas ) with isolated case reports of confirmation on histology and immunohistochemical staining for cd3 and cd20 to distinguish from adenocarcinoma of the pancreas . adequate sampling with confident pathological reporting may result in the avoidance of distal pancreatectomy and also of prolonged surveillance if a modern radiological techniques will lead to an increasing number of ipas identified and this poses a significant diagnostic and treatment challenge . pre - operative diagnosis based on radiological findings can be difficult and aspiration cytology can be misleading . identifying the ipas is very important as it can mimic either primary or secondary lesions of the pancreas which may result in an unnecessary operation with the involved risks entailed . in our case , emerging imaging modalities may have resulted in an operation being avoided with confident radiological / cytological diagnosis . emerging techniques such as eus with fna may provide confident diagnosis of ipas ; however , equivocal pathological findings will continue to lead to unavoidable operations for ipas .

intrapancreatic accessory spleens are common asymptomatic masses that generally cause no problems . usually , they are incidentally found on imaging as a pancreatic mass and they pose a diagnostic and management dilemma due to equivocal imaging findings . evolving imaging modalities and increasing use of endoscopic ultrasound with fine needle aspirate may result in the avoidance of unnecessary operations and surveillance . we report a case of distal pancreatectomy and splenectomy for a pancreatic tail solid lesion .

ganglioneuroma ( gn ) is a rare benign tumor that originates from neural crest cells of sympathetic ganglia or adrenal medulla , and usually occur in the retroperitoneum ( especially presacral space ) , posterior mediastinum , or adrenal gland , and occasionally in unusual locations.1,3,6,8 ) we report a giant paraspinal gn extending into extradural space and thoracic cavity . a 12-year - old girl presented with a one month history of sudden onset chest tightness and gradually increasing lower extremity weakness . , she was unable to stand or walk without support . a firm paraspinal mass measuring 121212 cm was seen at the upper thoracic vertebral level . magnetic resonance imaging showed a long intradural extramedullary tumor , extending from t1 to t4 levels . the tumor extended through the left t2/3 , t3/4 neural foramen into the left thoracic cavity . the lesion was mildly hypo - intense on t1-weighted imaging , and heterogeneously hyper - intense on t2 weighted imaging ( fig . a two - step surgical intervention was planned considering that a single stage surgery is potentially more complex , takes longer time , results in more bleeding , and is usually performed in younger patient . the prognosis was explained to her parents . after performing the left hemilaminectomy with cavitron ultrasonic surgical aspirator ( cusa ) and opening the dura from t1 to t4 levels , the cord was found to be severely compressed by the intradural tumor , which was totally resected under the microscope during surgery under careful neurophysiological monitoring which showed no obvious abnormalities . two weeks later , a second resection was performed to remove the tumor infiltrating into the thoracic cavity . the tumor was found connected to the nerve roots , and had involved the pleura at left cupula . subtotal resection for the foraminal portions was performed , and the left c3 nerve root was preserved . macroscopically , the tumor was smooth and well - encapsulated . on serial slicing , the tumor was firm and homogenous in appearance with no areas of hemorrhage , necrosis , or any signs of degeneration . microscopically , the tumor was composed of mature ganglion cells , surrounded by schwann cells in a fibrillary background . on immunohistochemical evaluation , the tumor cells were positive s-100 protein and neuron specific enolase , and the ki-67 proliferation index was less than 1% ( fig . the patient had an uneventful recovery in a one - year follow - up period . after performing the left hemilaminectomy with cavitron ultrasonic surgical aspirator ( cusa ) and opening the dura from t1 to t4 levels , the cord was found to be severely compressed by the intradural tumor , which was totally resected under the microscope during surgery under careful neurophysiological monitoring which showed no obvious abnormalities . two weeks later , a second resection was performed to remove the tumor infiltrating into the thoracic cavity . the tumor was found connected to the nerve roots , and had involved the pleura at left cupula . subtotal resection for the foraminal portions was performed , and the left c3 nerve root was preserved . the tumor was firm and homogenous in appearance with no areas of hemorrhage , necrosis , or any signs of degeneration . microscopically , the tumor was composed of mature ganglion cells , surrounded by schwann cells in a fibrillary background . on immunohistochemical evaluation , the tumor cells were positive s-100 protein and neuron specific enolase , and the ki-67 proliferation index was less than 1% ( fig . postoperative chest computed tomography confirmed volume reduction of tumor . the patient had an uneventful recovery in a one - year follow - up period . most gns are incidentally detected , and the symptoms , if any , are usually due to the mass effect . as this slow growing tumor extends through the neural foramen into the spinal cord , some patients may present with neurological deficits or scoliosis2 ) . thoracic intradural extramedullary gns are very rare , with only six cases reported so far to the best of our knowledge ( table 1 ) . in our patient , the characteristic feature was the remarkably large tumor size infiltrating into the thoracic cavity along with an intradural component . microscopically , these tumors contain large ganglion cells and show areas with smaller lymphocyte - like cells within a matrix of fibrous stroma and schwann cells . the distinction from malignant tumor is based on the absence of necrosis or presence of any immature ganglion cells7 ) . however , in case of multiple and/or large - sized tumors , multi - stage dissection should be considered . in the present case , there were dense adhesions of the tumor with the nerve roots at the foraminal portions , which were left undisturbed during dissection . this report describes a rare case of multiple gns of the thoracic spine with intradural extension . although complete surgical resection is the best treatment option , stage - wise surgical resection should be considered in large - sized and/or multiple tumors , with close follow up .

ganglioneuroma ( gn ) is a rare benign tumor of neural crest origin usually found in the abdomen , but may occasionally present at uncommon sites including the cervical , lumbar , or sacral spine . however , gns of thoracic spine are extremely rare . in this report , we describe a 12-year - old girl with giant gn in the thoracic spine , who underwent successful resection ( t14 level ) of the tumor . histopathological examination confirmed the diagnosis . gn should be considered in the differential diagnosis of any paraspinal mass . a high index of suspicion and correlation of clinico - radiological findings is necessary in differentiating a large benign tumor from a malignant growth . complete surgical excision is the treatment of choice ; however tumor size and location need to be considered for the surgical approach ( one - step or multiple surgeries ) . close follow - up after surgery is mandatory .

oral submucous fibrosis ( osmf ) is a fibrotic condition of the oral cavity and is always associated with chronic epithelial inflammation and progressive deposition of collagenous extracellular matrix ( ecm ) proteins in the subepithelial layer of the buccal mucosa . the disease is seen in those from indian subcontinent and from many parts of south - east asia such as taiwan . numerous etiologies have been suggested for the pathogenesis of this condition that include consumption of chillies , nutritional deficiency , chewing of arecanut , genetic susceptibility , altered salivary constituents , autoimmunity and collagen disorders . the cytotoxic effects of the chewing tobacco including pan masalas are mediated through the production of the reactive oxygen species ( ros ) . ros induced lipid peroxidation causes a loss of cell homeostasis by modifying the structure and functions of cell membrane . the most important characteristic of lipid peroxidation is to cause a considerable deoxyribose - nucleic acid malondialdehyde ( dna - mda ) adducts by interacting with cellular dna . we conducted a study to determine the levels of serum , salivary and tissue mda in patients with osmf . the influence of dietary pattern and habit frequency on the level of mda has also been investigated . eighty - six patients between the age range of 20 and 40 years , reporting to the department of oral medicine and radiology in a dental college in south india were enrolled into the study . the study subjects included 65 histopathologically confirmed cases of osmf and 21 age and sex matched healthy controls who required to undergo frenectomy or operculectomy . a detailed case history which included diet pattern and habit index was taken from each subject in the study . subjects with any other long - term systemic illness and long term medication were excluded from the study . five milliliter of unstimulated saliva was obtained by spit method after following standard precollection protocol . five milliliter of venous blood was obtained from the antecubital vein , centifudged and stored . tissue obtained during frenectomy , operculectomy from healthy controls and sectioned biopsy specimens from the osmf patients were dissolved by the nitric acid method . the malonaldehyde content of the dissolved tissue , serum and saliva of the study subjects were evaluated by the tbars procedure and sphectrophotometrically determined . of the 65 subjects in the control group , 22 , 20 , and 23 were categorized under grade 1 , 2 , and 3 , respectively [ figures 1a c ] after histopathological examination . the mean serum , salivary , and tissue malondialdehyde level of control group was significantly lower ( p<0.001 ) than the cases [ table 1 ] . increased levels of serum and salivary malondiadehyde was observed in all three study groups as the grading progressed but tissue malondialdehyde levels were lower in grade 3 osmf ( 0.02440.01043 nmol / mg ) compared to controls ( 0.02550.00593 nmol / mg ) . there was positive correlation between serum and salivary mda levels , in case and control groups but negative correlation between serum mda when compared to tissue levels . salivary mda had no significant correlation with tissue levels in case and control groups [ table 2 ] . there was no significant difference between the frequency of habits ( gutka chewing ) and mean serum , salivary , and tissue levels of mda . no significant difference was observed in diet pattern ( predominantly vegetarian / nonvegetarian ) between cases and controls . when intercomparison of the diet status was done among the groups , ( a ) photomicrograph ( 40 ) showing loose thin and thick fibers ; ( b ) photomicrograph ( 40 ) showing loose thin or thick fibers with partial hyalinization ; ( c ) photomicrograph ( 40 ) showing complete hyalinization comparion of malonaldehyde levels between cases and controls ( student 's unpaired t - test ) correlation of serum , salivary , and tissue levels in cases and control intergroup comparison of diet pattern so far studies have been conducted on serum and salivary levels of lipid peroxidation end product malondialdehyde in cancer and precancerous conditions . most of the studies report of increase in the levels of mda in oral cancer and osmf.[810 ] similar observations were reported in our study . a study were subjects were graded according to the classification by bhat and dholakia revealed significant elevation in serum mda levels as grading progressed . we have also analyzed the tissue levels of mda in different histopathological grades of osmf ( based on grading proposed by kiran et al . ) . tissue levels of mda were consistently higher in grade 1 and grade 2 osmf when compared to controls . elevated tissue mda levels have been observed in experimental animals when exposed to cigarette smoke and ischemic conditions . significantly higher levels of tissue mda were detected in tumor tissues of breast cancer patients . it has been shown by an amino acid analysis that malonaldehyde reacts in a significant way on lysine and tyrosine residues . we used nitric acid dissolution method for tissue dissolution and thiobarbutric acid method ( tbars ) for evaluation of malondialdehyde . similar nitric acid dissolution method was used for determination of tissue malondialdehyde in zinc deficient rats . we also investigated the dietary pattern and habit frequency of the subjects ; however , no relevant information was obtained . the decreased levels of tissue mda in the advanced histopathological grades of osmf could be probably due its utilization in pro - fibroblastic and collagen cross linking activities . however this finding requires further research which will enhance current knowledge about pathogenesis and progression of osmf .

background : oral submucous fibrosis is one of the most commonly occurring potentially malignant disorders in the south - east asia . levels of lipid peroxidation product malondialdehyde have been recently correlated with clinical grades of oral submucous fibrosis.aims:the aims of this study were to estimate the levels of malondialdehyde in serum , saliva and tissue in patients with oral submucous fibrosis , to correlate change in levels of malodialdehyde with the histopathological grading.materials and methods : the study group comprised of 65 clinically diagnosed and histopathologically confirmed cases of oral submucous fibrosis , 21 age and sex matched controls were also enrolled into the study . the serum saliva and tissue samples in the study groups were evaluated by the thiobarbutric acid reactive substances.results:there was a significant difference between the serum and salivary malondialdehyde among the histopathological grades of oral submucous fibrosis . tissue malonaldehyde levels were significantly higher as the grading progressed but tissue levels in grade 3 oral submucous fibrosis were lower than the controls.conclusion:this decrease in tissue malonaldehyde could possibly be associated to collagen cross linking occurring during the advanced stages of oral submucous fibrosis .

elevated serum alkaline phosphatase ( alp ) level is an essential marker for the diagnosis of vitamin d deficiency ( 1 ) . some cases of vitamin d deficiency are diagnosed accidentally on the basis of elevated alp levels . therefore , cases without high alp may be excluded from a diagnosis of vitamin d deficiency . hypophosphatasia is a congenital skeletal disease caused by mutation of the alpl gene , which encodes the alp isozyme , tissue - nonspecific alkaline phosphatase ( tnsalp ) ( 2 ) . hypophosphatasia is characterized by severe reduction of alp as well as various skeletal abnormalities such as rickets . since most cases are transmitted as an autosomal recessive trait , those heterozygous for alpl mutation are carriers who exhibit a low or normal alp level ( 3 ) . here , we describe a case of vitamin d deficiency without an elevated alp level in a patient that proved to be a heterozygous carrier of hypophosphatasia . a 1-year - old japanese girl was referred to our hospital for the evaluation of genu varum . she had no history of bone fractures . at her initial visit , her serum intact pth level was elevated ( 273 pg / ml , normal range : 1065 pg / ml ) while her serum alp , calcium , and inorganic phosphate levels were normal ( 527 u / l , normal range : 3951289 u / l ; 9.5 mg / dl , normal range : 8.810.6 mg / dl ; 5.9 mg / dl , normal range : 3.86.2 mg / dl , respectively ) . her percentage of tubular reabsorption of phosphate ( % trp ) was elevated ( 96.9% , normal range : 8095% ) . her urine calcium / creatinine level was reduced ( 0.019 , normal range : 0.0350.80 ) , and her urine cross - linked n - telopeptide of type i collagen ( ntx ) level was 1340 nmol bce / mmol creatinine ( normal range : 3692385 nmol bce / mmol creatinine ) . additional measurement of serum 25-hydoxyvitamin d ( 25-ohd ) was not performed , because of normal serum alp levels . on limb radiography , calcification of epiphyses was detected , and both flaring and fraying of metaphyses were also detected slightly ( fig . therefore , the patient was initially diagnosed with spontaneously half - healed vitamin d deficiency rickets and was followed closely without treatment . however , 3 months later , her serum intact pth level remained elevated and serum 25-ohd level was reduced ( 6 ng / ml , normal range : 20100 ng / ml ) . the patient was subsequently diagnosed with vitamin d deficiency . the serum intact pth level improved immediately after initiation of alfacalcidol administration and has not been elevated since the end of treatment . in addition , her serum alp level decreased gradually ( table 1table 1 laboratory data ) . the metaphyses were flared and frayed slightly . although these courses of treatment support the diagnosis of vitamin d deficiency , the relatively low alp level was atypical . low serum zinc level , which is one of the causes of reduced alp level , was not identified ( 71 g / dl , normal range : 64118 g / dl ) . mild elevation of the urine phosphoethanolamine ( pea ) level ( 279.1 mol / g creatinine , normal range : 83222 mol / g creatinine ) suggested hypophosphatasia ( 4 ) . genomic dna was extracted from peripheral blood leukocytes of the patient and her parents after obtaining written informed consent . all coding exons and flanking introns of alpl were analyzed using the pcr direct sequencing method . an alpl heterozygous mutation , c.1559delt , was detected in the patient and her father ( fig . black dots indicate heterozygous alpl carriers ( c.1559delt ) . ) , but no mutation was detected in her mother . the serum alp level of her father was mildly reduced ( 84 u / l , normal range : 96284 u / l ) and that of her mother was normal ( 180 u / l ) . this is the first report of vitamin d deficiency without an elevated serum alp level in a carrier of hypophosphatasia . vitamin d deficiency is reemerging worldwide ( 5 ) , and elevated serum alp is a hallmark of this disease ( 1 ) . vitamin d deficiency may fail to be diagnosed if serum alp is not elevated . however , simultaneous measurement of the serum intact pth level is helpful for diagnosis . measurement of urine pea was useful for the diagnosis of hypophosphatasia in the present case . while severe elevation of the urine pea level ( approximately > 1000 mol / g creatinine in childhood ) is detected in patients with hypophosphatasia , mild elevation suggests carrier status of this disease ( 3 ) . the alpl mutation c.1559delt is the most common mutation in japanese patients with hypophosphatasia ( 6 ) . a homozygous c.1559delt mutation is involved in the perinatal lethal form of hypophosphatasia with a severe reduction in serum alp ( 6 ) . the heterozygous mutation is found in carriers who present various levels ( either low or normal ) of serum alp without skeletal abnormality ( 3 ) . furthermore , urine pea levels also range from normal to high in such individuals ( 3 ) . the frequency of carriers is predicted to be high ( 1/480 ) ( 3 ) . since vitamin d deficiency is reemerging , the present case should be kept in mind , as the possibility of such conditions occurring more frequently is high . vitamin d deficiency rickets was reported to be associated with the infantile form of hypophosphatasia in a 9-month - old boy ( 7 ) . in that report , although the serum alp level increased from 66 u / l at baseline to 400 u / l at diagnosis , it decreased soon after treatment . on the other hand , the present case was considered to be mild vitamin d deficiency because of the mild elevation of serum alp level and lack of clinical findings of active rickets . in conclusion , an alpl heterozygous mutation was detected in a patient with vitamin d deficiency without an elevated serum alp level . measurement of serum intact pth and urine pea levels is helpful for diagnosing vitamin d deficiency and identifying carriers of hypophosphatasia , respectively .

elevated serum alkaline phosphatase ( alp ) is a screening marker for the diagnosis of vitamin d deficiency , which may fail to be diagnosed if serum alp is not elevated . here , we describe a case of vitamin d deficiency without elevation of serum alp . a 1-year - old japanese girl was referred to our hospital for the evaluation of genu varum . her serum intact pth level was elevated , while her serum alp level was normal . furthermore , her serum 25-hydroxyvitamin d level was reduced , and her urine phosphoethanolamine ( pea ) level was mildly elevated . alpl gene analysis revealed she was a heterozygous carrier of hypophosphatasia ( c.1559delt ) . serum intact pth and urine pea evaluations were helpful for diagnosing vitamin d deficiency and hypophosphatasia carrier status , respectively . therefore , the possibility of vitamin d deficiency without elevation of serum alp should be considered .

an otherwise healthy mother had a routine ultrasound at 20 weeks , which showed giant omphalocele with liver included in the omphalocele sac . karyotyping of the amniotic fluid cells showed a normal female karyotype ( 46 , xx ) , -fetoprotein ( afp ) in amniotic fluid was raised ( 38.7 mg / l ; 3 mom = 20.1 mg / l).these findings were discussed with the parents and it was decided to continue the pregnancy . the baby was born at 38 weeks and 2 days of gestation by elective cesarean delivery . the birth weight was 3,500 g and apgar scores were 8/9 at 1 and 5 minutes , respectively . the omphalocele contained a big part of the liver , almost the whole bowel , and the spleen . the omphalocele was covered with a sterile petrolatum ( vaseline , smith & nephew , kruisweg , hoofddorp , netherlands ) gauze dressing , which was changed every other day . the baby expelled meconium shortly after birth and also upon arrival in the neonatal intensive care unit . feeding was started via nasogastric tube and was well tolerated during the first days of life . on the 6th day after birth , , we resected the omphalocele sac ( which was vulnerable by manipulation ) and performed adhesiolysis to appropriately position the spleen and bowel in the abdominal cavity . the liver remained outside the abdominal cavity . a silo bag ( sb06 , 60-mm ; medicina ltd . , bolton , united kingdom ) was used to temporarily cover the defect and central venous access was obtained in the left subclavian vein ( supplementary fig . the biggest silo bag available ( 60-mm ) was not big enough to accommodate the liver and was therefore enlarged by attaching a triangular patch made of silastic mesh . because the use of a silo is not optimal for treatment when the liver is situated outside the abdominal cavity , alternative treatment approaches had to be considered . on the 14th day after birth , we removed the silo and placed non cross - linked intact porcine - derived acellular dermal matrix ( padm ; strattice reconstructive tissue matrix , lifecell corp . , branchburg , new jersey , united states ) at the fascia and sutured it with prolene 30 sutures ( ethicon , somerville , new jersey , united states ) ( fig . 1 ) . a vacuum dressing system was used to cover the padm with a negative pressure of 75 mm hg ( supplementary fig . the vacuum system was changed in the operation theater on postoperative days 3 ( supplementary fig . s3 in the online version of the article ) , 9 , and 12 and on the pediatric ward thereafter . amoxicillin / potassium clavulanate and gentamicin were initiated for prophylaxis against infection and then changed to meropenem . s4 in the online version of the article ) . completed suturing of the fascia to the porcine - derived acellular dermal matrix ( 14th day after birth ) . on the 26th day of life , the patient developed sepsis from the central venous catheter infection . central venous system blood cultures were positive and the patient experienced nephritis and renal insufficiency that subsided spontaneously . enteral feeding was suspended during the sepsis ; however , the patient was tolerating full enteral nutrition by 45 days postnatal age . on the 41st day of life the result of the postnatal array - cgh ( agilent technologies , santa clara , california , united states ) was returned , it showed a maternally inherited 780 kb deletion on chromosome band 3q28 containing part of the tp63 gene , and four more genes that cause autosomal recessive syndromes . the patient was discharged home at age 2 months and 10 days with the vacuum therapy , which was discontinued 1 week later . after removing the vacuum therapy , the patient was bathed daily by her parents and had a sterile petrolatum gauze dressing in place until the wound closed completely ( supplementary fig . ventral hernia repair was performed when the patient was 2 years and 3 months old ( supplementary fig . the padm had become integrated into the surrounding fascia and was used to close the abdominal wall ( supplementary fig . a sample of this padm taken during ventral hernia repair was sent for histological examination . s8 in the online version of the article ) and experienced no complications through 6 months of follow - up ( fig . omphaloceles are often associated with other malformations and chromosomal anomalies.1 2 the small chromosome 3 deletion in this case ( 1 ) is to our best knowledge ( based on queries in pubmed database and decipher database ) not known to be associated with omphalocele , ( 2 ) contains no genes explicitly associated with omphalocele,3 and ( 3 ) was inherited from a healthy mother.4 therefore , this deletion was considered to be most likely of neutral effect . the raised amniotic fluid afp was associated with the omphalocele.5 giant omphaloceles are not common , which makes it difficult for a single pediatric surgery department to gain extensive treatment experience . furthermore , most of the very large omphaloceles can be treated conservatively with sterile petrolatum dressing until the epithelialization of the defect results in a large ventral hernia that can be subsequently closed when there is adequate space in the abdominal cavity . in cases where the omphalocele sac has to be removed or when a rupture occurs the use of a combination of a biological matrix graft and vacuum therapy for treating abdominal wall defects has been previously reported in the medical literature6 7 8 ; however , the use of padm for this purpose has not yet been described in our knowledge . strattice is a non cross - linked porcine , acellular dermal matrix for use in xenograft transplantation , serving as a biological scaffold to support tissue regeneration.9 10 it is derived from porcine dermis and processed in a manner to remove the cells and porcine antigens which would provoke an immune response in humans , while retaining all its extracellular matrix ( ecm ) components , its three - dimensional structure and its biomechanical strength . as such when implanted , it acts as a scaffold to support tissue ingrowth . its ecm components attract in cells and vascularity from the patients adjacent tissue , and over time it is replaced by the patients ' own tissue with all components of the porcine matrix removed , in a regenerative tissue healing process.11 12 in this patient , the use of padm was successful and showed good long - term biological compatibility , as the histological examination of the collagen showed no difference with the human collagen 2 years after suturing the patch to the fascia ( supplementary fig . the microscopic examination showed dissections of tissue fragments , irregular collagen bundles containing numerous small vessels , and signs of very mild chronic infection . based on the histology examination , it was not possible to determine if the sample consisted of porcine collagen tissue or human collagen , even after applying sirius red and verhoeff van gieson staining . the padm became integrated with the fascia and was strong enough to be partially used to strengthen closure of the abdominal wall defect . however , management can be challenging if the omphalocele is ruptured or the sac has to be removed . we present padm with vacuum therapy as a good alternative in the treatment of giant complicated omphaloceles .

the management of giant omphaloceles at our department is primarily conservative . however , management can be challenging if the omphalocele is ruptured or the sac has to be removed . we report a case in which a giant omphalocele in a newborn female patient was managed by covering the abdominal defect with non cross - linked intact porcine - derived acellular dermal matrix ( strattice reconstructive tissue matrix , lifecell corp . , branchburg , new jersey , united states ) sutured to the fascia combined with vacuum therapy .

direct digital imaging continues to gain acceptance in dentistry . however , all the commercial systems currently available have , as a limitation , inferior spatial resolution compared to radiographic film . the spatial resolution has been reported to vary from 6 to 10 line pairs per millimeter ( lp / mm ) depending on the system , whereas film is up to 20 lp / mm.1 , 2the effect of resolution on observer performance is equivocal . in a recent study that used simulated enamel lesions , it was reported that film outperformed a photostimulable phosphor ( psp ) digital system.the video display used for picture archiving and communication systems ( pacs ) in the medical radiography field has been reported to be the weak link of the system . factors which determine monitor fidelity , i.e. accuracy of reproduction , include monitor resolution ( number of vertical lines , bandwidth , and refresh rate ) , bit depth , dot pitch , luminance , and display size . in addition to monitor fidelity , observer performances may also be limited by the resolving power of the human visual system . it has been reported that the minimum contrast threshold of the human eye corresponds to a spatial frequency of 5 lp / cm ( a 1 mm wide line paired with a 1 mm wide space ) which would correlate to a monitor pixel size of about 1 mm . most current cathode ray tube ( crt ) displays used with dental direct digital imaging systems have a pixel size of 0.3 mm , and the eye has been reported to become less sensitive to pixel sizes smaller or larger than 1 mm . for digital systems , most commercially available monitors have resolutions ( pixel matrix size ) of 1024768 , but some high performance monitors are available that have pixel matrices as high as 20482048.most gray - scale monitors commonly used with dental digital imaging systems have a maximal luminance that ranges from 86 cd / m to 240 cd / m , compared with 1542 cd / m to 1713 cd / m for typical film view boxes.background luminance levels may influence observer s ability to distinguish fine details and just noticeable differences on the display screen.6 , 7 cederberg studied influence of crt monitors in observer performance at caries detection and found that results were not statistically significant . in another study , cederberg et al studied the effect of different background lighting conditions on diagnostic performance of digital and film images in which bitewing exposures were made with d and e - speed films and psp plates . significant differences were found between observers , lesion size , and image receptor but no significant difference was found with background lighting . in the present study , we assess the influence of the display monitor on observer performance on caries detection . artificial lesions confined to enamel were created on 27 approximal surfaces of 40 caries - free ( as determined by visual inspection ) extracted human teeth using either a 1/2 round ( 0.5 mm diameter ) or a 1/4 round ( 0.2 mm in diameter ) bur and sinking the head of the bur to the junction of the neck . teeth were mounted in groups of eight in five stone blocks to simulate a hemidentition . the x - ray source was a planmeca operated at 70 kvp and 8 ma ( planmeca ) . 3-mm thick of plexiglass sheets were placed between the object and tube to act as a scattering medium.each of the five blocks was imaged with a xcp instrument to obtain images with paralleling techniques . tree oral radiologists scored each of the five images displayed on four different monitors : ( 1 ) lg flatron 700p ( lg electronics corp . , south korea ) ; ( 2 ) samsung magicgreen ( samsung electronics corp . , south korea ) ; ( 3 ) hansol 710p ( hansol electronics corp . , south korea ) and ( 4 ) toshiba satellite laptop ( toshiba computer corp . , philippines ) . each image was scored for the presence or absence of approximal lesions on a five - point scale : 1= definitely present ; 2= probably present ; 3= can not tell ; 4= probably not present ; 5= definitely not present . observers were instructed to adjust density , contrast and magnification of digital images to their preference . all images were viewed using the adobe photoshop 7.0 software ( adobe , usa ) . the mean score for the five blocks was used to construct roc curves for each monitor type . data was subjected to repeated measures analysis of variance ( anova ) to test for differences between observers , lesion size , examiner / monitor interaction and examiner / block interaction . ordinal logistic regression was used to estimate the extent to which the monitor affected the odds of detecting 1/2 and 1/4 round lesions . the absolute value of the difference between observer score ( 1 - 5 ) and whether a lesion was present ( 1 ) or absent ( 5 ) on each surface was used as the outcome ( dependent ) variable . higher scores indicated greater degrees of disagreement ( i.e. error ) on the part of the observer . odds ratios were calculated for differences in monitor , lesion size , and lesion size / monitor interaction . the mean roc curve areas ( az ) for the four monitors were as follow : lg=0.87 , toshiba=0.85 , hansol=0.84 and samsung=0.83 ( figure 1 ) . no difference was found between monitors . the results of the ordinal logistic regression to estimate odds ratios for lesion size and monitor are shown in table 2 . observers were one - third as likely ( or=0.334 ) to detect quarter - round lesions compared with detecting no lesion or half - round lesions ; less than one - half as likely ( or= 0.474 ) to detect a half - round lesion compared with detecting no lesion ; and approximately 70% more likely to detect half - round than a quarter - round lesion . the odds ratios for the monitors were not statistically different from unity , the value under the null hypothesis . the display and manipulation of digital images on a computer monitor is an essential element of computed radiography . the quality of an image is a function of the physical parameters of the system . the image sensor , computer hardware and software and external factors such as extraneous light and screen reflection , as well as the inherent limitations of the human visual system , all influence image quality . this study was designed to determine whether monitors with a relatively superior fidelity could enhance observer performance . the four monitors tested in this study were chosen as a cross section of those commercially available monitors that would likely be used with dental direct digital imaging systems . spatial resolution , screen size , bit depth , dot pitch and luminance are characteristics of monitors which may affect image quality . the spatial resolution of a monitor is most often expressed in terms of the size of the pixel matrix . high performance monitors are available with pixel matrices as high as 20482048 . however , the resolvable pixel matrix of such monitors is considerably smaller . commonly used monitors available for most computer systems have a nominal resolution ranging from 640480 to 16001200 . size of the monitor screen as well as type and memory size of the video card define or limit a monitor s resolution . monitors with a bit depth of 16 will be capable of displaying 65000 colors , but for radiographic images , gray levels are limited to 256 . wenzel found that indirectly acquired digital images displayed at a spatial resolution of 512512 and 64 shades of gray was equal to , or in some cases more accurate than , the original radiograph for the detection of bone lesions . the four monitors used in this study had almost the same resolution and gray scale display which was adequate for valid diagnosis , and as expected , did not influence the results of this study . dot pitch is a factor that has an influence on image quality , but only when the difference between two monitors is significant . difference of 0.01 for the monitors in this study is probably not perceptible considering the diagnostic task in question . modulation transfer function ( mtf ) measures the combined effects of sharpness and resolution . in practical terms , the ability of the display monitor to reproduce fine detail in an image depends less on the luminance it produces than on the mtf , fidelity with which the signal is recorded and the level of image noise . brettle et al found that psp systems were limited to a resolution between 6.3 and 7.1 lp / mm . the mtf of e - speed film is superior to that of psp systems at high spatial frequencies . it has been reported that larger simulated lesions are easier to detect than smaller ones . likewise , this study found that observers were 70% more likely to detect 1/2 round lesions compared with 1/4 round lesions . this difference in detection rates may be attributable in part to the differences in contrast seen with simulated lesions compared with natural caries . a wide variety of choices are available to the practitioner when deciding on computer hardware for the dental office . this study suggests that observer performance is independent of the visual characteristics of the display monitor . in this study , the type and fidelity of the monitor used with a direct digital imaging system did not alter observers diagnostic ability .

background and aims digital imaging continues to gain acceptance in dentistry and video display used for this becomes important . the aim of this study was to assess the influence of the display monitor on observer performance on caries detection . materials and methods artificial enamel lesions were created in 40 extracted teeth at random using 1/4 and 1/2 round burs . teeth were mounted in dental stone blocks to simulate a hemi - dentition . approximate exposures were recorded at 70 kvp using a planmeca ( planmeca co , helsinki , finland ) digital imaging system . three oral and maxillofacial radiologists rated each image on a five - point scale for the presence or absence of lesion . radiographic images were viewed on the following monitors : ( 1 ) lg flatron 700p ( lg electronics co. , south korea ) ; ( 2 ) samsung magicgreen ( samsung electronics corp . , south korea ) ; ( 3 ) hansol 710p ( hansol electronics corp . , south korea ) and ( 4 ) toshiba satellite laptop ( toshiba computer corp . , philippines ) . examiners were allowed to magnify and adjust density and contrast of each image at will . receiver operating characteristic ( roc ) analysis was performed . data was subjected to repeated measures analysis of variance and ordinal logistic regression to test for significance between variables and to determine odds ratios . results mean roc curve areas ranged from 0.8728 for the lg monitor to 0.8395 for the samsung . repeated measures analysis of variance showed significant differences between observers ( p<0.0001 ) , lesion size ( p<0.0001 ) , examiner / monitor interaction ( p<0.033 ) and examiner / block interaction ( p<0.013 ) . however , no significant difference was found between monitors . conclusion this study suggests that observer performance is independent of the visual characteristics of the display monitor .

the aetiology is unknown , but it has been associated in patients with allergies and atopy . patients commonly present with urinary frequency , dysuria , haematuria , and suprapubic pain which may lead to a diagnosis of a urinary tract infection . on cystoscopy , raised velvety , polypoid , oedematous lesions are usually noted , , , but to confirm diagnosis , a biopsy is required . in this case , a patient with haematuria is diagnosed with eosinohpilic cystitis after presenting to hospital . prior to this he was treated with antibiotics for a presumed urinary tract infection with no resolution of haematuria . a 73-year - old male presented to hospital with a one day history of haematuria , dysuria , and frequency . this was his first occurrence of haematuria and he was treated with antibiotics by his general practitioner for a presumed urinary tract infection . on examination he was afebrile , and haemodynamically stable . blood tests showed an elevated c - reactive protein of 121 mg / l ( normal range < 5 computed tomography ( ct ) intravenous pyelogram showed a thickened bladder wall with no focal lesion . there was small amount of stranding at the distal left ureter , and the prostate was not significantly enlarged . the bladder biopsies showed lamina propria with moderate inflammatory infiltrate rich in eosinophils and some lymphocytes suggestive of eosinophilic cystitis . post - operative recovery was unremarkable , and after consultations with the immunology team , he was commenced on prednisone . follow up four weeks later the patient was well with no further episodes of haematuria . eosinophilic cystitis is a relatively rare inflammatory condition of the bladder first reported by brown and palubinskas in 1960 , . it is more common in adults , affecting men and women equally , however in children there is a slight male predominance . the aetiology is unknown , but eosinophilic cystitis has been associated in patients with allergies and atopy . charcot - leyden crystals , which are often encountered with other eosinophilic disorders and asthma , have also been reported . an underlying dysfunction of the immune system has also been suggested due to reported cases of eosinophilic cystitis in patients with celiac disease . in this study by popescu et al . they also found further associations with lupus anticoagulant , bk virus , and antibacterial and proteus mirabilis infections . as shown by this case , eosinophilic cystitis commonly presents with urinary frequency , dysuria , haematuria , and suprapubic pain . less commonly there may be nocturia and urinary retention , with the latter being more frequently reported in women and children . non - genitourinary symptoms , although rare , include gastrointestinal symptoms ( vomiting , diarrhoea ) , and skin rashes , . physical examination , which is usually unremarkable , may find suprapubic tenderness as found in this case or lower abdominal mass as reported in some cases , , . investigations may show proteinuria and microscopic haematuria on urinalysis , however urine cultures are usually negative . eosinophiluria , which was not detected , is rare , as eosinophils are rapidly degraded or there is little mucosal shedding from the urothelium . presence of eosinophils is not diagnostic , as it is present in other renal and urological conditions . in blood tests , eosinophilia may be useful , however , it is found in approximately 50% of patients with a history of allergy or atopy . radiologically , variable thickening of bladder wall , from diffuse thickening to mass formation on ultrasound may be shown depending on the stage of eosinophilic cystitis . hydronephrosis , and bladder and ureteral filling defects , which were noted in some studies , , were not shown in this case . magnetic resonance imaging ( mri ) and cystogram have also been used in eosinophilic cystitis patients with bladder masses in other studies , but there were no characteristic appearances . it is difficult to distinguish eosinophilic cystitis from other forms of cystitis or bladder malignancy from cystoscopy . raised velvety , polypoid , oedematous lesions are usually noted , , but to confirm diagnosis of eosinophilic cystitis , a biopsy is required . histopathologically , there is transmural inflammation predominantly with eosinophils , with inflammation and oedema more intense in the lamina propria . in this case , patches of erythema were found and biopsied , showing multiple levels of oedematous bladder , with lamina propria containing moderate inflammatory infiltrate rich in eosinophils . the acute phase exhibits tissue eosinophilia , mucosal oedema , hyperaemia , and muscle necrosis . in the chronic phase , eosinophilia is not as prevalent , with variable chronic inflammation , and prominent scarring . in this context the chronicity and recurrence is difficult to predict given the variable natural history of eosinophilic cystitis . most will have a benign course with resolution with or without treatment , whereas some become chronic leading to bladder damage and renal failure . subequently , there may be a need for long - term monitoring with relevant blood and urine tests , imaging , and occasional cystoscopy , to ensure other causes such as urothelial cancers are not the cause . because of its rarity , there are no standardised treatment protocols . however , there have been algorithms described where the precipitating factor(s ) such as concurrent uti or medication are removed if identified . if no precipitant is found , non - steroidal anti - inflammatory drugs and anti - histamines have been recommended , followed by corticosteroids as second line , and cyclosporine - a and azathioprine as third line if there is no resolution . if medical management fails , then operative intervention may be indicated ranging from diathermy to resection of bladder lesion to radical procedures such as cystectomy . it may be precipitated or associated with other systemic or local conditions , making it difficult to distinguish from other urological conditions . in this case however , management may be modified by co - existing conditions , and the extent of effects on the bladder and upper tract . natural history is difficult to predict and long - term follow up may be warranted to ensure that more sinister cause such as cancer is not being masked . this case highlights the importance of investigating haematuria , a common presentation , that is unresponsive to antibiotic therapy . this will help rule out a sinister cause , but to also obtain a diagnosis , leading to definitive treatment , and prevent progression to a chronic disabling disease . there are no conflicts of interest , including specific financial interests or relationships and affiliations relevant to the subject matter or materials discussed in the manuscript . daniel chia single author : concept , case report , design , writing of paper , obtaining image . informed consent has been provided by the patient for this case report and accompanying image with guarantee of confidentiality .

highlightseosinophilic cystitis is a disease of unknown aetiology , however there is an association with a history of allergies and atopy.common presentations are urinary frequency , dysuria , haematuria , and suprapubic pain , leading to diagnosis of less sinister urinary causes such as urinary tract infections.natural history is difficult to predict , varying from acute self - resolving cases to chronic debilitating conditions requiring hospital admissions and radical interventions.it is difficult to distinguish from other forms of cystitis and biopsy is necessary for diagnosis.treatment can vary from medical to operative intervention , or a combination of both .

a patient was immediately referred to our department after epidural endoscopy with severe bilateral visual impairment and underwent complete ophthalmologic examination . a 45-year old man suffered from low back pain unresponsive to pharmacologic treatment , radiating to the left hip and left lower extremity , due to a back injury 4 years ago . other medical history was noncontributory and he was otherwise healthy without hypertension , diabetes mellitus , cardiovascular disease , or blood clotting abnormalities . the patient underwent an epidural endoscopy and endoscopic adhesiolysis in the level of l4l5 and o5s1 by infusion of 120 cc of normal saline . at the end of the procedure the patient received an epidural injection of 80 mg methylprednisolone . after the operation the general condition of the patient was good without clinical signs of elevated cerebrospinal pressure and blood pressure and heart rate remained stable . however , a few hours later , he became aware of a major decrease of vision in both eyes and was immediately admitted to the department of ophthalmology . at presentation , best corrected visual acuity ( bcva ) was 20/400 re and counting fingers le . the ophthalmic examination revealed the presence of extensive scattered preretinal , subhyaloid , and subretinal hemorrhages in both eyes and especially in the le ( figure 1 ) . ocular history before the operation did not reveal any ocular disease and bcva was 20/20 in both eyes . examination of the fundus showed mild vitreous hemorrhage with extensive intraretinal and subretinal hemorrhages involving the macula especially of the le . four months after the operation , bcva was 20/30 in both eyes . despite the improved vision fundus examination revealed a remarkable resolution of the retinal and subretinal hemorrhages bilaterally with mild pigmentary changes of the macula especially of the le ( figure 2 ) . intraocular hemorrhages often occur in association with acute subarachnoid hemorrhage and secondary aneurysms of the anterior communicating and internal carotid arteries ( terson 1900 ) . the present case represents an extremely rare incidence of intraocular hemorrhage following epiduroscopy and endoscopic adhesiolysis ( amirikia et al 2000 ; brian et al 2005 ) . several mechanisms have been proposed to explain the occurrence of intraocular hemorrhage ( purdy et al 1998 ) . it seems that a sudden increase of the epidural pressure after the epiduroscopy causes cerebrospinal fluid to effuse through the communication of the subarachnoid space within the optic nerve sheath and subsequently compresses the optic nerve and its vasculature . specifically , the retinochoroidal anastomosis and the central retinal vein are occluded resulting in venous stasis allowing extravasation of blood through the vessels causing subhyaloid , retinal , and subretinal hemorrhages . the different types of hemorrhages suggest an acute generalized extravasation of blood within the various layers of the posterior segment opposed to the direct tracking of blood from within the optic nerve sheath . more particularly , intracranial pressure can be directly affected if the dura is punctured and fluid is added to the subarachnoid space . the visual prognosis is considered to be good , with recovery occurring within 6 months ( tabandeh 2000 ) . the present case is rare and it represents a rare complication of a rather common operation . however , as endoscopic spinal procedures become widely established , it is anticipated that similar cases will be recognized more frequently in the future . therefore , surgeons should be aware of the possibility of possible vision loss after this procedure .

purposeto report a case of acute visual loss after endoscopic spinal surgery.methodsa patient was immediately referred to our department after epidural endoscopy with severe bilateral visual impairment and underwent complete ophthalmologic examination.resultsvisual acuity was decreased in both eyes . fundus examination revealed the presence of retinal and vitreous hemorrhages bilaterally . four months later , visual acuity increased and the hemorrhages were remarkably resolved.conclusionthe present case represents an extremely rare incidence of intraocular hemorrhage following epiduroscopy .

we analyzed the amino acid sequence of the receptor binding site of ha from the isolate a / jiangxi - donghu/346 - 1/2013 ( h10-jd346 ; global initiative on sharing avian influenza data [ gisaid , http://www.gisaid.org ] accession no . epi530526 ) from the first patient infected by influenza a(h10n8 ) virus . in addition , several human and avian influenza viruses ( sequences from gisaid or the national center for biotechnology information website ) and a recent harbor seal isolate ( 5 ) were compared with h10-jd346 ( table ) . we observed that residues involved in receptor binding for h10 subtype influenza viruses suggest avian - like receptor specificity . however , we identified 2 amino acids in avian and human h10 , t135 and s186 , that are common in circulating human influenza viruses and were associated with changes in receptor binding in other avian influenza a virus subtypes ( 6,7 ) . in accordance with this finding , vachieri et al . found substantial levels of binding of an avian h10 ha to sa2,6 that retained the ability to interact with sa2,3 ( 8) . * residues found in human h1 or h3 and in h10 hemagglutinin but not in other avian hemagglutinin sequences are shown in bold . given the role of receptor binding specificity of emerging influenza viruses , we analyzed the interaction of ha of the human h10-jd346 influenza a(h10n8 ) virus isolate in comparison with that of an avian h10n7 subtype virus . first , we used a solid - phase binding assay ( 9,10 ) and the following biotinylated glycans conjugated with a polyacrylamide ( paa ) support ( provided by the consortium of functional glycomics [ cfg ] ) : neu5ac2,6gal14glcnac-paa ( 6 sln - paa ) ; neu5ac26(gal14glcnac13)2-paa ( 6sdi - ln - paa ) ; neu5ac2,3gal14glcnac-paa ( 3 sln - paa ) ; neu5ac23(gal14glcnac13)2-paa ( 3sdi - ln - paa ) ; and neu5ac23(gal14glcnac-sp)3-paa ( 3stri - ln - paa ) . we also analyzed recombinant hexahistidine - tagged has ( 11 ) from h10-jd346 , an avian h10n7 subtype strain from north america ( a / mallard / interior alaska/10bm01929/2010 ; h10-mallard ) , a human h3n2 subtype seasonal influenza a virus ( a / panama/2007/1999 ; h3-p99 ) , and an h5n1 subtype avian influenza virus from a fatal human case ( a / vietnam/1203/2004 ; h5-viet ) . as expected , h3-p99 bound strongly to the sa2,6 tested , and h5 showed higher levels of binding to sa2,3 than to sa2,6 ( figure 1 , panel a ) . when we analyzed h10-mallard and h10-jd346 , we found a similar binding profile , which is consistent with the presence of similar amino acids affecting the receptor binding specificity ( table ) . although both h10 proteins had a prevalent avian - like binding profile , low levels of binding to sa2,6 were also observed . a ) binding of recombinant hemagglutinins to glycans in a solid - phase binding assay . ( human ) , h5-viet ( avian origin isolated from a human case ) , and h10-mallard ( avian ) viruses were included in the analysis for comparison and as controls . values at the top right of the dot plots indicate percentage of cells expressing matrix protein 2 ( m2 ) . fsc , forward - scattered light ; fitc , fluorescein isothiocyanate . to confirm this data , we used a flow cytometry based assay and the same synthetic glycans ( 9,10 ) . we infected mdck epithelial cells with h10-jd346 virus ( 6:2 re - assortant with the backbone of laboratory strain a / puerto rico/8/1934 [ pr8 ] , which was generated as described ) ( 9,10 ) ; h10-mallard ( wild - type ) ; human isolate h3-p99 ( wild - type ) ; and h5-viet 6:2 ( low pathogenicity reassortant with the backbone of pr8 ) ( 9,10 ) at a multiplicity of infection of 1 . cells were harvested 24-h postinfection and incubated with antibody against matrix protein 2 ( e10 ) , which was detected by using an antibody against igg ( alexa 647 antibody ; invitrogen , carlsbad , ca , usa ) as a control of infection and with the sialyl - glycans ( detected with streptavidin fluorescein isothiocyanate ; jackson laboratories , bar harbor , me , usa ) . we determined the percentage of infected cells in each sample and gated the infected population to determine the sa binding profile ( figure 1 , panel b ) . h3-p99 showed high levels of binding to sa2,6 and h5-viet bound more efficiently to sa2,3 than to sa2,6 , which is similar to observations with recombinant has in the solid - phase binding assay . h10-mallard and h10-jd346 showed similar binding profiles with preferential binding for sa2,3 and binding to sa2,6 slightly higher than that for the negative control . analysis of receptor binding of h10-jd346 and of h10-mallard with 2 independent assays indicated that the h10 subtype influenza virus interacts slightly with human - like receptors and maintains preferential binding to avian - like receptors . consequently , these data suggest that h10 subtype influenza virus might have the ability to interact with the upper human respiratory tract , which is rich in sa2,6 ( 3 ) . to test this hypothesis , we precomplexed h3-p99 and h10-jd346 with primary antibody ( mouse anti - his tag ) and secondary fluorescent antibody , then incubated the complex with 2 human tracheal samples ( 12 ) . as expected , recombinant h10-jd346 ha also interacted with respiratory epithelia ( figure 2 ) , which suggested that the virus might be able to attach and replicate in the human upper respiratory tract . however , the 6:2 reassortant virus h10-jd346 virus showed markedly decreased replication compared with that of an h3n2 subtype virus ( pr8 6:2 reassortant ) in a human lung epithelial cell line ( figure 3 ) . interaction of hemagglutinin ( ha ) of h3-p99 ( panels b and e ) and h10-jd346 ( panels c , f , and g ) isolates of influenza a(h10n8 ) viruses with human trachea . scale bars indicate 25 m . replication of influenza a(h10n8 ) h10-jd346 virus in human epithelial cells . a549 cells ( a human lung epithelial adenocarcinoma cell line ) were infected at a multiplicity of infection of 0.1 with the h10-jd346 virus ( 6:2 re - assortant with the backbone of pr8 ) and another 6:2 re - assortant virus expressing hemagglutinin and neuraminidase genes from a human influenza a(h3n2 ) virus ( a / wyoming/3/2003 ) . cells were incubated at 37c in dulbecco minimal essential medium containing 0.3% bovine albumin ( mp biomedicals , solon , oh , usa ) and 1 g / ml of tolylsulfonyl phenylalanyl chloromethyl ketone treated trypsin ( sigma , st . supernatants were collected at selected time points , and viral titers on mdck cells were determined by using a standard plaque assay . ha of novel influenza a(h10n8 ) virus interacts with sa2,3 and slightly with sa2,6 , at levels similar to that for an avian h10 subtype ha , and binds to cells in the human upper respiratory tract . variations in the experimental settings and protocols ( e.g. , concentration of ha or glycans used ) might account for these dissimilarities . an epidemic among seals caused by this virus subtype is currently ongoing in europe ( 5 ) . a study by beare and webster showed that 50% of volunteers experimentally infected with influenza a(h10n7 ) virus shed virus ( 15 ) , which our data suggests might be caused by initial attachment to the upper respiratory tract . immune responses were not detected in these volunteers , and mild , if any , symptoms developed , which indicated limited virus replication . the low incidence of h10 influenza virus indicates a limited pandemic potential of h10n7 and h10n8 viruses . therefore , further changes in receptor binding , as well as acquisition of genomic segments from other avian influenza virus strains through co - infection , would be required to increase fitness and transmissibility in mammals . isolate h10-jd346 amino acid sequence had a mixture of e and k in position 627 of basic polymerase protein 2 ; the k627 mutation is associated with mammal adaptation ( 1 ) . this finding highlights the need for an efficient surveillance network to track and identify possible changes , as well as extensive research to identify them and understand their functional consequences .

three cases of influenza a(h10n8 ) virus infection in humans have been reported ; 2 of these infected persons died . characterization of the receptor binding pattern of h10 hemagglutinin from avian and human isolates showed that both interact weakly with human - like receptors and maintain strong affinity for avian - like receptors .

light activated resin - based materials , such sealants and flowable composites , can be used as pit and fissure sealants.57 both of them are low - viscosity materials that , nevertheless , present differences in chemical components , which can influence upon their physical strength.7 since physical strength of resin - based dental materials is important for maximizing their clinical performance,8,9 obtaining the optimal physical properties of resin - based fissure sealing materials might increase their retention levels after curing . ultimate tensile strength ( uts ) is a physical property which shows the maximum cohesive resistance to tensile force of a material.10 thus , examination of cohesive strength of fissure sealer materials may predict their resistance to fracture in a clinical environment . it was demonstrated that increasing light exposition time improves the uts of flowable composites.10 however ; information is scarce regarding the effect of extending light polymerization time on the uts of the traditional pit and fissure sealant . both materials can be used to seal pits and fissures , so that clarifying their uts may help to predict whether extended photoactivation time would increase the materials self - fracture . the phenomena of sorption and solubility may be precursors to a variety of chemical and physical processes that promote biological concerns as well as having deleterious effects on the structure and function of resin matrixes.11 polymer structure quality such as the degree of conversion and crosslink density resulting from the photo - activation mode may lead to differences in sorption and solubility.12,13 it has been demonstrated that a flowable composite presented better degree of conversion and crosslink density than a fissure sealant even under conventional or extended photoactivation time.7 however , there is no data concerning water sorption and solubility of flowable composites and traditional fissure sealants when an extended photoactivation time is used to polymerize the samples . thus , the aim of this study was to evaluate the effect of extended photoactivation time on ultimate tensile strength , water sorption and solubility of a pit and fissure sealant and a flowable composite . the first hypothesis tested is that extended photoactivation time should improve uts values and decrease water sorption and solubility for both materials . another hypothesis is that the flowable composite should present better properties regardless of the extended photoactivation time . the factors under study were materials at two levels ( a pit and fissure sealant and a flowable composite ) and photoactivation time at two levels ( 20 s following manufacturer s instruction and 60 s uts , water sorption and solubility tests were performed to characterize the effect of extended light exposure time . the materials composition and batch numbers twenty hourglass samples were prepared from two investigated materials using silicon molds with a 6 mm length , 1 mm constriction areas for the uts test , while 20 disks ( 6 mm diameter , 1 mm thickness ) were prepared from the sealing materials following the experimental conditions . both materials were injected into silicon molds using the disposable tip supplied by the manufactured under controlled temperature and relative humidity conditions . materials surfaces were covered with a mylar strip and then photoactivated for 20 s or 60 s with the light - emitting diode ( led ) unit bluephase 16i ( vivandent , brs , austria ) set on 3 mm from the top surface of the sample.7 the 8mm - diameter tip of the led bluephase 16i covered all the samples length during photoactivation . after polymerization , the samples were removed from the matrices and dry stored in light - proof containers at 37c for 24 hours.14 any specimen with visible voids was discarded . the hourglasses samples were subjected to tension in a universal testing machine ( emic , so jos dos pinhais , pr , brazil ) . they were individually attached to a metallic device with cyanoacrylate - based glue ( locite super bonder , henkel ltda . , so paulo , sp , brazil ) and tested at a cross - head speed of 0.5 mm / min until failure . after failure , they were removed from the metallic device and the cross - sectional area at the site of failure was measured with a digital electronic caliper to the nearest 0.01 mm ( mitutoyo corporation , tokyo , japan ) . this study was performed in compliance with iso 4049:2000 standard specifications ( except for the specimen dimensions and curing protocol ) as follows . the samples were weighted daily in an analytical balance ( tel marke , bel quimis , so paulo , sp , brazil ) accurate to 0.001 mg , constituting a weighing cycle every 24 hours . the complete cycle was repeated until a constant mass ( m1 ) was obtained ( two days of no weight change ) . thickness ( four measurements at four equidistant points on the circumference ) and diameter ( two measurements at the right angles ) of each specimen were measured using a digital electronic caliper ( mitutoyo corporation , tokyo , japan ) . mean values were used to calculate the volume ( v ) of each specimen ( in mm ) . thereafter , the samples were stored in plastic containers with distilled water at 37c for 7 days . samples were again weighted daily , after being carefully wiped with an absorbent paper . when constant weight was obtained ( two days of no weight change ) , this value was recorded as m2 . after this weighing , the samples were returned to the first desiccators . the entire mass reconditioning cycle was repeated and the constant mass ( two days of no weight change ) was recorded as m3 . the values for water sorption ( ws ) and solubility ( wsb ) , in micrograms per cubic millimeters , were calculated using the following equations : ws=(m2-m3)/v;wsb=(m1-m3)/v exploratory analysis of data indicated that the presuppositions of a parametric test were met . two - way anova and a tukey s hsd test at a 5% of significance were executed to evaluate the impact of two factors under study on uts , ws and wsb of the investigated materials . the factors under study were materials at two levels ( a pit and fissure sealant and a flowable composite ) and photoactivation time at two levels ( 20 s following manufacturer s instruction and 60 s uts , water sorption and solubility tests were performed to characterize the effect of extended light exposure time . the materials composition and batch numbers twenty hourglass samples were prepared from two investigated materials using silicon molds with a 6 mm length , 1 mm constriction areas for the uts test , while 20 disks ( 6 mm diameter , 1 mm thickness ) were prepared from the sealing materials following the experimental conditions . both materials were injected into silicon molds using the disposable tip supplied by the manufactured under controlled temperature and relative humidity conditions . materials surfaces were covered with a mylar strip and then photoactivated for 20 s or 60 s with the light - emitting diode ( led ) unit bluephase 16i ( vivandent , brs , austria ) set on 3 mm from the top surface of the sample.7 the 8mm - diameter tip of the led bluephase 16i covered all the samples length during photoactivation . after polymerization , the samples were removed from the matrices and dry stored in light - proof containers at 37c for 24 hours.14 any specimen with visible voids was discarded . the hourglasses samples were subjected to tension in a universal testing machine ( emic , so jos dos pinhais , pr , brazil ) . they were individually attached to a metallic device with cyanoacrylate - based glue ( locite super bonder , henkel ltda . , so paulo , sp , brazil ) and tested at a cross - head speed of 0.5 mm / min until failure . after failure , they were removed from the metallic device and the cross - sectional area at the site of failure was measured with a digital electronic caliper to the nearest 0.01 mm ( mitutoyo corporation , tokyo , japan ) . this study was performed in compliance with iso 4049:2000 standard specifications ( except for the specimen dimensions and curing protocol ) as follows . the samples were weighted daily in an analytical balance ( tel marke , bel quimis , so paulo , sp , brazil ) accurate to 0.001 mg , constituting a weighing cycle every 24 hours . the complete cycle was repeated until a constant mass ( m1 ) was obtained ( two days of no weight change ) . thickness ( four measurements at four equidistant points on the circumference ) and diameter ( two measurements at the right angles ) of each specimen were measured using a digital electronic caliper ( mitutoyo corporation , tokyo , japan ) . mean values were used to calculate the volume ( v ) of each specimen ( in mm ) . thereafter , the samples were stored in plastic containers with distilled water at 37c for 7 days . samples were again weighted daily , after being carefully wiped with an absorbent paper . when constant weight was obtained ( two days of no weight change ) , this value was recorded as m2 . after this weighing , the samples were returned to the first desiccators . the entire mass reconditioning cycle was repeated and the constant mass ( two days of no weight change ) was recorded as m3 . the values for water sorption ( ws ) and solubility ( wsb ) , in micrograms per cubic millimeters , were calculated using the following equations : ws=(m2-m3)/v;wsb=(m1-m3)/v two - way anova and a tukey s hsd test at a 5% of significance were executed to evaluate the impact of two factors under study on uts , ws and wsb of the investigated materials . there was no statistically significant difference in uts and ws values between the materials and photoactivation time ( p>.05 ) . means and standard deviation of the uts and ws for each experimental group are shown in table 2 and 3 respectively . solubility value of flowable composite were negative at both times and similar to those presented by fluroshield at 20 s ( p>.05 ) but different from those polymerized at 60 s ( p<.05 ) , as shown in table 4 . optimal physical properties of the sealant are important for a successful fissure sealing in the oral environment . increased mechanical strength of a material placed over pit and fissures can support occlusal stresses during chewing , protecting the adhesive interface and increasing long - term retention . it has been shown that long - term retention of the sealant is a crucial requirement for effective caries prevention2,3 and for arresting caries progression.4 the first hypothesis tested in this study was rejected . it was demonstrated elsewhere10 that the degree of conversion is directly related to the uts of resin - based materials . recently , borges et al7 showed that permaflo presented a higher degree of conversion ( dc ) and crosslink density than fluroshield , and , in addition , that extended photoactivation time increased both physical properties of permaflo following similar experimental conditions to those established in the present investigation . thus , it seems to be logical to assume that permaflo would show higher uts and that extended light exposure time would increase the uts of permaflo . nevertheless , uts results obtained in the present work were similar for both materials and there were no demonstrable benefits to extending photoactivation time , thus rejecting the second hypothesis tested . this finding may be explained by the fact that uts is also influenced by the filler / matrix adhesion.15 possibly , the filler / matrix adhesion in both materials used in this study was similar , so that extended photoactivation time could not increase it . although the samples may have presented statistically significant differences in the dc after both photoactivation times , these might not be enough to provide differences in uts . water sorption in resin - based materials is a diffusion - controlled process and occurs mainly in the resin matrix.16 higher tegdma content in the matrix is responsible for increasing its water sorption.17 permaflo presents a lower monomer content than fluroshield , but a greater percentage of water soluble tegdma . thus , the high tegdma amount present in permaflo might have compensated the differences in matrix content between the materials , generating similar water sorption means for permaflo and fluroshield . in this study , although uts and water sorption of the two materials was not different , due to the results concerning dc and crosslink density obtained by a previous investigation,7 it can be suggested that using flowable composite and extended photoactivation time to seal pit and fissures may be suitable to decrease some adverse effects . dc of resin - based materials is directly related to the growth of certain caries - related bacteria around material margins.18 if a large number of microorganisms is able to grow around the sealant / tooth interface , the possibility of a caries lesion under the sealant increases , leading to a clinical failure . solubility of resin - based materials is directly related to their dc.19 in this study , the flowable composite permaflo showed lower solubility than the conventional pit and fissure sealant fluroshield , and this may be attributed to the higher dc obtained by the flowable composite compared to fluroshield.7 since solubility is reflected by the amount of leachable unreacted monomers , the higher dc obtained by permaflo in comparison with fluroshield previously7 reduced its solubility . in this case , the amount of unreacted monomers available for leaching out was lower in permaflo due to the high percentage of reacted aliphatic c = c bonds from the dimethacrylate monomers.20 however , negative solubility values obtained by the flowable composite indicate that not all the absorbed water could be removed by the drying process , thus increasing the mass of the material.20,21 water molecules that are firmly bound to polar sites along the polymer network after polymerization of resin - based materials exhibit a high plasticizing effect , thus causing the reduction of the polymers mechanical properties by altering the mobility of their chain segments.22 from a clinical standpoint , if a fissure sealer material becomes weakened , its long - term retention and consequently its effectiveness can be compromised . testing physical properties of materials used as pit and fissure sealants must be encouraged in pediatric dentistry , since their physical properties may predict and justify the clinical performance of these materials . although the results obtained from previous investigation7 showed improved polymer quality after curing for the low viscosity composite , this study indicates that the conventional pit and fissure sealant fluroshield may present a similar clinical performance to the flowable composite permaflo . extended photoactivation time did not increase ultimate tensile strength , nor did it decrease water sorption and solubility of fluroshield and permaflo . however , the conventional fissure sealant showed improved solubility over the flowable composite , since negative solubility values were obtained by permaflo .

objective : this study aimed to evaluate the impact of extended photoactivation time on ultimate tensile strength ( uts ) , water sorption ( ws ) and solubility ( wsb ) of resin - based materials used as fissure-sealants.methods:a fissure - sealant ( fluroshield ) and a flowable composite ( permaflo ) polymerized for 20 and 60 seconds were tested . for uts , 20 hourglass shaped samples were prepared representing two materials and two photoactivation time ( n=5 ) . after 24-h dry - storage , samples were tested in tension using a universal testing machine at a cross - head speed of 0.5 mm / min ( uts was calculated in mpa ) . for ws and wsb , 20 disks with 5 mm diameter and 1 mm height ( n=5 ) were prepared and volumes were calculated ( mm3 ) . they were transferred to desiccators until a constant mass was obtained ( m1 ) and were subsequently immersed in distilled water until no alteration in mass was detected ( m2 ) . samples were reconditioned to constant mass in desiccators ( m3 ) . ws and wsb were determined using the equations m2-m3/v and m1-m3/v , respectively . data were subjected to two - way anova and tukey s hsd test ( p<.05).results : there was no significant difference between materials or photoactivation times for the uts and ws . permaflo presented lower but negative wsb compared to fluroshield.conclusions:extended photoactivation time did not improve the physical properties tested . fluroshield presented physical properties that were similar to or better than permaflo .

cystic fibrosis is the most common recessive disease in caucasians with a prevalence of about 1 : 2500 . cystic fibrosis is characterized by progressive lung destruction due to chronic neutrophilic airway inflammation and bacterial infection . most of the morbidity and mortality of cystic fibrosis patients results from the lung disease . large amounts of neutrophils are targeted into the airways , mostly by the chemokine interleukin 8 , where they are primed , activated and engage bacterial phagocytosis releasing high amounts of oxidants and proteases . neutrophils derived from cystic fibrosis patients release significantly higher levels of neutrophil elastase when activated by interleukin 8 compared to healthy subjects or bronchiectatic patients . it was suggested that neutrophils in cystic fibrosis airway environment undergo necrosis , rather than apoptosis [ 6 , 7 ] . this leads to uncontrolled secretion of interleukin 8 with further chemotaxis and accumulation of neutrophils and an overwhelming release of neutrophil elastase . collateral damage of airway surface epithelium and destruction of neighboring structures allow bacterial persistence in niches and further perpetuation of inflammation [ 8 , 9 ] . with ongoing cystic fibrosis lung disease , a state termed as prolonged endobronchial protease activity ( pepa ) is established . we recently found that phagocytic activity is reduced in cystic fibrosis neutrophils supposedly due to proteolytic cleavage of the specific interleukin 8 receptor cxcr1 which plays a pivotal role in neutrophil phagocytosis of bacteria most likely by neutrophil elastase . since the introduction of antibiotics in the mid 1950s and the development of new antibiotic regimens , the mean survival in cystic fibrosis patients dramatically increased . after intravenous or inhaled antibiotic therapy bacterial burden is reduced in the airways of cystic fibrosis patients , as is neutrophil burden , free elastase , and associated inflammatory response [ 1316 ] . inhaled treatment of cystic fibrosis lung disease commonly includes nebulized antibiotics such as colistin and tobramycin . in addition to indirect mechanisms of the antibiotics to reduce host inflammation by the killing of bacteria and reduced concomitant inflammation , direct actions of the antibiotics on the proteolytic milieu are possible . indeed , a previous study suggested neutrophil elastase activation by colistin in cystic fibrosis patients in vitro . the purpose of this study was to compare directly , side by side , the effects of colistin and tobramycin on neutrophil elastase activity . neutrophil elastase activity was measured with the specific peptide substrate methoxysuccinyl - ala - ala - pro - val - p - nitroanilide ( msaapv - pna sigma - aldrich , munich , germany ) as previously described by hilliard et al . . purified human neutrophil elastase ( elastin products company , owensville , mo , usa ) was diluted to final concentrations of 0.5 , 1 , 2 , 4 , and 8 g / ml in an assay buffer ( dulbecco 's phosphate buffered saline , paa laboratories , pasching , austria ) in the presence or absence of albumin ( 0.1% bovine serum albumin , fermentas , st . leon - rot , germany ) to test whether the presence of additional protein has an effect on neutrophil elastase measurements . to investigate effects of antibiotics on neutrophil elastase measurements , colistin ( colistimethate sodium salt , colistin cf , gruenenthal , aachen , germany ) and tobramycin ( tobi , novartis , nuernberg , germany ) at concentrations of 1 , 10 , 100 and 1000 mol / l were added to neutrophil elastase for 10 min ( 20c ) prior to analysis . as a control for colistin we used the vehicle buffer provided by the manufacturer to dissolve the antibiotics . as a control for tobramycin we dissolved 11.25 mg of sodium chloride in 5 ml aqua ad iniectabilia and adjusted the ph to 6.0 according to the product sheet of the manufacturer . directly after addition of the substrate , 96-well plates ( greiner bio - one , frickenhausen , germany ) were measured at 405 nm absorbance on a plate reader ( anthos , krefeld , germany ) . samples were measured in duplicates and a standard curve ( range 0.58 g / ml ) was included within the assay . the used substrate is highly sensitive and specific to neutrophil elastase [ 20 , 21 ] , and change of optical density ( od ) is directly proportional to the rate of p - nitroanilide cleavage ; thus change of od indicates a change in specific activity . neutrophil elastase activity was calculated from the slope of the over - time increase in color formation ( change of od ) at a wavelength of 405 nm . the slopes were calculated by linear regression analysis of each experiment . to test effects of antibiotics on neutrophil elastase measurements , colistin and tobramycin were added in different concentrations ( final concentration of 1 , 10 , 100 , 1000 m ) to neutrophil elastase in presence or absence of albumin . following a preincubation of 10 minutes the substrate msaapv - pna was added directly before measurements and results were compared to samples without antibiotics or albumin . the minimal inhibitory concentration for tobramycin is 8 g / ml , whereas the antibiotic breakpoint for colistin is 2 g / ml . since inhaled antibiotics are known to reach high levels in airways , we used concentration ranges from 1 to 1000 m for tobramycin and colistin , which is equal to 0.47 to 467 g / ml and 1.16 to 1155 g / ml , respectively . data are presented as mean or mean + / standard error of mean for the number of independent experiments indicated . the nonparametric wilcoxon signed rank test was performed for comparison of neutrophil elastase measurements in the presence of albumin compared to that in the absence of albumin . repeated - measures analysis of variance with bonferroni post - hoc test was conducted to analyze the effect of different concentrations of antibiotics on neutrophil elastase measurements in the presence or absence of albumin . p - nitroanilide cleavage by neutrophil elastase was concentration - dependent over the range of neutrophil elastase investigated ( figure 1 ) and was linear for various time periods up to 30 minutes ( not shown ) . to test the effects of inhaled antibiotics used in the treatment of cystic fibrosis patients on neutrophil elastase measurements in vitro , we added colistin and tobramycin to the assay . this was significant for 1 m and 10 m of colistin ( p < .01 and p < .05 , resp . ) and for 1 m and 10 m of tobramycin ( p < .01 ) . at very high concentrations no or only very small effects were noted ( figure 1 ) . to assess if the presence of proteins could affect neutrophil elastase measurements , we added bovine serum albumin . p - nitroanalide cleavage was generally higher in the presence of albumin than in its absence ( p < .0001 ) . in order to assess neutrophil elastase activity , the change of optical density over time was calculated from the slope of the time curves ( figure 2 ) and the slopes were compared to each other . lastly , we investigated the effects of the antibiotics either in presence or absence of albumin . in the presence of albumin , colistin significantly inhibited neutrophil elastase activity by 16% to 24% ( p < .01 for 1 m and 100 m ; p < .001 for 10 m ; p < .05 for 1000 m ) and tobramycin by 23% to 37% ( p < .05 for 1 m , 100 m and 1000 m ; p < .01 for 10 m ) compared to controls without antibiotics . without albumin , colistin significantly inhibited neutrophil elastase by 73% to 79% at 1 m and 10 m ( p < .01 ) and tobramycin by 74 to 82% ( p similar effects were observed for the other neutrophil elastase concentrations ( data not shown ) . colistin and tobramycin are widely used nebulized antibiotics in cystic fibrosis patients and their efficacy in treatment of p. aeruginosa and the clinical amelioration of cystic fibrosis patients was shown in many studies [ 1417 , 2325 ] . surprisingly , a previous study suggested an activating effect of colistin on neutrophil elastase activity in vitro . therefore , we investigated direct effects of the antibiotics colistin and tobramycin used in patients with cystic fibrosis for inhalation on the measurements of neutrophil elastase activity . there was no significant enhancing effect of these antibiotics , both in the presence and absence of albumin . however , neutrophil elastase activity was also dependent on albumin and was significantly elevated in its presence . these in vitro data suggest that both colistin and tobramycin may be slightly inhibitory on neutrophil elastase activity . this result is in contrast to the previous study by jones et al . in which the effect of colistin on neutrophil elastase activity in cystic fibrosis sputum samples at increasing colistin concentrations ( 3.9500 m ) was studied and neutrophil elastase activity was already increased at lowest colistin levels ( 3.9 m ) compared to control incubations without the addition of colistin . reasons for these different results may include different colistin preparations and assay conditions used . as colistin represents mainly polymyxin e , however , more than 30 minor components have been isolated and its behavior is critically dependent on its source and preparation which were not indicated in the previous study . the presence of protein significantly affects activity ; however this does not change the direction of the modulatory effect of the antibiotics , whereas its magnitude was influenced . on the other hand , our results might lead to the assumption that albumin itself had activating effects on neutrophil elastase and reduced inhibitory effects of the antibiotics on neutrophil elastase . this seems to be unlikely , because there was no dose - dependent change of neutrophil elastase activity by the antibiotics . if protein - protein interactions between albumin and the antibiotics affect the pharmacokinetic activity of neutrophil elastase , higher concentrations of antibiotics would have had an influence on the measurements . instead , we suppose that the strong dependency of neutrophil elastase activity on albumin was due to variable binding of neutrophil elastase or substrate to tube surfaces , modulating the availability of these components to neutrophil elastase . the assay in the study of jones et al . was performed without addition of proteins like albumin . but the presence of proteins in the assay may more likely represent the real situation in cystic fibrosis airways where high concentrations of protein are present , affecting neutrophil elastase activity and therefore the experimental set - up with the presence of protein may more likely represent the conditions in cystic fibrosis airways . whereas our results suggest that both tobramycin and colistin , have no activating effect on neutrophil elastase , it is obvious that one can not predict in vivo effects from these data . therefore , clinical studies must assess potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways .

background . inhaled antibiotics are commonly used in the treatment of cystic fibrosis lung disease . a previous study suggested neutrophil elastase activation by colistin in vitro . here , we investigated direct effects of the commonly used antibiotics colistin and tobramycin on neutrophil elastase activity . methods . neutrophil elastase was measured spectrophotometrically . the antibiotics colistin and tobramycin were added in different concentrations with or without the addition of albumin . results . generally , neutrophil elastase activity was lower in the absence of albumin compared to its presence . both antibiotics , colistin and tobramycin , had inhibitory effects on neutrophil elastase activity except for high concentrations of colistin when albumin was absent . conclusions . our results suggest inhibitory effects of colistin and tobramycin in vitro . there was a clear dependency of neutrophil elastase measurements on the presence of albumin . clinical studies are needed to investigate potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways .

anaphylaxis is a rapid , potentially fatal , multiorgan system , allergic reaction caused by the excessive release of mediators including histamine and cytokines / chemokines from mast cells and basophils upon allergen / ige stimulation . it typically causes a number of symptoms including an itchy rash , throat swelling , and low blood pressure associated with low body temperature . a recent nationwide cross - sectional telephone survey in usa estimated that the prevalence of anaphylaxis in the general adult population is at least 1.6% and medications were the most common trigger ( 35% ) , followed by foods ( 32% ) and insect stings ( 19% ) . it is also recently reported that an estimated 1 in 300 of the european population at some time in their lives is affected . given the increased prevalence of anaphylaxis in industrialized countries , more basic research is urgently needed for better understanding of anaphylaxis that leads to efficient prevention of the disease . however , the pathophysiology of anaphylaxis is not fully understood . in mammals , the internal time keeping system circadian clock drives the daily rhythms in behavior and physiology ( e.g. , sleep - wake cycles , body temperature , blood pressure , and hormonal secretions ) that enable the organisms to keep track of the time of day according to daily changes in light intensity [ 4 , 5 ] . mammalian circadian clock system consists of the central oscillator located in the suprachiasmatic nucleus ( scn ) of the hypothalamus and peripheral oscillators present in virtually all cell types [ 4 , 5 ] . light activates a specific group of photoreceptors in the retina connected to the central scn clock which synchronizes and entrains peripheral circadian clock via neural and endocrine pathways . the molecular mechanisms of rhythm generation are cell autonomous , highly conserved in the scn and peripheral cells , and created and maintained by interlocked transcriptional - translational feedback loops consisting of several clock genes and their protein products [ 4 , 5 ] . we have recently shown that a passive systemic anaphylactic ( psa ) reaction in mice exhibits a time of day - dependent variation , relying on the normal activity of a key clock gene , period2 ( per2 ) , suggesting that the canonical clock gene is required for the daily rhythm generation observed in psa reaction . however , it remains obscure whether the daily rhythms are generated precisely by the circadian clock system or not , since per2 has nonclock functions and may regulate the daily rhythms independently of the circadian clock system [ 4 , 5 ] . therefore , this short study aimed to clarify the precise role of the circadian clock system in the generation of daily rhythms in anaphylaxis . for this purpose , we examined the effects of scn ablation on the time of day - dependent variations in psa reaction since scn ablation reliably eliminates the normal activity of the circadian clock system [ 4 , 5 ] . male 812-week - old icr mice ( japan slc , tokyo , japan ) were bred under specific pathogen - free conditions and 12-hour light/12-hour dark conditions ( l / d cycles ; the light was turned on at 6:00 a.m. , zeitgeber time ( zt ) 0 , and the light was turned off at 6:00 p.m. , zt12 ) with ad libitum access to food and water , for at least 2 weeks . all animal experiments were approved by the institutional review board of university of yamanashi and waseda university . bilateral thermal lesions of the scn were obtained stereotactically ( narishige co. , tokyo , japan ) under anaesthesia as described previously . one month after the surgery , we selected animals with complete lesioning of the scn after confirmation of arrhythmic general locomotor activity recorded with an infrared radiation sensor ( f5b , omron , tokyo , japan ) and analyzed with clocklab software ( actimetrics , wilmette , il , usa ) as described previously . a histological check of lesion sites was also performed after finishing the psa experiments using nissl staining . a passive systemic anaphylactic ( psa ) reaction was induced in mice as previously described with some modifications . briefly , mice were sensitized with an intravenous injection of 20 g with mouse anti - tnp ige in 0.2 ml pbs . the mice were intravenously challenged with 1000 g dnp - bsa in 0.2 ml pbs 24 hours later . their rectal temperature was measured with a digital thermometer ( shibaura electronics , tokyo , japan ) every 5 minutes from 20 minutes before dnp - bsa challenge and thereafter until 120 minutes after the start of the examination . the rectal temperature was also measured at 180 minutes after the start of the examination . serum samples were collected from the mice at 10 minutes or 180 minutes after induction of psa reactions . the amounts of mcp-1 ( ccl2 ) and il-6 in the serum at 180 minutes after induction of psa reaction were measured using the mouse mcp-1 and il-6 elisa kits ( r&d , minneapolis , mn ) . the amounts of histamine in the serum at 10 minutes and 180 minutes after induction of psa were measured using histamine eia kit ( oxford biomedical research , inc . , oxford , mi , usa ) . serum levels of total ige and corticosterone were determined by using the mouse ige elisa kit ( r&d , minneapolis , mn , usa , or morinaga institute of biological science , kanagawa , japan ) or assaymax corticosterone elisa kit ( assaypro , charles , mo , usa ) , respectively . statistical analysis was performed using an unpaired student 's t - test to compare data in different groups . in order to clarify the precise role of the circadian clock system in the generation of daily rhythms in systemic anaphylactic reaction , we examined the effects of scn ablation on a time of day - dependent variations in passive systemic anaphylactic ( psa ) reaction in mice , which is a representative model of anaphylaxis . we confirmed complete disruption of the scn in mice by a histological check of lesion sites by nissl staining after finishing all the experiments ( figure 1(a ) ) and by examining behavioral patterns ( general locomotor activity with arrhythmicity ) ( figure 1(b ) ) . the kinetics of psa reaction was then compared in sham - operated mice and mice with disrupted scn ( figure 2(a ) ) . sham - operated mice challenged with the antigen at 10:00 pm ( zt16 ) showed a smaller drop in the extent of rectal temperatures than the mice challenged at 10:00 am ( zt4 ) . however , such a time of day - dependent variation in psa reaction was absent in mice with disrupted scn . consistently , serum histamine , mcp-1 ( ccl2 ) , and il-6 levels following the induction of the psa reactions showed similar time of day - dependent variations to the psa reactions in sham - operated mice , but the variations were absent in mice with disrupted scn ( figures 2(b)2(d ) ) . the daily variations in serum corticosterone levels observed in sham - operated mice were also absent in mice with disrupted scn ( figure 2(e ) ) . in contrast , serum total ige levels were comparable between sham - operated mice and mice with disrupted scn ( data not shown ) . these results indicated that disruption of the central clock scn blunted a time of a day - dependent variation in psa reaction in association with a loss of rhythmic secretion of corticosterone . these findings suggest that the circadian clock system may contribute to the generation of daily rhythms in anaphylaxis . however , it appears that the basal body temperatures at zt4 and zt16 before induction of psa ( 020 minutes before the antigen challenge ) were comparable in control sham - operated mice ( figure 2(a ) ) . we speculate that this discrepancy might be caused , at least in part , by the experimental manipulation for measuring body temperature . direct insertion of a digital thermometer into the rectum every 5 minutes likely affects mouse activity in the resting phase and might upregulate the body temperature . in contrast , a time of day - dependent variation in psa reaction was clearly observed at zt4 and zt16 in control sham - operated mice ( figure 2(a ) ) . thus , it appears that the extent of a time of day - dependent systemic mast cell responses overrides the possible effects of the experimental manipulation on body temperature . the surgery for scn ablation may destroy other important nuclei located in this brain area such as temperature center and corticosterone releasing hormone ( crh ) neurons . we observed that body temperatures at 180 minutes after the examination were comparable between sham - operated mice and mice with disrupted scn ( figure 2(a ) ) , suggesting that the brain area for temperature regulation was functional in mice with disrupted scn . we also observed that basal levels of serum corticosterone were comparable between sham - operated mice and mice with disrupted scn ( figure 2(a ) ) , suggesting that the brain area for crh regulation was functional in mice with disrupted scn ( figure 2(e ) ) . these findings may support the specificity of the surgery to the scn although we can not completely exclude some of the nonspecific influences of the scn ablation on the current results . it remains to be determined precisely how the dysfunction of the circadian clock ( disruption of the scn ) affects the time of day - dependent variation in psa reaction . we have previously shown that daily rhythms observed in passive cutaneous anaphylactic ( pca ) reaction were absent in adrenalectomized mice , suggesting that humoral factors from the adrenal gland are necessary to maintain the daily rhythms . the central scn pacemaker primarily governs the daily rhythmic secretions of humoral factors such as corticosterone from the adrenal gland . therefore , the scn may control the time of day - dependent variation in psa ( and also pca ) reaction via regulation of the rhythmic secretion of humoral factors ( possibly corticosterone ) from the adrenal gland . the current findings that the time of day - dependent variation in psa reaction in sham - operated mice showed an inverse association with the serum corticosterone levels and the extent of psa reaction was severe in mice with disrupted scn in association with low serum corticosterone levels may support this hypothesis . in summary , the current findings provide additional support for the notion that the circadian clock system times ige - mediated systemic anaphylactic reaction . the findings may provide a novel insight into the pathophysiology of anaphylaxis and also implicate that environmental and intrinsic factors disrupting the normal activity of the circadian clock system , such as sleep disturbance and mental stress [ 5 , 6 , 10 ] , might predispose some types of allergic patients ( e.g. , patients with drug and food allergy ) to severe anaphylaxis . the circadian clock may be an important regulator of anaphylaxis , which will provide a novel insight into the pathophysiology of the disease .

anaphylaxis is a severe systemic allergic reaction which is rapid in onset and potentially fatal , caused by excessive release of mediators including histamine and cytokines / chemokines from mast cells and basophils upon allergen / ige stimulation . increased prevalence of anaphylaxis in industrialized countries requires urgent needs for better understanding of anaphylaxis . however , the pathophysiology of the disease is not fully understood . here we report that the circadian clock may be an important regulator of anaphylaxis . in mammals , the central clock located in the suprachiasmatic nucleus ( scn ) of the hypothalamus synchronizes and entrains peripheral circadian clock present in virtually all cell types via neural and endocrine pathways , thereby driving the daily rhythms in behavior and physiology . we found that mechanical disruption of the scn resulted in the absence of a time of day - dependent variation in passive systemic anaphylactic ( psa ) reaction in mice , associated with loss of daily variations in serum histamine , mcp-1 ( ccl2 ) , and il-6 levels . these results suggest that the central scn clock controls the time of day - dependent variation in ige - mediated systemic anaphylactic reaction , which may provide a novel insight into the pathophysiology of anaphylaxis .

we reviewed the clinical records of 326 patients with the diagnosis of diabetes ( age range at diagnosis 118 years ) , each consecutively referred to the pediatric diabetes clinic at san raffaele hospital during the years 20032006 . among these 326 , we identified 24 patients who were negative for all the common type 1 diabetes autoantibodies ( islet cell antibody [ ica ] , gad antibody [ gada ] , ia-2 antigen [ ia-2a ] , and insulin antibody [ iaa ] ) at the time of diagnosis . the cutoffs ( in arbitrary units ) were gada <3 , ia-2a < 1 , and iaa < 5 ; the threshold for positivity in each assay corresponds with 99th percentiles of 200 control subjects with normal glucose tolerance . from the 24 patients negative for autoantibodies , we excluded 4 patients with adolescent type 2 diabetes ( table 1 ) . among the remaining 20 patients , we selected those with diabetes in isolation , who were tested for the novel type 1 diabetes autoantibody against zn transporter 8 ( znt8a ; cutoff in arbitrary units < 12 ) ( 5 ) . seven patients who were negative for all antibodies were analyzed for insulin gene mutations by dna direct sequencing , along with four znt8a patients ( control subjects ) . when appropriate , mutations found were designated according to their position in the mature insulin chains ( 1 ) . in two patients , we detected a heterozygous missense mutation of the ins gene : the already described gs ( or g32s ) ( 2,3 ) and a novel mutation resulting in a serine for an alanine in the 23rd amino acid of the preproinsulin molecule as . dna sequencing of the ins gene of the probands parents showed a normal sequence ( i.e. , the mutations arose as spontaneous mutations ) . no mutation was found in 200 control subjects with normal glucose tolerance or in the znt8a patients . the child with the gs mutation was born after an uneventful pregnancy ( 39 weeks of gestation ) with a birth weight of 2,770 g ( 10th centile ) . at onset of diabetes , he was 2 years 10 months old and lean ( bmi 16 kg / m , 25th centile for corresponding age ) and showed a detectable c - peptide ( 0.49 ng / ml ) that was low , but still measurable 2 years after diagnosis ( 0.34 ng / ml ) . presently , he is 6 years old , his insulin dose is 0.7 units kg day , and his a1c is 8.7% ( normal reference < 6% ) . the individual with the as mutation ( birth weight 3,350 g , 2550th centile ) presented with typical symptoms of diabetes ( polyuria and polydipsia ) when he was 6 years 8 months old ( a1c 11% at diabetes onset ) . insulin was started and continued for 6 months ; during the following 2 years , the patient went off and on insulin several times ( a pattern that may resemble the so - called honeymoon phase of type 1 diabetes ) . his c - peptide levels , measured 11 and 24 months after onset of hyperglycemia , were 1.32 and 0.7 ng / ml , respectively . he is now 10 years old , his insulin dose is 0.17 units kg day , and his a1c is 6.4% . previously , heterozygous ins gene mutations had been detected in adult patients with so - called familial hyperinsulinemia or hyperproinsulinemia who presented with variable phenotypes ( mild diabetes or even hypoglycemia ) and high serum levels of radioimmunoassayable insulin or proinsulin - like material . more recently , ins mutations have been found to be associated with neonatal- and infancy - onset diabetes ( 13 ) . we demonstrated that mutant insulins with proteotoxic effect can not be secreted when expressed in hek 293 cell line ( 1 ) , and it is likely that s and s are also retained in the endoplasmic reticulum . nevertheless , the patient bearing the mutation in the signal peptide shows a milder clinical course , and we can not exclude that s preproinsulin may be partially processed and secreted . present knowledge indicates that insulin mutations with a proteotoxic effect cause apoptosis of the pancreatic -cell ( 1 ) , a process that in most patients takes several months after birth ( 13 ) or , in some individuals , years ( 14 and this report ) . of note , , edghill et al . , molven et al . , and colombo et al . ( 14 ) were diagnosed within the first 4 weeks of birth ( i.e. , the time interval still in use to define the neonatal period ) ; most of them ( more than 40 ) were diagnosed in the first year of life ( infancy ) . thus , we believe that classifying these patients as having permanent neonatal diabetes is misleading and that this term should be abandoned in favor of the term monogenic diabetes of infancy , as previously suggested by our group ( 1 ) . indeed , at least 12 patients with insulin gene mutations had the diagnosis of diabetes during childhood or adulthood ( 14 and this report ) , making the neonatal onset an exception . the italian proband bearing the gs ( g32s ) mutation had the diagnosis of diabetes at 3 years of age , 2 years later than patients carrying the same mutation as described by sty et al . ( 2 ) . presently , it is not clear why patients with the same ins gene mutation , even from the same family , can present with diabetes during infancy , childhood , or adulthood ( 14 ) . it is tempting to speculate that the apoptotic process in some of these patients may be modulated or slowed by the individual 's capacity to degrade misfolded insulin ( by a process known as endoplasmic reticulum associated degradation ) . another intriguing hypothesis , not mutually exclusive with the previous one , could be that -cell regeneration may take place in some individuals and not in others . the observation that in these two patients ( and in others previously described ) ( 1 ) insulin secretion was still detectable 2 years after onset of diabetes suggests that either of these mechanisms could be at work . in conclusion , insulin gene mutations are rare in absolute terms among patients clinically classified as type 1 diabetic ( 2 of 326 or 0.6% ) but can be identified after a thorough screening of type 1 diabetes autoantibodies .

objective heterozygous , gain - of - function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood . the aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies.research design and methods we reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies . we sequenced the ins gene in these seven patients.resultsin two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age , respectively , we identified the mutation gb8s and a novel mutation in the preproinsulin signal peptide ( asignal23s).conclusions insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic ( 0.6% ) but can be identified after a thorough screening of type 1 diabetes autoantibodies .

cerebral arterial air embolism ( caae ) has been reported as a rare complication of medical intervention . we present a case of a 7-month - old girl who was admitted to our emergency department ; post - mortem computed tomography ( ct ) showed a caae . she was known in our hospital because of prematurity ( gestational age , 30 weeks ) and an omphalocele , for which initial non - operative treatment with epithelialisation was instituted , and delayed surgical correction was planned . according to the mother , the child awoke at 3 o clock at night and , as what had happened before , her mother bottle fed her . during feeding the latter was first to arrive and transported the girl and her mother to the emergency department of the academic medical centre amsterdam . they arrived in our hospital approximately 45 min after the 911 call . upon physical examination , a non - responsive child without spontaneous several attempts were made to insert a central venous and arterial catheter , however , to no avail . to gain venous access , an intraosseous infusion ( ioi ) needle was placed in the right tibia . at 5:00 a.m. , she was pronounced deceased . although the clinical history and findings during resuscitation suggested food aspiration , questions regarding the cause of death remained therefore , according to our battered child protocol , the standard radiographs , following the guidelines of the american college of radiography were performed . in addition , a head ct , which was a standard in our hospital in children under the age of 2 years with unexplained trauma / death , was performed within 1h after death . the skeletal radiographs showed no abnormalities , except for the io infusion in the proximal right tibia ( fig . 1 ) . the head ct , however , showed a considerable amount of air within the arterial circulation ( fig . 2 ) . 2ct at the level of the circle of willis showing air within the circle of willis ( open arrow ) anterior cerebral artery ( small arrow ) and peripheral cerebral arteries ( solid arrow ) intraosseous infusion needle correctly positioned within the proximal right tibial metaphysis ct at the level of the circle of willis showing air within the circle of willis ( open arrow ) anterior cerebral artery ( small arrow ) and peripheral cerebral arteries ( solid arrow ) a full judicial autopsy was performed in the netherlands forensic institute , as is mandatory in children with a possible non - natural cause of death . the body showed normal measurements ( length , 64 cm , and 6,900 grams , both p50 ) and a known omphalocele . autopsy showed that the omphalocele contained a large segment of the right liver lobe and the ascending colon including the appendix , with adhesion to the abdominal wall ( fig . inspection of the heart revealed only minor congenital abnormalities , which consisted of a defect in the interatrial septum , fossa ovalis type with deficient flap valve , and slight hypertrabeculation of the ventricles , particularly the right ventricle ( fig . 4 ) . the latter findings , however , were clearly insufficient for a diagnosis of ventricular non - compaction . the trachea was without abnormalities and , in contrast to the clinical history , showed no signs of food aspiration ( fig . additional toxicological , microbiological and biochemical analyses of body fluids and tissues were all inconclusive . 3omphalocele containing a large section of the right liver lobe ( asterisk ) and the ascending colon including the appendix ( arrow)fig . 4view of the atrial septum showing a persistent foramen ovale ( arrow ) and a fenestration ( arrowhead)fig . 5view of the trachea devoid of food remnants , a small amount of saliva is seen ( arrow ) omphalocele containing a large section of the right liver lobe ( asterisk ) and the ascending colon including the appendix ( arrow ) view of the atrial septum showing a persistent foramen ovale ( arrow ) and a fenestration ( arrowhead ) view of the trachea devoid of food remnants , a small amount of saliva is seen ( arrow ) as no distinct cause of death could be established , the cause of death remains undetermined . caae is a rare finding ; it has been described after medical instrumentation in trauma patients , after mechanical ventilation or resuscitation [ 28 ] . in case of vascular access procedures , caae can occur as a result from backflow , a right to left shunt , or shunting through the pulmonary capillary bed [ 911 ] . backflow can be a result of manipulation of central lines ( not necessarily ioi ) and has been described in literature [ 12 , 13 ] . right to left shunting can be caused by an atrial septum defect ( estimated incidence in adult patients 0.20.7 in 1 , 000 ) , a ventricular septum defect ( incidence at birth ranging from 25% ; however , 8590% of these defects will close spontaneously by 1 year of age ) and persistent foramen ovale ( this has been reported to be present in up to 27% of autopsies ) [ 1416 ] . a special category are divers who suffer from decompression sickness after diving accidents [ 17 , 18 ] . in severe cases , caae can develop , which is reported to be the second most common cause of death in divers . recently , an animal study with sheep was performed to test the hypothesis that artifacts caused by postmortem off gassing is at least partly responsible for the presence of gas within the vascular system and tissues of the cadaver after death associated with compressed air diving . none of the control animals showed intravascular air on ct , respectively , 1 and 8 h after death ; only after 24 h after the time of death , relatively small amounts of gas were seen . although it is unknown how well sheep resemble 7-month - old infants , we assume that decay rates will not differ that much and certainly not to the extent that it can explain the amount of air visible on the ct scan . in our case , the only vascular access had been io infusion , which is a widely implemented technique and is part of the standard protocols , such as the advanced paediatric life support textbook . the advantage of io infusion over peripheral vascular access is that it provides a rapid and reliable access to the systemic venous circulation in children [ 2123 ] . it can be used in children of all ages , with the smallest child reported in literature weighing 800 g . this has led to io infusion having almost completely replaced saphenous cut down procedures in critically ill children in emergency situations . it is generally considered to be a safe technique with a reported complication rate of 1% . several complications resulting from the use of io infusion have been reported ; these consisted of extravasation in some cases leading to compartment syndrome ( in rare cases leading to limb amputation ) , osteomyelitis , fracture , skin necrosis and fat embolism [ 24 , 2732 ] . recently , investigators from the berne institute of forensic medicine ( switzerland ) reported on a case of air embolism after resuscitation and ioi in a 4-month - old boy . in their case , resuscitation was considered as the cause for caae ; however , whole - body ct showed air in the lower extremity , which was used for ioi . as in our case , io infusion was the only vascular access . given the patent foramen ovale and atrial septal defect , leading to a right to left shunt , we feel that the only logical explanation for the caae is that air is introduced into the bloodstream via this route . to the best of our knowledge , our case is the second reported case of an air embolism after the use of an io infusion . given the incidence of right - to - left shunts in the general population , this is a serious complication of ioi of which clinicians should be aware .

cerebral arterial air embolism ( caae ) has been reported as a rare complication of medical intervention . there has been one reported case of caae after the use of an intraosseous infusion ( io ) system . we report on a case of caae after tibial io infusion in a 7-month - old girl during resuscitation .

in modern society , as more people are sitting for longer periods and aging progresses , kyphosis in the thoracic vertebra has been increasing1 ; this results in rounded shoulders and a decrease in thoracic cavity and vital lung capacity2 . in addition , this slouched posture puts the upper and lower cervical spine into a relative tension state while forwardly inclining the lower part of the cervical spine3 . a sustained forward - bending posture in the cervical spine could increase the load around the tissues near the neck4 , as well as the activities of muscles near the neck ; additionally , the load increase in the assistant muscles and joints becomes a main cause of chronic pain near the neck and shoulder areas5 . many studies have sought to determine various causes of chronic neck pain , and to present therapeutic approaches from various aspects ; the results of studies on what constitutes the best therapeutic approach to chronic neck pain , however , have been divergent6 . among the studies , one study reported that abnormal movement of the thoracic vertebra is a fundamental cause of cervical disorder in terms of the biomechanical correlation between the cervical spine and thoracic vertebra7 . another study reported that not only direct joint mobilization of the cervical spine but also improvement of movement in the upper thoracic vertebra can increase the range of motion and reduce pain in the cervical spine8 . the most effective joint exercise therapy for increasing mobility in the thoracic vertebra is thoracic joint mobilization , which extends the joint in a direction in which movement is restrained9 . a self - stretching exercise can not only increase the flexibility of muscles in the joints but can also reduce muscle tension and increase blood circulation10 . although many previous studies have sought to determine the effect of thoracic joint mobilization and self - stretching exercise on pain and range of joint motion , previous studies have not addressed their effects on pulmonary functions . the aim of the current study was to determine the effect of such treatment and exercise on the pulmonary functions of patients with chronic neck pain and thoracic kyphosis . the subjects of this study were 34 patients with chronic neck pain during spinal flexion who visited hospital n located in daegu metropolitan city , south korea . age , height , and weight in the tjm group ( tjmg ; 7 males and 4 females ) were on average , 55.61.1 years , 164.52.6 cm , and 63.63.5 kg . in the sse group ( sseg ; 5 males and 6 females ) , they were 53.00.8 years , 166.82.8 cm , and 166.82.8 kg . finally , in the tjmsse group ( tjmsseg ; 5 males and 7 females ) , they were 54.40.6 years , 167.32.3 cm , 65.03.5 kg . prior to the experiment , all the subjects listened to an explanation of the study s purpose and exercise methods and provided written consent . ethical approval for the study was granted by the youngdong university institutional review board . those who had been diagnosed with neurological findings and undergone operations or who were receiving surgical treatment or taking medicines on a regular basis to relieve pain were excluded from the study . we selected those with a spinal angle of 45 degrees or higher when measured in a standing position using a spinal mouse and a minor disability with a neck disability index ranging from 5 to 14 points . during a six - week period , tjmg performed tjm for 15 min , sseg performed sses for 15 min , and tjmsseg conducted tjm for 15 min and sses for 15 min . each subject was instructed to sit on a therapeutic chair , cross his / her arms , and place them in the transverse in the jointed part of the cervical vertebrae behind the neck . the therapist stood to the left of the subject and fixed his / her vertebrae to the spinal segments intended to be treated . using his / her hands , the therapist then adjusted the back support of the therapeutic chair or a wedge placed between the subjects and chair ( original kaltenborn concept wedge , allgummi gmbh & co , germany ) . the therapist then wrapped the subject s crossed elbows with his / her hands and flexed the subject s trunk slowly while pressing both elbows in the rear lower direction of the back support . during this process , the therapist used his / her hand to check the amount of spinal movement and potential movement of the vertebrae . the therapist and the subject maintained the same posture as that of thoracic flexion mobilization . after wrapping the subject s crossed elbows with a hand , the therapist slowly stretched the subject s trunk backward by pressing both elbows in the rear upper direction of the back support . finally , the separation technique of thoracic facet joint distraction mobilization was then employed . the therapist then selected the segments with less movement among the spinal auricular surfaces using a wedge and placed across the wedge crossways the selected vertebrae . the therapist grabbed the wedge with both hands and exerted a force for joint traction using his / her weight . first , the subject sat on a chair with his / her back straightened and pulled in his / her jaw . the subject held a long belt with both hands and spread it wider than the distance between the shoulders . while bending the shoulders at 180 , the subject flexed the shoulders excessively , as if stretching . after maintaining this position for 10 sec , the subject returned to the original position . while seated with a correct posture on the chair , the subject fixed the hand intended to be extended behind a sheet placed under the hip to depress the shoulder . after this , the subject adopted a cervical posture ( flexion + side flexion + rotation ; non - coupled motion ) to extend the upper trapezius to the fullest and maintained this posture for 45 sec . finally , the sse was performed on the levator scapulae of the shoulder bone . in this exercise , the subject adopted the correct sitting posture on a chair and depressed the shoulders by fixing the hand intended to be extended behind the sheet under the hip . the subject then adopted a posture ( flexion + side flexion + rotation couple motion ) to extend the levator scapulae to the fullest and maintained it for 45 sec . to measure pulmonary functions , a cardiotouch 3000s ( bionet ; seoul , south korea ) was used while the subjects remained seated . the forced vital capacity ( fvc ) and forced expiratory volume at one second ( fev1 ) were measured , while the peak expiratory flow ( pef ) was measured to determine airway resistance . to reduce measurement error , in each case repeated one - way anova was employed for statistical processing to determine the pulmonary function within each group ; one - way anova , meanwhile , was conducted to compare the groups themselves . the current study used spss 12.0 for windows for statistical processing , and the significance level was set to 0.05 . comparisons within each of the groups showed that fvc , fev1 , and pef increased significantly ( p < 0.05 ) . among the study groups , fvc was significantly higher in tjmsseg than in tjmg after six weeks ; fev1 was significantly higher in tjmsseg than in tjmg and sseg after four and six weeks ( p < 0.05 ) ; and pef was significantly higher in tjmsseg than in tjmg and sseg after six weeks ( p < 0.05 ) ( table 1 table 1.variation of fvc , fev1 , and pef between groups ) . this study conducted experiments three times a week for six weeks to identify the effects of tjm and sses on pulmonary function in patients with chronic neck pain . jeong11 reported that the rom in the jointed part of the neck and spine and chronic neck pain show a high correlation . in other words , if the rom in the jointed part of the neck and spine increases , the vas and neck disability index also increase in patients with chronic neck pain . cleland et al.12 reported that manipulation of the upper vertebrae ( c7 to t2 ) and middle vertebrae ( t3 to t10 ) exercises resulted in a statistically significant decline in chronic neck pain . sterling et al.13 reported that the vas declined from 5.8 cm to 2.8 cm after applying the joint mobilization technique . hurwitz et al.14 suggested that a three - week program of electrical therapy and joint mobilization was more effective than joint exercise in patients with subacute neck pain . kim et al.15 noted that the range of motion of the upper spine was an effective intervention for dynamic stability among chronic neck pain patients in active exercise therapies , extension is effective in increasing the rom in soft tissues and the rom in reduced narrow rom structures16 . jung17 reported that an eight - week home - based cervical exercise program changes the curves in the right side . omer et al.18 also asserted that mobilization and stretching relaxation techniques are effective for reducing and increasing the rom of computer users who exhibit cervical and trapezius pain . yang19 showed that application of thoracic vertebra extension exercises resulted in statistically significant increases in vas , spinal length ( c7 to s3 ) , and flexibility of thoracic vertebra extension . seo20 found that male office workers who complained of cervical pain experienced a minor level of improvement after application of upper thoracic vertebra exercises , but this result was not statistically significant . as mentioned , comparisons of the individuals within tjmg , sseg , and tjmsseg showed that fvc , fev1 , and pef had increased significantly ; among the study groups , fvc was significantly higher in tjmsseg than in tjmg after six weeks ; fev1 was significantly higher in tjmsseg than in tjmg and sseg after four and six weeks ; and pef was significantly higher in the tjmsseg than in the tjmg and sseg , after six weeks . chronic neck pain patients with thoracic kyphosis develop round shoulders that stem from increased thoracic kyphosis ; this triggers decreases in vital capacity and thoracic cavity capacity . this is because thoracic joint mobilization or self - stretching exercises for the spine improve limited movements of the spine , recover facet joint sliding , and normalize the articular capsule , thereby decreasing kyphosis and enhancing the flexibility of thoracic extension . therefore , it is considered that increased mobility of the thorax ameliorates pulmonary functions . in addition , pulmonary functions were better in tjmsseg than in tjmg and sseg after six weeks because the simultaneous performance of thoracic joint mobilization ( a therapist s passive manual therapy ) and self - stretching exercise ( performed by patients themselves ) was effective in recovering facet joint sliding of the spine and normalizing the articular capsule . the main one is the limited number of subjects with chronic neck pain , resulting in difficulties generalizing the results . furthermore , this study failed to measure range of motion of thoracic kyphosis and the flexibility of spinal extension . future studies will be required to identify the effects of tjm and sses on the pulmonary functions of patients with stroke .

[ purpose ] the objective of this study was to determine the effect of thoracic joint mobilization and self - stretching exercise on the pulmonary functions of patients with chronic neck pain . [ subjects ] the present study was performed with 34 patients with chronic neck pain featuring thoracic kyphosis ; we divided them into a thoracic joint mobilization group ( tjmg , n = 11 ) , self - stretching exercise group ( sseg , n = 11 ) , and thoracic joint mobilization and self - stretching exercise group ( tjmsseg , n = 12 ) . [ methods ] treatments and exercise were conducted three times a week for six weeks in tjmg , sseg , and tjmsseg ; the subjects pulmonary functions in terms of forced vital capacity ( fvc ) , forced expiratory volume at one second ( fev1 ) , and peak expiratory flow ( pef ) were measured using cardiotouch equipment . [ results ] comparisons of the individuals within each of the tjmg , sseg , and tjmsseg showed that all of fvc , fev1 , and pef increased significantly ; comparisons within each of the showed that fvc , fev1 , and pef increased significantly . among the study groups , fvc was significantly higher in tjmsseg than in tjmg after six weeks ; fev1 was significantly higher in tjmsseg than in tjmg and sseg after four and six weeks ; and pef was significantly higher in tjmsseg than in tjmg and sseg after six weeks . [ conclusion ] the study results indicate that thoracic joint mobilization and self - stretching exercise are effective interventions for increasing fvc , fev1 , and pef among pulmonary functions .

the surface of a protein is the region where the protein interacts with other molecules such as other proteins , nucleic acids , membrane receptors and small ligands . the electrostatic potential is a fundamental property of the protein surface , playing a central role in recognition of other macromolecules ( 1 ) . when the first 3d structures of protein dna complexes were solved it was noticed that charges are distributed asymmetrically on the protein surface , creating a patch of positive charges which complements the negative charge of the dna ( 2 ) . it was further suggested that charge complementarity is one of the first steps of recognition between proteins and dna ( 3,4 ) . indeed , large patches of positive charges have been suggested to be characteristic of protein nucleic acid interfaces ( 58 ) . recently , several methods have been developed for automatic prediction of dna - binding proteins based on the existence of large positive patches on the protein surface ( 6,7,811 ) in addition to nucleic acid binding , other essential protein functions could be dependent on the presence of large patches of positive charges on the protein surface ( 12 ) . among these are proteins which bind negatively charged membranes and receptor - binding ligands . furthermore , although protein protein interactions are usually known to be stabilized by a net neutral charge , different studies have revealed that positive and negative patches are commonly involved in protein protein interfaces ( 13,14 ) . in general , positively charged surfaces can be detected by visualizing the electrostatic properties of the protein surface with graphical programs such as grasp or grass ( 15,16 ) . the first program for graphical representation and analysis of surface properties of macromolecules was the grasp software ( graphical representation and analysis of surface properties ) , developed by nicholls et al . the electrostatic potential displayed by grasp is calculated using the finite - difference poisson boltzmann equation ( fdpb ) . a newer version of the grasp program , grasp2 , was published more recently ( 16 ) . in addition , the grass web server was developed ( 15 ) to exploit many of the features calculated by the previous programs on a simple interface over the world wide web . these programs , however , are not designed to capture isolated patches on the protein surface . in order to specifically detect continuous regions on the protein surface that could be indicative of the protein function , we have previously developed an in - house program named patchfinder ( 6 ) , similar approaches have been developed later by several groups ( 7,8,18 ) . boltzmann electrostatic potential of the protein and to construct the largest continuous positive patch on the protein surface . earlier , we have shown that there is a high overlap between the largest electrostatic positive patches on protein surfaces and the dna - binding interfaces ( 6 ) . figure 1 and supplementary figure s1 demonstrate the overlap ( colored in green ) between the largest positive patch , calculated with the patchfinder algorithm ( blue ) and the real nucleic acid - binding interface ( yellow ) extracted from six selected co - crystal structures of dna and rna - binding proteins . furthermore , the percent overlap between the patch and the interface for a randomly selected set of dna protein complexes is given in supplementary table s1 ( the average percent - overlap for the random set was 75% ) . as shown in the figures , though the percent overlap varies between the different structures in all cases the calculated patch coincides with the binding site of the nucleic acids . figure 1.overlap between the largest positive patch of the hiv-1 nucleocapsid protein ( calculated with the patchfinder algorithm ) and the experimentally defined rna - interface ( 1a1 t ) . the overlap is shown in green , while the calculated patch that did not overlap with the real interface is colored in blue . overall , a high degree of overlap is observed between the largest positive patch calculated with the pfplus server and the actual rna - binding interface calculated as described in stawiski et al . overlap between the largest positive patch of the hiv-1 nucleocapsid protein ( calculated with the patchfinder algorithm ) and the experimentally defined rna - interface ( 1a1 t ) . the overlap is shown in green , while the calculated patch that did not overlap with the real interface is colored in blue . overall , a high degree of overlap is observed between the largest positive patch calculated with the pfplus server and the actual rna - binding interface calculated as described in stawiski et al . recently , ahmad and sarai ( 18 ) have developed the qgrid web server which identifies charge and hydrophobic clusters in proteins ( http://www.netasa.org/qgrid/index.html ) . the qgrid program calculates the distribution of charge and hydrophobic regions throughout the protein and applies a hierarchical clustering algorithm for clustering the atoms based on their charge . the output of qgrid is a tree diagram of all grid points from which the user can interpret the different charge and hydrophobic clusters within the whole protein and the relationship between the different clusters . here we describe a new web server , patchfinderplus ( pfplus ) , for extracting electrostatic patches on the protein surface . different than the qgrid algorithm , pfplus is designed to map only the largest continuous positive patch on the protein surface . furthermore , the pfplus algorithm searches for adjacent grid points above a given cutoff , and thus does not require any heuristic calculations , such as clustering . our server provides a graphical output of the surface patch which presumably corresponds to the region on the protein surface involved in interaction with other molecules . the pfplus algorithm automatically assigns surface - positive patches by looking for adjacent points on the protein surface that meet a given electrostatic potential cutoff . the algorithm is built of five major steps : calculating the electrostatic potential of the protein on a 3d grid , using the poisson boltzmann equation.defining the grid points that fall closest to the protein surface while emitting all non - surface points.extracting all 3d patches of adjacent grid points which meet the defined cutoff.choosing the largest positive patch for each protein chain.assigning the protein residues related to the patch . calculating the electrostatic potential of the protein on a 3d grid , using the poisson boltzmann equation . defining the grid points that fall closest to the protein surface while emitting all non - surface points . extracting all 3d patches of adjacent grid points which meet the defined cutoff . choosing the largest positive patch for each protein chain . assigning the protein residues related to the patch . in the first step , boltzmann equation using the university of houston brownian dynamics ( uhbd ) software package ( 19 ) . in order to calculate the electrostatic potential , after applying the uhbd software , each grid point associated with the protein surface is assigned an electrostatic potential value . in the current version of pfplus , table 1.parameters used for electrostatics calculationsparameterdefault valuesparameter setoplsprobe radii1.4 stern layer2.0 temperature298 kionic strength150 mmdielectric constant protein / solvent2.0/78.0grid dimension65 65 65grid spacing1.5 parameters used for electrostatics calculations in the second step , the patchfinder algorithm searches for continuous electrostatic patches on the protein surface . for this purpose , we first define all protein surface points using the open source dms program , downloaded from the computer graphics laboratory at ucsf , http://www.cgl.ucsf.edu/resources/index.html . the dms program applies richards model ( 21 ) for obtaining the surface accessibility by rolling a ball of radius r along the van der walls surface of the molecule . in the next step , we select the grid points , calculated by the uhbd program , which fall closest to the protein surface . at this stage pfplus then searches for adjacent surface points on the 3d grid which meet a potential cutoff of 2kt / e . in order to select the largest positive patch , the pfplus program calculates the size of each continuous surface patch , based on the number of grid points included within the patch . subsequently , the patches are sorted by size . in the current version of the program in which there is no surface grid point that meet the electrostatic potential cutoff ( 2kt / e ) no patches will be detected . finally , the protein residues related to the grid points are selected and displayed . it is important to note that a protein residue is included within the patch if at least one of its atoms falls within the continuous patch of grid points . in figure 2 , the largest positive patch extracted from the pfplus server for a novel rna - binding domain of the hsp15 protein ( pdb code 1dm9 ) is shown from two view points ( top left and right ) in comparison to the original electrostatic potentials calculated with the uhbd program ( with the same input parameters as used in pfplus ) and visualized with the vmd software http://www.ks.uiuc.edu/research/vmd/ ( bottom left and right ) . the figure clearly shows that the pfplus algorithm captures a continuous positive region on the molecular surface . supplementary figure s2 provides four other examples comparing the positive patch obtained from the pfplus server to the electrostatic potential mapped onto the same molecule surface . the examples shown in supplementary figure s2 include two nucleic acid - binding proteins ( the tata - binding protein and the nuclear autoantigen sp100-b , supplementary figure s2 a and b , respectively ) and two proteins which do not bind nucleic acid ( supplementary figure s2 c and d ) . among the non - nucleic acid - binding is the cytochrome p450terp ( 1cpt ) in which the large positive patch is known , to be functional , possibly involved in protein protein interaction ( 22 ) . in addition , we show a relative small patch found in the barstar protein ( 1bta ) which does not have a known functional role . as clearly demonstrated , both the small and large patches extracted with the pfplus algorithm correspond to the positive charged region on the molecular surface illustrated in the bottom panel . it is important to note that two of the examples shown in supplementary figure s1 ( b and c ) are protein structures that were solved by nmr , demonstrating that the pfplus method is applicable for low - resolution structures . figure 2.a comparison between the largest positive patch on the surface of the hsp15 protein ( 1dm9 ) calculated with the pfplus server ( top left and right ) using the 2kt / e cutoff and the poisson boltzmann electrostatic potentials ( bottom left and right ) calculated with the uhbd software ( using the same parameters as applied in the pfplus server ) . for better representation the surface of the proteins is shown from two view points rotated 180 ( left and right ) . as demonstrated the largest positive patch calculated by the pfplus server ( top left ) clearly corresponds to the continuous positively charged region on the molecular surface ( bottom left ) . a comparison between the largest positive patch on the surface of the hsp15 protein ( 1dm9 ) calculated with the pfplus server ( top left and right ) using the 2kt / e cutoff and the poisson boltzmann electrostatic potentials ( bottom left and right ) calculated with the uhbd software ( using the same parameters as applied in the pfplus server ) . for better representation the surface of the proteins as demonstrated the largest positive patch calculated by the pfplus server ( top left ) clearly corresponds to the continuous positively charged region on the molecular surface ( bottom left ) . to extract the largest positive patch on a protein surface , the user should provide a pdb code of a protein or a protein complex . the pfplus program displays the largest positive patch ( defined by the number of grid points ) without assigning a significance value . the pfplus algorithm does not require a minimal resolution for calculating the largest positive patch , as long as all amino acid atoms are provided ( models including only ca atoms are not accepted ) . thus , the pfplus algorithm can be applied to structures solved by both x - ray crystallography and nmr , as illustrated in supplementary figure s2 b and c. as a default , the patch calculations for nmr structures are applied to the first model . it is important to note that the calculated electrostatic potential can fluctuate when changing input parameter , such as the grid spacing . an example of the largest positive patch calculated on the surface of the tata - binding protein ( tbp ) from arabidopsis thaliana is shown in figure 3 and supplementary figure s3 ( 1qnc ) . supplementary figure s3 demonstrates the effect of the input parameters on the extraction of the largest positive patch , as exemplified on the tbp structure . a detailed output of the residues included in each patch notably , when using the 2kt / e cutoff for the electrostatic potential ( the default of the pfplus server ) the patch calculation does not seem to strongly depend on the grid parameter . nevertheless , when applying a higher cutoff for including a grid point within the continuous patch the definition of the patch seem to be much more sensitive to changes in the electrostatic potential parameters . this is probably due to the sparse data of grid points which extend the 3kt / e cutoff . figure 3.pfplus output for the tata binding protein from arabidopsis thaliana ( pdb code 1qnc ) . as illustrated in both cases , the saddle - shaped dna - binding domain of the tata - binding protein coincides with the largest positive patch on the protein surface . pfplus output for the tata binding protein from arabidopsis thaliana ( pdb code 1qnc ) . as illustrated in both cases , the saddle - shaped dna - binding domain of the tata - binding protein coincides with the largest positive patch on the protein surface . currently , the pfplus server provides the user with three different types of output . shortly after submission ( depending on the protein size and the number of chains ) a jmol molecular viewer window will appear displaying a representative protein chain ( usually the first protein chain in the pdb file ) in a spacefill full atom representation . all atoms affiliated to the largest positive patch are colored in blue ( as illustrated in figure 3 ) . in addition , a jmol script for displaying the patch residues is available for downloading , as well as an output file ( in pdb format ) that includes the patch residues extracted for each protein chain provided originally in the input file . preceding the atomic coordinates of each protein chain , a pdb header is supplied providing the residue numbers of the all residues included in the largest positive patch . the pfplus web server is designed to calculate and display the largest positive patch on any given protein surface . we are currently integrating several more features which will be implemented in the next version of the pfplus web server . in the current version the cutoff for including a surface point in the continuous positive patch is predefined as 2kt / e . this cutoff was chosen based on our comprehensive analysis of nucleic acid interfaces in protein dna complexes(6 ) . in addition , the pfplus algorithm uses a set of default parameters for calculating the boltzmann equations . in the next pfplus version , the user will be able to change default parameters within a given range specified by the program . generally the patchfinder algorithm can support calculations of any continuous electrostatic patch on a protein surface , either a positive or a negative patch . in addition , the patchfinder algorithm can provide a ranked list of surface patches for any given protein sequence . in the next version of pfplus the presence of positive patches on protein surfaces can be indicative of protein functions such as nucleic acid binding , membrane binding and others . previous studies have suggested that the largest positive patch on the protein surface overlaps to a high extent with the nucleic acid - binding interface . we have developed an online web server for calculating and displaying the largest positive patch on protein surfaces . it is important to note that the pfplus server is not intended for predicting specific binding sites , however , it can suggest the location of binding interfaces on the protein surface . the input of the server is a pdb code or an input file in pdb format . the largest positive patch is provided as an output , both visually , displayed on a jmol viewer , and as a text file ( in pdb format ) including a list of all patch residues .

positively charged electrostatic patches on protein surfaces are usually indicative of nucleic acid binding interfaces . interestingly , many proteins which are not involved in nucleic acid binding possess large positive patches on their surface as well . in some cases , the positive patches on the protein are related to other functional properties of the protein family . patchfinderplus ( pfplus ) http://pfp.technion.ac.il is a web - based tool for extracting and displaying continuous electrostatic positive patches on protein surfaces . the input required for pfplus is either a four letter pdb code or a protein coordinate file in pdb format , provided by the user . pfplus computes the continuum electrostatics potential and extracts the largest positive patch for each protein chain in the pdb file . the server provides an output file in pdb format including a list of the patch residues . in addition , the largest positive patch is displayed on the server by a graphical viewer ( jmol ) , using a simple color coding .

the m.3243a > g mutation is one of the most common point mutation of the mitochondrial genome ( mtdna ) . several clinical syndromes have been ascribed to this mutation , including mitochondrial encephalopathy with lactic acidosis and stroke - like episodes ( melas ) , maternally inherited deafness and diabetes and progressive external ophthalmoplegia , but heterogeneity is high . other features include pure myopathy , cardiomyopathy , seizures , migraine , ataxia , cognitive impairment , gastro - intestinal dysmotility and short stature . so far , there is a large amount of data supporting the involvement of small vessels in mitochondrial disease and their dysfunction in stroke - like episodes . the mitochondrial angiopathy is characterized by accumulation of mitochondria within vascular endothelial cells and smooth muscle cells in cortical , white matter and leptomeningeal small arteries and arterioles . only a few case on large vessels involvement in mitochondrial diseases are well documented . here we report two patients harbouring the m.3243a > g mutation in whom the diagnosis was performed after acute internal carotid artery dissection . a 37-year - old italian woman was admitted because of neck pain and intense headache associated with right eyelid ptosis and ipsilateral miosis . her past medical history revealed a progressive sensor neural hearing loss and migraine without aura from infancy , diabetes mellitus and macular retinopathy from age 36 routine laboratory exams revealed mild increment of basal lactate ( 24 mg / dl ; normal < 21 ) and glycaemia ( 136 mg / dl , range 50110 ) . the remaining exams , including thrombophilic and rheumatologic screening , were negative . the mr angiography ( mra ) of brain and neck vessels demonstrated occlusion of pre- and intra - petrosal right internal carotid artery ( fig . molecular analysis of tgfr1 , tgfr2 and col3a1 genes were normal . because of the mild hyperlactacidemia and the presence of mitochondrial red flags such as diabetes mellitus , hearing loss and maculopathy , a quadriceps muscle biopsy was performed , and numerous ragged red / ragged blue fibers and cox - negative fibers were detected . mtdna analysis revealed the a g transition at position 3243 of the mtdna encoded mt - tl1 gene , detected in 60% and 70% of mtdna form muscle and urinary sediment respectively . at one year follow up , mra showed partial recanalization of the right internal carotid and no evidence of pseudoaneurysmal dilatation . an italian 50 years - old woman developed sudden speech disturbances and mild right arm strength reduction , followed by epileptic seizures . her past medical history revealed a progressive deafness since her 30s , which was also present in her mother ( who died at 74-yrs because of stroke ) , her son and in a maternal aunt . a brain ct scan showed a left temporal - parietal cortical stroke - area , confirmed by a brain mri , and basal ganglia bilateral calcifications . 2 ) ; the left artery dissection brought to a stenosis and a pseudoaneurismatic lesion , while the right one was completely collapsed . blood tests , including basal lactate , rheumatological and thrombophilic screening , were normal , as well as the genetic screening for collagen syndromes ( col1a1 , col1a2 , col3a1 , col5a1 , col5a2 ) . the common mutation m.3243a > g was present in 30% of mtdna from urinary sediment , and absent on blood 's leukocytes . a 37-year - old italian woman was admitted because of neck pain and intense headache associated with right eyelid ptosis and ipsilateral miosis . her past medical history revealed a progressive sensor neural hearing loss and migraine without aura from infancy , diabetes mellitus and macular retinopathy from age 36 routine laboratory exams revealed mild increment of basal lactate ( 24 mg / dl ; normal < 21 ) and glycaemia ( 136 mg / dl , range 50110 ) . the remaining exams , including thrombophilic and rheumatologic screening , were negative . the mr angiography ( mra ) of brain and neck vessels demonstrated occlusion of pre- and intra - petrosal right internal carotid artery ( fig . molecular analysis of tgfr1 , tgfr2 and col3a1 genes were normal . because of the mild hyperlactacidemia and the presence of mitochondrial red flags such as diabetes mellitus , hearing loss and maculopathy , a quadriceps muscle biopsy was performed , and numerous ragged red / ragged blue fibers and cox - negative fibers were detected . mtdna analysis revealed the a g transition at position 3243 of the mtdna encoded mt - tl1 gene , detected in 60% and 70% of mtdna form muscle and urinary sediment respectively . at one year follow up , mra showed partial recanalization of the right internal carotid and no evidence of pseudoaneurysmal dilatation . an italian 50 years - old woman developed sudden speech disturbances and mild right arm strength reduction , followed by epileptic seizures . her past medical history revealed a progressive deafness since her 30s , which was also present in her mother ( who died at 74-yrs because of stroke ) , her son and in a maternal aunt . a brain ct scan showed a left temporal - parietal cortical stroke - area , confirmed by a brain mri , and basal ganglia bilateral calcifications . 2 ) ; the left artery dissection brought to a stenosis and a pseudoaneurismatic lesion , while the right one was completely collapsed . blood tests , including basal lactate , rheumatological and thrombophilic screening , were normal , as well as the genetic screening for collagen syndromes ( col1a1 , col1a2 , col3a1 , col5a1 , col5a2 ) . the common mutation m.3243a > g was present in 30% of mtdna from urinary sediment , and absent on blood 's leukocytes . our report describes two females in whom the diagnosis of mitochondrial disease was made after acute carotid artery dissection leading to a neurological syndrome . our findings further broaden the clinical spectrum of the m.3243a > g mutation , document a possible role of mitochondrial involvement in large vessels dissection , and suggest a mitochondrial screening in patients with carotid artery dissection , at least when canonical mitochondrial red flags are present . vascular pathology in m.3243a > g melas has been extensively described for small vessels . histological examination of muscle biopsy shows the so - called strongly sdh reactive blood vessels , indicating mitochondrial proliferation . the pathogenesis of stroke - like episodes in melas is not fully understood although two main theories have been proposed : the ischemic vascular hypothesis caused by a mitochondrial angiopathy and the metabolic and neuronal hyperexcitability hypotheses . a neuropathological study showed vascular abnormalities , characterized by proliferation of enlarged mitochondria in smooth muscle cells and endothelium of small cortico - leptomeningeal vessels . the same study also showed the highest m.3243a > g mutation load in the vessels wall ( 99% ) and severe cytochrome c oxidase ( cox ) deficiency , arguing that the mitochondrial pathology of small vessels leads to an altered vascular tone and that vascular abnormalities are the primary cause of ischemia and stroke - like episodes . the first report of large - vessels involvement in melas came from dr . di mauro 's lab , a 15-year old girl who died after minor surgical procedure of spontaneous rupture of thoracic aorta ; her mother also died of ruptured vessels . the authors observed severe mitochondrial dysfunction in the vessel wall leading to disruption of the smooth muscle layers directly or through impaired blood supply due to vasa vasorum angiopathy . immunohistochemical staining for cox showed decreased cox i staining in smooth muscle cells and endothelial cells of vasa vasorum . the m.3243a > g mutation load in the ruptured aortic wall was 85% compared with 40% in blood . nemes and coworkers studied ascending aorta elasticity through transthoracic echocardiography in m.3243a > g patients , and found an increased aortic stiffness , enlarged aortic dimension and reduced aortic strain and distensibility , suggesting vascular remodelling and alteration in aortic elasticity . another report suggested that in some cases stroke - like episode could subtend a large vessel dysfunction : during the acute phase of the first stroke - like episodes in a 26-year old woman with melas , a transient narrowing of the crural segment of posterior cerebral artery was observed . similarly , a case of melas who presented with stroke - like episode and reversible cerebral vasoconstriction syndrome involving cerebral arteries junction resolved after intravenous l - arginine supports the role of nitric oxide as a key factor in the pathogenesis of stroke - like episodes and vasospasm . moreover , transient and recurrent stenosis or occlusion of both carotid arteries with spontaneous resolution associated with stroke has been described in a case of mitochondrial encefalomyopathy due to a trnaphe mtdna mutation . the authors suggested degenerative changes or a developmental abnormality as main cause of the stenosis , because the carotids appeared smooth , thin and without calcification to vascular imaging and no signs of dissection of the wall were present . finally , vascular stenosis may be rarely progressive in the setting of mitochondrial disease ; longo and collaborators described the case of a child harboring a m.3243a > t mutation with a rapidly evolving brain involvement due to progressive stenosis of both distal carotid and origin of cerebral arteries with development of collateral circulation , resembling a moya moya syndrome . so far , although there is a growing list of monogenic disorders associated with cervical artery dissection , , only one case of dissection of the cervical arteries associated with the m.3243a > g has been described , a case of a 47-year old woman who underwent recurrent dissection of internal carotid artery during stroke - like episodes , as observed in our case 2 . our report provides further evidence about a large vessels involvement in mitochondrial diseases . in some cases , mitochondrial dysfunction in endothelium and in smooth muscle cells may cause energy failure of the carotid wall , thus predisposing to vessel pathology like dissection , vasospasm , rupture or ischemia contributing , by means of hypoperfusion and artery - to - artery embolism , to the overall stroke burden in mitochondrial disease . interestingly , both our patients suffered also of migraine which has been suggested as a risk factor for cervical artery dissection ; migraine is also a common sign of m.3243a > g population , and vascular and mitochondrial dysfunctions have also been implicated in migraine . though we can not provide histopathological demonstration of a mitochondrial dysfunction in the carotid artery , we can hypothesize that the dissection of the carotid artery as described in our cases could be seen as the tip of the iceberg of a more diffuse and subtle vascular mitochondrial dysfunction . moreover , additional canonical risk factors leading to ischaemic stroke or dissection were screened , and were negative in both cases . diabetes , present in our case 1 , should not play a major role in the pathogenesis of the dissection , because it is well known from the cadisp studies that all traditional vascular risk factors , including diabetes , are less frequent in cervical artery dissection patients compared with young patients with a non - cervical artery dissection ischaemic stroke . further studies are needed to evaluate the association between mitochondrial disease and large vessels pathology .

the common m.3243a > g mutation of the mitochondrial dna trnaleu ( uur ) gene is a maternally inherited mutation causing a wide spectrum of neurological and multisystemic disorders , including melas , characterized by recurrent cerebral infarction from young age . vascular pathology in mitochondrial diseases has been described for small vessels , while large vessels involvement in mitochondrial diseases is considered rare.here we report two female patients harboring the m.3243a > g mutation , in whom the diagnosis of mitochondrial disease was made after acute dissection of the internal carotid arteries . our cases expand the clinical spectrum of this mutation , and support the idea of large vessels vasculopathy due to impaired mitochondrial function in the vessel wall that may lead to arterial wall weakness . thus , stroke in mitochondrial diseases could also be related to large vessels disease , but further studies are strongly needed . moreover , mitochondrial aetiology should be kept in mind in patients with large vessel dissection , especially in those with additional mitochondrial red flags .

although infrequent ( 1% to 4% in the first year ) , infective endocarditis may occur after aortic valve replacement.13 when present , prosthetic valve endocarditis is a severe problem that is associated with considerable morbidity , especially related to peripheral embolism , perivalvular abscess , and sepsis.49 acute coronary syndromes are uncommon in prosthetic valve endocarditis , with a prevalence of between 1% and 3%.10 the most likely mechanisms responsible for myocardial ischemia are the presence of preexisting coronary artery disease and coronary emboli from aortic vegetations . other less frequent mechanisms have been described , such as obstruction of the coronary ostium due to large vegetation and severe aortic insufficiency.1014 external coronary artery compression due to infective endocarditis is also a described mechanism , but is a rare occurrence with only few cases reported in medical literature.11,1421 we report a 46-year - old patient who presented with acute myocardial infarction caused by an aortic root abscess , which resulted in the external compression of the left main coronary artery . a 46-year - old man presented at instituto de cardiologia do distrito federal , brasilia , brazil with a history of dyspnea and fatigue exacerbated by a recent hospitalization related to pulmonary edema . diagnosis was confirmed by echocardiography , which revealed the presence of a bicuspid aortic valve with mixed lesion , predominantly stenotic . the operation and his postoperative recovery were uneventful , and the patient was discharged home on the sixth day after the procedure in good condition . he was prescribed the following medications to take at home : enalapril 5 mg twice daily , carvedilol 6.25 mg twice daily , furosemide 20 mg daily , and ferrous sulfate 300 mg daily ( orally ) . approximately 1 month later , the patient returned , complaining of a high - grade fever and chills for a few days . he was admitted to the emergency department with acute onset chest pain , dyspnea , and vomiting . on physical exam , he was lethargic , febrile , pale , and hemodynamically unstable , with cold extremities and faint pulses . admitting electrocardiogram revealed normal sinus rhythm , signs of left ventricle hypertrophy , and st depression on posterior and lateral leads ( figure 1 ) . the cardiologist on call interpreted the patient as having non - st elevation acute coronary syndrome , and treated him with aspirin , clopidogrel , morphine , and heparin . an emergent coronary angiogram ( figure 2a ) revealed a long , complex lesion on the left main coronary artery ( 80% lumen obstruction ) with tapering contor , suggesting extrinsic compression . due to ongoing myocardial ischemia and hemodynamic compromise , an intra - aortic balloon pump was inserted . before the blood cultures results were available , broad - spectrum anti biotics ( vancomycin , rifampicin , and imipenem ) and also an anti - fungal drug ( amphotericin b ) were initiated empirically . transesophageal echocardiog - raphy showed vegetations attached to the prosthesis , aortic root abscess , and an aortic - to - right - atrium fistula . left ventricle ejection fraction was 36% , and there were wall motion abnormalities on lateral and anterior walls . chest computed tomography ( figure 2b ) suggested that left main compression was due to aortic root abscess or hematoma . urgent reoperative aortic valve replacement was indicated . the operation was performed with the aid of hypothermic cardiopulmonary bypass with aortic and bicaval cannulation . myocardial protection was achieved with cold blood cardioplegia delivered through the coronary ostium and coronary sinus . an oblique aortic arteriotomy revealed a large anterior aortic root abscess , which had invaded the left and right coronary cuspids . the bioprosthesis was removed , and the abscess was evacuated ; complete debridement of all infected material was also performed . the aortic - to - right atrium fistula was closed with an autologous pericardium patch . additionally , a coronary artery bypass grafting with a reversed saphenous vein graft to left anterior descending artery was performed . prolonged cardiopulmonary bypass and mediastinal bleeding were problems in the operating room , requiring vigorous transfusion and delayed chest closure on the next day . postoperatively , the patient had acute renal failure requiring hemodialysis , sepsis , transient liver failure , prolonged mechanical ventilation , and complete atrioventricular block requiring permanent pacemaker . antibiotic therapy , as previously mentioned , was initiated empirically with vancomycin , rifampicin , imipenem , and amphotericin b. rifampicin was discontinued on the second day of use due to mild liver failure . vancomycin was replaced by teicoplanin shortly after the operation due to acute renal failure , and it was used until the 30th postoperative day . then , it was replaced by fluconazole , which was continued for a year thereafter . a month after the operation , the left ventricular function had improved ( ejection fraction of 58% ) with a mildly dilated ventricle and a normal aortic valve function . the patient was discharged home 6 weeks after surgery in good condition , with no signs of active infection . at 36-month follow - up , the patient is currently in new york heart association functional class i with no recurrent infection , and the ventricular function is normal . the left main is widely patent and the saphenous vein graft is occluded on control chest computed tomography ( figure 3 ) . the present case describes a rare complication of prosthetic valve endocarditis , an aortic root abscess causing external coronary artery compression and acute myocardial infarction . this mechanism of myocardial infarction has already been described.11,1421 the most likely mechanisms responsible for myocardial infarction during infective endocarditis are preexisting coronary artery disease and coronary artery emboli from vegetations . prosthetic valve endocarditis is associated with elevated hospital mortality ( approximately 40%)22 and morbidity dependent on the infecting pathogen , duration of illness prior to therapy , and underlying comorbidities.23 mansur et al24 presented a total of 386 complications in 223 episodes of endocarditis ( 74% complication rate ) , being 100 occurrences of cardiac complications ( severe heart failure , valve injury , pericarditis , acute myocardial infarction , conduction abnormalities , fistulous communication , perivalvular abscess , and others ) , 72 neurologic complications ( cerebral embolism , mycotic aneurysms , meningitis , stroke , intracranial hemorrhage , cerebral abscess , and others ) , 46 septic complications ( infection unresponsive to treatment , persistent fever , disseminated intravascular coagulation , and others ) , 27 renal complications ( renal failure , nephrotic syndrome ) , 16 extracranial systemic arterial complications , 26 septic pulmonary embolisms , three splenic infarctions or abscesses , and some other complications associated with infective endocarditis . clinical presentation of acute coronary syndromes in patients with endocarditis is similar to those with coronary artery disease . as systems attempt to meet stringent door - to - balloon initiatives , it becomes imperative that a detailed history and physical exam be performed in this narrow time window in order to avoid unnecessary tests and/or therapeutic regimens . for instance , the diagnostic work - up of a patient with a clinical history of high - grade fever and chills within a month after a straightforward aortic valve replacement with known absence of coronary artery disease includes , firstly , a transesophageal echocardiography.17 it has a sensitivity and a specificity for abscess detection of 87% and 95% , respectively.25 coronary angiogram in this particular patient was indicated based on a misdiagnosis of coronary artery disease . although the angiographic appearance is typical ( complex and long lesion that often disappears on diastole ) , coronary angiogram should be avoided because it may cause dislodgment of septic fragments , which fortunately did not occur in this particular case . the isolation of the causative organism of prosthetic valve endocarditis is essential , and antibiotic therapy should be delayed pending the blood culture results in cases of patients who are hemodynamically stable with an indolent clinical course . however , patients presenting hemodynamic instability or acute disease should receive empiric broad - spectrum antibiotic therapy promptly.26 therapy should be subsequently adjusted according to the culture results . the american heart association ( aha ) and the european society of cardiology ( esc ) guidelines recommend that prosthetic valve endocarditis should be treated for at least 6 weeks with adequate bactericidal agent . presence of acute coronary syndrome in the setting of prosthetic valve endocarditis carries an elevated morbidity and mortality rates.27 although uncommon , external compression of coronary artery should be considered in the differential diagnosis of these patients , and adequate diagnostic work - up and treatment should be indicated.11 treatment with anti - platelet agents increased the risk of cerebral bleeding and certainly complicated the operative treatment in this patient.28 although the patient was a very high - risk surgical candidate , the urgent operation was justified due to patient s age and treatable heart problems , despite the presence of active infection , aortic root invasion , and abscess . the root abscess perforated the membranous septum , causing aortic to right atrium fistula , and there was a huge invasion of the left coronary cuspid around the left main coronary artery , which caused its extrinsic compression and myocardial ischemia . the treatment of prosthetic endocarditis was standard : extensive debridement , patch closure of fistula , and aortic root replacement with cryopreserved homograft.29 coronary artery bypass to left anterior descending was also performed in order to guarantee an adequate myocardial blood flow shortly after the operation . the adequate coronary button re - implant and obstruction relief established good coronary perfusion , and the saphenous vein graft has occluded due to competitive flow . we experienced a rare complication of prosthetic valve endocarditis : external coronary artery compression due to aortic root abscess . although uncommon , this mechanism should be considered in the differential diagnosis of patients presenting acute coronary syndrome in the setting of prosthetic valve endocarditis , and adequate diagnostic work - up and treatment should be indicated .

a 46-year - old man with bicuspid aortic valve and severe calcific aortic stenosis was submitted to aortic valve replacement with a stented bioprosthesis . he developed staphylococcus epidermidis prosthetic valve endocarditis a month later , presenting in the emergency room with acute myocardial infarction . the mechanism of myocardial ischemia was a large aortic root abscess causing left main extrinsic compression . he was urgently taken to the operating room , and an aortic root replacement with cryopreserved homograft was performed , associated with autologous pericardium patch closure of aortic to right atrium fistula and coronary artery bypass grafting of the left anterior descending . after a difficult postoperative period with multiple problems , he was eventually discharged home . at 36-month follow - up , he is asymptomatic with no recurrent infection , and the left main coronary artery is widely patent on control chest computed tomography .

we report a case of a female patient on aspirin and warfarin who developed a retropharyngeal haematoma following minor blunt head and neck trauma . an 84 year old woman had a mechanical fall at ground level resulting in neck hyperextension . a rigid cervical collar was applied and anterior neck and chest swelling and bruising were noted beneath this . a massive retropharyngeal haematoma was observed extending between c2 and t4 vertebral body levels with displacement and compression of the trachea ( figure 1,2 ) . there was no evidence of carotid , vertebral or internal jugular vein injury and no cervical fracture . contrast enhanced axial ct image taken at the level of the hyoid bone shows a large retropharyngeal haematoma ( star ) with active intravenous contrast extravasation ( arrow ) contrast enhanced sagittal ct image shows a large retropharyngeal haematoma ( star ) extending from the c2 vertebral level to below the level of the sternal notch with tracheal compression ( arrow ) nine hours from the time of injury the patient developed stridor . although significant subglottic swelling was evident at intubation , a 6.5 mm diameter endotracheal tube was successfully and atraumatically positioned into the distal trachea . a four vessel angiogram was then obtained which revealed an actively bleeding branch of the right inferior thyroid artery . the patient was managed non - operatively with intravenous antibiotics , steroids and inr reversal . over the coming days her neck swelling decreased and serial ct showed a reduction in size of the haematoma . dysphagia necessitated nasogastric feeding for a further week and mild dysphonia persisted for two weeks . the patient otherwise made a good recovery , returning to her previous level of function by six weeks . aetiological factors implicated in retropharyngeal haematoma include blunt head and neck trauma , cervical spine injury , anticoagulation , bleeding diatheses and tumors . most cases are thought to be due to bleeding from vessels covering the anterior longitudinal ligament.(2 ) less commonly bleeding has been reported to originate from the thyrocervical trunk ( 3 ) as was likely the situation in this case . the classic clinical presentation comprises capp s triad of airway compression , displacement of the trachea anteriorly and bruising of the neck and chest.(1 ) however , the clinical presentation is highly variable and may range from mild sore throat to hoarseness , dysphagia , odynophagia , dyspnoea or stridor.(15 ) an asymptomatic interval between time of injury and onset of stridor has been described(4 ) as in this case . the first step is to secure the airway if there is any evidence of airway obstruction . the haematoma may distort the anatomy of the upper airway making visualization of the cords difficult . a surgical airway is advocated by some authors as the preferred method because endosopic intubation may be difficult and carry a higher risk of perforating the haematoma.(3 ) we elected to trial an awake endoscopic intubation method with tracheostomy equipment available if required . this intubation method allowed direct visualization of the laryngeal anatomy with minimal manipulation of the haematoma whilst maintaining cervical spine alignment . with the airway secured , most patients are successfully managed conservatively with observation , supportive treatment and monitoring with serial ct . the haematoma usually resolves but can take four weeks or more.(5 ) surgical evacuation or transoral aspiration is generally reserved for a haematoma that is rapidly expanding , impeding mechanical ventilation or failing to resolve . although surgery may lead to an earlier extubation and recovery , it does carry an increased risk of infection . ( 1 ) we have presented a case of a large retropharyngeal haematoma in an elderly anticoagulated patient following minor blunt head and neck trauma . the patient presented insidiously with capp s triad and developed delayed airway obstruction necessitating emergency fibreoptic endoscopic intubation . conservative management may be appropriate in patients with non expanding haematomas that show improvement on serial ct .

retropharyngeal haematoma is a rare and potentially fatal cause of airway obstruction . the treatment of retropharyngeal haematoma is contentious . we report a case of an 84 year old woman on aspirin and warfarin who developed a retropharyngeal haematoma following minor blunt head and neck trauma . the patient presented insidiously with capp s triad and developed delayed airway obstruction necessitating emergency fibreoptic endoscopic intubation . both tracheostomy and surgical drainage were avoided and she recovered well .

supplementary figure 1 pilot experiments to optimize pooling strategy for next - generation sequencing of orf clones . supplementary figure 4 alignment results of 14,524 completely sequenced clones with current ncbi refseq transcripts . supplementary figure 5 plasmid maps of plx lentiviral expression vectors created as part of this study . supplementary figure 8 virus titer and orf expression are maintained across a wide range of orf lengths . supplementary table 1a clonal and sequenced orf gateway entry clone collections supplementary table 1b comparison of nomura and ccsb - broad orf collections supplementary table 2 illumina sequencing pilot data supplementary table 3 overview of next generation sequencing results supplementary table 4 annotated list of horfeome v8.1 and ccsb - broad lentiviral expresson library . supplementary note 1 availability of clones and distribution procedures supplementary note 2 pilot experiments to determine number of colonies to isolate per polyclonal orf . supplementary note 4 challenges of completing the human orfeome supplementary note 5 detailed high - throughput protocol of single colony isolation . supplementary note 7 computing virus titers . supplementary note 8 li - cor in - cell western and immunoblotting .

functional characterization of the human genome requires tools for systematically modulating gene expression in both loss- and gain - of - function experiments . we describe the production of a sequence - confirmed , clonal collection of over 16,100 human open - reading frames ( orfs ) encoded in a versatile gateway vector system . utilizing this orfeome resource , we created a genome - scale expression collection in a lentiviral vector , thereby enabling both targeted experiments and high - throughput screens in diverse cell types .

before discussing the methodology , a detailed understanding of finite element method and its significance is essential . the basic idea in finite element method is to find the solution for a complicated problem by replacing it by a simpler one . in finite element method , the actual continuum or body of the matter these elements are considered to be interconnected at specified points , which are called nodes or nodal points . a variety of element types and shapes are available to provide users with the required flexibility to meet the compatibility and completeness requirements . it is useful in solving complex structural problems by dividing the complex structures into many simpler and smaller segments . the technical improvement in computers and finite element software , has improved accuracy and speed of this analysis . in the general field of medicine microsoft windows 98 se ( operating system)computer aided designing ( cad ) or modeling software proe-2001msc microsoft windows 98 se ( operating system ) computer aided designing ( cad ) or modeling software proe-2001 msc the creation of geometric model , mesh generation , and boundary conditions were applied . in the case of postprocessing simulating , creation of geometric model before developing a finite element model of any system , a geometric model should be generated using cad software . the three - dimensional model to create is a maxillary four incisors and its surrounding structures such as alveolar bone and its periodontal ligament . the morphological dimensions of the teeth used were as given by wheeler 's dental anatomy ( 6 edition ) . from the standard dimensions , the bounding points of the cross - section ( in space x , y , and z coordinates ) were determined and plotted in the cad graphics screen . with the bounding points called the key points , smooth lines were drawn connecting all the key points simulating the profile of the natural tooth . with the sketch model , volume for the section of the body is created ( solid modeling ) [ figures 1 and 2 ] . in a similar manner , the periodontal ligament surrounding the tooth and alveolar bone as it was difficult to obtain the hourglass shape of the periodontal ligament in our study , it was assumed to be 0.25 mm thickness around the radicular portion , although the thickness varies from the alveolar crest to the apex . the alveolar bone was modeled as a rectangular block of structure with labial thickness of 3 mm apically and 5 mm distally to the existing tooth [ figure 4 ] . sectioned natural tooth sectioned natural tooth periodontal ligament surrounding alveolar bone and tooth are modeled alveolar bone modeled in rectangular block finite element model generation ( mesh generation ) this forms the backbone of the finite element analysis . in this stage , the geometric model is converted into the finite element model . the cad model was meshed or divided into several three - dimensional tetrahedral shaped finite elements [ table 1 ] . tetrahedral elements are used in order to precisely mesh the curved and irregular regions present in the tooth [ figure 5 ] . the mechanical properties of each material such as bone , periodontal ligament and the tooth are taken from the previously published values [ table 2 ] . number of elements and nodes in the model mechanical properties for tooth , periodontal ligament and alveolar bone superior surface of bone model the boundary conditions with the areas where the model was restrained from any further movements were assigned as follows , at the superior surface of the bone model ( area representing the palatal surface ) , the area was constrained at their bases to avoid overall rigid body motion 3 [ figure 5 ] . the three - dimensional model was oriented in such a way that the mesiodistal plane was represented by x axis , the vertical plane by the y axis and the labiolingual plane by the z axis . to evaluate the center of resistance the force was applied at a distance of 5.2 mm from the incisal edge of the modeled tooth in the labiolingual direction ( along the z axis ) . the magnitude of force given was 15 g of intrusive force and 120 g of retractive force for each tooth . determination of center of resistance center of resistance of a tooth is a point through which a pure force if acts will produce linear movement without rotation . since , it is a geometric property the finite element analysis itself can easily locate it . microsoft windows 98 se ( operating system)computer aided designing ( cad ) or modeling software proe-2001msc microsoft windows 98 se ( operating system ) computer aided designing ( cad ) or modeling software proe-2001 msc the creation of geometric model , mesh generation , and boundary conditions were applied . in the case of postprocessing simulating , the tooth movement and determination of center of resistance were done . creation of geometric model before developing a finite element model of any system , a geometric model should be generated using cad software . the three - dimensional model to create is a maxillary four incisors and its surrounding structures such as alveolar bone and its periodontal ligament . the morphological dimensions of the teeth used were as given by wheeler 's dental anatomy ( 6 edition ) . from the standard dimensions , the bounding points of the cross - section ( in space x , y , and z coordinates ) were determined and plotted in the cad graphics screen . with the bounding points called the key points , smooth lines were drawn connecting all the key points simulating the profile of the natural tooth . with the sketch model , volume for the section of the body is created ( solid modeling ) [ figures 1 and 2 ] . in a similar manner , the periodontal ligament surrounding the tooth and alveolar bone as it was difficult to obtain the hourglass shape of the periodontal ligament in our study , it was assumed to be 0.25 mm thickness around the radicular portion , although the thickness varies from the alveolar crest to the apex . the alveolar bone was modeled as a rectangular block of structure with labial thickness of 3 mm apically and 5 mm distally to the existing tooth [ figure 4 ] . sectioned natural tooth sectioned natural tooth periodontal ligament surrounding alveolar bone and tooth are modeled alveolar bone modeled in rectangular block finite element model generation ( mesh generation ) this forms the backbone of the finite element analysis . in this stage , the geometric model is converted into the finite element model . the cad model was meshed or divided into several three - dimensional tetrahedral shaped finite elements [ table 1 ] . tetrahedral elements are used in order to precisely mesh the curved and irregular regions present in the tooth [ figure 5 ] . the mechanical properties of each material such as bone , periodontal ligament and the tooth are taken from the previously published values [ table 2 ] . number of elements and nodes in the model mechanical properties for tooth , periodontal ligament and alveolar bone superior surface of bone model the boundary conditions with the areas where the model was restrained from any further movements were assigned as follows , at the superior surface of the bone model ( area representing the palatal surface ) , the area was constrained at their bases to avoid overall rigid body motion 3 [ figure 5 ] . the three - dimensional model was oriented in such a way that the mesiodistal plane was represented by x axis , the vertical plane by the y axis and the labiolingual plane by the z axis . to evaluate the center of resistance the force was applied at a distance of 5.2 mm from the incisal edge of the modeled tooth in the labiolingual direction ( along the z axis ) . the magnitude of force given was 15 g of intrusive force and 120 g of retractive force for each tooth . determination of center of resistance center of resistance of a tooth is a point through which a pure force if acts will produce linear movement without rotation . since , it is a geometric property the finite element analysis itself can easily locate it . creation of geometric model before developing a finite element model of any system , a geometric model should be generated using cad software . the three - dimensional model to create is a maxillary four incisors and its surrounding structures such as alveolar bone and its periodontal ligament . the morphological dimensions of the teeth used were as given by wheeler 's dental anatomy ( 6 edition ) . from the standard dimensions , the bounding points of the cross - section ( in space x , y , and z coordinates ) were determined and plotted in the cad graphics screen . with the bounding points called the key points , smooth lines were drawn connecting all the key points simulating the profile of the natural tooth . with the sketch model , volume for the section of the body is created ( solid modeling ) [ figures 1 and 2 ] . in a similar manner , the periodontal ligament surrounding the tooth and alveolar bone were also modeled [ figure 3 ] . as it was difficult to obtain the hourglass shape of the periodontal ligament in our study , it was assumed to be 0.25 mm thickness around the radicular portion , although the thickness varies from the alveolar crest to the apex . the alveolar bone was modeled as a rectangular block of structure with labial thickness of 3 mm apically and 5 mm distally to the existing tooth [ figure 4 ] . sectioned natural tooth sectioned natural tooth periodontal ligament surrounding alveolar bone and tooth are modeled alveolar bone modeled in rectangular block finite element model generation ( mesh generation ) this forms the backbone of the finite element analysis . in this stage , the geometric model is converted into the finite element model . the cad model was meshed or divided into several three - dimensional tetrahedral shaped finite elements [ table 1 ] . tetrahedral elements are used in order to precisely mesh the curved and irregular regions present in the tooth [ figure 5 ] . the mechanical properties of each material such as bone , periodontal ligament and the tooth are taken from the previously published values [ table 2 ] . number of elements and nodes in the model mechanical properties for tooth , periodontal ligament and alveolar bone superior surface of bone model the boundary conditions with the areas where the model was restrained from any further movements were assigned as follows , at the superior surface of the bone model ( area representing the palatal surface ) , the area was constrained at their bases to avoid overall rigid body motion 3 [ figure 5 ] . the three - dimensional model was oriented in such a way that the mesiodistal plane was represented by x axis , the vertical plane by the y axis and the labiolingual plane by the z axis . to evaluate the center of resistance the force was applied at a distance of 5.2 mm from the incisal edge of the modeled tooth in the labiolingual direction ( along the z axis ) . the magnitude of force given was 15 g of intrusive force and 120 g of retractive force for each tooth . determination of center of resistance center of resistance of a tooth is a point through which a pure force if acts will produce linear movement without rotation . since , it is a geometric property the finite element analysis itself can easily locate it . the location of center of resistance has been studied over the years with numerous model systems , these studies include , analytical models , direct measurement in vivo , photo elastic technique , strain gauge technique , laser reflection technique , and holographic method , etc . although these model systems have provided some insight into the displacement characteristics of the tooth to the applied forces , these studies have obvious limitations such as direct measurement in vivo have a distinct disadvantage of being invasive . furthermore , it is difficult to apply controlled force variables on human subjects because of anatomic constraints . the major limitation in studies that used physical models was that synthetic substances were used to simulate the periodontal ligament . many of those materials did not have physical properties exactly duplicating that of the periodontal ligament . in the analytical techniques , the root morphology has been approximated to parabolid , conical or wedge shape leading to different results . to overcome the essence of this method is that a predetermined force is idealized into an assemblage of separated finite regions or elements . these are then considered to be interconnected at specific points called nodes on their common boundaries.[5 . the results obtained in this study is in accordance with the study of matsui et al .

aim : the aim of this study is to evaluate the center of resistance of maxillary incisors during simultaneous intrusion and retraction.subjects and methods : in this study , the following steps were employed namely , ( 1 ) preprocessing - the creation of geometric model , mesh generation and boundary conditions . ( 2 ) postprocessing - the tooth movement and determination of center of resistance.results:the center of the mid - sagittal plane approximately 6 mm apical and 4 mm posterior to a line perpendicular to the occlusal plane from the labial alveolar crest of the central incisor resistance for the maxillary four incisors was located within the.conclusion:finite element is a sound mechanical method of analysis as it was sufficient enough to provide insight into interactions between orthodontic forces , and dental tissues and reliability of this study . further by using this study clinically , the center of resistance can be precisely located in single rooted tooth during orthodontic treatment .

the elderly population has increased tremendously in the past few decades all over the world . the number of people aged 65 or older is projected to grow from an estimated 524 million in 2010 to nearly 1.5 billion in 2050 , with most of the increase in developing countries . the 2011 , united nations population division reports that the share of india 's population ages 60 and older is projected to climb from 8 percent in 2010 to 19 percent in 2050 . about 75% of persons of age 60 and above reside in rural areas . enhanced survival into old age is the result of changes in the socioeconomical development within societies and will inevitably affect the pattern of disease . in geriatric patients , chronic diseases such as hypertension ( ht ) , diabetes mellitus ( dm ) , thyroid disorders etc . , are commonly seen , at the same time geriatric skin is more prone to skin diseases . icmr study of 19841985 showed that 13.3% of skin problems were seen in elderly persons over 60 years of age . a progressive degenerative change , which is intrinsic to aging skin and with susceptibility to many cutaneous and systemic diseases , significantly impairs the quality of life in geriatric population . this retrospective study aimed to know the association of dermatosis and systemic diseases in geriatric age group . by knowing the association we can detect , counsel , treat , and protect them at earliest , helping them to grow old gracefully . this retrospective cross - sectional study aimed at finding association of systemic diseases with dermatosis in geriatric population . study was carried out on all patients of both genders with 60 years and above who attended skin out - patient department of rural tertiary care centre , shree krishna hospital , karamsad , gujarat , between june 2009 to may 2010 having any dermatosis . a detailed history was taken with general , systemic , and cutaneous examination after prior consent . investigations such as koh smear , tzanck smear , and skin biopsy were done in relevant cases . total 457 geriatric patients with dermatosis were enrolled in the study , all above 60 years of age . of the total , males were 282 ( 61.7% ) and females were 175 ( 38.3% ) [ table 1 ] . systemic diseases such as ht , dm , asthma , thyroid disease etc . , were seen in 203 patients ( 44.43% ) [ figure 1 ] , while 254 patients had only cutaneous disorders . among 203 patients , 112 were males ( 55.1% ) and 91 were females ( 44.8% ) . different form of addictions such as smoking , betel chewing , tobacco , and alcohol was observed in 100 patients ( while 103 patients had no addictions ) . systemic disease in geriatric patients with dermatosis systemic disease observed with cutaneous disorders in geriatric population hypertension was the most common systemic disease seen in the study , that is , 144 patients with cutaneous disease . commonest dermatosis seen in hypertension was eczema , that is , 33 patients ( 22.92% ) followed by senile pruritus and dermatophytes in 10 patients ( 6.9% ) each [ table 2 ] . dermatosis seen in minority were atrophic vaginitis , leprosy , bcc , photolichenoid rashes , drug reaction , purpura , insect bite , phn , pruritus vulva , igh , neurofibromatosis , skin tags , vitiligo , nodular scabies , pellagra , oral pemphigus , pih , miliria , ppk , candidiasis , pyoderma , alopecia aerata , senile comedones , lichen amyloidosis and schambergs disease . major dermatosis in patients with hypertension among 66 patients of diabetes mellitus , 22 ( 33.33% ) had generalized pruritus which was commonest dermatological problem seen followed by superficial fungal infections and eczema in 15 each [ table 3 ] , phn , xerosis , scabies , vitiligo , urticaria , lichen amyloidosis were seen in few patients . major dermatosis in patients of dm other systemic diseases seen associated with cutaneous dermatosis are shown in table 4 . who reports that the most significant emerging demographic phenomenon in the world would be that it will have more older people than children and more people at extreme old age than ever before . with the projected exponential ageing of almost all industrialized societies , a greater commitment there are studies showing association of dermatosis with specific systemic diseases like diabetes or cardiovascular conditions in general population , but not specifically in the geriatric age group . this study focuses only on the geriatric age group , studies on them showing the association of dermatosis with systemic diseases is lacking . in this study , systemic diseases associated with cutaneous disorders was found to be higher in 203 patients ( 44.42% ) compared to study by patange ( 35% ) and lower than grover ( 64.5% ) . among 203 patients of dermatosis associated with various systemic diseases 112 ( 55.1% ) were males and 91 ( 44.8% ) were females . the reason may be under reporting of female population at skin clinic or awareness of health issues among females in general is less . hypertension was the commonest systemic disease seen in 144 patients ( 70.9% ) , which is higher than studies by radhakrishnan ( 59% ) . in patients with hypertension , ivanov and fedotov study has shown that 24.8% of eczema patients had hypertension , which is comparable with our study . he emphasized that the detected specificities of eczema course in the presence of hypertension indicate a certain relationship between these diseases involving manifest abnormalities in the skin microcirculatory bed . diseases such as hyperlipidemia and hypertension decreases blood flow to skin decreasing the ability of the elderly to fight the infection , decreased blood flow slows wound healing , increases xerosis and allows pathogens to enter the broken skin . diabetes was seen in 66 patients ( 14.44% ) which is quite lower than other studies by radhakrishnan ( 36% ) , najdawi ( 25.9% ) but higher than in sahoo ( 10.5% ) , and patange ( 9% ) of the 66 patients of dm , 22 ( 33.33% ) had generalized pruritus followed by superficial fungal infections in 15 ( 22.72% ) . in study by najdawi on 60 elderly patients with diabetes , pruritus was seen in 13 ( 21.66% ) patients and superficial fungal infections in 16 ( 26.66% ) patients , which is comparable with our study . diabetes is one of the most common metabolic disorders predisposing to skin and soft tissue infection . bacterial and fungal infection are most common skin diseases associated with dm in elderly leading to increased morbidity . poor glycemic control , poor microcirculation , peripheral vascular disease , peripheral neuropathy , and decreased immune response have been implicated in increased susceptibility to infection . the presence of pruritus is one of the four diagnostic hallmarks of diabetes mellitus ( i.e. polyuria , polydipsia , polyphagia , and pruritus ) , although early studies found that itching was present in only 7% of patients with diabetes . the cause of the intense itching experienced by diabetic patients is unclear , but it may be related to secondary conditions such as xerosis or infections . several case studies have identified generalized pruritus as a symptom of thyroid disease due to the presence of antithyroid antibodies . pruritus in patients with hyperthyroidism may be caused by the warm , moist skin that accompanies this disorder , although the exact cause is unknown but it can also be due to cholestatic jaundice while in patients with hypothyroidism , pruritus is usually due to xerosis . among nine patients of thyroid disorders in our study three association of thyroid disease with lichen planus seems to be due to their common autoimmune aetiology . xerosis with pruritus is seen in 60% patients of chronic renal failure ( crf ) by falodun . pruritus occurs in up to 90% of patients with renal failure or uremia who are receiving maintenance dialysis . in a study by peres on crf the most common cause of xerosis , secondary to dialysis , is due to imbalance of calcium , magnesium , and phosphorus . in addition , the patient 's uremic condition acts as a chronic inflammatory process , causing the release of proinflammatory cytokines and histamine . systemic inflammation and dysregulated immune function in copd is hypothesized to predispose patients to herpes zoster . the risk of hz is greatest in patients using oral steroids than inhaled steroids according to the study by yang . in this study , two patients with lung cancer had pigmentation of face . marked increase in the level of acth levels in a small - cell lung cancer leads to pigmentation of face . in this study , eczema was found to be the most common dermatosis , that is , in 63 patients ( 31.03% ) followed by senile pruritus in 35 ( 17.2% ) patients . aging skin is susceptible to pruritic disorders because of the cumulative effects of environment . loss of skin hydration , loss of collagen , impaired immune system responses , impaired function of the skin as a barrier to pathogens , impaired blood circulation all plays the role . the presence of co - morbid conditions , the lack of mobility , and the increased use of medications may also contribute to the prevalence of pruritus in elderly individuals . in older people , pruritus is often associated with dry skin resulting in altered skin pigmentation and increased skin fragility . co - morbid xerosis resulting from decreased skin hydration may exacerbate pruritus in older patients with systemic diseases . this is especially true for institutionalized geriatric patients or for individuals with dementia whose general inactivity allows them to be distracted by pruritic stimuli . as skin ages , the vasculature progressively atrophies , supporting dermis deteriorates , and collagen and elastin fibers become sparse making skin susceptible to vascular disorders as stasis dermatitis and pressure ulcers , with a steadily decreasing ability to repair . skin diseases cause considerable morbidity in elderly , particularly if associated with other comorbid conditions , so health promotion and education can do much to reduce the risk . further studies in the field are needed to help reduce the burden in elderly population who are at greater risk of disorders with advanced age , general health issues , drug therapy and chronic diseases . as the proportion of the world 's population in the older ages continues to increase , the need for more knowledge of this group becomes essential to assist policy makers in their role to define , formulate programs , and also to raise public awareness .

introduction : aging population is susceptible to many cutaneous and systemic diseases , simultaneously leading to impairment of quality of life in them.aim:to know the association of dermatosis and systemic diseases in geriatric age group.materials and methods : a retrospective study was carried on patients above 60 years of age who visited the dermatology opd at rural tertiary care centre from june 2009 to may 2010 . patients were assessed on a prescribed 30 point proforma.results:total 457 geriatric patients with dermatosis were registered under the study , of these 203 patients had one or more systemic diseases . hypertension ( 70.9% ) was the commonest disease , followed by diabetes ( 32.5% ) . eczema was commonest dermatosis in patients with hypertension and generalized pruritus in diabetes.conclusion:skin diseases cause considerable morbidity in elderly , particularly if associated with other comorbid conditions , so health promotion and education can do much to reduce the risk .

although tuberculosis , one of the most common causes of morbidity and mortality in the indian subcontinent , commonly involves the lung , fistula formation between the bronchi is quite rare . interbronchial or broncho - bronchial fistula occurs either due to direct bronchial wall involvement by the tuberculosis infection or more commonly as a sequel to nodal disease eroding into the bronchial tree . these fistulae can be noninvasively diagnosed using multislice computed tomography ( ct ) scans which also give information about the cause of the fistula as well as other associated findings and complications . here we report a young male who incidentally showed a small inter bronchial fistula during a ct examination done for work up of cough of 4 weeks duration . a 30-year - old male patient presented to our radiology department for the ct chest examination with complaints of fever , cough , and abdominal pain for a period of 4 weeks . ct chest showed a small thin air filled communication between the right and left main bronchi ~67 mm below the carina level [ figure 1a c and video 1 ] . multiple nodes were seen in prevascular , pretracheal , preaortic , precarinal and subcarinal region , largest measuring ~ 17 mm in short axis in subcarinal region [ figure 1d ] . multiple small nodules with tree - in - bud appearance were seen in the superior segment of left lower lobe [ figure 1e ] . moderate right pleural effusion with passive atelectasis of posterior basal segment of right lower lobe was seen . virtual bronchoscopy showed small openings in the medial wall of a proximal portion of bilateral major bronchi [ figures 2 and 3 and video 2 ] . at present patient is on anti - tuberculous treatment and he reported significant improvement of symptoms at 3 months , though the tiny fistulous tract still persists on follow - up imaging . ( a - c ) axial and curved coronal reformat shows thin small thin air filled communication between the right and left main bronchi ~6 - 7 mm below the carina level . ( d ) coronal reformat computed tomography shows a large node in the subcarinal region . ( e ) axial computed tomography in lung window shows multiple small nodules with tree - in - bud appearance in the superior segment of left lower lobe . ( f ) axial computed tomography shows bilateral pleural effusion virtual bronchoscopy images show small openings in the medial wall of proximal right and left main bronchi close up image of virtual bronchoscopy images show small openings in the medial wall of proximal right and left main bronchi tuberculosis is one of the leading causes of morbidity and mortality in the indian subcontinent . thoracic tuberculosis can present as parenchymal , airway , pleural , mediastinal , vascular , and chest wall complications . patients with pulmonary tuberculosis present with various symptoms of fever , fatigue , weight loss , night sweats , and cough with or without hemoptysis . fistulas are known to occur with tuberculosis of the chest in the form of bronchopleural fistula , bronchopleurocutaneous fistula , bronchoesophageal fistula , and interbronchial fistula with bronchopleural fistulas being the most common . endobronchial tuberculosis in patients with active tuberculosis has a prevalence of about 1040% with the most common complication being bronchial stenosis . tracheobronchial involvement may occur due to lymphatic spread of the infection from parenchymal lesions or due to direct invasion of the trachea or bronchi by the enlarged lymph nodes . granulomatous reaction with destruction of the wall forms the basis of tracheobronchial stenosis / fistula . site of involvement was subcarinal region with fistula between the right and left main bronchi . all the patients recovered following or during the course of anti - tubercular therapy [ table 1 ] . review of literature for interbronchial fistula the patient described here happens to be the first male patient apart from being the youngest to be described with relevance to tuberculous interbronchial fistula . this patient also happens to be immunocompetent with similar subcarinal region involvement between the right and left main bronchi . however , the size of the fistulous tract depicted here appears to be the smallest . this patient also showed significant improvement with anti - tubercular therapy , as has been the case with the other patients . this is also the first instance where the diagnosis appears to have been made using only multislice ct generated virtual bronchoscopy without the aid of fiber optic bronchoscopy . multislice ct generated virtual bronchoscopy allows excellent noninvasive visualization of the lumen and wall of the trachea and proximal part of the bronchial tree with dynamic / fly through images resembling the fiber optic bronchoscopy images . applications of virtual bronchoscopy include evaluation of bronchial stenosis due to intra / extraluminal lesions , assessment of tracheobronchial tree abnormalities including fistulas and guidance of transbronchial biopsy . interbronchial fistula in tuberculosis may occur either due to direct tracheobronchial wall involvement or secondary to lympho bronchial / bronchonodal fistula . multislice ct due to the availability of multiplanar reformation and virtual bronchoscopy is extremely useful in the detection of broncho bronchial and bronchoesophageal fistulas of any etiology .

although tuberculosis is a rather common disease in the indian subcontinent , tracheobronchial involvement in tuberculosis is still rare . fistula formation between bronchi is very rare considering that only four cases have been published in the english literature . we present a case of multislice computed tomography ( ct ) and virtual bronchoscopy diagnosis of interbronchial fistula in a patient with tuberculosis along with a review of literature of the same . this happens to be the smallest of the interbronchial fistula identified on imaging so far and the first case from the indian subcontinent . this is also the first instance where the diagnosis appears to have been made using only multislice ct generated virtual bronchoscopy without the aid of fiber optic bronchoscopy .

following the pioneering and most promising work of billingham , brent , and medawar in newborn mice , many experimental and some clinical studies have focused on means to induce transplantation tolerance . in human patients , full tolerance has yet been developed in two circumstances only : ( a ) when the transplant recipient is not immunologically competent or mature and ( b ) when the transplant involves full replacement of host lymphocytes by donor lymphocytes . the latter condition is obtained by myeloablation and immunosuppression , followed by stem cell transplantation ( sct ) . the former mode of tolerance induction is seen in patients with severe combined immunodeficiency disease ( scid ) treated with sct or in fetal patients subjected to sct prior to their immunological maturation . we review herein our results in infants and human fetuses who were treated by fetal liver sct and who developed full tolerance to both donor and host antigens [ 513 ] . nineteen patients with scid , including 17 infants and 2 fetuses , received fetal liver sct [ 4 , 7 ] . fetal livers were obtained from dead human fetuses under conditions approved by the french national committee for bioethics . a cell suspension was prepared , cell viability was checked , and cells were administered by intravenous or intraperitoneal injection . in the two fetal recipients with scid , the cells were injected into the umbilical vein in utero . fourteen of the 19 patients had evidence of donor cell engraftment and developed immunological reconstitution . all were subjected to immunological investigations , especially on peripheral blood lymphocytes ( pbls ) . the studies reported herein mainly concern three children who were analyzed more extensively over a long period of time ( 2134 years ) . three nonimmunodeficient fetuses with various diseases ( thalassemia major , niemann - pick type a disease and hemophilia a ) were also analyzed for at least 2 years after the in utero sct ( which was performed by the intraperitoneal route ) . hla typing was initially carried out on pbl , t - cell clones , and ebv - transformed b - cell lines using a previously described cytotoxicity assay and was confirmed more recently using molecular biological methods . to analyze responses in mixed leukocyte cultures ( mlcs ) , pbl from the patients the proliferative response of t lymphocytes to these stimulator cells was determined by the degree of tritiated thymidine incorporation . the experiments were performed in triplicate , and the results are expressed as the mean standard deviation ( sd ) . table 1 summarizes the hla phenotypes ( class i and class ii ) of cells of donor and host origin that were prepared from the three most extensively studied patients , all of whom have had a stable chimerism for many years . they had received fetal liver scts from several donors but only the hla phenotype of the permanently engrafted cells is reported here . over the past 34 years , many investigations have been carried out in these three patients . on all occasions , most b - cells and antigen - presenting cells were found to be of host origin while all t - cells were of donor origin . accordingly , t - cell clones prepared from the pbl of these patients only exhibited the hla determinants of the donor . with the exception of patient 2 , for whom the hla - a2 antigen was shared by the donor and the host , all patients had a complete mismatch between host - derived and donor - derived cells . t lymphocytes and b lymphocytes or antigen - presenting cells share no class ii determinant and almost no class i hla antigen , since the former are derived from donor stem cells and the latter from host cells . after immunological reconstitution had developed in the scid patients treated postnatally , pbls were prepared and used as responders while irradiated cells of various origins were employed as stimulators . the 2 patients reported in table 2 demonstrate an inability to mount a proliferative response to host stimulator cells . in contrast , the t lymphocytes from these patients proliferated readily when stimulated by allogeneic cells or by cells from their parents ( table 2 ) . among t - cell clones ( e.g. , tetanus - toxoid - specific t - cell clones ) prepared from patients ' pbl , virtually none recognized donor hla antigens , whereas 15 of 50 clones directly recognized hla antigens of the host and mounted strong proliferative and cytotoxic responses to host - derived cells [ 9 , 13 ] . the high frequency of cd8 + host - reactive cells in the chimeric patients was comparable with that of alloreactive cells , in contrast with the lack of cells that reacted with the donors . mlcs were performed in 6 additional patients , including the 2 scid patients treated at the fetal stage , in utero . the results were comparable with those described above , with a specific lack of proliferative response to host stimulator cells . again , such an absence of proliferation in mlc did not indicate lack of recognition of host antigens , since some t - cell clones could be shown to be host reactive . the production of lymphokines by host - reactive t - cells from these patients was characterized by high levels of gamma - interferon and , following activation , granulocytic - monocyte - colony - stimulating factor , interleukin-5 , and interleukin-2 . interestingly , no interleukin-4 was produced , irrespective of the mode of activation [ 12 , 13 ] . spontaneous secretion of interleukin-10 by the patients ' cells was regularly found to be increased [ 5 , 6 ] . we report here 3 human fetal patients who have been treated by in utero sct at the age of 1214 weeks postfertilization . after birth , engraftment was ascertained in blood and bone marrow by the presence of ( a ) hemoglobin a , ( b ) cells with the donor y chromosome , and ( c ) cells with the donor hla phenotype . however , the number of donor cells remained limited and tended to decrease with age . at 4 years of age , 0.51% of bone marrow cells only expressed simultaneously the cd34 marker and the hla - a32 phenotype of donor origin . this low chimerism on the long - term was not sufficient to ensure significant clinical benefit , but it suggested maintenance of tolerance to donor antigens . the two other patients had evidence of donor cell survival , in the absence of immunosuppression at any time , with the prolonged presence of cells with hla markers of the donor . this engraftment was made possible by the immune immaturity of recipients at 1214 weeks of fetal age . however the number of donor cells did not increase with time . actually , it became lower after the first 1 or 2 years . the hemophiliac did not generate any antifactor viii antibody , suggesting tolerance to this factor , possibly as the result of factor viii production by donor - derived cells and its presentation to the immune system of the developing fetus . because of immune incompetence , scid patients on the one hand and humans in the early stage of fetal development on the other hand can benefit from engraftment of mismatched stem cells . as a source of stem cells to treat our patients , we have used fetal livers , taking advantage of the relative competitive engraftment superiority of fetal liver cells over adult bone marrow cells , especially in fetal recipients . despite the lack of hla antigens shared by donor - derived t lymphocytes and the other cells of the body , efficient immune interactions develop in scid patients treated pre- or postnatally [ 3 , 4 , 7 , 16 , 17 ] . in particular , there appears to be no restriction of function of helper or cytotoxic t - cells [ 3 , 5 , 7 , 8 , 11 ] , and immune reconstitution of the host progresses up to a full degree [ 7 , 18 ] . the immune immaturity of the host explains the lack of donor cell rejection that of the donor explains the lack of graft - versus - host disease ( gvhd ) induced by transplanted cells . following sct in our scid patients , donor - reactive ( but not host - reactive ) cells have been shown to be deleted from the t - cell repertoire . clonal deletion is therefore responsible for immunological tolerance to antigens of the donor and this process of negative selection is likely to occur in the host thymus , as a result of contact between thymocytes and dendritic cells or macrophages of donor origin ( figure 1 ) . in contrast , host - reactive t - cells ( also designed as alloreactive t - cells since the stem cells that generated t - cells are allogeneic to other cells of the host body ) remained present and relatively numerous in these chimeric patients . that no detrimental effect ( gvhd or autoimmunity ) occurs at any stage of t - cell development suggests that donor - derived t lymphocytes have been suppressed or anergized in the host . this hypothesis is supported by the specific absence of proliferative response to host stimulator cells in mlc . further evidence of clonal anergy or suppression has been obtained in experiments involving transplantation of human fetal liver and thymus of similar or different origins in scid mice . tolerance to host antigens appears to develop in human t - cells present in these experimental animals as the result of a clonal anergy that follows contact of human thymocytes with human epithelial cells of the host thymus fragment . transplantation tolerance is therefore induced by two different mechanisms : tolerance to donor by clonal deletion and tolerance to host by clonal anergy ( figure 1 ) . in nonimmunodeficient fetuses , tolerance was also apparently induced but , in contrast with scid patients , the number of donor cells did not expand significantly over the years . various hypotheses may account for this limited development of donor cells : selective advantage of host stem cells over donor stem cells , lack of space in the hematopoietic niches , allogeneic reactions from the progressively immunomature lymphocytes of the host , and allogeneic reactions from the maternal t - cells that have been shown to reduce engraftment after in utero sct . when allogeneic and autologous sct in fetal sheep were compared , however , no significant difference was found between the two groups . low engraftment did not appear to result mostly from major histocompatibility complex - driven allogeneic reactions but rather from donor / host competition of another kind . nevertheless , since donor - specific tolerance induction requires relatively minimal engraftment , clinical application may take advantage of such a tolerance produced at the fetal age to procure further treatment with allogeneic cells of similar origin , in larger numbers and with appropriate adjunctive treatment , later on in life .

patients transplanted with hla - mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens . engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity , especially t - cell differentiation . the chimeric patients have donor - derived t lymphocytes which progressively demonstrate positive interactions with other host cells . they also can be shown to be tolerant toward both host and donor antigens . the latter tolerance relies upon clonal deletion from the t - cell repertoire , and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells . the former tolerance does not imply clonal deletion of t - cells with host reactivity . numerous t - cells recognizing the allogeneic , host - type antigens are identified in these patients , but these cells are anergized , following interaction with epithelial cells of the host thymus . induction of transplantation tolerance at the fetal stage requires minimal engraftment only ; in the future it will be possible to further amplify the clinical benefit , using additional cell transplants after birth .

the periodic removal of accumulated material from the teeth and preparing the root surface by root planing is essential for controlling periodontal disease . it was believed that these instruments produced a smooth root surface , but considerable manual dexterity is required for their effective operation . moreover , hand instruments are more time consuming and are unable to reach the deeper root surface , where pockets are more than 4 mm deep . ultrasonic instruments were originally designed for gross scaling and removal of supragingival calculus and stains . more recently , these power - driven instruments have been modified to have smaller diameter tips and longer working lengths , thereby providing better access to deep probing sites and more efficient subgingival instrumentation . ultrasonic instruments are simple to use , but it is often difficult to achieve smooth and calculus - free root surface . to overcome the challenges associated with the use of ultrasonic and hand scalers , rotary instruments for scaling and root planing have been developed . these are found to be more effective in root furrows , furcation areas and root surfaces in deep , narrow infra bony pockets . it has now been well documented that all the hand- and power - driven instruments cause some gouging and removal of tooth substance . this could have an important clinical implication keeping in view the problems of hypersensitivity and roughness of root surface . hence , the present study aimed to evaluate root surface characteristics following treatment with hand- and power - driven instruments . the teeth selected for the study were extracted from patients that reported to the outpatient department of oral and maxillofacial surgery of sh . ( c ) dental college and hospital , yamuna nagar , haryana ( india ) . teeth that had undergone a root canal treatment , any periapical lesion , caries and history of scaling and root planing in previous 6 months were excluded from the study . twenty single rooted human teeth , extracted due to severe chronic periodontitis having hopeless prognosis with bone loss > 70% and grade iii mobility , were used in this study . the teeth were then washed with distilled water and treated with 2% sodium hypochlorite solution and then stored in normal saline until further study . two specimens were used as control and the remaining 18 specimens were equally divided in three groups . group i specimens treated with hand instruments group ii specimens treated with ultrasonic instruments group iii specimens treated with rotary instruments the specimens of the control group were thoroughly cleaned and washed using toothbrush only . 1 - 2 and 3 - 4 gracey curettes ( hu - friedy chicago , il , usa ) were used for instrumentation . instrumentation was performed with a piezo - electric ultrasonic scaling unit ( ems sa , mnchen , germany ) . a subgingival ps ultrasonic tip was used according to the manufacturer 's instruction under profuse rinsing with water spray at a medium power setting . unidirectional strokes were given on the proximal surface along the long axis of the teeth . these rotary burs for root planing [ desmoclean ( hager , germany ) ] were used at 8000 rpm with light pressure and water spraying . unidirectional strokes were given on the proximal surface along the long axis of the teeth . measurement of time required for scaling and root planing the length of time was measured with a stopwatch from start until the root surface appeared smooth upon visual inspection and examination with an explorer . the sem photomicrographs at 100 and 500 were scored blindly and independently by two investigators using roughness and loss of tooth substance index ( rltsi ) [ table 1 ] . to eliminate bias , the study was designed such that the person who evaluated roughness was unaware of the procedure used . roughness and loss of tooth substance index scored by two examiners for three experimental groups 1.smooth and even root surface without marks from instrumentation and with no loss of tooth substance.2.slightly roughened and corrugated local areas confined to the cementum.3.definitely corrugated local areas where cementum may be completely removed , although most of the cementum is still present.4.considerable loss of tooth substance with instrumentation marks into the dentin . the cementum is completely removed in large areas or it has a considerable number of lesions from the instrumentation . smooth and even root surface without marks from instrumentation and with no loss of tooth substance . definitely corrugated local areas where cementum may be completely removed , although most of the cementum is still present . the cementum is completely removed in large areas or it has a considerable number of lesions from the instrumentation . twenty single rooted human teeth , extracted due to severe chronic periodontitis having hopeless prognosis with bone loss > 70% and grade iii mobility , were used in this study . the teeth were then washed with distilled water and treated with 2% sodium hypochlorite solution and then stored in normal saline until further study . two specimens were used as control and the remaining 18 specimens were equally divided in three groups . group i specimens treated with hand instruments group ii specimens treated with ultrasonic instruments group iii specimens treated with rotary instruments 1 - 2 and 3 - 4 gracey curettes ( hu - friedy chicago , il , usa ) were used for instrumentation . instrumentation was performed with a piezo - electric ultrasonic scaling unit ( ems sa , mnchen , germany ) . a subgingival ps ultrasonic tip was used according to the manufacturer 's instruction under profuse rinsing with water spray at a medium power setting . unidirectional strokes were given on the proximal surface along the long axis of the teeth . these rotary burs for root planing [ desmoclean ( hager , germany ) ] were used at 8000 rpm with light pressure and water spraying . unidirectional strokes were given on the proximal surface along the long axis of the teeth . measurement of time required for scaling and root planing the length of time was measured with a stopwatch from start until the root surface appeared smooth upon visual inspection and examination with an explorer . the sem photomicrographs at 100 and 500 were scored blindly and independently by two investigators using roughness and loss of tooth substance index ( rltsi ) [ table 1 ] . to eliminate bias , the study was designed such that the person who evaluated roughness was unaware of the procedure used . 1.smooth and even root surface without marks from instrumentation and with no loss of tooth substance.2.slightly roughened and corrugated local areas confined to the cementum.3.definitely corrugated local areas where cementum may be completely removed , although most of the cementum is still present.4.considerable loss of tooth substance with instrumentation marks into the dentin . the cementum is completely removed in large areas or it has a considerable number of lesions from the instrumentation . smooth and even root surface without marks from instrumentation and with no loss of tooth substance . definitely corrugated local areas where cementum may be completely removed , although most of the cementum is still present . the cementum is completely removed in large areas or it has a considerable number of lesions from the instrumentation . the mean roughness scores for the gracey curette , ultrasonic and rotary instrument groups were 2.5 , 2.0 and 0.667 , respectively [ table 2 ] . results were significant when the rotary instrument group was compared with the gracey curette and ultrasonic groups . however , non - significant differences were found while comparing the gracey curette and the ultrasonic group . comparison of root roughness in all the three experimental groups the time required for treatment using a rotary instrument was significantly longer than that required for gracey curette and ultrasonic instrument . the mean score for the gracey curette , ultrasonic and rotary instrument groups were 42.50 , 35.83 and 54.50 s [ table 3 ] . comparison of time spent by rotary instrument group with the other two groups was significant . but , there were no significant differences in the ultrasonic and gracey curette groups [ table 4 ] . measurement of time ( in seconds ) for instrumentation in three experimental groups comparison of time in seconds for instrumentation in all the three experimental groups the mean roughness scores for the gracey curette , ultrasonic and rotary instrument groups were 2.5 , 2.0 and 0.667 , respectively [ table 2 ] . results were significant when the rotary instrument group was compared with the gracey curette and ultrasonic groups . however , non - significant differences were found while comparing the gracey curette and the ultrasonic group . the time required for treatment using a rotary instrument was significantly longer than that required for gracey curette and ultrasonic instrument . the mean score for the gracey curette , ultrasonic and rotary instrument groups were 42.50 , 35.83 and 54.50 s [ table 3 ] . comparison of time spent by rotary instrument group with the other two groups was significant . but , there were no significant differences in the ultrasonic and gracey curette groups [ table 4 ] . measurement of time ( in seconds ) for instrumentation in three experimental groups comparison of time in seconds for instrumentation in all the three experimental groups in the present study , the effectiveness of scaling and root planing was evaluated by an in vitro method , as an in vitro study would facilitate the selection of comparable test surface and would permit a standardization of the experimental procedures . root surface roughness and tooth substance loss has been evaluated by measuring the size of the instrument marks , by calculating the weight of the removed tooth surface , by inspecting the surface under light microscope and by measuring the surface roughness using a profilometer . the results of such studies have been variable and inconclusive , but the use of scanning electron microscopy can eliminate various difficulties encountered with other techniques of examining root surfaces . some studies reported significant differences in tooth topography with respect to type and/or sharpness of the instrument , number of strokes used and whether the tooth was moist , under copious lavage or dentifrice was used . sharp hand curette clearly planed away considerably more accretions and dental tissue than its dull counterparts . hand instrument often produced a haphazard , irregular pattern , particularly when vertical and horizontal strokes were combined . in the present study , microscopic examination of control specimens affected with other areas on the root surface appeared amorphous and were suggestive of aggregates of microorganism or plaque . specimens treated with gracey curette were comparatively smoother as compared with the control specimens [ figures 3 and 4 ] . but , deep scratches and strae were present , representing the pathway of instrumentation and considerable loss of tooth substance during root planing . wilkinson suggested that even a delicate hand instrument creates irregularities and scratches on the root surface , which would possibly be attributed to the microscopic roughness of the instrument 's cutting edge . this high mean value suggested that more of tooth substance was removed by curette , which resulted in a roughened root surface . morphology of the root surface of the control specimen ( scanning electron microscopy photograph , 100 ) morphology of the root surface of the control specimen ( scanning electron microscopy photograph , 500 ) morphology of the root surface planed with curette ( scanning electron microscopy photograph , 100 ) morphology of the root surface planed with curette ( scanning electron microscopy photograph , 500 ) until relatively recently , all ultrasonic tips were large and bulky , making them generally suitable only for supragingival or subgingival scaling , where tissue was inflamed and retractable . however , newly designed thin ultrasonic tips have allowed better access to subgingival areas previously accessible only with a hand instrument . earlier studies using older tips designed generally showed that ultrasonic instruments left a stippled root surface and had a greater potential for producing root surface damage than curettes . more recent studies , especially those using the newer , thinner tips , show that ultrasonic instruments can produce root surfaces as smooth as or smoother than those that can be produced by curettes . current evidence suggests that ultrasonic instruments used on medium power may do less damage to the root surface than hand or sonic scalers . some studies suggested that the rotary instruments at high speed ( 2,00,000 revolutions per minute ) and ultrasonic instruments caused more damage to the root surface when compared with hand curettes . lie and mayer found that diamond points with a constant speed of 3000 rpm produced the roughest surface among hand curette and ultrasonic instrument . the specimens treated with ultrasonic instrument provided an interesting topography [ figures 5 and 6 ] . the specimens treated with rotary instrument were flat and smooth , with no sign of gouging and scratching [ figures 7 and 8 ] . but , the cracks were consistently present on the surface , representing the artifact produced by dehydration during specimen processing . the mean score for rltsi was 0.667 , which represented the smooth flat and clear root surface . morphology of the root surface planed with the ultrasonic instrument ( scanning electron microscopy photograph , 100 ) morphology of the root surface planed with the ultrasonic instrument ( scanning electron microscopy photograph , 500 ) morphology of the root surface planed with a rotary bur ( scanning electron microscopy photograph , 100 ) morphology of the root surface planed with a rotary bur ( scanning electron microscopy photograph , 500 ) comparison of gracey curette and ultrasonic instrument group suggested that more of tooth substance was removed by curette as compared with ultrasonic instruments . this might be because of the newer , thinner tip of the ultrasonic instrument , which caused less damage to the root surface . the specimens treated with the rotary instrument produced the smoothest surface , which might be because the burs had non - cutting , elliptical , hexagonal heads . the effectiveness of the ultrasonic instrumentation as a function of time was proved by the present study . the mean time for gracey curette , ultrasonic instrument and rotary instrument group was 42.50 , 35.83 and 54.50 s , respectively . the result showed that far more time was required by the rotary instrument than the ultrasonic and hand instruments . but , the comparison of curette and ultrasonic groups was not significant ( p > 0.01 ) . historically , it was generally agreed that aggressive scaling and root planing with hand instruments was necessary to remove tenacious calculus deposits and endotoxins . based on current evidences , it is now known that endotoxicity is a weekly adherent phenomenon and hand / power - driven instruments can be used to accomplish definitive root detoxification without overinstrumentation of the root and without extensive cementum removal . in the present study , it was proved that all the three instruments , namely curette , ultrasonic and rotary instruments , were effective in mechanical debridement of the root surface . the root surface treated with the rotary instrument appeared flat and glossy to the naked eye and sem pictures revealed its smoothest surface . the roughness produced by the gracey curette was found to be high , followed by ultrasonic tip and rotary bur . the time spent for scaling and root planing with rotary bur was significantly longer than the time needed for the gracey curette and ultrasonic tip . the results favored the use of rotary instruments for root planing to achieve a smooth clean root surface . however , the use of rotary bur was more time consuming , which might limit its use in clinical practice .

aim : the aim of this study was to compare root surface characteristics following root planing with various hand- and power - driven instruments.materials and methods : a total of 20 single , rooted teeth were used in this study ; two specimens were used as control ( no instrumentation done ) and the remaining 18 specimens were equally divided into three groups . specimens from each group were then subjected to root planing by one of the following instruments : ( 1 ) a gracey curette , ( 2 ) ultrasonic tip and ( 3 ) a rotary bur . in each case , the time required for scaling and root planing and surface roughness using the roughness and loss of tooth substance index ( rltsi ) was measured.result:the mean rltsi scores for the gracey curette , ultrasonic and rotary instrument groups were 2.5 , 2.0 and 0.667 , respectively . the mean scores of time spent for scaling and root planing by the gracey curette , ultrasonic and rotary instrument groups in seconds were 42.50 , 35.83 and 54.50 , respectively.conclusions:all the three instruments , namely gracey curette , ultrasonic tip and rotary bur , were effective in mechanical debridement of the root surface . the results favored the use of rotary instruments for root planing to achieve a smooth , clean root surface ; however , the use of rotary instrument was more time consuming , which might limit its use in clinical practice .

case histories , hematological investigations including hemoglobin estimation , fasting blood glucose level , impressions and photographs of the maxillary and mandibular arches were taken after obtaining informed consent from the patients . following this , age and sex matched healthy controls , were selected randomly from the patients visiting the various departments of college of dental sciences and the impressions of their maxillary and mandibular arches were recorded . the dental casts and photographs were analyzed for the following variations between the two groups , morphological alterations : size microdontia / macrodontia shape standard dental morphology as described by woelfel , wheeler was taken for reference and statistical analysis was done using unpaired t - test . the dentition of the healthy control group did not show any morphological alterations , while the following morphological alterations were observed in dentition of test group ( type i dm group ) . presence of 6 cusp in mandibular first molars 7 casespresence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case)y pattern in mandibular first premolar 1 case4 cusps in mandibular second premolar 1 caseflower shaped mandibular molar 1 caseprominent cusp of carabelli and oblique ridge in maxillary molar 1 casepresence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . presence of 6 cusp in mandibular first molars 7 cases presence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case ) y pattern in mandibular first premolar 1 case 4 cusps in mandibular second premolar 1 case flower shaped mandibular molar 1 case prominent cusp of carabelli and oblique ridge in maxillary molar 1 case presence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . microdontia 4 cases . microdontia 4 cases . attrition 11 cases in type i dm groupattrition 2 cases in control group . attrition 11 cases in type i dm group attrition 2 cases in control group . the results are tabulated in table 1 and are statistically highly significant with p < 0.001 . presence of 6 cusp in mandibular first molars 7 casespresence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case)y pattern in mandibular first premolar 1 case4 cusps in mandibular second premolar 1 caseflower shaped mandibular molar 1 caseprominent cusp of carabelli and oblique ridge in maxillary molar 1 casepresence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . presence of 6 cusp in mandibular first molars 7 cases presence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case ) y pattern in mandibular first premolar 1 case 4 cusps in mandibular second premolar 1 case flower shaped mandibular molar 1 case prominent cusp of carabelli and oblique ridge in maxillary molar 1 case presence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . presence of 6 cusp in mandibular first molars 7 casespresence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case)y pattern in mandibular first premolar 1 case4 cusps in mandibular second premolar 1 caseflower shaped mandibular molar 1 caseprominent cusp of carabelli and oblique ridge in maxillary molar 1 casepresence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . presence of 6 cusp in mandibular first molars 7 cases presence of extra cusps in mandibular second molar 5 cusps ( 1 case ) , 6 cusps ( 1 case ) y pattern in mandibular first premolar 1 case 4 cusps in mandibular second premolar 1 case flower shaped mandibular molar 1 case prominent cusp of carabelli and oblique ridge in maxillary molar 1 case presence of 4 cusps in mandibular first molar 2 cases ( being normal variation , not included as anomaly ) . attrition 11 cases in type i dm groupattrition 2 cases in control group . attrition 11 cases in type i dm group attrition 2 cases in control group . the results are tabulated in table 1 and are statistically highly significant with p < 0.001 . type i dm ( insulin dependent diabetes mellitus [ iddm ] ) is due to autoimmune destruction of the beta cells ( the so called type i process ) . a similar clinical picture of insulin dependence can be caused by other forms of severe pancreatic damage . several years of progressive autoimmune damage usually precede the clinical onset of this type of diabetes . early diagnosis in the prediabetic phase can provide an opportunity to prevent subjects with active insulitis from developing clinical disease . provision of immunosuppressive and immunomodulatory treatments at this prediabetic phase are currently undergoing clinical trials to prevent development of clinical disease . hence , diagnosis at the prediabetic stage becomes the need of the hour and it is here , where as a dentist , our careful observations can aid in early diagnosis . though various soft tissue pathologies occurring in oral cavity of these patients are well - established , identifying through morphological alterations in dentition can help to diagnose still earlier as these morphological alterations occur quite early . type i diabetes is considerably rarer than type ii , accounting for between 5% and 15% of all diabetes . it appears predominantly in childhood , with a peak age at presentation of about 11 years in girls and 14 years in boys hence the old description of juvenile onset . in this study , the mean age of presentation was 12.4 years in boys and 11.1 years in girls [ table 2 ] . from the study results , no significant correlation was found between the age at diagnosis of diabetes and the occurrence of morphological alterations . morphological alterations of the dentition are only be brought about by changes during the odontogenesis stage . the established protracted prediabetic phase in the disease can be assumed to explain the changes without any correlation with the age at diagnosis . similarly duration of diabetes , fasting blood sugar level , and hemoglobin percentage on the day of examination had no correlation with the presence or absence of morphological alterations . regarding the morphological alterations , the results of the study showed more marked alterations in cuspal number and position , in particular mandibular first molar . tuberculum intermedium and tuberculum sextum . a third lingual cusp developing on mandibular molars on the lingual surface if this extra cusp is located on the distal marginal ridge , it is called as tuberculum sextum . in this study , seven cases showed 6 cusp in mandibular molars , among them five showed tuberculum intermedium [ figure 1 ] and two showed tuberculum sextum [ figure 2 ] . none of the controls showed this anomaly and similarity in the occurrence of this anomaly in notable number of iddm patients suggests that this finding can not be incidental . tuberculum intermedium in left mandibular first molar other observations included 4 cusps in mandibular second premolar [ figure 3 ] , y shaped occlusal pattern in mandibular first premolar [ figure 4 ] , mandibular second molar with 5 cusps [ figure 5 ] and 6 cusps [ figure 4 ] , mandibular first molar with 4 cusps [ figure 6 ] , flower shaped mandibular molar [ figure 7 ] , prominent cusp of carabelli and oblique ridge in maxillary molar [ figure 8 ] . furthermore , 4 cases showed localized microdontia in second premolar ( 1 case ) and second molars ( 3 cases ) . four cusps in right mandibular second premolar ( lingually 3 cusps ) y type occlusal pattern in mandibular first premolar along with tuberculum intermedium in first and second molars left mandibular first molar with 6 cusps and second molar with 5 cusps right mandibular first molar showing 4 cusps flower shaped left permanent mandibular first molar prominent cusp of carabelli and oblique ridge in left maxillary first molar thus , totally out of 30 patients , 14 ( 46.5% ) showed developmental variations in size and shape . in contrast , the control group showed no anomalies . this statistically significant ( p < 0.001 ) morphological alteration provides a link between the altered endocrine function and morphodifferentiation stage of odontogenesis . it may be hypothesized that hyperproductivity of the inner enamel epithelium or an altered genetic pathway controlling the enamel knot function cause occurrence of 6/supernumerary cusp anomaly in these patients . the study found regressive alteration in the form of , marked attrition in 11 of the type i dm patients ( 36.6% ) which was more severe than in the two patients ( 6.8% ) of control group . studies at ultrastructural level on the teeth of diabetic rodents have shown that the dm directly causes enamel hypoplasia , which inturn may contribute to this increased attrition . the occurrence of enamel hypoplasia in dm is well - explained by the following hypotheses . due to the secondary effects of dm such as microangiopathy , less calcium is integrated in both the enamel and the bone of diabetic animalssecond , secondary effectors such as proteins , which control the exact arrangement of the prisms , are absent . in such case , the function of the ameloblasts would also be remarkably decreasedalso , increased blood glucose concentration would be directly responsible for the irregular prism structure in enamel by influencing the secretory ameloblasts . due to the secondary effects of dm such as microangiopathy , less calcium is integrated in both the enamel and the bone of diabetic animals second , secondary effectors such as proteins , which control the exact arrangement of the prisms , are absent . in such case , the function of the ameloblasts would also be remarkably decreased also , increased blood glucose concentration would be directly responsible for the irregular prism structure in enamel by influencing the secretory ameloblasts . no other studies in the literature have focused on the morphological alterations in these patients . findings similar to our study are also seen in berardinelli seip syndrome and alstrom 's syndrome , where dm is one of the features . here enamel hypoplasia and occurrence of talon 's cusp are reported , with etiology probably due to this endocrine disturbance , dm . the proposed hypothesis for the formation of talon 's cusp in this study are hyperproductivity of the anterior ends of dental lamina , disturbances during morphodifferentiation , such as altered endocrine function , which may affect the shape and size of a tooth without impairing the functions of ameloblasts or odontoblasts , and malinteraction between ectoderm and mesoderm at the time of complex odontogenesis process on the epithelial buddings of the premaxillary region . thus , the results of this study suggest that though all the dental anomalies occurring in different individuals can not be due to dm , the presence of such anomalies should arouse the suspicion of dm and further signs and symptoms should be elicited and the physician can be consulted for intense blood glucose examination . genetically induced diabetes like juvenile type i diabetes may lead to much more destruction in the quality and quantity of life than type ii diabetes . as our keen observation can interrupt the progress of the disease at the prediabetic phase itself , the value of such reflectors of systemic conditions should not be overlooked or neglected . further studies on larger sample population and advanced research on odontogenesis can lead this affected young generation toward disease free future . the encouraging results of our study strongly suggest that remarkable morphological alterations do occur in the dentition of type i dm patients . the exact mechanism whereby diabetes affects the hard tissue development is as yet to be studied with advanced research on odontogenesis .

introduction : type 1 diabetes mellitus ( dm ) is an endocrine disorder that occurs commonly in an age group , where the development of primary and permanent dentition takes place . as altered endocrine functions may affect the shape and size of teeth leading to dental anomalies , this study was conducted to look for the occurrence of any dental anomalies in type i dm patients.materials and methods : a diabetic camp was conducted at alur chandrashekharappa memorial hospital , davangere , where 30 diabetic patients were examined and the impressions of their maxillary and mandibular arches were recorded . age and sex matched controls were selected randomly , and similar recordings were done.results:type i diabetic patients showed statistically significant ( p < 0.001 ) morphological alterations of total number of cusps , including presence of 6th cusp in mandibular molars and extra cusps in mandibular premolars . other alterations such as microdontia , flower shaped mandibular molars , prominent cusp of carabelli , and oblique ridge in maxillary molars were also noted . severe attrition was found in 11 ( 36.6% ) of the diabetic patients , whereas the control group showed attrition only in 2 ( 6.8% ) patients.conclusion:remarkable morphological alterations do occur in the dentition of type i dm patients .

gestational diabetes mellitus ( gdm ) may give rise to higher risks of multiple complications for mother and fetus , including miscarriage , preterm delivery , pregnancy hypertension , embryonic abnormalities , macrosomia , and even fetal death . prevalence of gdm in china is increasing , from 3.7% in 1995 to 5.1% in 2008 . increased insulin resistance is one of the main mechanisms for the development of gdm . one is called as physiological insulin resistance , which is mediated by pregnancy - related hormones and will aggravate during the third trimester . the other however , in some patients it may extend to postpartum . near half of gdm patients will develop to type 2 diabetes and obesity in the future . furthermore , the risk of type 2 diabetes in their offspring is also increased [ 79 ] . adiposity fatty acid - binding protein 4 ( fabp4 ) is a member of the lipid - binding protein super - family . as an important intracellular fatty acid carrier protein , the roles of fabp4 in the development of metabolic syndrome , type 2 diabetes mellitus , cardiovascular disease , preeclampsia and gdm are of great concern . phosphatase and tensin homolog ( pten ) was first discovered as a tumor suppressor gene . recent findings indicate that it plays a role in the regulation of the insulin signal transduction pathway . a complex of fabp4 and pten was recently detected and is presumed to play a role in the pathogenesis of insulin resistance . therefore , we hypothesized that increased levels of plasma fabp4 and pten are associated with gdm . the relationship between fabp4 , pten , homa - ir , and other biochemical parameters in gdm were further investigated . a total of 30 pregnant women with gdm ( gdm group ) and 30 euglycemic pregnant women ( control group ) were recruited . the mean age of the gdm patients and the control group was 31.833.91 and 26.531.91 years ( p>0.05 ) . gdm was diagnosed if 1 or more plasma glucose levels were elevated during an oral glucose tolerance test with 75 g glucose , according to the criteria of standards of medical care in diabetes 2011 . homa - ir was calculated as previously described : homa - ir=(fpg fins)/22.5 ( fins , fasting insulin ) . blood samples were taken after an overnight fast . at the time of blood sampling , serum insulin was determined by 2-site chemiluminescent enzyme immunometric assay in an immulite automated analyzer ( dpc , siemens , marburg , germany ) . fabp4 and pten were measured by elisa according to the manufacturers instructions ( r&d systems china , shanghai ) . tg , total cholesterol ( tc ) , hdl - c , low - density lipoprotein cholesterol ( ldl - c ) , fpg , and 2-hpg were measured by standard laboratory methods in a certificated laboratory . correlations were conducted by using the pearson correlation analysis method . to evaluate the effects of covariates on insulin resistance , multivariate linear regression analyses were undertaken . before performing multivariate analyses , non - normally distributed parameters were logarithmically transformed . a p - value < 0.05 was considered as statistically significant . a total of 30 pregnant women with gdm ( gdm group ) and 30 euglycemic pregnant women ( control group ) were recruited . the mean age of the gdm patients and the control group was 31.833.91 and 26.531.91 years ( p>0.05 ) . gdm was diagnosed if 1 or more plasma glucose levels were elevated during an oral glucose tolerance test with 75 g glucose , according to the criteria of standards of medical care in diabetes 2011 . homa - ir was calculated as previously described : homa - ir=(fpg fins)/22.5 ( fins , fasting insulin ) . blood samples were taken after an overnight fast . at the time of blood sampling , serum insulin was determined by 2-site chemiluminescent enzyme immunometric assay in an immulite automated analyzer ( dpc , siemens , marburg , germany ) . fabp4 and pten were measured by elisa according to the manufacturers instructions ( r&d systems china , shanghai ) . tg , total cholesterol ( tc ) , hdl - c , low - density lipoprotein cholesterol ( ldl - c ) , fpg , and 2-hpg were measured by standard laboratory methods in a certificated laboratory . correlations were conducted by using the pearson correlation analysis method . to evaluate the effects of covariates on insulin resistance , multivariate linear regression analyses were undertaken . before performing multivariate analyses , non - normally distributed parameters were logarithmically transformed . a p - value < 0.05 was considered as statistically significant . the gdm group had higher levels of bmi , bmi , tg , fpg , 2-hpg , fins , homa - ir , fabp4 , and pten than the control group ( table 1 ) . no significant differences in tc and ldl - c were found between the 2 groups . the plasma fabp4 in the gdm and control group was 1.470.25 vs. 0.200.07 ng / ml ( p<0.0001 ) , respectively ; the pten in the gdm and control group was 6.461.57 vs. 4.720.82 ng / ml , p<0.0001 , respectively ( figure 1 ) . when all samples ( including the gdm and control groups ) were statistically analyzed , there was a positive relationship between pten and fabp4 ( r=0.64 , p<0.0001 ) ( figure 2 ) . in the gdm group , there was positive relation between plasma fabp4 and homa - ir ( r=0.566 , p=0.001 ) . a similar relation were also found between pten and homa - ir ( r=0.542 , p=0.002 ) in the gdm group . in the gdm group , the influence of parameters such as bmi , bmi , tg , tc , ldl - c , hdl - c , 2-hpg , and fins on homa - ir was further investigated by multiple linear regression analysis , which showed that fabp4 and tg are 2 significant independent factors influencing homa - ir , while the effect of pten on homa - ir was nearly significance ( p=0.053 , table 2 ) . the multiple linear regression equation was y=0.484 + 0.807x1 + 0.224x2 + 0.07x3 ( x1 : fabp4 ; x2 : tg ; x3 : pten ; y : homa - ir ) , r=0.931 , r=0.867 , f=121.882 ( p<0.001 ) . we found that the gdm group had a higher homa - ir than the control group , which is consistent with previous studies [ 1517 ] . several case - control studies found that increased insulin resistance is associated with abnormalities in body weight , blood glucose , lipids , and lipoprotein . for example , higher pre - pregnant bmi is coupled with increased risk of gdm . another study showed that the fpg , 2-hpg , fins , 2-hfins , tg , ldl - c , and homa - ir in gdm patients were significantly higher than that of euglycemic pregnant women and a positive relation was found between pregnant age , pre - pregnant bmi , and homa - ir . our study also found that the gdm patients had a higher concentration of fabp4 compared to the controls . furthermore , the multiple regression analysis revealed that plasma fabp4 is an independent risk factor for insulin resistance . in a study by ortega et al . , the gdm group ( n=98 ) had a higher fabp4 level than the control group ( n=86 ) , 19.91.0 vs. 17.70.8 ng / ml , p=0.0493 . these results consistently indicate that a higher level of fabp4 is associated with increased insulin resistance and may play a significant role in the pathogenesis of gdm [ 2022 ] . as an important intracellular fatty acids carrier protein , fabp4 , is released from adipocytes and plays an important biologic role in fatty acid uptake , transport , and metabolism . increased fabp4 can promote the accumulation of short - chain fatty acids in cells and decrease pi3k - akt protein activity , thereby inhibiting glucose oxidation and glycolysis and significantly reducing glucose uptake and utilization in muscle and liver [ 2427 ] . therefore , the pathway from glucose to triglyceride is disturbed and the increased insulin resistance may lead to gdm [ 2427 ] . however , why adipocytes in gdm patients produce higher levels of fabp4 is still unknown . the relation between gdm and the plasma levels of pten has not been investigated . our study found for the first time that gdm patients had a significantly higher level of pten than normal controls and that this is positively associated with homa - ir , indicating that the increased pten levels may also contribute to the pathogenesis of increased insulin resistance . pten , as a tumor - suppressive protein , has been widely investigated in recent years , but its role in insulin sensitivity and glucose metabolism is largely unknown . increased expression of pten may result in more severe insulin resistance by blocking the intracellular insulin - signaling pathway , catalyzing phosphatidylinositol-3,4,5-triphosphate ( pip3 ) degradation , and inhibiting the transportation of glucose into the cells . in pten knockout experimental animals , insulin sensitivity is increased in liver , muscle , and adipose tissue [ 2932 ] . cowden disease , caused by a pten gene inactive mutation , also shows improved insulin sensitivity . all these findings strongly suggest that the lost function of pten can increase insulin sensitivity . our study showed that there is a positive correlation between plasma fabp4 and pten , indicating that the interaction of these two factors may cause more severe insulin resistance . a recent study revealed that a complex of fabp4 and pten was found in differentiated adipocytes , showing that the complex may enhance the potential activity of pten and result in more severe insulin resistance , but the underlying mechanisms need further investigation . as a cross - sectional study , we could not make a cause - and - effect conclusion between higher levels of fabp4 , pten , and increased insulin resistance . furthermore , we did not know whether the higher levels of fabp4 and pten already existed before the pregnancy or whether they extend after delivery . gdm patients had more severe insulin resistance than the control group , partially contributed to by elevated plasma fabp4 and pten . the net increment of body weight during pregnancy and dyslipidemia were independent factors for insulin resistance .

backgroundthe aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 ( fabp4 ) , phosphatase and tensin homolog ( pten ) , and insulin resistance in patients with gestational diabetes mellitus ( gdm).material / methodsplasma fabp4 and pten were determined by elisa in gdm patients ( gdm group , n=30 ) and in euglycemic pregnant women ( control group , n=30 ) . the clinical features , body mass index ( bmi ) , homeostasis model assessment of insulin resistance ( homa - ir ) , and lipid profiles were compared between the 2 groups . the influence of risk factors on insulin resistance , including bmi , lipid profiles , fabp4 , and pten , were further investigated by multiple - factor stepwise regression analysis.resultshigher levels of bmi , bmi , triglyceride ( tg ) , fasting plasma glucose ( fpg ) , 2-hour plasma glucose ( 2hpg ) , fasting insulin , homa - ir , fabp4 , pten , and lower level of high - density lipoprotein cholesterol ( hdl - c ) were found in the gdm patients than in the controls ( all p<0.005 ) . the plasma fabp4 was 1.470.25 vs. 0.200.07 ng / ml in the gdm and control group , respectively ( p<0.0001 ) . plasma pten was 6.461.57 vs. 4.720.82 ng / ml in the gdm and control group , respectively ( p<0.0001 ) . there was a positive relation between plasma fabp4 and pten when all blood samples , including gdm and control groups , were analyzed ( p<0.05 ) . the multiple - factor regression analysis revealed that plasma fabp4 , tg , and pten were independent risk factors for increased insulin resistance.conclusionsgdm patients have more severe insulin resistance compared to euglycemic pregnant women . higher levels of plasma fabp4 and pten are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation .

serum tumor markers including -human chorionic gonadotrophin , -fetoprotein , and lactate dehydrogenase were within normal limits . 1b ) imaging showed a 2.5-cm - sized poorly enhancing cystic mass at the right testis . pathological examination demonstrated that the cystic mass was confined within the testicular parenchyma , with a size of 2.52.41.7 cm . on macroscopic examination microscopically , the cyst was surrounded by a thick fibrous wall and was filled with mucinous material ( fig . the cyst had a single layer of columnar mucinous epithelial cells without nuclear atypia ( fig . the inflammatory cells were composed of lymphocytes , plasma cells , and histiocytes ( fig . teratomatous elements , such as cartilage , bone , or other mesenchymal teratomatous components , were not found . microscopically , the tumor was limited to the testicular parenchyma without involvement of the tunica albuginea . immunohistochemically , the lining epithelial cells were positive for cytokeratin 20 ( ck20 ) ( fig . 3c ) , as well as focally positive for cytokeratin 7 ( ck7 ) ( fig . 3d ) , d2 - 40 , wt-1 , and cytokeratin 5/6 ( ck5/6 ) . this study was approved by the institutional review board ( irb ) of seoul national university hospital . mucinous neoplasms of the testis or paratestis are rare and not well described in the medical literature . the first reported case of mucinous neoplasm was mucinous cystadenoma in the paratestis of an 11-year - old boy by kellert in 1959 . to date , most reported testicular / paratesticular ovarian - type surface epithelial neoplasms have been of the serous subtype , and previous papers reported approximately 24 cases of mucinous neoplasms of the testis or paratestis ; among these , only four reports described three cases of serous borderline tumors of the testis / paratestis and two cases of paratesticular mucinous cystadenomas were found , but there has been no report of any mucinous cystadenoma of the testicular parenchyma to date [ 3 - 7 ] . the histologic features of mucinous cystadenomas of the testis resemble those of common ovarian mucinous cystadenomas . that is , the cyst is typically composed of mucinous epithelium with tall , columnar endocervical - like cells lacking nuclear atypia . however , there are several histologic differences between testicular mucinous cystadenomas and ovarian mucinous cystadenomas . testicular mucinous cystadenomas are generally not as large as ovarian tumors , purportedly because the testicular tumors are found by patients earlier than their ovarian counterparts due to the sites at which the tumors arise . testicular tumors are more often unilocular and more frequently exhibit mucus extravasation associated with fibrosis or calcification than ovarian tumors , possibly because of trauma due to their superficial location . the origin of testicular mucinous neoplasms has not yet been clarified ; thus , several hypotheses have been suggested . ulbright and young supported the theory that the tumors arise from metaplasia of the mesothelium of the visceral tunica vaginalis . the theory that the tumors arise from the remnants of the mllerian ducts persisting in the male appendix , testis , or extratesticular scrotal contents is considered the most reasonable by some researchers . differential diagnoses include testicular mucinous borderline neoplasms / carcinomas , germ cell tumors , mesotheliomas , and metastatic mucinous tumors . in comparison with mucinous borderline tumors or mucinous carcinomas , mucinous cystadenomas testicular mucinous carcinomas or borderline neoplasms have been reported more frequently than testicular mucinous cystadenomas . to date , seven mucinous borderline neoplasms and four mucinous carcinomas have been reported . it is also important to rule out germ cell tumors , for example , teratomas with prominent mucinous components . teratomas almost always have components other than mucinous epithelial lined cysts , and 90% of those tumors occurring in adults are accompanied by intratubular germ cell neoplasia of unclassified type . unlike testicular mucinous cystadenomas , mesotheliomas exhibit positivity for calretinin , which is known to be expressed in mesothelial cells . the appropriate immunohistochemical staining , cytologic atypia , and history of mucinous carcinoma are critical for determining the origin of the tumor . the immunohistochemical profile of the tumor has not been specified until now . however , in several reports , testicular mucinous neoplasms have shown immunostaining that is positive for both ck7 and ck20 or positive for ck20 and negative for ck7 . the present case showed positive staining for ck20 and focal positive staining for ck7 , a result similar to previous studies . additionally , the present case also showed positive staining for cdx2 and negative staining for pax8 , d2 - 40 , and ck5/6 . cdx2 is known to be useful in distinguishing primary ovarian mucinous tumors from metastases of lower gastrointestinal tract origin . there has been only one case report of cdx2 expression in testicular or paratesticular mucinous neoplasms , revealing cdx2-positive and pax8-negative staining . together with the results of this report , testicular or paratesticular mucinous tumors may express cdx2 . immunohistochemical results for calretinin , ck5/6 , d2 - 40 , and pax8 suggest that testicular mucinous cystadenoma does not originate from mesothelium or mllerian duct remnants , while the results support the possibility of monodermal teratoma differentiation . although only a small number of testicular mucinous cystadenomas have been reported , these reported cases have shown good prognosis , similar to the prognosis of ovarian mucinous cystadenomas . in conclusion , mucinous cystadenoma of the testis is an extremely rare benign tumor and likely expresses cdx2 .

mucinous cystadenoma of the testis is a very rare tumor . herein , we report a case of mucinous cystadenoma arising in the testis of a 61-year - old man , along with a literature review . computed tomography showed a 2.5-cm - sized poorly enhancing cystic mass . grossly , the tumor was a unilocular cystic mass filled with mucinous material and confined to the testicular parenchyma . histologically , the cyst had a fibrotic wall lined by mucinous columnar epithelium without atypia . immunohistochemical staining was positive for cytokeratin 20 and cdx2 , as well as focally positive for cytokeratin 7 . the pathologic diagnosis was mucinous cystadenoma .

in the absence of curative treatment options , patients with crohn 's disease require continuous therapeutic management and monitoring by a physician . therapeutic choices depend on location of inflammatory lesions , severity of disease , and complications . treatment goals for crohn 's disease , like those for many other chronic diseases , include eradication of disease - related symptoms and restoration of the patient 's quality of life while minimizing complications or therapy - related toxicities . success depends in part on patient adherence to the therapeutic regimen , which is influenced by many factors including the physician - patient relationship , disease awareness , effectiveness of the prescribed regimen , and adverse events associated with treatment . patients often doubt the severity of their crohn 's disease and , therefore , empirical evidence of their disease and an objective measurement of disease severity can be a powerful tool to motivate adherence , especially after symptoms improve . the case presented here was chosen to illustrate the importance of ongoing therapy to a positive outcome based on objective diagnostic findings and patient education . a 21-year - old man was admitted to the emergency department of a hospital in december 2007 complaining of nausea / vomiting and periumbilical pain . computed tomography of the abdomen / pelvis revealed ileal thickening and a small bowel obstruction . the patient was admitted to the hospital and treated with nasogastric suction , intravenous fluids , and antibiotics . he subsequently improved and was discharged . soon after , the patient presented at our office with complaints of recurrent abdominal pain , new - onset diarrhea , and rectal bleeding . a colonoscopy in april 2008 demonstrated ulcerations of the ileum and colon consistent with crohn 's disease ; the ileum was notably stenotic , and only the distal few centimeters could be visualized ( fig . a small bowel follow - through study with barium contrast showed the stenoses and ulcerations extending over the distal 30 cm of the ileum and confirmed a diagnosis of crohn 's disease . treatment with mesalamine 4 g / day and a 14-day course of metronidazole relieved the abdominal pain and bleeding , but the diarrhea persisted . over the next 2 weeks , the patient developed epigastric pain and nausea and was admitted to the hospital for severe pain . a diagnosis of pancreatitis likely due to the mesalamine prompted discontinuation of the drug and initiation of budesonide 9 mg / day . symptoms of pancreatitis subsequently improved , and the patient was discharged from the hospital after a short stay . over the next 3 weeks , the diarrhea , bleeding , and pain resolved . however , by the end of august 2008 , the diarrhea and cramping periumbilical pain recurred , and an immunomodulator was added to the therapeutic regimen . ten days later , the patient was admitted to the hospital with a high fever ( 103f ) associated with elevated liver enzymes and lymphopenia . the immunomodulator was discontinued as it was presumed that the lymphopenia had made the patient susceptible to the infection . in november 2008 , at the follow - up appointment in the physician 's office , a lengthy discussion with the patient included the care of crohn 's disease and the risks and benefits of biologic therapy . a decision was made to initiate induction therapy with the anti - tumor necrosis factor ( tnf ) agent adalimumab 160 mg s.c . 2 weeks later , followed by maintenance therapy at a dose of 40 mg s.c . a follow - up colonoscopy demonstrated complete healing of the colonic mucosa and significant ileal healing as well ( fig . he preferred to stop the medication because he was feeling well and because he was concerned about the potential for adverse effects . a prometheus ibd serology 7 test was ordered to help assess the need for ongoing therapy based on serologic markers . results revealed elevations of the following biomarkers for crohn 's disease : asca ( both iga and igg ) , anti - ompc iga , anti - cbir1 , and inflammatory bowel disease ( ibd)-specific panca ( table 1 ) . after additional discussion about the prognostic value of elevations of multiple markers and the high risk for disease progression , the patient agreed that continued anti - several studies have examined nonadherence to treatment for ibd . in one such prospective study , cerveny et al . found that 38.9% of patients were intentionally nonadherent to their ibd regimen during the 2 weeks prior to being interviewed and that patients ' disease awareness and medication knowledge are important influences on adherence . serologic testing such as with the prometheus ibd serology 7 panel has evolved over time from its initial use in helping differentiate ulcerative colitis from crohn 's disease to further evaluating indeterminate colitis , stratifying disease , predicting the potential course of ibd , determining more severe disease phenotypes , and guiding treatment based on the prognosis of the patient . serologic testing can determine the level of immune reactivity to various markers of disease and , therefore , can be used to predict an increased risk of complicated disease requiring ongoing treatment . the serologic results for our 21-year - old patient were communicated clearly to him , improving his disease awareness and ability to make informed decisions during treatment . the results facilitated an extensive discussion that strengthened his knowledge of the medication and increased his appreciation of the importance of adherence . were the first investigative group to associate increased levels of immune response with complications of crohn 's disease . specifically , these investigators showed that specific serologic markers are present in patients with a more aggressive disease phenotype , in whom both the number and level of antibody responses were significantly associated with an increased likelihood of fibrostenosis , internal perforating disease , and the need for small bowel surgery . . also found an association between immune responses to asca , anti - i2 , anti - ompc , and panca in patients with a more severe crohn 's disease phenotype that included small bowel disease , longer duration of disease , a higher risk for progression , and the need for intestinal surgery . similar correlations between the number and level of immune response and more severe disease phenotype have been observed in the pediatric population as well . the ibd serology 7 results obtained in this case served as a valuable tool for overall disease management and facilitated physician - patient communication on disease prognosis and a continued need for therapy .

patients with crohn 's disease require long - term therapy and physician follow - up to treat symptoms , minimize complications of the disease , and address side effects that may occur due to therapeutic interventions . once stabilized , it is not unusual for patients to question the need for continued therapy . this may be related to various factors including poor disease awareness , lack of adequate communication between the physician and the patient , not wanting to take medications chronically , and/or financial issues among a host of other possibilities . however , nonadherence can have a serious impact on morbidity and mortality in patients with crohn 's disease . this case illustrates the management and stabilization of a patient with active crohn 's disease and the use of diagnostic serological testing to aid in disease risk assessment and treatment guidance .

in india , anemia is a common and serious health disorder among both sexes and all age groups , although it has a higher prevalence among women than men . anemia of chronic disease ( acd ) is the second most prevalent anemia after iron deficiency anemia , and occurs in patients with acute or chronic immune activation . acd is defined as anemia occurring in chronic infections , inflammatory conditions , or a neoplastic disorder , which is not caused by marrow deficiencies or other diseases , and occurring despite the presence of adequate iron stores and vitamins . typically , acd is a mild - to - moderate , normochromic / normocytic anemia , and is characterized by decreased serum iron and total iron - binding capacity , with normal or increased iron stores . it is immune driven ; cytokines and cells of the reticuloendothelial system induce changes in iron homeostasis , proliferation of erythroid progenitor cells , production of erythropoietin , and life span of red cells , all of which contribute to the pathogenesis of anemia . periodontitis is an inflammatory disease of the supporting tissues of the tooth caused by specific microorganisms in a susceptible host . just as the periodontal tissues mount an immune inflammatory response to bacteria and their products , systemic challenges with these agents also induce a major vascular response . chronic periodontitis is the most common form of periodontal disease , which progresses relatively slowly and is more common in adults . it is , therefore , speculated that periodontitis results in low - grade systemic inflammation , which may cause lower number of erythrocytes and , consequently , lower hemoglobin ( hb ) concentration . however , conflicting results have been reported regarding the association of periodontal disease and anemia . the purpose of this study is to investigate whether patients with chronic periodontitis have an anemic status and the effect of non - surgical periodontal therapy on red blood cell ( rbc ) analyses of patients with chronic periodontitis over a 6-month period . in this 6-month follow - up randomized controlled double - blind study , male patients of age between 20 and 50 years were selected from the outpatient department . the patient and the pathologist who performed the blood analysis were blinded to the study . patients with a history of systemic diseases or conditions that may adversely affect periodontal health were excluded from the study . the exclusion criteria for the study were as follows : ( 1 ) female patients ; ( 2 ) smokers ; ( 3 ) history of periodontal treatment or use of vitamin , antibiotics , or iron supplements within previous 6 months ; ( 4 ) individuals who suffered from any acute or chronic medical conditions including diabetes , or viral , fungal , or bacterial infection ; and ( 5 ) individuals who suffered from malaria or jaundice in the last 1 year [ table 1 ] . clinical parameters assessed were probing pocket depth ( ppd ) , clinical attachment loss ( cal ) , gingival index ( gi ) , and plaque index ( pi ) . patients diagnosed with chronic periodontitis , having a probing depth of 5 mm in > 30% sites and cal 2 mm at 30% sites , were included in the test group ( n = 50 ) . the control group ( n = 50 ) included periodontally healthy male patients with no ppd and cal [ figures 1 and 2 ] . patients were informed regarding the benefits and protocol of the study and a written informed consent was taken from all the patients . demographic characteristics of the study population formula for sample size estimation at baseline : all the blood samples of the test and control groups were assessed at the pathology laboratory . ten milliliters of venous blood samples were collected by venipuncture under aseptic conditions in the antecubital fossa . the samples were processed within 4 h of collection in an automated hematology analyzer and semi - automated ( ok ) 3-part differential cell counter act-8 beckham coulter . the parameters assessed were rbc count , hb concentration , hematocrit value , mean corpuscular volume ( mcv ) , mean corpuscular hemoglobin ( mch ) , and mean corpuscular hemoglobin concentration ( mchc ) . non - surgical periodontal therapy consisting of scaling and root planing was performed on patients in the test group ( n = 50 ) and oral prophylaxis was performed in the control group ( n = 50 ) . patients were advised to use 0.2% chlorhexidine mouthwash , 10 ml twice daily for 15 days . at 6 months : patients of the test and control groups were recalled . student 's t - test was performed with appropriate microsoft excel software for a comparative analysis of outcome parameters between test and control groups at baseline and 6 months . means and standard deviations of all the parameters were calculated for both groups . to illustrate the differences between groups , two - tailed p value was used , which was considered statistically significant if < 0.05 . at baseline : all the blood samples of the test and control groups were assessed at the pathology laboratory . ten milliliters of venous blood samples were collected by venipuncture under aseptic conditions in the antecubital fossa . the samples were processed within 4 h of collection in an automated hematology analyzer and semi - automated ( ok ) 3-part differential cell counter act-8 beckham coulter . the parameters assessed were rbc count , hb concentration , hematocrit value , mean corpuscular volume ( mcv ) , mean corpuscular hemoglobin ( mch ) , and mean corpuscular hemoglobin concentration ( mchc ) . non - surgical periodontal therapy consisting of scaling and root planing was performed on patients in the test group ( n = 50 ) and oral prophylaxis was performed in the control group ( n = 50 ) . patients were advised to use 0.2% chlorhexidine mouthwash , 10 ml twice daily for 15 days . at 6 months : patients of the test and control groups were recalled . clinical parameters and rbc parameters student 's t - test was performed with appropriate microsoft excel software for a comparative analysis of outcome parameters between test and control groups at baseline and 6 months . means and standard deviations of all the parameters were calculated for both groups . to illustrate the differences between groups , two - tailed p value was used , which was considered statistically significant if < 0.05 . the mean and standard deviation of all blood and clinical parameters in the test and control groups are presented in tables 2 and 3 , respectively . hb concentration , hematocrit value , and rbc count in the test group at baseline were below the normal reference range [ table 2 , graphs 13 ] , whereas in the control group , they was well within the normal reference range [ table 3 , graphs 13 ] . this suggested that patients with chronic periodontitis had hb concentration , hematocrit value , and rbc count below the normal reference range at baseline , as compared to the controls at baseline . at 6 months after non - surgical periodontal therapy , hb concentration , hematocrit value , and rbc count in the test group showed a statistically significant increase , indicating that non - surgical periodontal therapy has a positive effect on the anemic status of the patients [ tables 2 and 3 , graphs 13 ] . hematological parameters at baseline and 6 months in the test group hematological parameters at baseline and 6 months in the control group comparison of hb at baseline and 6 months in the test and control groups comparison of hematocrit value at baseline and 6 months in the test and control groups comparison of rbc count at baseline and 6 months in the test and control groups mcv , mch , and mchc values at baseline in the test as well as the control group were well within the normal reference range [ tables 2 and 3 , graphs 46 ] , indicating that patients with chronic periodontitis had acd which is a normocytic , normochromic anemia . comparison of mcv at baseline and 6 months in the test and control groups comparison of mch at baseline and 6 months in the test and control groups comparison of mchc at baseline and 6 months in the test and control groups clinical parameters measured showed a statistically significant decrease from baseline to 6 months after non - surgical periodontal therapy in the test group [ table 4 , graphs 710 ] . clinical parameters in the control group were within the normal reference range at baseline and 6 months [ table 5 , graphs 710 ] . clinical parameters at baseline and 6 months in the test group comparison of gi at baseline and 6 months in the test and control groups comparison of pi at baseline and 6 months in the test and control groups comparison of ppd at baseline and 6 months in the test and control groups comparison of cal at baseline and 6 months in the test and control groups clinical parameters at baseline and 6 months in the control group in the present study , the hb concentration , hematocrit value , rbc count , mcv , mch , and mchc in the control group at baseline and 6 months were in the normal reference range . these results are in accordance with the results of the studies conducted by hutter et al . the hb concentration , hematocrit value , and rbc count in the test group at baseline were below the normal reference range , whereas the mcv , mch , and mchc were in the normal reference range . these results are in accordance with the results of the studies conducted by lainson et al . , hutter et al . , gokhale et al . , and naik et al in their studies found no correlation between hb levels and periodontal status , when they compared hb levels in patients with periodontitis of different severity , whereas in the present study , hb level in periodontitis patients versus healthy controls was compared . after non - surgical periodontal therapy which included scaling and root planing , a statistically significant increase in the hb concentration , hematocrit value , and rbc count in the test group at 6 months was seen . these results are in accordance with the results of the studies conducted by hutter et al . , gokhale et al . , naik et al . , and pradeep et al . according to these authors and a few studies in the past , periodontitis patients have elevated levels of acute phase proteins , interleukin ( il)-1 , il-6 , and tumor necrosis factor ( tnf ) . these inflammatory mediators are shown to suppress mature erythroid progenitors and inhibit in vitro colony formation by erythroid burst - forming units and erythroid colony - forming units from normal human marrow . some studies also showed a disturbance in iron regulatory system . in vitro stimulation of fresh human hepatocytes with il-6 showed strong induction of hepcidin , a liver hormone which caused disturbance in iron regulatory mechanism . hepcidin causes ferroportin internalization and degradation , thereby decreasing iron transfer into blood plasma from the duodenum , from macrophages involved in recycling senescent erythrocytes , and from iron - storing hepatocytes , with the iron stores being adequate . this response restricts the iron supply to erythropoietic precursors , and hence , a decrease in hb count was seen . the gi , pi , cal , and ppd values showed a significant improvement in the test group from baseline to 6 months after non - surgical periodontal therapy consisting of scaling and root planing . epidemiological studies suggest that periodontitis is associated with an increased risk for systemic diseases like cardiovascular diseases , cerebrovascular ischemia , atherosclerosis , and preterm low birth of infants . in india , anemia is more prevalent in females because of poor nutrition , increased menstrual losses , high incidence of tropical and intestinal infections , and other miscellaneous factors . females are also prone to hormonal imbalance during puberty , during the reproductive phase , and toward menopausal age . the microbial flora and host immune response are altered leading to exaggerated response of the periodontal tissues to local factors . various studies have evaluated the ppd , cal , pi , gi , and radiographic bone measurements of smokers and non - smokers , and found a positive correlation between smoking and these clinical parameters . the present study shows an association between chronic periodontitis and signs of anemia , which suggests a measurable effect of periodontitis on the systemic condition of the patient . this study also suggested that non - surgical periodontal therapy had a positive effect on the hb count , rbc count , and hematocrit value at the end of 6 months . decreased mcv values suggest microcytosis which is most commonly caused by iron deficiency anemia and elevated levels of mcv suggest macrocytosis caused by vitamin deficiency . in this study , mcv values were in the normal reference range for both chronic periodontitis group and periodontally healthy group at baseline as well as 6 months post non - surgical periodontal therapy . this suggested that the anemic status was not due to iron deficiency or vitamin deficiency , as the mcv values decrease or increase in such conditions . a decrease in the mch value is seen in microcytic anemia caused due to iron deficiency , whereas an increase in mch value is seen in macrocytic anemia caused due to vitamin deficiency . the present study shows mch values within the reference range for both the groups at baseline and 6 months , indicating the anemia to be normocytic as seen in acd . though the mean hb count is lower than the normal values , mchc is within the normal reference ranges in both the groups at baseline and 6 months , indicating that the hb concentration per volume of packed red cell is normal . the limitation of this study was that an analysis of serum ferritin levels and the soluble serum transferring receptor concentration , or a bone marrow examination was necessary to quantify the iron stores and definitely distinguish between acd and iron deficiency anemia . therefore , further studies with a larger sample size should be conducted and the serum ferritin levels must also be assessed . a correlation was found between chronic periodontitis and decreased levels of hb , hematocrit value , and rbc count , suggesting that anemia is induced by inflammation caused in patients suffering from periodontal disease . the study also provides evidence that non - surgical periodontal therapy can improve the anemic status of the patients . further cohort studies with a larger sample size are needed to find an association between chronic periodontitis and anemia and the effect of periodontal treatment on the anemic status of these patients .

background : in india , anemia is a common and serious health disorder among both sexes and all age groups , with anemia of chronic disease ( acd ) being the second most prevalent anemia . periodontitis is an inflammatory disease of the supporting tissues of the tooth caused by specific microorganisms . an immune response to bacteria and their products induces a major vascular response , offering explanatory mechanisms for the interactions between periodontal infection and a variety of systemic disorders . therefore , periodontitis results in low - grade systemic inflammation , which may cause lower number of erythrocytes and , consequently , lower hemoglobin concentration.materials and methods : a total of 100 systemically healthy male patients visiting the outpatient department participated in the study . of these , 50 patients had healthy periodontium and 50 patients had chronic periodontitis . clinical parameters and red blood cell parameters of all the patients were assessed at baseline and 6 months after non - surgical periodontal therapy . statistical analysis using student 's t - test was performed.results:data analysis revealed that patients with chronic periodontitis showed an improvement in both clinical and red blood cell parameters from baseline to 6 months after non - surgical periodontal therapy.conclusion:from the present study , it can be concluded that like any other chronic condition , chronic periodontitis can lead to acd . it also provides evidence that non - surgical periodontal therapy can improve the anemic status of patients with chronic periodontitis .

rasmussen 's encephalitis ( re ) is a rare but severe immune - mediated brain disorder leading to unilateral hemispheric atrophy , associated progressive neurological dysfunction with intellectual decline , and intractable seizures , , , . antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua ( epc ) , which often requires surgical intervention . given the presence of autoantibodies in many cases , particularly glur3 autoantibodies , a variety of immunotherapy treatments have been attempted with varied success , , . a viral cause of re was suggested by rasmussen et al . in 1958 ; however , reliable identification of an offending infectious agent has not been successful . microscopic analysis usually reveals inflammatory hallmarks of the disease , consisting of widespread perivascular t - cell infiltration and microglial nodule formation with neuronal cell death and cortical atrophy characteristic of advanced disease stage , . co - occurrence of the destructive pathology of re with dysplastic features in cortical architecture has only rarely been described but may have implications regarding pathophysiology and management , , , , , . therefore , we describe a rare case of dual pathology of re presenting as a focal cortical dysplasia ( fcd ) and discuss the literature on this topic . a previously healthy , 10-year - old right - handed girl with prior normal development presented at 8.5 years with twitching of the right side of her body initially involving the face and , later , arm , and leg . the twitching became essentially continuous during both wakefulness and sleep and evolved into epilepsia partialis continua ( epc ) . electroencephalogram ( eeg ) showed frequent left - side spikes , but the initial mri was normal and did not show any hemiatrophy . one month postseizure onset , she developed recurrent fever , rash , lymphadenopathy , and mouth ulcers . she underwent an extensive infectious / inflammatory work - up which was significant for positive cerebral spinal fluid ( csf ) oligoclonal bands . fujimoto disease , an idiopathic disorder characterized by fever and lymphadenopathy that may have an autoimmune basis and a possible association with systemic lupus erythematosus . the patient 's epc remained refractory to multiple anticonvulsant medications and a course of transcranial magnetic stimulation ( tms ) . she developed significant functional impairment initially affecting speech articulation and later developed an expressive aphasia with impaired processing and comprehension . follow - up mri 2 months postseizure onset demonstrated blurring of the gray white junction in the left precentral gyrus and was concerning for a cortical dysplasia ( fig . 1 ) . however , differential diagnosis still included a rasmussen 's encephalitis or a nonspecific autoimmune process . positron emission tomography ( fdg - pet ) showed an area of hypometabolism in the left precentral gyrus , but there was no focal increased radiotracer uptake with ictal single - photon emission computed tomography . motor mapping performed with tms and functional mri ( fmri ) showed typical contralateral motor innervation but was directly related to the left precentral gyrus of concern . language fmri activation patterns recorded during passive language tasks were consistent with bilateral language activation in temporoparietal regions slightly favoring the left hemisphere and typical left - lateralizated frontal lobe processing . given the concordant data for a left precentral lesion , the patient underwent invasive eeg monitoring to better localize the seizure onset zone . grids and strips were placed over the left hemisphere convexity , and a wedge biopsy of the cortex was taken . this confirmed that the seizure onset zone overlapped the eloquent left hemisphere primary motor cortex for the contralateral hand , throat , and jaw and the left sensory cortex for the face . biopsy subsequently showed a mild to moderate t lymphocyte predominant inflammatory infiltrate in the cortex and white matter with microglial nodules , which was consistent with rasmussen 's encephalitis , but the overall pathological picture was mild ( fig . 2 , fig . 3 ) . in addition , rare dysplastic neurons were seen , suggesting a possible cortical dysplasia ( fig . there was reactive gliosis , without vasculitis or viral inclusions . in an attempt to avoid any deficits , the patient underwent a partial resection in the left frontal lobe , avoiding areas which mapped to hand motor function and language , and multiple subpial transections in the area of hand motor function were performed . tissue taken during following surgery , the patient started a monthly course of intravenous immunoglobulin ( ivig ) . at 3 months postop , her family felt that she had started to show some improvement , with her right hand becoming more functional and with decreased hand twitching , especially during sleep . rasmussen 's encephalitis is a rare syndrome characterized by intractable seizures , often associated with epc and symptoms of progressive hemispheric dysfunction , , , . the typical features of re are onset in childhood with a peak of incidence at the age of 6 years and development of slowly progressive , neurological deterioration including hemiparesis , cognitive impairment , aphasia when the dominant hemisphere is involved , and imaging evidence of progressive , usually unilateral , cerebral atrophy . evidence supporting glur3 autoantibody - induced injury is conflicting , and there are cases in which such autoantibodies do not appear to exist . rasmussen 's encephalitis is now believed to be an ongoing and progressive immune - mediated process which induces apoptotic neuronal cell death and involves the neuroglial and lymphocytic response , leading to progressive deterioration of a single hemisphere , . these findings suggested a potential benefit of antiinflammatory and immune - suppressive therapy in patients with re in order to attenuate seizures as well as progressive neurological deficits . indeed , antiepileptic drug treatment fails in most patients and is ineffective against epc . on the other hand , immunomodulation , plasmapheresis , and antiviral treatment approaches were reported to be beneficial to only a limited extent , slowing cognitive decline but having no effect on established epc , , , . indeed , our case had significant evidence for immune activation with oligoclonal bands present in the csf and lymph node biopsy showing features of kikuchi fujimoto disease , justifying immunotherapy in this patient prior to establishing the diagnosis of re . dual pathology may be noted in 10% of patients and varies from low - grade tumor , cortical dysplasia , tuberous sclerosis , mesial temporal sclerosis , vascular abnormalities , or old ischemic lesions . the earliest mri changes include firstly cortical swelling , with a hyperintense t2/flair signal ( stage 1 ) . later , normal volume and hyperintense signal were seen ( stage 2 ) , followed by atrophy and hyperintense signal ( stage 3 ) and then progressive atrophy with normal signal ( stage 4 ) . in addition , other findings include atrophy of the ipsilateral head of the caudate nucleus in the majority of cases , . the persistent mri finding of blurring of the gray white junction in the left precentral gyrus was concerning for a cortical dysplasia . in addition , fdg - pet showed an area of hypometabolism in the left precentral gyrus , giving further evidence towards a focal lesion in our case . all cases of re and fcd involve children with a seizure onset in the first decade of life , , , , , . in all cases , the perioperative imaging studies did not reveal dual pathology , although fcd was considered in some . this current report is different in that a lesion concerning for fcd was identified on neuroimaging , but there was no evidence of re . instead , the combined clinical picture of epc along with a t - cell - dominated encephalitis with activated microglia fulfilled the diagnostic criteria for re in our case . according to the new ilae classification system of fcd , fcd type iiid is associated with lesions acquired during early life , i.e. , traumatic brain injury , glial scarring after prenatal or perinatal ischemic injury or bleeding , and inflammatory or infectious diseases . wang et al . identified four patients with re and fcd type iiid . this finding further supports a role for the concept of acquired and postmigrational pathomechanisms in the etiology of fcds . brain barrier , allowing circulating antibodies , antigens , and inflammatory cells access to the brain and promoting development of rasmussen 's encephalitis . another explanation could be that neurogenesis may be induced by seizures produced by rasmussen 's encephalitis resulting in a cortical dysplasia in the affected area . hemispherectomy , a surgical procedure for total or partial removal of a cerebral hemisphere , is considered a highly effective therapy to achieve seizure control in re . either anatomical or functional hemispherectomy has been proposed , . anatomical hemispherectomy has largely been abandoned because of postoperative mortality caused by hydrocephalus , hemosiderosis , and trivial head traumas . the goal of hemispherectomy is to achieve complete seizure control , promote neurodevelopmental progress in the unaffected contralateral hemisphere , and avoid seizure - related comorbidities . in our case , the mapped seizure onset zone overlapped the eloquent motor and sensory cortex . as the family was unwilling to proceed with a hemispherectomy but was keen for more limited surgical intervention , we opted to perform a partial cortical resection and multiple sub pial transections in order to limit any motor deficits . while this surgery appears to have reduced the severity of epc three months postoperation , it is likely that she will require a more definitive hemispherectomy in the future . the authors have no conflict of interests in the publication of this report to reveal .

rasmussen 's encephalitis is a rare syndrome characterized by intractable seizures , often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction . seizures are usually the hallmark of presentation , but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua , which often requires surgical intervention . co - occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management . we describe a rare case of dual pathology of rasmussen 's encephalitis presenting as a focal cortical dysplasia ( fcd ) and discuss the literature on this topic .

devic 's disease , also known as neuromyelitis optica ( nmo ) , is an autoimmune and inflammatory disorder that combines optic neuropathy and acute or subacute transverse myelitis which may occur simultaneously or after some time . the typical presentation of optic neuritis is visual impairment with acute decrease of visual acuity . brainstem affection can lead to a sensitivity reduction , muscle weakness and loss of bladder and bowel control , although unusual conditions as hiccups or narcolepsia have also been reported . the most common neurological symptoms are legs or limbs weakness ( paraparesis or tetraparesis ) with sensorial signs . the origin of nmo , since devic defined it in 1870 , was unknown and some authors thought that it was a variant of multiple sclerosis ( ms ) . in the last years , nmo - igg antibodies have been described as the physiopathological cause of devic 's disease . the antibodies ' target is aquaporin 4 , a protein which acts as a water transport channel across the astrocyte cell membrane . the function of aquaporin 4 is important for the maintenance of the blood - brain barrier . immunosuppressive treatments for nmo have a low effectiveness and prognosis is poor with some cases having an acute and devastating evolution . intravenous corticosteroids , as methylprednisolone , are usually used to treat new attacks of optic neuritis or myelitis . some authors have reported little evidence for immunosuppressive treatment in nmo , especially using mitoxantrone , azathioprine and mycophenolate mofetil [ 9 , 10 ] . internuclear ophthalmoplegia ( ino ) is a disorder affecting eye movements caused by medial longitudinal fasciculus affection . patients affected by ino present nystagmus in one eye when the other eye is in abduction , and it can also cause diplopia . usually , ino is unilateral , but it can also affect both sides . we present a case of a woman diagnosed with nmo who had acute and bilateral ino and tetraparesis without response to immunosuppressive treatments . a 32-year - old pregnant woman at 34 weeks ' gestation presented to the emergency department complaining of headache and sudden reduction of visual acuity in her re to counting fingers at one meter . her medical history revealed neurologic symptoms as paresthesia of the legs and the right arm 18 months ago . at the visual field exam , the patient was diagnosed with retrobulbar neuritis in the re with an abnormal ishihara test , a relative afferent pupillary defect in the re and normal fundoscopy . seven days later , re visual acuity improved to 5/100 , pupillary reflexes and ishihara test were normal and the visual field scotoma decreased . one month after the initial episode , eye evaluation was normal and visual acuity in the re was 7/10 . two days after delivery , she experienced paraparesis and l'hermitte 's sign . repeated blood cultures for common pathogens and mycobacteria were negative . serologic testing for human immunodeficiency virus , human t - lymphotrophic virus , cytomegalovirus , herpes simplex viruses , poliomyelitis and tetanus resulted negative . antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative , but anti - dna antibodies were elevated . brain magnetic resonance images ( mri ) showed no alterations , but a longitudinal lesion that affected four segments was seen in the cervical spinal cord mri ( fig . 1 ) . empirical therapy with methylprednisolone 1 g / day during 3 days ( solumoderin ; pfizer , madrid , spain ) and azathioprine ( imurel ; glaxo - welcome , paris , france ) was administered , but the patient 's neurologic status remained stable . three months later , paraparesis improved , but the patient was admitted to the hospital with abdominal pain and fever without response to antibiotic therapy ( amoxicillin - clavulanic 875/125 mg ) . two days after admission , she presented acute tetraplegia with loss of sensibility in the cervical area , babinsky sign and areflexia of both legs and of her right arm . the combined anti - infective and steroid therapy was administered with absence of clinical improvement . as the patient did not respond to the previous treatments , plasmapheresis for 15 consecutive days two months later , the patient presented an acute limitation in adduction of both eyes and bilateral nystagmus in abduction which was diagnosed as bilateral ino ( online suppl . usa , 2008 ) , an anti - cd20 monoclonal antibody , separated by 2 weeks in combination with methotrexate were administered to the patient . suddenly , her systemic state worsened and she presented hallucinations and astonishment , needing intravenous nutrition and bladder catheter . after six months , the patient was still at the hospital with bilateral paresis of the right arm and leg . double vision and ino disappeared , but residual nystagmus of the re and limitation in adduction of the le persisted ( online suppl . video 2 ) . visual acuity was 9/10 in both eyes ; pupilar reflex , ishihara test , visual field and eye fundus were normal . optical coherence tomography ( stratus oct 3000 ; carl zeiss meditec , dublin , calif . , usa ) showed slight reduction of the retinal nerve fiber layer ( rnfl ) thickness in the superior and nasal area of the re and an increase of the rnfl in the superior quadrant of the le ( fig . the spinal cord damage in nmo can range from inflammatory demyelination to necrotic damage of the white and grey matter [ 6 , 14 ] . inflammation may also affect the brain and sometimes neurologic symptoms suggest acute disseminated encephalomyelitis or ms . in 2006 , the mayo clinic proposed a revised set of criteria for the diagnosis of devic 's disease . our patient fulfilled the two major criteria and two of the three supportive criteria : brain mri not meeting criteria for ms at disease onset , and spinal cord mri with contiguous t2-weighted signal abnormality extending over three or more vertebral segments . she was seronegative for nmo - igg , but the presence of anti - dna antibodies suggests an autoimmune disease such as nmo . some patients with nmo may be negative for nmo - igg , while some patients with nmo - igg may not fulfill clinical criteria for nmo [ 2 , 17 ] . typically , the disease affects the brainstem , but not the brain nerves ; however , unusual conditions of the brain nerves in nmo have been reported [ 18 , 19 ] .

an unusual presentation of devic 's neuromyelitis optica ( nmo ) disease associated with bilateral internuclear ophthalmoplegia ( ino ) is described . a 32-year - old pregnant patient was diagnosed with nmo . first symptoms were headache and sudden visual loss in her right eye ( re ) . eighteen months ago , she reported other neurologic symptoms such as paresthesia . based on her visual field , fundoscopy and ishihara test , she was diagnosed with retrobulbar neuritis of the re . after delivery , new neurologic symptoms resembling transverse myelitis appeared . she was treated with methylprednisolone and plasmapheresis , which improved her visual acuity ; however , a sudden bilateral ino appeared , with adduction defect and nystagmus with abduction in both eyes . no improvement was obtained after treatment with azathioprine and rituximab . paresis of the legs and the right arm persisted , but double vision and oin gradually disappeared . at the end , the patient had a residual exophoria in the re and nystagmus with abduction in the left eye . prevalence of nmo is lower than one case per one million inhabitants , and it is not likely to affect the encephalic trunk ; furthermore , bilateral ino in nmo is rare . two major criteria and at least two of the three minor ones are required to confirm a nmo diagnosis , and our patient fulfilled these diagnosis criteria .

central giant cell granuloma ( cgcg ) , first described by jaffe in 1953 , is a benign intraosseous lesion consisting of cellular fibrous tissue that contains multiple foci of hemorrhage , aggregations of multinucleated giant cells , and occasionally trabeculae of woven bone that usually involves mandible than maxilla ( 2:1 ) before the age of 30 years . occurrences in other facial bones , such as the sphenoid and temporal , as well as in hand , foot , and humerus , have also been reported.[46 ] a clinically and histologically similar lesion occurs as a result of increased parathyroid hormone ( pth ) levels which cause an imbalance between osteoclastic osteoblastic homeostasis and calcium phosphate regulation , leading to bone resorption with fibrous replacement of the marrow and thinning of the cortex . excessive pth secretion may be due to problems in the glands themselves , in which case it is referred to as primary hyperparathryroidism and which leads to hypercalcemia . it may also occur in response to low calcium levels , as encountered in various situations such as vitamin d deficiency or chronic kidney disease ; this is referred to as secondary hyperparathyroidism . it is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism , as continuous stimulation of the parathyroids may result in adenoma formation and autonomous pth secretion . there are no clinical , histological , cytometric , or immunohistochemical differences between the aggressive and nonaggressive cgcgs , and it is found that the giant cell tumors ( gcts ) of long bones and the central giant cell tumors ( cgcg ) of jaws may be just variants of the same disease entity , with age- and site - specific features . in all cases , recent evidence suggests that vitamin d deficiency / insufficiency plays a role in the development of hyperparathyroidism . here , we report on a rare case of vitamin d malabsorption and secondary hyperparathyroidism , presenting as an asymptomatic brown tumor of mandible , treated conservatively . a 12-year - old female patient reported with the chief complaint of swelling in the right mandibular angle region since 8 months [ figure 1 ] . the swelling was slowly growing , bony hard in consistency , and not associated with any symptoms , non - tender , and not mobile . diffuse obliteration of right mandibular buccal vestibule , retromolar trigone , and expansion of lingual cortex distal to mandibular right second molar was evident . radiograph revealed tooth bud of third molar , unilocular radiolucency extending from apical and distal of mandibular right second molar to ramus , with sclerotic border at the body region anteriorly and scalloped at the ramus , expanded , leaving thin cortices toward the lower and posterior border of mandible , the third molar apparently pushed upward when compared with the left mandibular third molar , and no evidence of root resorption [ figure 2 ] . fine needle aspiration cytology ( fnac ) was done with positive aspiration of little frothy appearing blood . meanwhile , the histopathology reported it as cgcg with sections showing fibrocellular connective tissue stroma with numerous plump fibroblasts and multinucleated giant cells , few osteoblasts , and numerous blood vessels [ figure 3 ] . preoperative view swelling at the right mandibular angle region pre op orthopantomogram showing radiolucency at right angle and ramus of mandible with upward displacement of third molar bud histopathology showing fibrocellular connective tissue stroma with fibroblasts , giant cells , osteoblasts and blood vessels considering the histological diagnosis of a giant cell lesion , the patient was subjected for pth estimation , renal function tests ( rft ) , and complete blood investigation . the pth was 635.5 ( 14.072.0 ) pg / ml , alkaline phosphatase 421 ( 3396 ) u / l , total calcium 7.8 ( 8.710.2 ) mg / dl and phosphorous was 4.10 ( 2.54.3 ) mg / dl . the patient was treated conservatively with surgical debridement alone using modified brosch 's procedure , sacrificing the third molar and preserving the inferior alveolar nerve [ figure 4 ] , followed by maxillo - mandibular fixation for 6 weeks . on endocrinologist 's reference , the patient was diagnosed to be suffering from hypocalcemia / secondary hyperparathyroidism , the cause being nutritional or vitamin d deficiency . calcium carbonate , chewable , thrice daily , with cholecalciferol sachet 60 000 u once a week , after a stat dose of inj . arachitol 6 lakh unit along with calcium rich diet , and suggestion to increase sunshine exposure through outdoor activities . intra operative view showing post debridement site using brosch procedure and preserved inferior alveolar nerve the patient was reviewed 6 months postoperatively , and a series of immediate , 2-week , 8-week , and 6-month post - op radiographs [ figures 5a c ] showed satisfactory evidence of bone formation . a repeat blood examination reported pth as 27 ( 14.072.0 ) pg / ml , total calcium as 9.7 mg% ( 8.710.2 mg / dl ) , phosphorous to be 4.5 mg% ( 2.54.3 mg / dl ) , and alkaline phosphatase activity as 212 ( 3396 ) the parathyroid glands , situated behind the thyroid , are not regulated by the pituitary gland , but respond directly to changes in serum ionized calcium concentrations . pth is a single - chain polypeptide of 84 amino acids , which is synthesized by the chief cells and released in response to a fall in serum ionized calcium concentration . this hormone interacts with vitamin d and its metabolites in regulating calcium absorption and excretion . pth has direct effects which promote reabsorption of calcium from renal tubules and also has indirect effects , mediated by increased conversion of 25-hydroxycholecalciferol ( i.e. vitamin d ) to the more potent hormone 1,25-dihydroxycholecalciferol , which results in increased calcium absorption from food and enhanced mobilization of calcium from bone [ figure 6 ] . normal functioning of parathyroid glands vitamin d deficiency can be caused by conditions that result in little exposure to sunlight , such as living in northern latitudes , dark skin , infants or elders having less chance to go outside , and covering one 's face and body mainly due to religious reasons . particularly , women may acquire vitamin d deficiency , even though they live in a sunny climate . pth plays a central role in regulating calcium homeostasis because vitamin d and dietary calcium are rarely deficient . moreover , 99% of the total body calcium is in bone , but this pool is in dynamic equilibrium with the extracellular fluid by processes of bone resorption and deposition . the initial effect of pth on bone is to stimulate osteolysis , returning calcium from bone to extracellular fluid . prolonged exposure of bone to pth is associated with increased osteoclastic activity , extensive bone remodeling , and osteoblastic repair . in some species , calcitonin , a hormone secreted from the parafollicular c cells of the thyroid gland , also regulates calcium metabolism . however , although calcitonin is a useful tumor marker in medullary carcinoma of thyroid , it is of no clinical relevance to calcium homeostasis in humans . it is customary to distinguish three categories of hyperparathyroidism [ table 1 ] . in primary hyperparathyroidism , there is usually autonomous secretion of pth by a single parathyroid adenoma varying in size from a few millimeters to several centimeters in diameter , and seen in postmenopausal women . secondary hyperparathyroidism is present when there is hyperplasia with increased pth secretion in an attempt to compensate for prolonged hypocalcemia caused by chronic renal failure or prolonged dialysis , or severe malabsorption . in a very small proportion of cases of secondary hyperparathyroidism , classification of hyperparathyroidism primary hyperparathyroidism is the most common of the parathyroid disorders , with a prevalence of about 1 in 800 . it is 23 times more common in women than men and 90% of the patients are over 50 years of age . the incidence of primary hyperparathyroidism is 0.2% in patients older than 60 years and the estimated prevalence is over 1% , including undiscovered symptomatic patients . in the present case , the various reasons are listed out [ table 2 ] , which need to be considered as the differential diagnosis in hypocalcemia . subtotal thyroidectomy for graves disease causes transient hypocalcemia in 10% of patients , 1236 hours following surgery . idiopathic hypoparathyroidism may develop at any age , and is sometimes associated with autoimmune disease of the adrenal , thyroid , or ovary , especially in young people . pseudohypoparathyroidism is usually an autosomal dominant syndrome in which there is tissue resistance to the effects of pth . the pth receptor is normal , but there is a defective post - receptor mechanism . in our patient , the lack of dietary calcium and vitamin d deficiency activated the excessive secretion of pth , which then is known to mobilize calcium from body skeleton , and in the case discussed here , the mandible was involved . differential diagnosis for hypocalcemia an increased pth level in the patient created imbalance in osteoclastic - osteoblastic homeostasis and calcium phosphorous regulation [ figure 7 ] , which presented as cgcg of mandible as a first sign of hyperparathyroidism , which is rare . however , brown tumors in the mandible are diagnosed in 4% of all cases of hyperparathyroidism . the true incidence and prevalence of brown tumor , however , must be higher and the most likely explanation is that in most patients , the jaw lesions are never diagnosed and will spontaneously disappear when the pth and calcium levels are corrected . effect of increased parathyroid hormone and homeostasis the recurrence rate of cgcgs after initial conservative surgical therapy ( curettage ) is reported as 1237% ; repeat curettage usually prevents further recurrence . but in cases of vitamin d deficiency and secondary hyperparathyroidism , the lesion usually resolves after surgical debridement and replacement therapy . rubio et al . treated two cases with enucleation which included removal of teeth involved in the lesion and the surgical site treated with tricloroacetic acid 50% and cryosurgery , and bone stabilized using reconstruction plate . bone regeneration has been excellent as the ages of patients were 26 and 9 years , respectively . other treatment modalities tried for treating cgcg include intralesional injection of corticosteroids,[1619 ] calcitonin,[2022 ] cryotherapy , antiangiogenic therapy with interferons . in a recent review of literature by lang et al . , they tested the rank and rankl ( an essential cytokine for osteoclastogenesis , demonstrated in cgcg ) inhibitors such as osteoprotegrin ( opg ) and monoclonal antibody to rankl , amg 162 , with promising results when tried with caution . theoretically , opg / amg 162 and calcitonin could be synergistic since opg / amg 162 inhibits the formation of osteoclast - like cells , while calcitonin hampers their function . since rank and rankl modulate nf - kappa - b activity , which has a key role in regulation of the immune response , cell growth , differentiation , and apoptosis , the side effects , especially in systemic treatment , warrant careful attention .imatinib , a protein tyrosine kinase inhibitor used to treat chronic myeloid leukemia ( cml ) and gastrointestinal stromal tumors , is found to be an effective anti - osteolytic agent and could therefore be useful in the treatment of skeletal disease involving excessive osteoclast activity , such as cgcg . based on clinical , radiological , and histopathologic findings of our patient , we categorized the condition under nonaggressive type of cgcg and decided for conservative treatment . a modified brosch 's procedure was performed with lateral mandibular cortex based on the periosteum and thorough surgical debridement was done . the ramus was stabilized using a 24-g wire and water - tight closure achieved with a tube drain in place . the patient was put on maxilla mandibular fixation for 6 weeks and started on medical line of treatment as described above [ figure 8 ] . a 6-month postoperative pth assay , calcium , phosphorous , and alkaline phosphatase levels showed remarkably reduced values , with homogenous bone opacification at the ramus and body regions . vitamin d deficiency , secondary hyperparathyroidism , hypocalcemia , and cgcg as a first presentation in the mandible is relatively a rare combination reported in the literature . there is a possibility of spontaneous regression of lesion once the deficiency is corrected , which could be the reason for less number of reports in the literature . a parathyroid estimation , calcium and phosphorous , alkaline phosphatase levels should be made a mandatory investigation in all cases of cgcg . though the case treated with conservative surgical debridement and replacement therapy yielded satisfactory results in 6 months , long - term follow - up is necessary to understand the tumor behavior .

central giant cell granulomas ( cgcgs ) are uncommon but the most aggressive benign intraosseous tumors of jaws , with an unpredictable outcome . they account for less than 7% of all benign jaw lesions , with a female to male ratio of about 2:1 . the classical brown tumor is commonly seen in the long bones , pelvis , and ribs . facial bone involvement is rare and usually appears as solitary or multilocular soap bubble like radiolucencies . cgcgs are traditionally treated by both surgical and intralesional injection , with a variable recurrence rate . here , we report a 12-year - old female patient with mandibular brown tumor as a first sign of secondary hyperthyroidism induced due to vitamin d deficiency and hypocalcemia .

ciprofloxacin is a fluorinated quinolone having broad antimicrobial activity and is effective after oral or parenteral administration . it is used in urinary tract infection , sexually transmitted diseases , and infections of the gut , respiratory tract , bones and soft tissues . a few cases of ciprofloxacin - induced photosensitivity , hypersensitivity , anaphylaxis , vasculitis , erythema multiforme and steven - johnson syndrome or toxic epidermal necrolysis have been reported so far . there are very few detailed case reports of erythema multiforme due to use of ciprofloxacin . in this report , we discuss the case of a 40-year - old female patient clinically diagnosed with ciprofloxacin - induced erythema multiforme . a 40-year - old female patient reported to our clinic with complaints of painful ulcers , hemorrhagic crusts on the lips and fever . patient also reported with conjunctival soreness and multiple , erythematous , discrete , confluent blanchable macules and papules all over the body since four days . because patient had the history of urinary tract infection , she had been using ciprofloxacin . the presentations of the patient were strongly correlated with the intake of ciprofloxacin , as the signs and symptoms have started appearing four days after intake of ciprofloxacin . two days after discontinuation of the drug , the patient developed bullous lesions and bullae on lips , which subsequently ruptured to leave large raw painful areas followed by crustations of lips [ figure 1 ] . the patient 's family history was non - contributory . the hemoglobin estimation , total and differential wbc count , esr , chest x - ray , and blood sugar were all within normal limits . prednisone 20 mg two times daily and tab paracetamol 500 mg three times daily for 1 week . after 15 days of prescription , there was complete resolution of swelling and crustations on the lips [ figure 2 ] . the patient was kept under observation for 2 months ; in this period there was no recurrence . naranjo algorithm theory explains and scales the adverse drug reactions associated with the drugs . in this case , naranjo score is 6 in association with the drug ciprofloxacin . swelling and crustations on the lips swelling and crustations on the lips resolved after 15 days it is characterized by a skin eruption , with or without oral or other mucous membrane lesions . drugs and infectious agents most commonly associated with erythema multiforme and related disorders em is an immune - mediated disease that may be initiated either by deposition of immune complexes in the superficial microvasculature of skin and mucosa , or cell - mediated immunity . kazmierowski and wuepper studied specimens of lesions , less than 24 hours old from 17 patients with em ; 13 of the 17 had deposition of immunoglobulin m ( igm ) and compliment ( c ) 3 in the superficial vessels . other healthcare workers have detected elevated levels of immunocomplexes and decreased compliment in fluid samples taken from vesicles . the disease is more common in males than in females in a ratio of 3:2 . erythema multiforme has been classified as minor and major ( steven - johnson syndrome or toxic epidermal necrolysis ) . the erythema multiforme minor is the mildest type of lesion and toxic epidermal necrolysis is the most severe . fever , lymphadenopathy , malaise , headache , cough , sore throat and polyarthralgia may be noticed as much as 1 week before the onset of surface erythema or blisters . lesions may appear as irregular red macules , papules and vesicles that collapse and gradually enlarge to form plaques on the skin . crusting and blistering sometimes occur in the center of the skin lesions , resulting in concentric rings resembling a bull 's eye ( target lesion ) . on the other hand , oral lesions are usually erythematosus macules on the lips and buccal mucosa , followed by epithelial necrosis , bullae and ulcerations with an irregular outline and a strong inflammatory halo . although the histopathology is not specific , two major histologic patterns have been described : an epidermal pattern characterized by lichenoid vasculitis and intraepidermal vesicles , and a dermal pattern characterized by lymphocytic vasculitis and subepidermal vesiculation . although our patient 's history and clinical features were very supportive of em , biopsy could not be performed . mild cases of oral em may be treated with supportive measures only , including topical anesthetic mouthwashes and a soft or liquid diet . moderate - to - severe oral em may be treated with a short course of systemic steroids . patients with severe cases of recurrent em have been treated with dapsone , azathioprine , levamisole or thalidomide . antiherpes drugs such as acyclovir or valacyclovir can be effective in preventing susceptible patients from developing herpes - associated em , if the drug is administered at the onset of recurrent hsv lesion . ciprofloxacin is one of the widely used antibiotics in infections of oral cavity and other systemic diseases . care should be taken while prescribing , and patient should be counseled about the possible side effects . patient should be advised to discontinue the medicine and consult the physician immediately after development of any itch , redness or rash .

ciprofloxacin is one of the most commonly used antibacterial agents with relatively few side effects . serious adverse reactions reported with ciprofloxacin are rare with an incidence of 0.6% . one of the side effects of ciprofloxacin is erythema multiforme ( em ) . em is an acute , self -limiting mucocutaneous hypersensitivity syndrome . it exhibits a diverse etiology , often recurs , has unusual clinical features and is of uncertain etiopathogenesis . it usually exhibits a distinctive skin or mucosal lesions that are characterized by combination of bullae , papules , macules or ulcers . it is most probably an immunologically mediated process . with the use of ciprofloxacin becoming more and more widespread , fatal complications of ciprofloxacin should be borne in mind . in this article we present a case of ciprofloxacin induced erythema multiforme in 40 year old woman .

the official implementation of the concept of primary health care ( phc ) in saudi arabia,1 involved the development and promotion of existing health centers and the forging of links with hospitals as secondary health care facilities . for many years , many questions have been raised throughout the world about the impact that training in different specialties might have on the quality , cost and distribution of medical care.2 one of these questions is related to how well the training in different specialties prepares young physicians to assume the responsibilities involved in primary care delivery.23 in order to acquire the correct attitude for the delivery of primary health care , training in different specialties should include the moulding of attitudes.23 the objective of this study is to assess the attitudes of medical interns , who have undergone rotation in the department of family and community medicine of a large university hospital , on the provision of primary care and compare these attitudes with those of a reference group of consultants in different specialties . a cross - sectional study was carried out on a sample of interns graduated from king faisal university , at dammam , saudi arabia . the total number of interns involved was 106 , 70 ( 66.0% ) of whom were males and 36 ( 34.0% ) females . this represented the number of interns doing their rotation in family and community medicine , within a period of one year , from 1994 - 95 . during a one - month rotation , the intern is required to attend family medicine clinics under the close supervision of consultants and senior residents in the department of family and community medicine . during this period , the intern is trained to be competent in providing comprehensive and humane care to families in the community he or she is serving , using the problem - solving approach in diagnosis and management . the questionnaire was adapted from similar studies carried out elsewhere.34 the institute of medicine identified the following four attributes of primary care as important : comprehensiveness , coordination , continuity of care , and accessibility.5 throughout the study , the term primary care was avoided because of its tendency to varying interpretations other than the components of health care it is meant to describe . primary care in usa may mean family medicine , general internal medicine or general pediatrics , whereas , in saudi arabia it means family medicine only . the questionnaire included items grouped into four sets eliciting information on various aspects of patient care . the third and fourth sets ( two and four questions respectively ) dealt with the coordination of patient care , and physicians accessibility to patients . the same questionnaire was administered to 20 consultants in the teaching hospital as a reference group . five consultants were selected randomly from each of the following specialties : internal medicine , surgery , obstetrics & gynecology , and pediatrics . data was entered and analyzed using a personal computer , incorporating the statistical package for social sciences ( spss pc+ ) version 6.0 ( 6 ) . chi - squared test ( with yates 's correction ) was used to test the differences between categorical data . a p - value of 0.05 or less was considered as indicative of statistical significance . the total number of interns involved in the study was 106 , and the consultants was 20 . the mean age of the interns was 26.01.67 years and males and females constituted 66.0% and 34.0% , respectively . the mean age of consultants was 48.6 7.7 years , and they comprised 18 ( 90% ) males and 2 ( 10% ) females . on the question of attitudes towards the continuity of care , the responses of the interns and consultants were as follows : almost all interns and the majority of consultants ( 90.0% ) agreed that patients should always be managed by the same doctor . if a patient called in for advice without a scheduled appointment , 73.6% of the interns would be ready to see him / her , whereas 50.0% of the consultants ( p < 0.03 ) would ( table 1 ) . attitude of consultants and interns towards continuity of care on the comprehensiveness of patient care , significantly fewer interns than consultants believed in periodic screening tests for common diseases ( 21.7% and 45.0% , respectively , p < 0.05 ) . both groups were similar in their attitudes towards sharing patient care with other specialties when they see those patients in their own clinical sessions ( 92.5% and 90.9% , respectively ) . similarly , interns and consultants had the same attitude towards being comfortable with practising ongoing patient care ( 66.9% and 65% , respectively ) . with regard to patients with psychological problems , 80.0% of consultants were of the view that these patients should be referred to the psychiatrist , while 50.0% of interns thought that they could be managed with the help of paramedical staff such as psychologists and social workers ( table 2 ) . attitudes of consultants and interns towards comprehensiveness of care on the coordination of care , 91.5% of interns as against 80% of consultants agreed that patients should always be seen by the same physician , but the difference was not statistically significant . on doctors attitudes towards their responsibility for the coordination of total hospital ambulatory care , or the management of specific organic problems , or both , 59.4% of interns and only 45.0% of consultants responded that they would carry both responsibilities ( p < 0.03 ) ( table 3 ) . attitudes of consultants and interns towards coordination of patient care when asked about patients accessibility to physicians for care , significantly more interns than consultants felt that patients could communicate with them between appointments ( 83.9% and 60% , respectively ; p<0.002 ) . almost three - quarters of the interns ( 70.8% ) , in comparison with 60% of consultants , agreed that patients could call them directly between appointments ( p<0.0004 ) . moreover , 30.2% of the interns and 10% of the consultants expressed their agreement that patients could call them at home outside working hours ( p<0.0005 ) . few interns ( 15.1% ) and consultants ( 10% ) said that they would feel comfortable if patients called them while they were busy with other patients , but the difference was not statistically significant . interns and consultants who thought that patients on appointment might wait for 30 minutes or less , if doctors were delayed , constituted 87.7% and 70% , respectively ; ( p<0.005 ) ( table 4 ) . . however , the most valuable is their orientation on the principles of continuity of care , comprehensiveness , and coordination of care and physicians accessibility to patients in need . this study attempted to assess attitudes of a sample of interns who had undergone training rotation in family practice , towards the above - mentioned aspects of care . in this study , medical interns were generally more in favor of the attributes of primary care . consultants , on the other hand , were less inclined to provide this type of care for their patients . as a group , medical interns were also more oriented towards the actual delivery of primary care than consultants . these results might simply reflect the impact of the training of the consultants during different residency programs and their lack of involvement in the general practice of medicine . the attitudes of the consultants may have been influenced by their faculty status , since almost all of them were sub - specialists . sub - specialists are known , to underrate the attributes of primary care , when they assume the values of subspecialty care . association has been observed and extensively studied.7 it appears that following their sub - specialization period , consultants do not wish to treat medical problems outside their specialties . although , in general , relatively little is known about the persistence of attitudes and values in the face of changing roles.7 proper orientation of young physicians towards attributes of primary care will help to avoid the stance of consultants . this study supports results of similar studies , which showed that positive attitudes towards primary care formed by interns during medical school training actually diminish and sometimes eventually disappear altogether when they become consultants and assume new roles.8 if young physicians follow the pattern of the consultants towards primary care practice , a situation may arise in which there may be a conflict between the type of patients they prefer to see , and those they actually see . this is because older patients , and those with chronic illnesses , who are the most likely to receive subspecialty care , value the primary care attributes of coordination , continuity and comprehensiveness very highly.910 the main difference between interns and consultants in this study is that the former had undergone training rotations in family and community medicine . the training is known to instill into the trainees positive attitudes towards the attributes of primary care.11 this can be further improved by restructuring the period of internship more appropriately for the teaching of the primary care attributes and skills.12 therefore , the inclusion of training in family and community medicine during internship should be mandatory for graduation . however , this will always be influenced by the attitude of hospital consultants with whom interns are attached most of the time.1314 in conclusion , this study proves that the training in family medicine can create a positive attitude towards primary health care . it also shows that unless consultants change their attitude towards the importance of primary care , the quality of patient care as well as physicians training will suffer . the college of medicine should therefore , examine how negative attitudes towards primary care attributes develop , and their impact on patient care , and future residency training .

background : training in different specialties should prepare young physicians to assume responsibilities in primary care . training for the acquisition of the proper attitude for health care , should be given in the course of the training in different specialties.objective:to assess the attitudes of medical interns who have undergone rotation in the department of family and community medicine of a large university hospital , towards the provision of primary care.methods:a cross - sectional study incorporating a structured questionnaire was carried out on a sample of 106 interns ; and 20 consultants were selected as a reference group.results:all medical interns almost unanimously endorsed continuous , coordinated , accessible and comprehensive care . in contrast , consultants less often supported the provision of such care for their own patients.conclusions:unless consultants change their attitudes towards the attributes of primary care , the quality of patient care as well as physician training would suffer .

tumefactive demyelinating lesions ( tdls ) are a rare inflammatory demyelinating disease of the central nervous system ( cns ) that can mimic the clinical and radiological features of intracranial neoplasms ( 1 ) . therefore , brain biopsy is often needed for an accurate diagnosis , particularly if tdls occur in patients without a pre - existing diagnosis of demyelinating disease , such as multiple sclerosis ( ms ) or neuromyelitis optica spectrum disorder ( nmosd ) . although tdls are generally considered a single event , previous studies have indicated that the majority of patients with tdls ultimately develop definite relapsing - remitting multiple sclerosis ( rrms ; 2 , 3 ) . the management of tumefactive demyelinating disease is a challenge , as standardized guidelines do not exist . we herein report a patient with relapsing - remitting tumefactive ms characterized by recurrent large demyelinating lesions that successfully responded to natalizumab treatment . a 57-year - old woman with a 1-month history of slowly progressive left - sided hemiparesis visited another hospital in november 2013 . brain magnetic resonance imaging ( mri ) showed a well circumscribed rounded mass lesion in her right frontal lobe accompanied by mild perilesional edema ( figure a - d ) . given the possibility of a brain tumor , she was transferred to the neurosurgical department of our hospital , and brain biopsy was performed . histology revealed a loss of myelinated fibers with relative axonal preservation , lipid - laden macrophages , bizarre astrocytes , and perivascular lymphocytic inflammatory infiltration ( figure q - t ) as well as occasional creutzfeldt cells , findings compatible with tumefactive demyelination . a - c : axial and coronal t2-weighted magnetic resonance imaging ( mri ) images , and axial fluid - attenuated inversion recovery ( flair ) mri image obtained at the clinical onset reveal a high - intensity tumefactive lesion with mild perilesional edema in the right frontal lobe . d : axial post - contrast t1-weighted mri image obtained at clinical onset shows open ring enhancement . e - g : axial t2 weighted and coronal flair mri images obtained on her first admission ( 2.5 months after the clinical onset ) show enlargement of the pre - existing tumefactive lesion and a new hyper - intense lesion in the left basal ganglia . h : magnetic resonance spectroscopy ( mrs ) performed on her first admission shows an abnormal elevation of the glutamate / glutamine ( glx ) peaks , a decreased n - acetylaspartate ( naa ) level , and elevation of the choline ( cho ) , lipid , and lactate levels . i - l : axial and coronal flair mri images obtained on her second admission ( 9 months after the clinical onset ) reveal multiple new tumefactive lesions in the right frontal and temporal lobe . m , n : axial and coronal flair mri images obtained 2 weeks after her second admission show new lesions in the right frontal lobe . o , p : axial t2-weighted and coronal flair mri images obtained on her third admission ( 13 months after the clinical onset ) reveal a new high - intensity tumefactive lesion in the left temporal lobe . q - t : brain biopsy of the tumefactive lesion revealed the characteristic features of active inflammatory demyelination consisting of perivascular lymphocytic infiltration ( q ; hematoxylin and eosin staining ) , gliosis of reactive astrocytes ( q ) , myelin loss ( r ; kluver - barrera ) , relative axonal preservation ( s ; neurofilament ) and macrophage infiltration ( t ; cd68 ) . . the patient 's neurological status did not deteriorate until january 2014 , when she began to suffer from progressive gait disturbance and rapid cognitive deterioration , and so she entered our department . a neurological examination uncovered left - sided paresthesia and motor weakness , and her mini mental state examination ( mmse ) score was 14/30 . a repeat mri demonstrated an increase in the size of the pre - existing lesion ( figure e and f ) and one new lesion in the left basal ganglia ( figure g ) . magnetic resonance spectroscopy ( mrs ) showed an abnormal elevation of the glutamate / glutamine ( glx ) peaks , a decreased n - acetylaspartate ( naa ) level , and elevated levels of choline ( cho ) , lipids , and lactate ( figure h ) . a cerebrospinal fluid ( csf ) analysis showed a protein concentration of 62 mg / dl and a myelin basic protein ( mbp ) level of 712 pg / ml . her glucose level was normal , and oligoclonal bands were negative . a diagnosis of tumefactive demyelinating disease was confirmed , and 3 courses of intravenous methylprednisolone pulse ( ivmp ) therapy ( 1,000 mg / day for 3 days ) were started , followed by maintenance therapy with oral prednisolone ( psl ; 30 mg / day ) . thereafter , the patient 's serum collected on admission was reported as being negative for anti - aquaporin-4 ( aqp4 ) antibody as assessed by an enzyme - linked immunosorbent assay . furthermore , her mental activity had gradually decreased , and she had become apathetic . the psl dose at that time was 5 mg / day . brain mri showed multiple new lesions involving both cortical gray and white matter in the right frontal and temporal lobes ; however , the pre - existing lesion in the left basal ganglia had decreased in size ( figure a csf sample showed elevated mbp ( 615 pg / ml ) and was negative for cultures , cytology , and viruses , including jc polyomavirus , based on the results of polymerase chain reactions . as 3 courses of ivmp therapy did not ameliorate the disease progression ( her mmse score decreased to 7/30 ) and follow - up mri revealed another new lesion in the left frontal lobe ( figure m and n ) , plasma exchange ( plex ) therapy was subsequently initiated , resulting in improvements in her mental and cognitive dysfunction . she became able to walk unassisted , and her mmse recovered from 7/30 to 17/30 following completion of the seventh plex cycle . another brain mri disclosed an additional lesion in the left temporal lobe ( figure o and p ) , leading to the discontinuation of ifn-1a therapy . three additional courses of ivmp and 7 cycles of plex improved her symptoms partially . at this time her clinical condition did not respond to this natalizumab therapy , but follow - up mri revealed a reduction in the size of the left temporal lesion . she became stable with neither clinical relapse nor new mri lesions throughout the following 16 months of clinical follow - up . our patient presented with pathologically confirmed tdl and recurrently developed multiple cortical and subcortical lesions , despite short - term positive responses to ivmp and plex . the radiological characteristics of tdls are lesions a diameter larger than 2 cm , located mainly in white matter , with varying degrees of mass effect or perilesional edema and often complete or incomplete ring enhancement ( 2 ) . the initial lesions in the present case had these mri characteristics consistent with a diagnosis of tdls . however , the recurrent lesions were large , intracranial ones exceeding 2 cm in size , although these lesions did not resemble brain tumors . mrs of the tdls may cause a decrease in the naa / creatine ( cr ) ratio and an increase in the cho / cr ratio , but this is also a common finding in gliomas ( 4 ) . a few previous reports have indicated that an abnormal elevation of the glx peaks appears to favor tdls ( 5,6 ) , a finding which was in accordance with our results . recurrence of a tumefactive lesion itself is infrequent in patients who present with a tumefactive lesion . stated that only 16.7% of patients developed new lesions exceeding 2 cm in diameter , with a median follow - up of 38 months after the first attack with tdl ( 3 ) . in addition , jeong et al . reported that only 16.1% of 31 patients with initially diagnosed tdl developed new lesions exceeding 2 cm in diameter over a median follow - up period of about 38 months ( 7 ) . our patient had a third large demyelinating attack during the first year of follow - up . our case met the 2010 mcdonald criteria for ms ( 8) , as there were two or more attacks disseminated in time and space with clinical evidence of two or more lesions . however , a diagnosis of ms appeared unlikely , as there were several discrepancies between the present case and typical ms cases , including the superficial gray matter involvement , the presence of recurrent large demyelinating lesions , the absence of small ovoid lesions typical of ms , the lack of oligoclonal bands in the csf , and the unresponsiveness to ifn-1a therapy , which has been demonstrated to have beneficial effects in rrms patients . anti - aqp4 antibody was not found , but the presence of anti - myelin oligodendrocyte glycoprotein ( mog ) antibody has not yet been investigated in our case . given that autoantibodies against mog are reportedly found in patients with acute disseminated encephalomyelitis , ms , and aqp4-seronegative nmosd ( 9 ) , further analysis and longer follow - up will be required for a definitive clinical diagnosis of ms . hardy et al . proposed an algorithm for the acute management using ivmp and/or plex followed by disease modification with ifn or glatiramer acetate ( ga ; 1 ) . as tdls have also been reported as a first clinical event in patients with nmosd ( 10,11 ) , we decided to continue the maintenance therapy with oral psl after pulse therapy . however , the possibility of nmosd was excluded based on the diagnostic criteria ( 12 ) and serologic test findings for aqp4 antibody , and so oral psl was tapered . six months later , when the psl dose had been reduced to 5 mg / day during tapering , the patient relapsed severely . we commenced ifn-1a treatment to prevent the attacks as disease modification therapy ( dmt ) , but she experienced another event 1 month after the start of ifn-1a . at present , second - line dmts , such as fingolimod and natalizumab , are available in japan . given the increasing evidence of an association between tdls and fingolimod treatment ( 13 - 15 ) and the fact that natalizumab has been recommended for the treatment of rrms in patients with not only insufficient response to ifn/ga but also aggressive ms ( 16 ) , we decided to initiate natalizumab therapy , regardless of the lack of seropositivity for jc polyomavirus . in our case , treatment with natalizumab effectively suppressed disease activity . although the clinical outcomes have only been reported in a few cases , natalizumab seems to be effective in treating patients with relapsing - remitting tdls ( 17 - 19 ) . the findings in our present case further suggest that natalizumab may also be used to prevent new events as an immunomodulatory treatment for tumefactive demyelination with relapsing episodes . in conclusion , we presented a case of rapidly evolving severe relapsing - remitting tumefactive ms , where the patient showed no evidence of disease activity after the initiation of natalizumab treatment . the management of tumefactive demyelinating disease can be a challenge , as tdls are pathologically heterogeneous . when a diagnosis of relapsing ms is supported , we should consider natalizumab therapy as soon as possible for patients presenting with recurrent large demyelinating lesions .

we herein report the case of a 57-year - old woman presenting with a biopsy - proven tumefactive demyelinating lesion as her first clinical event . subsequently , she displayed a relapsing - remitting course with recurrence of large demyelinating lesions exceeding 2 cm in diameter rather than the small ovoid lesions characteristic of multiple sclerosis . administration of interferon beta did not suppress the disease activity . finally , treatment with natalizumab , which is a humanized monoclonal antibody against the cell - adhesion molecule 4-integrin , was initiated , resulting in clinical and radiological stabilization . our experience here suggests that natalizumab may be an effective therapeutic option for relapsing - remitting tumefactive multiple sclerosis with high disease activity .

landiolol is an intravenous short - acting beta - adrenoreceptor blocker , and its wide use is exhibited by rapid wash out and a less - sustained effect on cardiac function after decreasing the dose or stopping its administration . we present a patient with drug - resistant and persistent inappropriate sinus tachycardia ( ist ) , who also had palpitations . the patient underwent an electrophysiological study and ablation , and high - dose administration of landiolol played a great role in disease treatment . the electrocardiogram ( ecg ) exhibited a heart rate ( hr ) of 126 beats / min ( bpm ) with positive p waves in leads ii , iii , and avf ( fig . 1 ) . bisoprolol , 2.5 mg / day , was administered for six months , but the 24-h holter ecg still showed an average hr of 110 bpm . ivabradine is recommended as an effective medicine , but unfortunately , it is unavailable in japan . an electrophysiological study was performed because no improvement was seen after four months of medical treatment . the session was performed with the assistance of a three - dimensional ( 3d ) electro - anatomic mapping system ( ensite navx system , st . the reentrant mechanism was excluded by high - frequency stimulation performed from the right atrium ( ra ) , wherein tachycardia did not stop . the ra mapping was performed , and the earliest activation site was observed on the high lateral side , which was suspected to be around the sinus node ( fig . the hr decreased from 126 to 116 bpm after starting a continuous intravenous administration of landiolol from 3. the hr gradually decreased by increasing the administration rate of landiolol . when landiolol was increased to 8 , the patients hr suddenly dropped from 95 bpm to 78 bpm with a slight change in the p wave on the ecg ( fig . the earliest activation site moved approximately 8 mm to a lower anterior site from the map performed during tachycardia ( fig . the systolic blood pressure was monitored carefully during the administration of high - dose landiolol and was approximately 100 mmhg without any symptoms from the patient . landiolol was stopped , and tachycardia eventually recurred with the earliest activation site returning to a higher lateral site . because this patient needed a continuous high - dose intravenous administration of landiolol to maintain a normal hr , delivery of radiofrequency energy a local potential preceded the p wave onset by 25 ms at the earliest activation site during tachycardia , and a qs pattern was observed in the unipolar potential . radiofrequency ablation was performed using a maximum power of 25 w , maximum electrode tissue interface temperature of 50 c , and keeping a safe distance from the earliest activation site during the use of landiolol . the termination of the tachycardia was obtained by radiofrequency applications , but it eventually recurred after a few minutes . bisoprolol 2.5 mg / day was continued after the session , and the hr was maintained between 70 and 80 bpm , without any palpitations . high - dose use of beta - adrenoreceptor blockers is difficult due to the risk of the appearance of hypotension and autonomic nervous system disorders . landiolol was capable of subtle adjustments due to its rapid effect and shorter half - life . because of the short - acting property of this agent , we could reveal a spatial difference in the earliest site between the ist and normal sinus rhythm in a reversible manner , even during a time - bound procedure . the underlying mechanism of ist remains poorly understood , and this case was difficult to conclude . the reentrant mechanism was excluded , and tachycardia immediately showed a recurrence after the cessation of landiolol . thus , cardiac beta - adrenergic receptor disorders , which induce abnormal automaticity , were strongly considered , but 2.5 mg / day bisoprolol was ineffective . as a high dose of the beta - adrenoreceptor blocker was needed to control the hr , several causes of tachycardia such as decrease in the parasympathetic activity may have played a role in the maintenance of tachycardia . landiolol showed a guide for safe rf application in this case , but various responses may be observed in other ist cases . in addition , acceleration of the automaticity from other sites such as the arterioventricular junction may occur in some ist cases , and landiolol administration may not be an effective method . thus , further sties focusing on landiolol administration during the ist ablation is needed . the outcome of sinus node modification with radiofrequency ablation has been reported , but it involves a high invasive risk associated with the ablation . thus , careful confirmation of the earliest activation site and ablation of that site is important , . the clinical use of the 3d - mapping system for ist ablation has been reported , and our case suggested that a temporal modification of the sinus node tachycardia by landiolol administration combined with 3d mapping is useful to avoid complications

a 20-year - old woman underwent an electrophysiological study for drug - resistant persistent inappropriate sinus tachycardia ( ist ) . use of a high - dose continuous intravenous administration of landiolol , a short - acting beta - adrenoreceptor blocker , made the patients heart rate suddenly drop with a slight change in the p - wave morphology . three - dimensional right atrial ( ra ) activation mapping revealed that the earliest activation site moved 8 mm to a lower anterior site around the high lateral ra . radiofrequency energy applied to the earliest activation site during tachycardia was successful . a temporal sinus node modification with landiolol administration was useful for mapping and for safe catheter ablation of ist .

. however , a gap still exists between doctors and patients in understanding clinical conditions . emergency conditions such as strokes widen this gap , as patients and their family have difficulty understanding technical terms under time constraints . we created medical comics about subarachnoid hemorrhage and intracerebral hemorrhage , which illustrated the pathogenesis , clinical condition , treatment , and prognosis including rehabilitation of the disease . these comics may help doctors obtain informed consent intuitively , quickly , and comprehensively . however , empirical research examining the advantages and disadvantages of these medical comics has never been conducted . the purpose of this study was to determine whether medical comics facilitate in obtaining informed consent during an emergency condition . in order to evaluate our methodology , we carried out a questionnaire survey to investigate how these comics could help the patient in terms of time efficiency , level of understanding , and applicability to other medical cases . between september 2010 and september 2012 , we carried out a questionnaire survey with the families of patients admitted to the department of neurosurgery , university hospital , kyoto prefectural university of medicine for intracerebral or subarachnoid hemorrhage . after initial management of the patients in the emergency room , we explained the medical condition , necessary examinations , treatment , and predictable prognosis to the patient 's family with the help of pictures in medical comics . we then gave them medical comics , which were 25 pages long for subarachnoid hemorrhage and 35 pages long for intracerebral hemorrhage , and requested them to read them and answer the questionnaire survey . the questionnaire consisted of 6 questions inquiring about their mental condition , reading time , usefulness of medical comics in understanding brain function and anatomy , pathogenesis , doctor 's explanation , and applicability of medical comics ( table 1 ) . we utilized a five - level rating system , except for reading time , where we utilized a four - level rating system . questionnaire survey about medical comics this study was approved by the ethics committee of kyoto prefectural university of medicine . we gave detailed descriptions of the study to each patient 's family , and all participants signed informed consent forms before participation . the survey was answered by a total of 16 people , 7 males and 9 females ( 1 or 2 individuals from each patient 's family ) , with an average age of 46.9 years ( range : 2668 years ; table 2 ) . the results showed that 93.8% of the responders read medical comics in < 30 min , and would prefer or strongly prefer that they be applied to other medical cases . when considering the level of understanding of brain function and anatomy , pathology of disease , and doctor 's explanation , 81.3% , 75.0% , and 68.8% , respectively , rated medical comics as very useful or useful ( table 3 ) . according to our survey , medical comics seemed to have the capability to facilitate in obtaining informed consent during emergency conditions , such as strokes , as they encourage the patients and their families to understand the facts , implications , and future consequences of an action within a short period of time . we were able to obtain good results for the level of understanding of brain function and anatomy , pathology of disease , and doctor 's explanation . almost all the readers hoped that medical comics like these would be utilized in other medical cases . comics have evolved over the past 100 years and have become a popular source of amusement for both children and adults , particularly in japan . government offices and self - governing bodies have also adopted comics as public relation tools . moreover , they can serve educational purposes by combining pictures and words and giving visual cues to what the text is explaining . they also have a remarkable capacity to convey information visually , attract the interest of readers , and are overall pleasurable to read . moreover , the contents tend to remain in the memory for a longer period of time because of their contents in the form of a story . in medical practice , comics are used to provide explanations , particularly to children with low levels of literacy and immigrants . their powerful visual messages convey immediate pictorial understanding in ways that conventional texts can not . however , this is the first time these medical comics have been tried in an emergency situation , and the patient 's families can use them to educate themselves on the continuum of care . the peak age of onset and background of patients are reflected in the characters of our medical comics . comic begins with a middle - aged man , in the prime of his working life , suffering from sudden severe headaches ( figure 1 ) . further descriptions are provided in auxiliary text , so that readers can deepen their understanding . deformed pictures are inserted in explanations for anatomy or pathogenesis , so that readers can be sociable to them ( figure 2 ) . we think that these familiarities would be effective in high stress situations , such as in an emergency room . these books have stories that include onset , doctor 's explanations , treatments , and rehabilitation for the disease ( figure 3 ) . the explanation of rehabilitation is very important as most patients families are often worried about the patient 's functional prognosis at the time of first visit . almost all participants of this survey were able to read the medical comics in less than 30 min . another advantage of medical comics is that the readers can read them repeatedly , after they hear the explanation from the doctors . this page depicts the scene in which a middle - aged man in the prime of his working life begins to experience sudden severe headaches . ( 2 ) yes . ( 3 ) take one of those to the department of general affairs . ( a ) explains how intracerebral hematoma destroys perihematomal neurons and ( b ) the image of how aneurysms rupture . translation : ( 1a ) therefore , although it stops bleeding , symptoms will worsen during periods of perihematomal edema , which compress normal tissue strongly and make it hypoxic . ( 3a ) we administer patients an intravenous drip injection , which improves brain edema during periods of perihematomal edema . ( 2b ) a subarachnoid hemorrhage is defined as bleeding into the subarachnoid space for some reason . ( 3b ) this may occur usually from a ruptured blood - filled balloon - like bulge in the wall of a blood vessel . scenes of doctors explaining ( a ) surgical treatment and ( b ) rehabilitations ( c ) . translation : ( 1a ) surgical clipping of the aneurysm is the most certain means of preventing rebleeding . ( 2b ) depending on the location of the aneurysm , craniotomy is performed and the brain tissue is exposed . ( 4c ) however , she still had right hemiparesis and aphasia which made it difficult for her to say what she meant to say . we think the visual and narrative illustration in the medical comics would be more helpful for patients and their families , than a lengthy explanation conducted by a doctor . medical comics could work as a new communication tool for informed consent between doctor and patient .

abstractinformed consent has now become common in medical practice . however , a gap still exists between doctors and patients in the understanding of clinical conditions . we designed medical comics about subarachnoid hemorrhage and intracerebral hemorrhage to help doctors obtain informed consent intuitively , quickly , and comprehensively.between september 2010 and september 2012 , we carried out a questionnaire survey about medical comics with the families of patients who had suffered an intracerebral or subarachnoid hemorrhage . the questionnaire consisted of 6 questions inquiring about their mental condition , reading time , usefulness of the comics in understanding brain function and anatomy , pathogenesis , doctor 's explanation , and applicability of these comics.the results showed that 93.8% responders would prefer or strongly prefer the use of comics in other medical situations . when considering the level of understanding of brain function and anatomy , pathology of disease , and doctor 's explanation , 81.3% , 75.0% , and 68.8% of responders , respectively , rated these comics as very useful or useful.we think that the visual and narrative illustrations in medical comics would be more helpful for patients than a lengthy explanation by a doctor . most of the responders hoped that medical comics would be applied to other medical cases . thus , medical comics could work as a new communication tool between doctors and patients .

economic development in low - income countries is accompanied by an increase in the burden of trauma , particularly injuries due to road traffic accidents . it also provides the opportunity to improve on the management of some of those injuries , such as fractures of the femur . skeletal traction or closed manipulation and casting remain the most common treatments of long bone fractures in resource - poor settings . the literature from developed countries is replete with studies showing better functional outcomes with locked intramedullary nails for femoral [ 10 , 16 ] and tibial [ 2 , 4 , 15 ] fractures over conservative management , even in the adolescent population . in poor countries , lack of human and material resources , and an often unsafe surgical environment , may preclude internal fixation of long bones . femoral shaft fractures are thus treated with skeletal traction with its known complications of prolonged bed rest and hospitalisation , along with pin tract infections , decubitus ulceration , malunion / nonunion and shortening . the kingdom of cambodia , in south - east asia , has a population of around 14 million people , with a per capita nominal gdp of $ 606 , which is slowly but steadily increasing . battambang , the capital of the northwest province of the same name , is the second largest city in the country with a population slightly over a million . all major injuries from the province are treated at the emergency surgical centre , a hospital almost exclusively devoted to trauma . emergency is an italian non - governmental organisation ( ngo ) that provides surgical care to all , free of charge . until recently , all adolescent and adult femoral shaft fractures were treated with perkin s skeletal traction , allowing early knee mobilisation but requiring a minimum of six weeks in bed . in early 2007 , the surgical implant generation network ( sign ) nailing system was introduced . it is a solid nail , designed to be inserted without image intensification , fracture table or powered reaming , thus specifically adapted to resource - poor environments . the nail has a typical tibial nail configuration , but is also used for femurs and humeri , simplifying significantly the necessary inventory . the purpose of this paper was to try to compare the costs and the change in outcomes ( if any ) from this transition . economic evaluations , such as a cost - effectiveness analysis ( cea ) , are widely used tools in developed countries to compare different interventions or strategies [ 1 , 3 , 7 , 13 ] . although the world health organisation ( who ) has published standard guidelines for ceas , there is a dearth of such studies in low income countries . the purpose of a cea is to assess the relative value of one intervention over another , for a given problem or condition . one intervention is more cost - effective if : ( 1 ) it is less costly with an equal or better outcome , ( 2 ) it is less costly with a worse outcome , but the added benefit of the alternative is not worth the extra cost , or ( 3 ) it is more costly with better outcomes , and the added benefit is worth the added cost . the answer depends on availability of human and material resources , and also moral , economical , legal and societal values . only isolated fractures of the femoral shaft not involving either metaphyses were included . at the time of data collection , the first 49 consecutive sign nails had a follow - up of at least 16 weeks . the last 50 consecutive patients with femoral shaft fractures treated in skeletal traction formed the comparison group , so as to minimise the effect of time on costs . the hospital records , x - ray files and outpatient records were reviewed for all patients and data collected for age , sex , type of fracture , time of fracture , time in traction , length of hospital stay ( los ) , weight bearing status at discharge and fracture healing at last follow - up . of the 49 nails , 38 were inserted for fresh fractures ( i.e. less than six weeks ) , including one tibial nailing which was excluded , and 11 for nonunion , including three tibial nails . these nonunions were excluded from the analysis , leaving 87 patients aged 14 years or more , with 89 femoral shaft fractures , covering a seven - month period . a nonunion was diagnosed in the traction group if at last follow - up ( minimum four months , mean 6.5 months ) the fracture was still mobile clinically and there was little or no progress in radiological consolidation . in the nail group it was diagnosed if at last follow - up ( minimum four months , mean 5.5 months ) there was little or no progression of callus on x - rays , or evidence of hardware failure . a malunion was diagnosed if a fracture had healed with a 20-degree or more angulation in any plane , a 20-degree malrotation or shortening of more than 2.5 cm . other recorded complications included superficial ( above fascia ) or deep ( below fascia ) infections , and nerve damage . fixed costs such as infrastructure costs and depreciated costs for initial equipment were the same for both groups . variable costs were different ; they included hospital per diem , operating room time , equipment , use of blood products , physiotherapy , x - rays , and supplies such as dressings , drugs and/or orthotics . the vast majority of patients were farmers , often sustenance farmers with no fixed income , so it was not possible to factor in societal costs , such as lost wages . unfortunately , because of the retrospective nature of the study , no data were collected about time to return to normal daily activities . statistical analysis was done using the stata i / c 9.0 software package , with significance at p < 0.05 . mean age , mean time since injury , proportion of open versus closed , and simple versus comminuted fractures were not statistically different between groups . in the perkins traction group , 50 patients with 52 femoral fractures had a mean length of stay ( los ) of 52.3 days , with a mean time in traction of 45.6 days . of the 37 patients in the nail group , there were eight who were already in perkins traction when the sign program was started , and before the backlog was cleared , some new patients were put in temporary traction for a longer period than those toward the end of the series . the average los for this group was 34.9 days , with an average time in traction of 20.7 days and an average los after nailing of 14.2 days . eight of 50 patients ( 16% ) in the traction group and 21 of 37 patients ( 57% ) in the nail group were fully weight bearing ( p < 0.001 ) , as shown in table 2 . the mean length of nailing surgery was 2.5 hours , which reflects the repeated learning curve of rotating surgeons . a total of 29 of 37 nails were inserted in an antegrade fashion , and all but one were statically interlocked using all four screw holes , another reason for prolonged surgery time . of interest is that , even if they are excluded from the study , the 11 nailings for nonunion , six of which were emergency patients that had failed perkins treatment , averaged 3.8 hours in operative time . for the fresh fractures , the pre and post - op hb averaged 11.1 and 8 gms , respectively , and 22 patients in the nail group received an average of 2.5 whole blood units . table 1data summary for traction and nails groupsvariabletractionnailspatients5037fractures5237mean age ( years)33.6 ( 1472)32.1 ( 1468)femurs5237closed / open36/1630/7simple / comminuted16/3616/21mean time since injury ( days)3.1 ( 035)3.7 ( 142)mean length of stay ( los ) ( days)52.334.9mean time in traction ( days)45.620.7mean length of surgery ( hours)2.5table 2weight - bearing status at time of dischargewb statustraction ( total 52)nails ( total 38)full wb8 ( 16%)21 ( 57%)partial wb41 ( 78%)16 ( 41%)non wb3 ( 6%)1 ( 2%)wb weight bearing data summary for traction and nails groups weight - bearing status at time of discharge medical records and complete x - ray files were available for 46 patients in the perkins group and 36 patients in the sign group . the 46 traction patients had 46 fractures , 34 of them ( 74% ) showing clinical and radiological signs of consolidation , ten ( 22% ) signs of delayed or nonunion and two ( 4% ) malunions . a total of 33 of the 36 ( 92% ) of the nailed femurs showed radiological evidence of advanced or complete healing and only three ( 8% ) did not show significant amounts of callus on x - rays ( p < 0.001 ) . table 3outcomes at minimum 16 weeks follow - upoutcometractionnailsfollow - up > 16 weeks4636fractures healed34 ( 74%)33 ( 92%)malunion2 ( 4%)0nonunion10 ( 22%)3 ( 8% ) outcomes at minimum 16 weeks follow - up the total costs in $ us are summarised in table 4 . costs incurred in euros or in the local currency , the riel , were converted to $ us at the prevailing rate for the sample period . there were an average of six x - rays taken for the nail group and ten for the traction group . most patients in the nail group received two hours of physiotherapy every day , whereas the perkins group received one hour a day , doing most of the exercises on their own . the per diem was calculated by dividing the average monthly operating costs ( $ 50,803 ) by the number of beds / days ( 106 31 ) = $ 15.50/day , which includes nursing care , food , laundry and hospital cleaning . twenty - two patients in the traction group needed a cast - brace before discharge at a unit cost of $ 120 ; there were none in the nail group . the sum cost for the 50 patients treated in traction was $ 47,060 , or $ 941 per patient . the costs for per diem alone in this group account for 88% of the total costs . the sum cost for the 37 patients treated with a sign nail was $ 30,347 , or $ 820 per patient . table 4comparative total costs of inputs for both groups , $ uscost categorytractionsign nailpins15624temporary traction060perkin 's frame25040crutches750555x - rays442189physiotherapy21501113length of stay ( per diem ) pre - op11872 post - op8143 total4053220015cast - brace26400implant05550operating room time02082transfusion0460miscellaneous ( drugs , lab)140259total47,06030,347total per patient941820 comparative total costs of inputs for both groups , $ us there was one deep peroneal nerve palsy , which resolved completely in the hospital without further treatment . there were 14 pin tract infections in the perkins group , two of which required surgical debridement , adding less than $ 50 to the total costs . there was one superficial infection in the nail group , which responded well to surgical debridement , and one deep infection which required nail removal and delayed re - nailing . this added less than $ 250 to the overall costs , bringing the per patient costs up to $ 826 . if we also include the surgical treatment of nonunions , and assume that all three in the sign group and all ten in the traction group will be nailed or re - nailed , the overall costs in the sign group increases to $ 32,828 or $ 888 per patient , and the overall costs in the traction group increase to $ 55,330 or $ 1,107 per patient . in this scenario , others have reported on its success in resource - poor settings . as with any new technology , there is a learning curve , no matter how user - friendly the sign system is . as surgeons and operating theatre nurses become more proficient with its use , operative time should decrease substantially , and be more in line with the 6090 minutes reported elsewhere . at the time of data collection , patients were kept in bed and received antibiotics for a week after surgery , and discharged only after suture removal at 14 days . now patients are mobilised the first day after surgery , receive antibiotics for 48 hours , and are most often discharged within a week . throughout the world , there are dozens of sites that have considerable experience with the sign system and they report an average los of five days . if this were true at this site , the costs per patient would actually drop to around $ 350 ( ideal scenario ) . obviously , costs are very context - specific , and a $ 15.50 per diem might not be reproducible in many settings . with a difference of $ 219 per patient in the complication scenario , it would require treatment of five patients surgically to make up for the costs of treating the sixth one . in other words , the cost of treating one patient in traction would be approximately the same as treating three patients with a nail . the 16-week minimum follow - up is short and many would argue that nonunion can not be discussed before six months , so the 22% and 8% nonunion rates in the traction and nail groups , respectively , may be falsely high , but it still seems reasonable to assume that the outcomes are better with internal fixation , as suggested by most of the literature . the fact that 57% of patients treated with nails and only 16% of those treated in traction were full weight - bearing upon discharge also supports this . although unsubstantiated , it is probably not unreasonable to think these patients will return sooner to gainful employment . it took no more than 30 nails for the costs per patient to equal those treated in traction . as the surgical centre moves closer to the ideal scenario , costs will continue to fall . it seems safe to conclude that , in this particular setting , better outcomes at lower expenditure make sign nailing of adult femoral shaft fractures much more cost - effective than perkins skeletal traction .

in this article the costs and effectiveness of introducing the sign nailing system for femoral shaft fractures in a provincial trauma hospital in cambodia are compared to those of perkin s traction treatment . at an average cost per patient of $ 1,107 in the traction group and $ 888 in the nail group ( p < 0.01 ) , and with better clinical outcomes in the nail group , internal fixation is more cost - effective than conservative treatment .

very recent studies in iran displayed the prevalence of the obesity , hypertension , and hypercholesterolemia are 30.9% , 23% , and 41.6% , respectively . the statin group of drugs is widely used to treat hypercholesterolemia in patients at cvd risk . statins inhibit the rate - limiting enzyme in cholesterol biosynthesis , hydroxymethylglutaryl - coenzyme a ( hmg - coa ) reductase , and reduce serum low - density lipoprotein cholesterol ( ldl - c ) levels substantially . further to their conventional lipid - modulating effects , statins possess so - called pleiotropic properties , which comprise improvement of endothelial function , antioxidant properties , anti - inflammatory properties , plaque stabilization , and inhibition platelet aggregation and thrombus formation . it has been reported that statins treatment may be associated with an improved vitamin d status , but this is not a consistent finding . there is emerging evidence suggesting that a decreased vitamin d concentration might rise the possibility of several conditions including cancers and cvd . if statins do have an impact on vitamin d concentration this could be a reasonable elucidation of the described results of diminished risk of fracture ; moreover , reduced risk of malignant illnesses in patients on this class of drugs . thus , the present randomized controlled study set out to investigate the effects of treatment with simvastatin on serum vitamin d in a group of dyslipidemic patients who were suitable for statin therapy . a total of 102 male and female patients , age ( 2088 old ) , who were not formerly receiving lipid - lowering drugs , registered from the clinics of ghaem hospital , a teaching hospital located in mashhad , iran , between june 2010 and august 2012 . the study was a randomized placebo - controlled cross - over trial ; in this study , each patient took simvastatin or a placebo and next crossed over to the substitute . cardiovascular risk factors were defined as age more than 65 years old , receiving antihypertensive medication or systolic blood pressure of more than 140 mmhg or diastolic blood pressure of more than 90 mmhg , fasting blood glucose ( fbg ) greater than or equal to 126 mg / dl , positive family history of cvd , smoking , male sex , body mass index ( bmi ) more than or equal to 30 kg / m . history of malignancy , recent history of infections , connective tissue disorders , treatment with immunomodulatory drugs ( e.g. , corticosteroids ) , liver or renal disease , leukocytosis ( white blood cell count > 10,000/l ) , thrombocytosis ( platelet count > 450,000 10/l ) , and anemia ( hematocrit < 40% ) were the exclusion criteria . each subject gave informed written consent to participate in the study , which had previously been approved by the ethics committee of mashhad university of medical sciences ( code : 88585 ) . each treatment period takes 1 month and there was a 14-day washout between the treatment periods . we asked the people to do not change the lifestyles during the trial also medications . at the first visit , patients were randomly assigned ( random number tables ) to one of the two treatment regimens . fifty - one patients received 40 mg / day simvastatin for 1 month , and another group ( 51 ) received a placebo ( same size and color with treatment capsules and filled with starch ) for 30 days . after a further 2-week washout period the sample size was based on the between - group mean comparison formula , according to the study conducted by hu et al . with confidence interval of 95% , and power of 80% serum vitamin d levels were measured using a competitive electroluminescence protein binding assay with the roche diagnostics vitamin d total assay kit ( roche diagnostics , mannheim , germany ) . the interday precision of this assay has been reported to be 4.9% and 1.9% at mean concentrations of 43.3 and 105 nmol / l , respectively , using the manufacturer 's original control material . as previously described for each subject , weight , height , and bmi were measured two times ( before randomization and at the end of each period observation ) according to standard methods previously described . sas software ( version 8) ( sas institute inc . , cary , nc ) was used for statistical analysis . t - test was used for a comparison between before and after treatments . for the analysis , the differences of these cross - over analyses were compared ; they were normally distributed . the primary end - point was the change in serum fasting lipid profile and vitamin d after treatment for 4 weeks . the secondary endpoints were changes in fasting blood glucose and high sensitive c - reactive protein ( hscrp ) . a total of 102 male and female patients , age ( 2088 old ) , who were not formerly receiving lipid - lowering drugs , registered from the clinics of ghaem hospital , a teaching hospital located in mashhad , iran , between june 2010 and august 2012 . the study was a randomized placebo - controlled cross - over trial ; in this study , each patient took simvastatin or a placebo and next crossed over to the substitute . cardiovascular risk factors were defined as age more than 65 years old , receiving antihypertensive medication or systolic blood pressure of more than 140 mmhg or diastolic blood pressure of more than 90 mmhg , fasting blood glucose ( fbg ) greater than or equal to 126 mg / dl , positive family history of cvd , smoking , male sex , body mass index ( bmi ) more than or equal to 30 kg / m . history of malignancy , recent history of infections , connective tissue disorders , treatment with immunomodulatory drugs ( e.g. , corticosteroids ) , liver or renal disease , leukocytosis ( white blood cell count > 10,000/l ) , thrombocytosis ( platelet count > 450,000 10/l ) , and anemia ( hematocrit < 40% ) were the exclusion criteria . each subject gave informed written consent to participate in the study , which had previously been approved by the ethics committee of mashhad university of medical sciences ( code : 88585 ) . each treatment period takes 1 month and there was a 14-day washout between the treatment periods . we asked the people to do not change the lifestyles during the trial also medications . at the first visit , patients were randomly assigned ( random number tables ) to one of the two treatment regimens . fifty - one patients received 40 mg / day simvastatin for 1 month , and another group ( 51 ) received a placebo ( same size and color with treatment capsules and filled with starch ) for 30 days . after a further 2-week washout period the sample size was based on the between - group mean comparison formula , according to the study conducted by hu et al . with confidence interval of 95% , and power of 80% serum vitamin d levels were measured using a competitive electroluminescence protein binding assay with the roche diagnostics vitamin d total assay kit ( roche diagnostics , mannheim , germany ) . the interday precision of this assay has been reported to be 4.9% and 1.9% at mean concentrations of 43.3 and 105 as previously described for each subject , weight , height , and bmi were measured two times ( before randomization and at the end of each period observation ) according to standard methods previously described . t - test was used for a comparison between before and after treatments . for the analysis , the differences of these cross - over analyses were compared ; they were normally distributed . the primary end - point was the change in serum fasting lipid profile and vitamin d after treatment for 4 weeks . the secondary endpoints were changes in fasting blood glucose and high sensitive c - reactive protein ( hscrp ) . from 102 patients , who came into the trial , 25 ( 24.5% ) dropped out ; hence , the final sample size was 77 ( 78.2% ) . noncompliance with the study protocol ( n = 21 ) , drug intolerance ( n = 2 ) , and relocation ( n = 2 ) were the reasons for the drop - out . we failed to find any significant difference ( p > 0.05 ) when we compared the baseline data of biochemical and anthropometric factors before the first treatment period with those before the second treatment period . moreover , no significant difference was found for age , sex , presence of hyperlipidemia , bmi , presence of hypertension , presence of diabetes , and smoking status between the two groups [ table 1 ] . comparison of baseline characteristics of subjects statin therapy did not have a significant effect on serum levels of vitamin d in either the statin - placebo or the placebo - statin group [ p = 0.90 , table 2 ] . bivariate correlations were assessed between baseline values of vitamin d and other evaluated biochemical parameters ( total cholesterol , ldl - c , high - density lipoprotein cholesterol [ hdl - c ] , triglycerides [ tgs ] , fbg , and hs - crp ) , as well as between changes in vitamin d and other parameters during each study period . no significant correlation was found between baseline values of vitamin d and evaluated biochemical parameters ( p > 0.05 ) [ table 3 ] . furthermore , significant correlations were observed between serum vitamin d and the following parameters : fbg ( statin - placebo group , second period ; p < 0.01 ) , tgs ( placebo - statin group , second period ; p < 0.05 and statin - placebo first period ; p < 0.01 ) , ldl - c ( placebo - statin group , first period ; p < 0.05 ) , and hdl - c ( statin - placebo group , first period ; p < 0.05 ) [ table 4 ] . effect of simvastatin versus placebo on vitamin d status correlation between baseline biochemical parameters and vitamin d in placebo - statin group and statin - placebo group correlation between changes in biochemical parameters in two periods of placebo - statin group and statin - placebo statin therapy did not have a significant effect on serum levels of vitamin d in either the statin - placebo or the placebo - statin group [ p = 0.90 , table 2 ] . bivariate correlations were assessed between baseline values of vitamin d and other evaluated biochemical parameters ( total cholesterol , ldl - c , high - density lipoprotein cholesterol [ hdl - c ] , triglycerides [ tgs ] , fbg , and hs - crp ) , as well as between changes in vitamin d and other parameters during each study period . no significant correlation was found between baseline values of vitamin d and evaluated biochemical parameters ( p > 0.05 ) [ table 3 ] . furthermore , significant correlations were observed between serum vitamin d and the following parameters : fbg ( statin - placebo group , second period ; p < 0.01 ) , tgs ( placebo - statin group , second period ; p < 0.05 and statin - placebo first period ; p < 0.01 ) , ldl - c ( placebo - statin group , first period ; p < 0.05 ) , and hdl - c ( statin - placebo group , first period ; p < 0.05 ) [ table 4 ] . effect of simvastatin versus placebo on vitamin d status correlation between baseline biochemical parameters and vitamin d in placebo - statin group and statin - placebo group correlation between changes in biochemical parameters in two periods of placebo - statin group and statin - placebo the aim of this study was to investigate the impact of simvastatin therapy on serum vitamin d levels in dyslipidemic patients . our results showed that simvastatin therapy for 4 weeks ( 40 mg / day ) does not alter serum vitamin d levels . previous investigations on the impact of statin therapy on circulating vitamin d levels have been inconsistent . while atorvastatin and rosuvastatin have been shown to raise 25(oh ) vitamin d levels , there are reports with opposite findings showing that hmg - coa reductase inhibitors do not affect serum vitamin d concentrations . it is not well known how statins might affect vitamin d concentration , and numerous potential mechanisms have been put forward . the first and by far the most plausible mechanism regards to the common metabolic fate of statins and vitamin d. both 25(oh ) vitamin d , and statins are metabolized in the liver by cyp3a4 . therefore , the occupation of the active site of this enzyme by statins may account for the elevated 25(oh ) vitamin d levels reported in some trials . indicated that rosuvastatin ( 40 mg / day ) as monotherapy and rosuvastatin ( 10 mg / day ) plus fenofibrate ( 200 mg / day ) or omega-3 fatty acids ( 2 g / day ) cause substantial elevations in the 25(oh ) vitamin d levels ( 53% , 64% , and 61% , respectively ) . moreover , in study by thabit et al . , they found that simvastatin and atorvastatin , at any dose for duration of more than 1 year , have no additive effect on 25(oh)d level . unlike rosuvastatin and atorvastatin , no considerable change in vitamin d concentration has been reported in patients that used fluvastatin . a new randomized controlled trial could not prove an effect of 12 months simvastatin therapy ( 40 mg / day ) on vitamin d concentration . the physicochemical characteristics of different statins may also play a role in their differential effects on vitamin d metabolism . first , the study design did not allow adequate time for a new steady - state level of vitamin d , did not control or report vitamin d intake , did not analyze for seasonal effects , and the 25(oh ) vitamin d assay was not the ms / ms gold standard . the main strength of the present study was being based on a robust placebo - controlled and cross - over design as well as being conducted in a target population , not under concomitant lipid - lowering therapy . therefore , many of the confounding factors that may generally affect lipid alterations were eliminated from the present trial . we found that statin had no significant effect on serum vitamin d status in dyslipidemic patients . further research might explore the effects of long - term statin therapy on vitamin d status .

background : hydroxymethylglutaryl - coenzyme a reductase inhibitors ( statins ) are antihyperlipidemic drugs with an established efficacy in stabilizing atherosclerotic plaques and preventing atherogenesis and reducing cardiovascular events . the purpose of this study was to determine the effect of simvastatin on serum vitamin d status in dyslipidemic patients as vitamin d status has an impact on monocyte / macrophage function and may also contribute to cardiovascular risk.methods:selected individuals ( n = 102 ) were treated with simvastatin ( 40 mg / day ) , or matching placebo in a randomized , double - blind , placebo - controlled , crossover trial . each treatment period ( with simvastatin or placebo ) lasted for 30 days and was separated by a 2-week washout phase . serum vitamin d concentration was assessed pre- and post-treatment.results:seventy-seven completed the trial , noncompliance with the study protocol and drug intolerance or relocation were the causes for drop - out . no significant carry - over effect was observed for the assessed parameters . there was a reduction in the serum levels of low - density lipoprotein cholesterol ( p < 0.001 ) , total cholesterol ( p < 0.001 ) , and triglycerides ( p < 0.05 ) . nevertheless , simvastatin therapy did not significantly affect serum level of high - density lipoprotein cholesterol and vitamin d level ( p > 0.05).conclusions : short - term treatment with simvastatin ( 40 mg / day ) does not have a significant affect on serum levels of vitamin d.

diabetic macular edema is the leading cause of significant loss of visual acuity in patients with diabetic retinopathy . it results from the damage and increased permeability of macular capillaries in the course of hypoxia , leading to increased levels of antivascular endothelial growth factor ( vegf ) and release of inflammatory factors such as cytokines , which result in the loss of endothelial cells and pericytes . the treatment of diabetic macular edema is still difficult and involves a high percentage of failures . the gold standard for laser photocoagulation can indeed maintain and even improve the long - term observation of patients with baseline visual acuity , but in others it is ineffective , and , besides , it leads to reduction in the field of vision , impaired colour perception , and reduced feeling of contrast [ 24 ] . used interchangeably , but often in addition to laser , steroids increase the chance of improving visual acuity in patients with dme [ 3 , 5 , 6 ] . corticosteroids demonstrating strong anti - inflammatory properties reduce the formation of secondary macular edema of various etiologies by reducing capillary permeability , inhibiting fibrin deposition , and retarding the loss of endothelial tight junction proteins . restricting the migration of leukocytes inhibits the formation of vegf factor , prostaglandins , and other proinflammatory cytokines . it seems that the route of administration of steroid drugs is crucial for the effectiveness of their action . orally administered , with the highest concentration in serum , they may cause a significant number of side effects such as cushing 's syndrome , osteoporosis , or exacerbation of diabetes and , at the same time , low levels of steroid concentration in the vitreous . the topical , subconjunctival , and peribulbar method of administration provides a relatively high concentration in the vitreous and in serum ; the risk of complications of general administration is similarly high [ 8 , 9 ] . the use of drugs administered directly into the vitreous can result in achieving the appropriate concentration of the drug directly at the site of the disease with decreasing systemic side effects . its effect is six times stronger than that of triamcinolone acetonide . due to the short half - life of dexamethasone in the vitreous , triamcinolone acetate ( kenalog-40 , bristol - myers squibb , princeton , nj ) is widely used in the treatment of secondary macular edema , including diabetic retinopathy , of which lipophilic crystals are deposited in the vitreous for several months . however , this form of triamcinolone acetonide deposit , administered at a dose of 4 mg in a single injection , did not provide a constant level of drug in the vitreous even during the initial period of observation and was associated with side effects such as increased intraocular pressure and steroid cataracts [ 11 , 12 ] . introduction in 2009 of the treatment intravitreal implant dexamethasone 0.7 mg ( ozurdex allergan inc . , irvine , ca ) in the form of a copolymer of lactic acid and glycolic acid plga ( novadur allergan inc.)by the progressive biodegradation made it possible to obtain a comparable concentration in the vitreous chamber for a period of up to 180 days after a single injection . for as long as that , the drug should provide a better therapeutic effect and reduce the number of intravitreal injections of drugs with a shorter duration of action as well as reduce the risk of adverse effects associated with multiple injections and high concentration immediately after injection . this retrospective analysis was to evaluate the effectiveness of treatment of persistent diabetic macular edema with intravitreal injections of 0.7 mg dexamethasone implant ozurdex . the study comprised three male patients ( 6 eyes ) , aged on average 52 and with average diabetes duration of 13.3 years . in each eye , persistent macular edema occurred for more than six months despite the treatment of grid macular photocoagulation and antivessel growth factor ( ranibizumab ) 0.5 mg intravitreal injections . the initial and control studies evaluated the best corrected visual acuity ( bcva logmar lines ) , corrected intraocular pressure , and examination of the anterior and posterior segment of the eye with central retinal thickness measurements using optical coherent tomography spectral cirrus hd - oct zeiss . each patient received 0.3% ciprofloxacin in the eye drops four times a day two days before and four days after the treatment ( figure 3 ) . before the injection of intravitreal implant ozurdex , each of the six eyes presented significant edema of the retina treated before with grid laser photocoagulation and three intravitreal injections of anti - vegf factor . the last injection of ranibizumab 0.5 mg was performed at least 3 months before starting the treatment with ozurdex . five eyes indicated with the numbers 4 , 5 , 6 , 7 , and 8 received a single injection dose of 0.7 mg ozurdex , while one eye injection numbered 1 , 2 , and 3 received three ozurdex doses at six - month intervals ( table 1 ) . the average thickness of the retina at baseline was 632 m , the medial bcva was 0.8 logmar , and corrected intraocular pressure was 13.7 mmhg . the maximum decrease in mean retinal thickness was observed at four weeks following the treatment and was 365 m ( 267 m ) and visual acuity improved by an average of two lines and was 0.6 logmar ( figure 2 ) . a slight decrease in retinal thickness to 346.13 microns ( 18.87 microns ) and mean visual acuity of 0.65 logmar lines were observed in week 8 . at 12 weeks , the average thickness of the retina increased to 381.13 microns ( + 35 m ) and visual acuity remained stable ; however , the results of injection number 3 were excluded because of the occurrence of steroid cataract which significantly reduced visual acuity in the study eye . the largest increase in mean retinal thickness to average 528 m ( + 164 microns ) occurred at 16 weeks and average bcva was 0.614 lines bcva logmar ( figure 1 ) . five - month observation of the patients with chronic diabetic macular edema previously treated with grid photocoagulation and ranibizumab injections shows that it is not possible to obtain a continuous improvement of the local conditions in visual acuity and decrease in central retinal thickness , which has also been confirmed by other authors [ 14 , 15 ] . after 4 weeks of injections , all of our patients had a significant decrease in the central retinal thickness and improvement in visual acuity . this condition continued until 12 weeks of observation . in the four - month follow - up , all patients had a gradual increase in the central retinal thickness and their visual acuity after 5 months was similar to that of the pretreatment . in none of the treated patients after this period the central retinal thickness and in accordance with other literature , the results indicate that the greatest effectiveness of ozurdex can be seen in the first 4 weeks after administration ; it lasts for up to 12 weeks of observation and then gradually decreases . most likely , this should be associated with the decrease in the vitreous concentrations of dexamethasone released . that confirms the observation that reinjection of ozurdex after a period of six months produces a similar effect as the first injection . in our follow - up following administration of 0.7 mg dexamethasone implant , there was no increase in the intraocular pressure requiring medical treatment in any of the eyes . in one eye , there was a steroid cataract development after the third dose of 0.7 mg dexamethasone implant , which coincides with the observations of other authors . in conclusion , the intravitreal dexamethasone implant treatment of patients with persistent diabetic macular edema in whom laser photocoagulation proved to be ineffective and who , as a result , required a monthly injection of anti - vegf factors ( ranibizumab , bevacizumab ) may be a good alternative as it allows extending the interval between injections .

aims . this retrospective analysis was aimed at evaluating the effectiveness of treatment of persistent diabetic macular edema with intravitreal injections of 0.7 mg dexamethasone implant ozurdex . the study comprised three male patients ( 6 eyes ) . results . the average thickness of the retina at baseline was 632 m , the medial bcva was 0.8 logmar , and corrected intraocular pressure was 13.7 mmhg . the maximum decrease in mean retinal thickness was observed at four weeks following the treatment and was 365 m ( 267 m ) and visual acuity improved by an average of two lines and was 0.6 logmar . the largest increase in mean retinal thickness to average of 528 m ( + 164 m ) occurred at 16 weeks and the average bcva was 0.614 lines bcva logmar . in one eye , there was a steroid cataract development after the third dose of dexamethasone implant of 0.7 mg . conclusions . the intravitreal dexamethasone implant treatment of patients with persistent diabetic macular edema in whom laser photocoagulation proved to be ineffective and as a result they required a monthly injection of anti - vegf factors ( ranibizumab , bevacizumab ) may be a good alternative to extending the interval of injections . however , reinjections involve a high risk of developing poststeroid cataracts , which is not without significance in middle - aged patients .

posttransplant lymphoproliferative diseases ( ptld ) are recognized as a main complication following solid organ transplantation . they generally occur in the 1st posttransplant year and may be triggered by epstein - barr virus ( ebv ) infection . lymphomatoid granulomatosis ( lyg ) is a rarer disease , characterized by angiocentric and necrotising lymphoproliferation [ 1 , 2 ] its low prevalence and its lethal outcome did not allow to well establish an obvious treatment . we report here a case of a patient who had developed lyg with cerebral and pulmonary localization , treated successfully with rituximab . to our knowledge a 70-year - old woman , with renal failure secondary to chronic glomerulonephritis , had her 1st renal transplantation in 1993 , after being on haemodialysis for 54 months . she was treated with an immunosuppressive regimen including lymphoglobuline , corticosteroids , azathioprine , and ciclosporine . next , a transplantectomy was realized on day 15 as she developed candida glabrata septicaemia . her second transplantation was performed in 2001 . the initial immunosuppressive treatment consisted of thymoglobuline , corticosteroids , mycophenolate mofetil ( mmf ) and tacrolimus . her serological tests for cytomegalovirus ( cmv ) and ebv were positive indicating previous infection , whereas that of toxoplasma was negative ( negative igg and igm ) . donor igg of cmv and ebv were positive , in contrast , igg and igm of toxoplasma were negative . during the first posttransplant year , the patient presented cmv invasive infection with cmv - pneumonia ; she was treated by iv ganciclovir . after this episode , the patient was stable for almost 2 years . during the 4th year posttransplantation , she had presented multiple episodes of bronchopulmonary infection . 54 months after transplantation , she had presented low - grade fever 38c , posterior and temporal headache , progressive gait , and balance disorders , then a persistent cough . at this moment , her immunosuppressive treatment associated mmf(1,5 g / d ) , tacrolimus(1,5 mg / d ) , and prednisone(5 the laboratory results revealed no elevated inflammatory markers , normal hepatic enzymes , and normal ldh ; creatinine clearance according to mdrd formula was 42 ml / mn/1,73 m and tacrolimus trough level was 5 the bacteriological , virological , mycological , and parasitological tests of the cerebrospinal fluid were all negative . the mri performed 3 days later detected diffuse periventricular cerebral and cerebellar contrast - enhanced lesions ( hypersignal flair ) ( figure 1 ) . in view of these findings , a reduction of immunosuppression ( mmf 1 g / d ) was performed and an antitoxoplasma treatment ( malocide + sulphadiazine ) was started . one month later , due to the absence of any clinical improvement with the treatment , a stereotactic cerebral biopsy was carried out . the histological study ( figure 2 ) showed a heterogeneous necrotising lesion , with cellular remnants , granulomatous clusters of giant cells , with circumvented nuclei and well visible nucleoli , which looked like lymphoplasmocyte cells . the cells created dense castings on the meninges and were infiltrating the wall of several vessels . the immuno - histochemical study showed granulomatous cells stained by antibodies ( ab ) anti - cd68 ( macrophages ) , anti - cd20 ( b cells ) , and anti - cd30 . the reaction to anti - ebv ab ( anti - lmp1 ) was positive ; conversely , the reaction to antitoxoplasma ab was negative . in view of these results , we concluded a grade iii lymphomatoid granulomatosis according to lipford classification [ 3 , 4 ] . a complete workup including chest and abdominal ct was carried out . the ct scan of the thorax showed 6 pulmonary nodules of tissular density in the left lung and one pulmonary nodule in the right lung ( figure 3(a ) ) . the subjacent chorion was composed of an inflammatory polymorphic infiltrate , rich in polynuclear eosinophils with small growing granulomas . mmf was discontinued ; tacrolimus was reduced to 1 mg / d , to achieve trough levels around 3 ng / ml , whereas prednisone was increased to 0.5 mg / kg / d . two months following immunosuppression reduction , the lesions were persistently unchanged . a treatment by anti - cd20 antibodies was then initiated ( rituximab : 375 mg / m weekly for 4 weeks ) . markedly , after the first two doses , a significant clinical improvement was noted . six months later , the patient reported a complete disappearance of headache and a significant regression of gait disorders . two years later ( december 2007 ) , there was no clinical sign of recurrence , the renal function was stable , and the brain mri showed the persistence of hypersignals and infarction zones remnants . the thoracic ct scan showed only a single nodule ( figure 3(b ) ) . the immunosuppressive treatment consisted of tacrolimus 1 mg / d and prednisone 0.2 mg / kg / d . the last thoracic and brain ct scans ( february 2010 ) showed a complete disappearance of the pulmonary and cerebral lesions . laboratory results revealed creatinine level 1.1 mg / dl ( 101 mol / l ) , negative proteinuria , normal ldh level , and negative ebv plasmatic pcr . our patient presented many risk factors of this disease including : age , immunosuppression , administration of antilymphocyte sera for her two renal transplants , and the reactivation of cmv . the clinical presentation demonstrated the heterogenecity and the abundance of the symptoms . it should be noted a clinicoradiological delay for the diagnosis of pulmonary lesions . our therapeutic approach was sequential , initially by a reduction in the immunosuppression , then rituximab was introduced . it affects males > females ( 2 men for 1 woman ) and affects primarily immunocompromised patients . lyg is a serious disorder with a median survival of 2 years in the general population . the main cause of death is the progression of pulmonary lesions . in renal transplantation , the literature reported 6 cases among which 3 cases were diagnosed postmortem and 3 other cases with good outcome ( one case after a reduction in immunosuppression , 2 cases after chemotherapy ) [ 1 , 2 , 811 ] . cutaneous lesions ( 2550% of cases ) were also reported , as well as central nervous system lesions ( 2535% of cases ) with multiple and focal localizations . other organs can be affected : the kidneys ( 20 30% ) , the liver ( 20 30% ) , and , less frequently , gastrointestinal tract [ 8 , 12 ] . due to its rarity , its various clinical presentations , and the absence of clinical , biological , or radiological specificity , the recognition of lyg is usually complex . this explains the delay of the diagnosis which can go up to 3 to 6 months after the beginning of the symptoms . unfortunately , the diagnosis is realised by autopsy in many cases [ 810 ] . after treatment , an enhanced t2 can persist ; however , a complete disappearance of the cortical infarction zones can be reached , as happened in our patient . the thoracic ct scan demonstrates multifocal infiltration in the lungs , predominating the lower lobes , with variable radiological aspects : reticulonodular alveolar opacities , pleurisy , or nodules [ 15 , 16 ] . three - tiered grading system ( i , ii , and iii ) have been proposed by lipford et al . this classification predicts the response to treatment and the survival [ 3 , 17 ] . nevertheless , it is important to note the difficulty of the histopathological diagnosis , as the presence of wide zones of inflammation and necrosis may suggest an infectious origin ( such as toxoplasmosis ) rather than lyg . they were gathered in granulomatous clusters with lymphoid abnormal cells of type b and lymphoplasmocyte cells . the immunophenotyping illustrated a positive stain by anti - cd20 + ab ( b cells ) , anti - cd68 + ab ( macrophages ) , anti - cd30 ab , and ebv - lmp1 + ab revealing ebv infection . ebv is the principal trigger factor of lymphoproliferation ( especially in cases of donor ebv+/recipient ebv ) . ebv viral load is considered to play a key role in mediating the disease process . infection with cmv , which occurred in our patient , may also contribute in lymphoproliferation development . the over - immunosuppression is supposed to be responsible , in particular the cumulative doses of antilymphocyte sera . moreover , the impact of other factors as age and cigarette smoking have been also reported [ 4 , 18 ] . there are scanty data in the literature concerning the management of lyg . in our patient , we considered that it might be beneficial to reduce calcineurin inhibitors by 50% and withdraw antiproliferative medications ( mycophenolate or azathioprine ) based on data previously reported in overall ptld [ 1 , 19 ] . an early trial showed improved survival with therapy comprising corticosteroids and cyclophosphamide , but mortality of lyg remained very high . combined chemotherapy using chop protocol ( cyclophosphamide , doxorubicine , vincristine , and prednisone ) was also proposed . more recently , few reports have tried a targeted therapy with the anti - cd20 antibody rituximab with or without traditional combined chemotherapy . to date , a total of 12 cases were published in the literature . the responses were successful in 9 cases [ 6 , 13 , 2127 ] , or ineffective in 3 cases [ 2830 ] ; however , none of those series concerned renal transplant patients . lyg diagnosis is complex because of the diversity of its clinical presentation , the nonspecific imaging aspects , and the difficulty of histopathological reading . our report showed that rituximab could be considered a valuable option for the treatment of lyg in renal transplant patients .

lymphomatoid granulomatosis ( lyg ) in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential . here , we describe lyg in a 70-year - old renal allograft recipient who , 4 years after transplantation , on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression , complained of low - grade fever , persistent headache and gait disturbance . the mri of the brain revealed diffuse periventricular cerebral and cerebellar contrast - enhanced lesions . the ct scan of the thorax showed multiple pulmonary nodular opacities in both lung fields . the patient was diagnosed lyg based on the cerebral biopsy showing perivascular infiltration of cd20-positive b - lymphocytes with granulomatous lesions and immunofluorescence staining with anti - ebv antibodies . with careful reduction of the immunossuppression combined with the use of rituximab , our patient showed a complete disappearance of lyg , and she is clinically well more than 4 years after the diagnosis , with good kidney function . no recurrence has been observed by radiological imaging until now . this is the first report of a durable ( > 4 years ) complete remission of lyg after treatment with rituximab in renal transplantation .

human parvovirus b19 ( hpv - b19 ) infection is generally encountered in 4- to 10-year - old children.1 aside from asymptomatic mild flu - like symptoms , most children present with typical symptoms of erythema infectiosum ( slapped - cheek rash ) because the primary targets are erythroid progenitor cells . because the temporary bone marrow infection causes transient erythropoiesis arrest,2 this infection is particularly problematic for patients with hematological disorders , such as chronic hemolytic anemia , which includes sickle cell disease , hereditary spherocytosis , and infection with human immunodeficiency virus ( hiv).1 during hpv - b19 infection , these patients fail to increase erythroid progenitor cell formation to compensate for red blood cell lysis , leading to acute erythroblastopenia ( aplastic crisis ) . therefore , it is important to diagnose all cases of hpv - b19 , even if the infection generally subsides without medication , in case the patient has an undiagnosed hematological disorder . immunity prevalence for hpv - b19 increases with age and exceeds 60% in adults.3 however , cases of infection have been reported in adults , most of which present milder erythema infectiosum , arthralgia , and purpuric papular eruptions on hands and feet ( gloves and socks syndrome).1 we encountered three cases of hpv - b19 in adult patients presenting with unusual symptoms , such as leukopenia and low platelet counts . the patient was a 40-year - old female office worker with no children . there was no indication of cytopenia in past health examinations . on 16 january 2011 , the patient developed a fever of 39 c , systemic pain , fatigue , and loss of appetite . because the symptoms persisted , the patient was readmitted to our hospital on 19 january 2011 . leukopenia ( 1,000/l ) and low platelet counts ( 15 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 immunoglobulin m ( igm ) antibody titer was 2.64 . in all , 14 days later , the patient showed a leukocyte count of 2,800/l and a platelet count of 34.74 10/l , which were indicative of recovery . the patient was a 36-year - old housewife , with children aged 2 and 7 years , who were not suffering from erythema infectiosum . starting on 5 august 2010 , the patient experienced general fatigue and a mild fever of 38 c . on 9 august 2010 , the fever progressed to 39 c , and the patient noticed erythema on her extremities and trunk . therefore , she was admitted after examination to our internal medicine outpatient department on 10 august 2010 . she had no lymphadenopathy on admission but had lacy erythematous rashes on her trunk and bilateral upper extremities and thighs . leukopenia ( 2,000/l ) and low platelet counts ( 8.9 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 igm antibody titer was 11.63 . in all , 14 days later , the patient showed a leukocyte count of 3,600/l and a platelet count of 25.7 10/l , which were indicative of recovery . the patient was a 31-year - old female office worker ( number of children not disclosed ) . starting on 12 december 2010 , the patient experienced flu - like symptoms of pharyngodynia and fatigue . therefore , she was admitted following examination to our internal medicine outpatient department on 15 december 2010 . her body temperature was 38.2 c , and there were rashes on her trunk and extremities . leukopenia ( 1,400/l ) and low platelet counts ( 10.6 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 igm antibody titer was 2.24 . in all , 14 days later , the patient showed a leukocyte count of 4,300/l and a platelet count of 23.8 10/l , which were indicative of recovery . the fact that three cases were observed over the stated time period at our hospital , which is located in nagoya city , was indicative of a transition to a slightly higher level of incidence than the annual average ( fig . 1 ; according to documents from port of nagoya s public health center ) . the patient was a 40-year - old female office worker with no children . there was no indication of cytopenia in past health examinations . on 16 january 2011 , the patient developed a fever of 39 c , systemic pain , fatigue , and loss of appetite . because the symptoms persisted , the patient was readmitted to our hospital on 19 january 2011 . leukopenia ( 1,000/l ) and low platelet counts ( 15 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 immunoglobulin m ( igm ) antibody titer was 2.64 . in all , 14 days later , the patient showed a leukocyte count of 2,800/l and a platelet count of 34.74 10/l , which were indicative of recovery . the patient was a 36-year - old housewife , with children aged 2 and 7 years , who were not suffering from erythema infectiosum . there was no indication of cytopenia in past health examinations . starting on 5 august 2010 , the patient experienced general fatigue and a mild fever of 38 c . on 9 august 2010 , the fever progressed to 39 c , and the patient noticed erythema on her extremities and trunk . therefore , she was admitted after examination to our internal medicine outpatient department on 10 august 2010 . she had no lymphadenopathy on admission but had lacy erythematous rashes on her trunk and bilateral upper extremities and thighs . leukopenia ( 2,000/l ) and low platelet counts ( 8.9 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 igm antibody titer was 11.63 . in all , 14 days later , the patient showed a leukocyte count of 3,600/l and a platelet count of 25.7 10/l , which were indicative of recovery . the patient was a 31-year - old female office worker ( number of children not disclosed ) . starting on 12 december 2010 , the patient experienced flu - like symptoms of pharyngodynia and fatigue . therefore , she was admitted following examination to our internal medicine outpatient department on 15 december 2010 . her body temperature was 38.2 c , and there were rashes on her trunk and extremities . leukopenia ( 1,400/l ) and low platelet counts ( 10.6 10/l ) were observed ( table 1 ) . the patient tested negative for hiv-1 and hiv-2 antibodies , and her hpv - b19 igm antibody titer was 2.24 . in all , 14 days later , the patient showed a leukocyte count of 4,300/l and a platelet count of 23.8 10/l , which were indicative of recovery . the fact that three cases were observed over the stated time period at our hospital , which is located in nagoya city , was indicative of a transition to a slightly higher level of incidence than the annual average ( fig . 1 ; according to documents from port of nagoya s public health center ) . we encountered three cases of acute hpv - b19 infection in adult females for which a definitive diagnosis is made by confirming the presence of hpv - b19 igm antibodies or an increase in igg antibody titer paired serum . in these cases , an increase in hpv - igm antibodies was observed in blood tests upon admission . hayakawa et al.4 reported the clinical findings of 21 consecutive patients with adult hpv - b19 infection . in that report , the predominant signs and symptoms were fever exceeding 38.3 c ( 81% ) , skin rash ( 47.6% ) , arthralgia / myalgia ( 61.9% ) , general fatigue ( 42.9% ) , lymph node swelling ( 38.1% ) , edema ( 38.1% ) , and petechiae ( 14.3% ) . in our cases , the predominant signs and symptoms were fever exceeding 38.2 c ( 100% ) , general fatigue ( 100% ) , skin rash ( 66.6% ) , and arthralgia / myalgia ( 33.3% ) . they also exhibited concomitant leukopenia and low platelet counts . because hematopoietic disease could not be excluded , bone marrow aspiration was conducted in one case , but no obvious hematopoietic dysfunction profile was observed . cases of acute hpv - b19 infection exhibiting leukopenia and low platelet counts have been reported sporadically over the past 15 years.511 although there are various theories regarding the cause , nothing has been specified . there are reports of a connection with hemophagocytic syndrome accompanying infection,1215 but bone marrow examinations did not reveal a hemophagocytic profile in any one of our three cases , and the involvement of hemophagocytic syndrome could be excluded based on their clinical courses . furthermore , b19 receptors are believed to be erythrocyte - like p antigens,1618 which lead to anemia in patients with a background of accelerated erythropoiesis ( eg , hemolytic diseases ) . precursor cells outside the hematopoietic stem cell erythroid lines can also be infected , and some are of the opinion that this causes leukopenia.19 however , bone marrow is not necessarily hypoplastic in cases with b19-induced neutropenia , and in bone marrow examinations in case 3 , no hypoplasia was observed . sakai et al.20 suggested that neutropenia caused by b19 is not because of the direct effect of the virus but rather because of secondary leukocyte elimination and consumption . in addition , there are reports that anti - neutrophil antibodies are commonly detected in chronic neutropenia in infant b19 infections.21 it is also suggested that the mechanism of b19-induced leukopenia and low platelet counts may be different from that of anemia . furthermore , although it is unknown whether there was a decrease in serum granulocyte colony - stimulating factor ( g - csf ) as quantification of serum g - csf was not conducted in any of our three cases , none of the cases required g - csf administration . there are reports of g - csf administration,5 but administration is considered unnecessary in the absence of serious life - threatening complications such as septicemia . as the other complications , hpv - b19 has been reported in association with a wide range of diseases and clinical manifestations , including arthritis , vasculitis , myocarditis , nephritis , lymphadenitis , immune thrombocytopenia ( itp ) , meningitis and encephalitis , hemophagocytic syndrome , fulminant liver disease , and generalized edema , as well as many other conditions.22 also , the observation that many cases of chronic fatigue syndrome ( cfs ) begin with a flu - like illness prompted the hypothesis that viral infections were implicated in the disease , and several viruses were suggested as etiological agents for cfs . hpv - b19 has been reported to be one of these viruses.23,24 in conclusion , we encountered three adults who were diagnosed with acute hpv - b19 infection after the simultaneous observation of acute flu - like symptoms , leukopenia , and low platelet counts . this case series emphasizes that the epidemic period should also be considered and hpv - b19 infection should be actively suspected in adult patients with hematocytopenia even if typical clinical findings ( ie , skin rash ) are absent .

we encountered three adult patients with flu - like symptoms diagnosed with human parvovirus b19 ( hpv - b19 ) infection . blood serum analysis also revealed leukopenia , with white blood cell counts ( wbcs ) of 1,0002,000/ml and low platelet counts of 89150 109/l . typical skin rash was absent in one patient . bone marrow examination of another patient showed hypoplastic marrow with < 5% blast cells . all patients recovered without administration of granulocyte colony - stimulating factor ( g - csf ) . therefore , hpv - b19 infection with leukopenia should be considered in adult patients with leukopenia during erythema infectiosum epidemics , even if typical clinical findings ( ie , skin rash ) are absent . further , the fact that three cases were observed over the stated time period at our hospital , which is located in nagoya city , showed a transition to a slightly higher level of incidence than the annual average .

hirayama disease , a rare neurological disease , is characterized by insidious unilateral or bilateral muscular atrophy and weakness of the forearms and hands , without sensory or pyramidal signs . the disease progresses initially , but spontaneous arrest is known to follow several years after the onset , unlike motor neuron disease with which it is commonly confused . hirayama disease is characterized by focal ischemic changes in the anterior horn cells of the lower cervical cord that result in amyotrophy , which is usually unilateral but may also be bilateral . we describe the characteristic findings of flexion magnetic resonance imaging ( mri ) suggestive of hirayama disease . a 17-year - old male reported in the medicine out patient clinic with a one year history of slowly progressive weakness and atrophy that started in the left hand and the forearm and gradually involved the right hand . the hand weakness limited several activities of his daily living and he could no longer play cricket because of the same . his past medical history was noncontributory ; he denied any allergic disease and none of his family members had similar symptoms . neurological examination revealed severely wasted and weak forearms and hands , tremors but no evidence of pyramidal , spinothalmic , posterior column lesions , polyminimyoclonus or autonomic disturbances . plain cervical spine radiographs showed no abnormalities , or misalignment of the vertebral bodies [ figure 1 ] . plain cervical spine ( lateral view ) radiograph shows no abnormality and no misalignment of the vertebral bodies mri was performed on magnetom concerto 2002b siemens 0.2 tesla mr unit . the following mr sequences were used : 1)precontrast axial , sagittal and coronal t1 and t2-weighted spin - echo.2)post gadolinium contrast axial and sagittal t1-weighted spin - echo.3)axial and sagittal gradient - refocused echo ( gre ) flexion cervical mr study . cervical mr images in the neutral position showed focal atrophy of the lower cervical cord at the c4 - 7 vertebral levels but no abnormal intramedullary high signal intensity [ figure 2 ] . when the neck was flexed , the posterior wall of the cervical dural sac between c4 and d1 vertebral levels was seen to shift anteriorly ; the markedly flattened and anteriorly displaced cervical cord was compressed over the posterior surface of the c4 to d1 vertebral bodies . an enhancing epidural space , isointense with the cord on t1-weighted images and hyperintense on t2-weighted images was noted at the posterior aspect of the lower cervical canal [ figures 3 and 4 ] . cervical t1w - sagittal mr image in the neutral position shows focal atrophy of the lower cervical cord at the c4 - 7 vertebral levels but no abnormal intramedullary high signal intensity cervical gre - sagittal mr image in the flexion position shows the posterior wall of the dural sac between c4 and d1 vertebral levels to shift anteriorly , and the anteriorly displaced cervical cord compressed over the posterior surface of the vertebral bodies cervical gre - axial mr image in the flexion position shows the markedly flattened , anteriorly displaced cervical cord due to the epidural lesion ( black arrow ) the patient was prescribed a cervical collar to prevent neck flexion . this disease was described first by , and named after , hirayama in 1959 and most cases of this disease have been reported from japan and india . this non - familial disorder mostly hits young men , progresses slowly and is often self - limited . researchers argue that wasting and weakness associated with this disease is because of imbalanced growth between the patient 's vertebral column and spinal canal contents . the imbalanced growth causes a tight dural sac and displaces posterior dural wall anteriorly when the neck is flexed . normally , the spinal dura mater is loosely anchored to the vertebral canal by the nerve roots and the periosteum at ( a ) the foramen magnum and the dorsal surfaces of c2 and c3 and ( b ) the other at the coccyx . the dura mater is slack enough to adjust to the increased length of cervical spine in flexion . in patients with hirayama disease , however , the tight dural sac separates the posterior dural sac from its subjacent lamina and on neck flexion , can not compensate for the increased length of the posterior wall . the posterior dural wall shifts anteriorly , and the cervical spinal cord gets compressed against the posterior margin of adjacent vertebral bodies . this compression affects the anterior spinal artery and causes microcirculatory disturbances in its territory in the lower cervical cord ; the anterior horn cells which are vulnerable to ischemia begin to degenerate , resulting in localized cord atrophy of the lower cervical region , weak and wasted hands and forearms . hirayama disease is also associated with raised levels of serum ige and several allergic disorders . blood often stagnates in the compressed lower cervical cord allowing platelets to aggregate and cause histamine to be released , factors that cause arterial spasm and microcirculatory disturbances . moreover , the finding that atopic disorders affect young people more than the elderly , men more than women , and asians more than non - asians may in part explain the distribution of hirayama disease . the key to diagnose this disease during mri scanning is to obtain images when the neck is flexed . mr studies in flexion not only show the anterior displacement of the posterior wall but also a well - enhanced crescent - shaped lesion in the posterior epidural space of the lower cervical canal . although hirayama disease is a self - limiting disorder , early diagnosis is necessary because a cervical collar , by preventing neck flexion , may arrest the progression of the disorder . in conclusion , this case showcases how cervical mri , with neck flexed , can pick up dynamic cord compression and contribute to the diagnosis of hirayama disease

a 17-year - old male , who gave up his favorite sport cricket and started playing football , presented with one - year history of slowly progressive atrophic weakness of forearms and hands . neurological examination showed weak and wasted arms , forearms and hand but no evidence of pyramidal tract , spinothalmic tract and posterior column lesions . plain cervical spine radiographs showed no abnormal findings . cervical magnetic resonance imaging ( mri ) showed asymmetric cord atrophy ; images obtained with neck flexed showed the anterior shifting of the posterior wall of the lower cervical dural sac resulting in cord compression . these findings suggest hirayama disease , a kind of cervical myelopathy related to the flexion movements of the neck .

the so - called fine needle aspiration biopsy for cytodiagnosis of deep - seated abdominal tumors has been accepted as an inevitable diagnostic technique of the new trend since 1970 , when examination of aspiration biopsy specimens was begun by kline and neal . the accurate localization and guidance of the lesion by current medical imaging methods kline and neal describe the technique to be essentially complication free with an over - all accuracy of 90% . however , cancer recurrence along the biopsy needle track has been reported in malignant tumors of the pancreas , kidney , parotid gland , prostate , and lung . there have been only a few reports in cases of primary hepatocellular carcinoma since 1983 , when sakurai et al . reported the first case , we herein document another case of such an ocurrence following fine needle aspiration biopsy of a primary hepatocellular carcinoma and consider its possible implication . a 67-year - old male was admitted to catholic university medical college , kangnam hospital on october 18 , 1987 , for the evaluation of a right hepatic mass that was detected incidentally by ultrasonograhy . on admission , the liver function tests revealed total protein ( 68 g / dl ) 7.7 g / dl , albumin ( 3.55.0 g / dl ) 4.1 g / dl , globulin ( 2.03.5 g / dl ) 3.7 g / dl , aspartate aminotransferase ( 40 units ) 72 units , alanine aminotransferase ( 40 units ) 64 units , r - glutamyl transpeptidase ( upto 80 mu / ml in adult male ) 294 mu / ml , and alkaline phosphatase ( upto 150 an abdominal ct scan confirmed a large ovoid inhomogeneous hypodense mass involving the right posterior area of the liver , measuring about 99 8 cm . 1 ) . on october 20 , we did a peritoneoscopy that showed neither the cirrhotic nodules nor the abnormal protruding masses within the area of the visible hepatic surface . on oct . 23 , a percutaneous ultrasono - guided needle biopsy was done by a fine needle followed by transcatheter chemoembolization , a combination of transarterial infusion of lipiodol and mitomycin - c 2 mg . on histopathologic examination , the tissue specimens taken by peritoneoscopic guided biopsy with a menghini needle and ultrasono - guided aspiration biopsy showed chronic persistent hepatitis ( fig . the patient was discharged on november 16 , 1987 , with a sense of well - being . on june 10 , 1988 , he was readmitted for a regular check - up and the anticancer chemotherapy . on examination , two subcutaneous lumps were noted at the previous ultrasono - guided needle biopsy site ( fig . he had first noticed them about 3 months previously , approximately 4 months after the chemoembolization . they were movable without tenderness and round in shape , measuring 2 cm in diameter . an abdominal ct scan showed a more enlarged size ( 10 10 11 cm ) with evidence of metastasis to the abdominal wall ( fig . the patient was discharged after the first anticancer chemotherapy , a combination of 5-fu , adriamycin and mitomycin - c ( fam ) . the patient was followed by a second fam chemotherapy from august 3 to 10 , 1988 . on september 9 , 1988 the cancer was more enlarged in size and had made a few daughter nodules around the main lesion that were evidenced ultrasnographically . the two subcutaneous nodules were not changed in movability , size , and number . on september 15 , a needle aspiration on them was done . the tumor histopathology showed an irregular sheet of malignant epithelial cells which had anisonucleosis , hyperchromatism and occasional distinct nucleoli ( fig . the resectability rate of these cancers is very low because of late discovery of the tumor and the frequent association with cirrhosis . in recent years , however , the development of a screening program for early diagnosis of primary hepatocellular carcinoma , such as a regular check - up for alpha - fetoprotein levels and an ultrasonogram in the high risk patient group , makes it possible to discover even small tumors which can be completely cured . if a tumor is detected by the screening test or other diagnostic tools , a needle biopsy is indicated to establish an accurate diagnosis . conventional needle biopsy of the liver has been a useful diagnostic tool for the histopathologic confirmation and prognostic assessment . but it has some serious complications including hemorrhage , bile peritonitis and injury to neighboring organs . besides these , needle track seedings occur , especially in the case of a cutting needle of the vim - silverman type . on the other hand , the usefulness and safety of guided percutaneous fine needle aspiration biopsy of the liver ho et al . recommended this technique for pathologic diagnosis of hepatic malignancy because of its simplicity , high yield , and reasonable safety . some considered this procedure to be questionable because it might elicit tumor implantation in the needle track and there are a few well documented cases and experimental evidence to support such implantation . therefore , guided fine needle aspiration biopsy of the liver is no longer free from cancer spread . sakurai et al . suggested that the reason for its rarity would likely be that most primary hepatocellular carcinomas were so malignant that the ensuing life span of the patient was too short for the disseminated malignant cells to mature into detectable neoplastic masses . new diagnostic developments for early detection of primary hepatocellular carcinoma will give us more opportunity to use guided fine needle aspiration biopsy for smaller cancers . some researchers insist that needle biopsy of a malignant tumor of the liver should be performed only after all other possible diagnostic procedures fail because curative liver tumor resection can now be done with low operative morbity and mortality , and a good outcome should not be put at risk by an unnecessary percutaneous needle biopsy , on the contrary , others indicate that it appears unnecessary to revise the indications for hepatic needle aspiration biopsy in view of the obvious rarity of malignant implantation , as the risk of spreading cancer by percutaneous fine needle aspiration biopsy is more of theoretical than practical significance . we suggest that fine needle track implantation should not be ignored even in small hepatic cancer , especially after multiple aspirations , although it is rare . it is obligatory , however , to confirm the histologic diagnosis before the determination of suitable therapy .

cancer spread along the needle track following fine needle aspiration biopsy is said to be a rare complication . the authors report a case of subcutaneous implantation of hepatocellular carcinoma following ultrasono - guided fine needle aspiration biopsy . the patient , a 67-year - old korean male was found to have a large hepatocellular carcinoma diagnosed by fine needle aspiration biopsy . four months later , the patient felt two subcutaneous growing lumps at the previous aspiration site . the authors confirmed them histologically 11 months after aspiration .

3d printing, has been used in the clinical sciences for planning complex surgeries and designing custom implants . the introduction of low - cost consumer - grade 3d printers enables this technology to be used for more routine procedures , although its application in rt has not been widely published . these 3d printers deposit 0.1 mm- to 0.3 mm - thick layers of hot acrylonitrile butadiene styrene or polylactic acid plastic . the resulting model ( 3d printout ) in addition , there are several software packages that import medical magnetic resonance or computed tomography ( ct ) images and enable the creation of models suitable for printing . the use of medical imaging and 3d printing had previously been used for radiation therapy applications at cancercare manitoba . additionally , the institution s medical devices department regularly modifies tracheostomy tubes and , thus , has developed a strong collaborative relationship with the respiratory therapists of the long term ventilator service ( ltvs ) , winnipeg regional health authority ( manitoba ) . it was natural then that this unique collaboration may lead to an innovative approach to client care by applying 3d printing technology to rt practice . the ltvs provides rt services to long - term clients in the community who require support for medically complex needs . these needs frequently include tracheostomy airway management in clients who may or may not also require mechanical ventilation . there are several well - known long - term effects of tracheostomy , including dysphagia , inability to phonate , tracheal granuloma and tracheomalacia ( 9,10 ) . respiratory therapists at the ltvs use various methods of customizing tracheostomy tubes to mitigate anatomical or other therapeutic challenges , or to manage complications resulting from long - term use of the airway itself . routine diagnostic techniques , such as bronchoscopy , broncheolar lavage , radiography and ct , have been used to diagnose and monitor these long - term effects . although a cornerstone of management , these diagnostic techniques have occasionally proven insufficient for identifying the etiology of symptoms related to long - term tracheostomy use that have appeared clinically . this has limited the ability of the respiratory therapists to determine appropriate clinical interventions such as tracheostomy type , position and need for customization . for example , occasionally complicated tracheal anatomy may make airway visualization highly challenging and , thus , limit the ability to determine a differential diagnosis in the presence of multiple long - term complications . one approach that has been used to give a detailed and informative understanding of the etiology of client symptoms has been the use of 3d printing technology to reproduce the results of high - resolution ct scanning . the genesis of the idea to use 3d printing technology in cases such as these came as a result of collaborative review and a shared desire to design a solution for these clinical concerns . the existing relationship between the respiratory therapists of the ltvs and personnel in the medical devices department at cancercare manitoba served as an important environmental factor , which facilitated the connection of ideas . encouraging professionals to connect ideas and expertise with those of colleagues and others in this manner brought individuals together and supported a sense of collective cognitive responsibility ( 11 ) . through sharing in the responsibility for knowledge creation , both the individual goals of the respiratory therapist and the patient , as well as the collective goals of the organization were achieved in an innovative way . as a result , 3d printing was used as a means of assessing airway abnormalities and symptomology not explained by traditional diagnostic and assessment techniques . the resulting images were then imported into 3d modelling software ( 3d doctor v5 , able software corp , usa ) in which the trachea was outlined . although parts of this task were automated , several hours of manual work by the medical devices personnel was necessary . a significant challenge is that because a trachea tube was in place during the ct scan , it was subsequently necessary to remove it from each image manually ( figure 1 ) . the resulting outline of the trachea was then exported as a stereolithography ( stl ) file from which tracheal models were printed using a consumer - grade fused - deposition printer ( solidoodle 3 , solidoodle llc , usa and makergear m2 , makergear llc , usa ) ( figures 2 and 3 ) . printing the tracheal models was relatively straightforward as either a positive that was a copy of the patient anatomy , or as a negative that revealed the lumen of the trachea . furthermore , the ability to physically fit the tracheostomy tube into the positive model enabled the team to better determine the most appropriate airway specification relative to the anatomical limitations and other complications . figures 4 , 5 and 6 demonstrate three different models of the trachea that were printed using the 3d printer . these models provided a profound visual aid in understanding the unexpectedly extensive anatomical abnormality of this symptomatic client . an additional strength of 3d printing is that the models may be sliced in any plane before printing , and producing additional copies is simple . although 3d printing technology holds much potential for use in rt and in tracheostomy management , one notable limitation of this approach is the lengthy process of outlining the trachea on the ct images . although this step is partially automated , the presence of the trachea tube in the images complicates the process considerably . the use of 3d printing technology to enhance clinical evaluation of clients with long - term tracheostomy provides an example of how innovative ideas lead to practical solutions using new technologies . the adoption of 3d printing in rt practice has not previously been reported in the literature . as is the case in many innovation - generating organizations , the roots of a new practice concept rest in sharing and synthesizing multiple perspectives , problem solving and collective knowledge construction ( 12 ) . through dissemination of this idea , it is hoped that others will be prompted to share in further exploration and development of this particular idea , thus fostering new insights . an interesting array of issues worthy of further inquiry have emerged from this innovation . to evaluate the possible scope of applicability of 3d printing in tracheostomy management , it would be valuable to quantify the prevalence and morphology of tracheal abnormalities in clients with long - term tracheostomy . additionally , it would also be of great interest to determine whether routine assessment using 3d printing technology could impact client outcomes . finally , we need to consider its application as a tool for professional and client education . beyond spurring interest and inquiry in this new assessment technique , it is also hoped that this discussion will promote wider awareness and use of the structural mechanisms available to respiratory therapists for sharing knowledge . supporting an environment of information exchange and community knowledge generation will lead to enhancements in the support we provide to those with respiratory challenges .

technological advances have influenced practice patterns and innovation in many health disciplines , including respiratory therapy . collaborative approaches and knowledge - sharing environments are vital in addressing problems and adopting emerging technology . this article illustrates how the emergence of low - cost three - dimensional printing technology to physically reproduce the results of computed tomography imaging data can provide ways to assess airway abnormalities and symptomology not explained by traditional diagnostic methods .

lymphedema ( le ) is a condition in which lymphatic transport is compromised , allowing lymph fluid to accumulate between tissues . the accumulation causes progressive fibrosis between the skin and subcutaneous tissue , and is characterized by non - pitting swelling . this fibrosis and swelling damage lymphocytes and weaken the immune system , which eventually progresses to chronic inflammation and degeneration in the lymphatic system and peripheral tissues1 . le causes various problems such as pain , tingling sensation , loss of sensation , muscle weakness , stiffness , and reduced joint range of motion ( rom)2 . according to previous studies , complex decongestive therapy ( cdt ) for le includes manual lymph drainage , application of a short stretch compression bandage ( sscb ) , reduction of edema , and skin care . however , an sscb does not continuously maintain the pressure and must be rolled back every day6 . if adverse effects on the skin occur and a sscb can not be applied , therapeutic exercises can not be safely performed . after right breast resection on june 2 , 2006 , a 57-year - old woman underwent axillary lymph node dissection and radiotherapy on october 24 , 2012 . beginning in december 2013 , edema developed in the right upper extremity , for which she presented to the department of rehabilitation . she was diagnosed with le and received treatment of edema three times weekly . on the day of presentation , a physical therapist partially measured the circumference of the upper extremity by using a tape measure as follows : axillary , at 10 cm above the elbow , at the elbow , and at 10 cm below the elbow , wrist , and hand7 . the measurements for the right upper limb were 34 , 28 , 28.5 , 23 , 16 , and 19 cm , respectively . those for the left upper limb were 32 , 25 , 25 , 22 , 16 , and 18 cm , respectively . the moisture ratio between the body water and the intracellular fluid in the upper extremity was measured by performing a biological analysis with inbodys10 ( biospace ltd . , the body water volume in the right arm was 1,550 ml , and the extracellular to total cellular ( e / t ) fluid ratio was 0.384% . the body water volume in the left arm was 1,390 ml , and the e / t fluid ratio was 0.378% . furthermore , the patient showed a restricted rom in the right arm as follow 120 flexion , 80 abduction , 15 external rotation , and 15 internal rotation . on the day of evaluation , the treatment was explained to the patient , and the patient underwent cdt and sscb application . on the next treatment day , because of the skin condition , cdt was administered without a sscb three times per week for 14 weeks . after the treatment on march 27 , 2014 , the patient was reevaluated . the measurements of the upper right limb ( axillary , at 10 cm above the elbow , at the elbow , and at 10 cm below the elbow , wrist , and hand ) were reduced to 34.5 , 29 , 24.5 , 25 , 16 , and 18.5 cm , respectively . the body water volume was 1,680 ml ( 10.8% ) , and the e / t fluid ratio was 0.387% in the inbody biological analysis . rom improved to 160 flexion , 120 abduction , 40 external rotation , and 35 internal rotation . however , even though the values of the parameters of the right upper extremity were reduced , the le increased . next , the patient underwent pnf d2 flexion and breathing exercises three times a week for 14 weeks ( 36 sessions in total ) . the starting position for the exercise is the supine position , with the shoulder joint in extension , adduction , and internal rotation ; the elbow in extension ; and the forearm , wrist , and fingers in pronation . the shoulder was slowly stretched by flexion , abduction , external rotation , elbow extension , and forearm supination , and the wrist and finger were slowly stretched by extension . the arm and ear were 810 inches apart , and the thumb was pointed toward the floor . the patient stretched her upper extremities as much as possible and maintained the position . at the same time , breathing was stopped and held for 5 seconds . after that , while exhaling , the arm should be slowly returned to the starting position . this treatment is performed for 10 repetitions ( three sets ) , followed by 1 minute of rest . this study conformed to the ethical standards of the declaration of helsinki ( 1975 , revised 1983 ) . the protocol for this study was approved by the institutional review board of hanyang university ( hyi-15 - 046 - 1 ) . after the pnf d2 flexion and breathing exercises , parameters of the right upper extremity and the body water volume were reduced . moreover , the restricted rom of the right side was improved . in the reevaluation on july 1 , 2014 , the parameters of the right upper extremity ( axillary , at 10 cm above the elbow , at the elbow , and at 10 cm below the elbow , wrist , and hand ) were reduced to 34 , 28 , 24 , 24 , 16 , and 18 cm , respectively . in addition , the e / t fluid ratio was improved to 0.382% , and rom was improved to 180 flexion , 180 abduction , 80 external rotation , and 45 internal rotation . in this study , the effects of pnf d2 flexion and breathing exercises were studied in a patient with upper extremity le for whom the sscb treatment method could not used . as a result of the intervention , the circumference of the armpit was reduced by 0.5 cm ; that of 10 cm above the elbow , by 1 cm ; that of the elbow , by 0.5 cm ; that of 10 cm below the elbow , by 1 cm ; and that of the back of the hand , by 0.5 cm . a total of 100 ml ( 9.4% ) of body water volume in the right upper extremity was eliminated , and the e / t fluid ratio was decreased by 0.005% . in addition , the rom of the extremity was improved to 20 flexion , 60 abduction , 40 external rotation , and 10 internal rotation . this study showed that pnf d2 flexion and breathing exercises were effective in reducing le and improving rom . this study suggests the cdt method and pnf d2 flexion and breathing exercises for patients for who a sscb could not be applied . in addition , it is already known that sscb compression force helps the natural pumping action of the muscle to increase circulation of venous and lymphatic fluid in edematous areas3 . however , in a research by irdesel et al.8 , comparison between a group that maintained pressure during the exercise and an opposition group did not show a beneficial difference in circulation . previous studies have shown that pnf exercise improves joint mobility and muscle function9,10,11,12 . moreover , in a study by sharman et al.9 , active pnf stretching was found to be the most effective method to improve rom . in addition , in a study by hindle et al.10 , pnf stretching was found to improve rom , although plyometric , high - intensity , or maximum - intensity exercise reduced muscle consumption . after gonzlez - rav et al.11 implemented different exercises for 13 weeks and compared overall rom and shoulder rom in pnf groups , rom improved by 5.91 ( 70.9676.01 ) and 5.08 ( 71.8476.88 ) , respectively , in the manual exercise groups but was reduced by 2.57 ( 68.1166.06 ) in the non - exercise group . however , in a comparison between the results of their study and those of previous studies , the same results could not be concluded owing to differences in study subjects . therefore , studies on increasing muscular strength through performance of pnf are needed in order to determine their effect on edema . moseley et al.13 analyzed breathing and gentle arm exercises , and observing le reduction in the upper extremity by 46 ml ( 5.8% ) immediately after exercise , 50 ml ( 5.3% ) after 30 minutes , 46 ml ( 4.3% ) after 24 hours , and 33 ml ( 3.5% ) after 1 week . this parameter was remeasured 1 month after exercise and was reported to have decreased by 101 ml ( 9.0% ) . although their research method differed , they reported a positive effect on le reduction because of the combined effects of breathing and upper extremity exercises . this study is a case report of individual treatment results in one patient , without a control group . because of this limitation , correlation could not be conclusively determined between the effects pnf d2 flexion and those of breathing exercises on le and rom . therefore , the present authors referred to studies such as that by moseley et al.11 and concluded that pnf d2 flexion and breathing exercises improved le and rom . although this study is a case report of a single patient , its results indicate that these exercises should be studied on a larger scale .

[ purpose ] the aim of this study was to evaluate the effects of proprioceptive neuromuscular facilitation ( pnf ) d2 flexion and breathing exercises in a patient with lymphedema ( le ) . [ subject ] this report describes a 57-year - old woman with le in whom a short - stretch compression bandage ( sscb ) could not be used for treatment because of skin itching and redness . [ methods ] the patient received complex decongestive therapy without a sscb . next , pnf d2 flexion and breathing exercises were conducted three times per week for 14 weeks ( 36 times ) . [ results ] as a result , the circumference of the armpit was reduced by 0.5 cm ; that of 10 cm above the elbow , by 1 cm ; that of the elbow , by 0.5 cm ; that of 10 cm below the elbow , by 1 cm ; and that of the back of the hand , by 0.5 cm . a total of 100 ml ( 9.4% ) of body water was eliminated from the right upper extremity , and moisture ratio was reduced by 0.005% . finally , range of motion was improved to 20 flexion , 60 abduction , 40 external rotation , and 10 internal rotation . [ conclusion ] this study showed that pnf d2 flexion and breathing exercises were effective in reducing le and improving range of motion .

there are about 190 cases reported with higher prevalence of diagnosis in pediatric age group . with first histological confirmation in 1895 polyorchidism can clinically have varied presentations as inguinal swelling , cryptorchidism , testicular torsion , hydrocele and varicocele with majority being asymptomatic . the most common form of polyorchidism is triorchidism ( or 3 testes ) with left sided predominance ( 65% ) over the right . a higher tendency for malignant transformation in non - functional testis necessitates the radiological and functional assessment of polyorchid testes . we hereby report a case of 24-year old male with left side super - numerary non - functional testis , presenting as left sided inguinal hernia . a 24-year old young male came with reducible swelling in left inguinal region since 4 years without associated history of trauma or pain . on detailed local examination , a reducible swelling in the left inguinal region with positive cough impulse and positive deep ring occlusion test was noted . the right testis was normal in size , whereas left testis was smaller in size 332 cm ( about 50% ) compared to the right side . intraoperative findings of indirect inguinal hernia sac was present with small undescended super - numerary testis of size 2.52.51 cm at the deep inguinal ring ( figure 1 ) having short vas deferens and a normally located left testis with epididymis and vas deferens in the scrotal sac . due to anomalous anatomy of super - numerary inguinal testis , orchidectomy with excision of indirect sac was performed . the histopathological examination of the specimen reported thickened capsule of testis and tubules with arrest of development of the germ cells ( figure 2 ) . a prominence of sertoli and leydig cells along with hyalinised , thickened basement membrane of seminiferous tubules and dense intervening stroma was found . a follow up tumor marker assay showed negative study , which can likely be present in burned out tumor in spite of negative histology . polyorchidism presents itself more commonly in the 2 to 3 decade , with approximately 50% of cases reported between 15 to 25 years of age . the common presentations of polyorchidism manifests as maldescent ( 40% ) , hernia ( 30% ) , torsion ( 15% ) , hydrocele ( 9% ) , malignancy ( 6% ) , infertility and epididymitis . the testis takes its origin from the medial part of primitive genital ridge while the epididymis and vas deferens develop from the wolffian duct . the exact etiology of polyorchidism is unclear , however accidental division of genital ridge before 8 week of gestation could be a possible cause . there are theories proposing the probable presence of multiple testes first being duplication of longitudinal genital ridge resulting into separate testes so total volume of testis exceeds of one . the second theory explains transverse division of genital ridge at different levels resulting into different combination of testes , epididymis and vas deferens . based on site of testes they can be classified as scrotal ( 66% ) , inguinal ( 23% ) and abdominal ( 9% ) . leung ( 1988 ) classified polyorchidism based on embryological development with possible anatomical distinct epididymis or vas deferens . singer ( 1992 ) and colleagues proposed classification based on anatomical and functional potential of supernumerary testis to epididymis and finally by vas deferens . an effort to restore the functionality of undescended testes can be attempted if surgically corrected before age of 4 - 5 years . a significant risk of malignancy is reported in undescended non - functional testis before puberty being 2.2% while after puberty it rises substantially to 5.4% . recent publications also suggest higher incidence of testicular malignancies ( 4 to 6% ) in cryptorchid testis compared to normal testis . there is higher risk of testicular malignancy in polyorchidism cases of about 7% especially in non - scrotal testis . of these the management of supernumerary testes has been a topic of much debate and different factors like age of patient , location of testes , functional status and lastly compliance and accessibility for follow up have to be taken into consideration . broadly in pediatric age group or patients with reproductive desire and uncomplicated polyorchidism should have conservative approach like orchidopexy , however a strict vigilant follow up is mandatory . while adults without reproductive desire , complicated polyorchidism and with inaccessibility for follow up should not be considered for conservative management . in our view supernumerary testis with complications like cryptorchidism , torsion and intraoperative non - functional testis i.e. , without a draining vas deferens or epididymis , excision can be performed due to higher risk of malignancy in polyorchidism . while conservative approach is recommended for uncomplicated polyorchidism in functional testis with a dedicated follow up . current review of literature recommends conservative management for uncomplicated functional testes and regular follow up in polyorchidism . a surgical approach is advisable in complicated , non - compliant and non - reproductive patients in view of higher risk of malignancy in these patients .

triorchidism is the commonest variety of polyorchidism , an entity with more than two testis is an extremely rare congenital anomaly of the testis . although excision of the abnormal testis is a safer alternative proposed , recent literature suggests more conservative approach in normal testes with watchful regular follow up to screen for malignancy . this case presented as a left inguinal swelling diagnosed as indirect left inguinal hernia . the left side testis was of smaller size ( about half ) with normal sperm count , morphology and motility . intraoperatively indirect inguinal hernia was noted with supernumerary testis at deep ring in addition to normal left testis in left scrotal sac . the ectopic testis were small ( 2.52.51 cm ) lacking epididymis and with short vas deferens . an evident normal semen analysis and varied anatomy , the decision for orchidectomy of ectopic testis was taken . the histopathological finding was consistent with arrest in germ cell development .

il-15 plays a pivotal role in t - cell activation and effector functions , including t cell proliferation , interferon- and tumor necrosis factor- production , chemokine production , and cytotoxicity . in combination with other common gamma - chain cytokines , il-15 also influences memory t cell homeostasis through the regulation of memory t cell numbers [ 6 - 8 ] . in this context , il-15 drives the generation of antigen - specific memory t cells , promotes the survival of memory cd8 t cells , and stimulates the homeostatic proliferation of memory phenotype cd8 t cells [ 10 - 12 ] . recent publications have described new roles for il-15 in primary immune responses , where it provides a survival signal to effector cd8 t cells during primary responses to pathogens . recently , sanjabi et al . demonstrated that transforming growth factor-tgf- and il-15 have opposing effects on the survival of the short - lived effector t cells ( defined on the basis of klrg1 [ killer cell lectin - like receptor g1 ] and cd127 expression ) . using a model system of listeria monocytogenes infection , the authors demonstrated that tgf- promoted apoptosis of effector cd8 t cells whereas il-15 promoted their survival . the opposing effects of tgf- and il-15 were not a result of direct inhibition of signaling in the respective signaling pathways ; rather , the differential survival appeared to result from the competing effects of these pathways on the anti - apoptosis molecule bcl-2 ( b - cell lymphoma 2 ) . importantly , these data supported a role for il-15 in promoting the survival of effector t cells during the contraction phase of the t - cell response to infection . this concept was extended by mcgill et al . , who revealed a role for il-15 in promoting the survival of antigen - specific cd8 t cells in the lung after influenza virus infection . using a dendritic cell ( dc ) depletion / reconstitution model , their previous work had demonstrated that influenza - specific cd8 t cell responses in the lung depended on t - cell interactions with pulmonary dcs . when pulmonary dcs were depleted using clodronate - liposomes , antigen - specific cd8 t cell responses were decreased , and the virus was not cleared as efficiently . the blunting of the cd8 t - cell response was not due to reduced proliferation of t cells in the absence of dc signals , as dc depletion did not significantly alter the proliferation of antigen - specific cd8 t cells responding to the infection . instead , it appeared that the pulmonary dcs were promoting the survival of the antigen - specific t cells in the lung environment . this enhanced cd8 t - cell survival was dependent on trans - presentation of il-15/il-15 receptor ( il-15r ) complexes by pulmonary dcs , as blocking il-15 or il-15r on dcs resulted in increased cd8 t - cell apoptosis in the lung . together , these data support a two - hit model for promoting effective cd8 t cell responses : a first hit in the lymph node that primes t - cell proliferation and migration to infected tissue , and a second hit that provides a survival signal to the effector t cells . while il-15 has been best - appreciated for its contributions to memory t cell homeostasis , these new findings highlight the importance of il-15 in promoting the survival of antigen - specific cd8 t cells during primary responses to infection and suggest several areas for further investigation . first , the location of the dc - t - cell interaction that promotes the survival of the cd8 t cells needs to be determined . one possibility is that il-15 trans - presentation by dcs takes place in inducible bronchus - associated lymphoid tissue that develops in the lungs after infection . alternatively , the dc - t - cell interactions could take place in the lung - draining lymph node , as the pulmonary dc subsets continue to migrate to the lung - draining lymph node through day 9 post - infection . second , the importance of il-15 for the survival of memory t cell populations during a secondary pathogen challenge needs to be examined . finally , the contribution of il-15 trans - presentation to the survival of cd4 t cells during the primary immune response to pathogens needs to be determined . in this regard , il-15 promotes the activation of cd4 t cells including their cytokine production , cd154 expression , proliferation , and the maintenance of memory populations yet the effect of il-15 on cd4 t - cell survival during primary immune responses is unknown . manipulating t cell survival via the il-15 pathway offers the potential for the development of novel disease therapies . one such therapeutic approach was recently reported by wang et al . , who alleviated joint inflammation in a model of arthritis by targeting toxins to il-15r - expressing cells . this report revealed the potential for elimination of immunopathogenic t cells and offers a possible therapeutic pathway to treat t - cell - mediated diseases like multiple sclerosis or type i diabetes . alternatively , the anti - apoptotic effects of il-15 could also be utilized to enhance survival of effector t cells . toward this end , hoyos et al . engineered tumor - specific t cells with an il-15 construct , which enhanced t - cell survival and resulted in improved anti - tumor effects . together , these studies reveal the potential for therapies targeting the il-15 pathway in the treatment of disease and reinforce a role for il-15 in promoting the survival of effector cd8 t cells during the immune response .

interleukin-15 ( il-15 ) is generally considered to be a regulator of t cell homeostasis because it works with other common gamma - chain cytokines like il-2 and il-7 to control the maintenance of naive and memory t cell populations . however , recent reports highlight new roles for il-15 during the primary immune responses that involve promoting the survival of antigen - specific cd8 + t cells . these findings illuminate a previously unanticipated role for il-15 in the generation and resolution of the effector cd8 + t cell response to pathogens .

since the 1952 outbreak of tbe in roava , slovakia , all registered cases of tbe have been required to be reported to the national health institute . we analyzed 1,786 tbe cases registered in slovakia by the regional institute of health during 19612004 . we calculated the average altitude of cadastral units corresponding to the reported tbe cases by using an altitudinal model of the country and arcgis 9.2 software ( www.esri.com ) . a tbe focus was defined as a location at which tbe infection occurred at least 1 time in a given year . the yearly average altitude for tbe was plotted against time , and temporal trends were identified by linear regression analysis . frequency distribution of tbe foci in relation to altitude was plotted , and 5-year periods were aggregated . to eliminate locations with single , possibly accidental , cases of the disease , we considered established tbe foci where tbe had occurred in at least 2 of 5 years .the series of yearly mean altitudes of tbe foci was tested against the null hypothesis of random elevation by using the spearman rank correlation ( 2-tailed test ; null hypothesis = temporal and altitudinal rankings are uncorrelated ) and the test for stationarity of kwiatkowski et al . ( 11 ) ( null hypothesis = time series in question is stationary ; i.e. , no change over time ) . a series of yearly mean altitudes for tbe was analyzed for correlations with mean yearly temperature and precipitation derived from 12 meteorologic stations throughout slovakia . statistical tests were performed by using spss 14.0 for windows ( chicago , il , usa ) and gretl 1.8.5 ( 12 ) . during 19611979 , the mean altitude for tbe varied between 180 m and 340 m above sea level . time series of mean altitudes for tbe showed random elevation , and statistical analysis showed no temporal trend . during this period , however , during the following period , 19802004 , the mean altitudes for tbe showed nonrandom variation over time . an analysis of trends ( linear least - square fit ) showed a mean sd annual ascension rate of 5.32 0.63 m ; r = 0.76 , p<0.001 ( figure 1 ) . the relationship can be expressed as the following equation : annual rise in the mean altitude of tbe incidents ( meters above sea level ) = ( 222.80 + 5.32 ) ( year from 1980 inclusive ) 0.63 . * tbe , tick - borne encephalitis ; rs , spearman rank correlation test , a nonparametric test ; kpss , kwiatkowski - phillips - schmidt - shin test , a test of stationarity ( no change with time ) . probability of adopting the null hypothesis of randomness ( spearman rs ) and stationarity ( kpss ) . mean altitude of reported cases of tick - borne encephalitis ( tbe ) , slovakia , 19802004 . black line , mean altitude ; red line , linear least - square fit ; gray lines , 95% confidence intervals . the observed rise in mean altitude for tbe corresponds with a mean sd rate of tbe ceiling ( uppermost limit ) rise of 5.4 1.7 m yearly during the past 3 decades in the neighboring czech republic ( 2 ) . during the same frame , an analysis of trends ( linear least - square fit ) showed an annual increase of 0.067c 0.019c ( r = 0.36 , p = 0.002 ) . the mean altitude for tbe in this period was significantly correlated with mean annual air temperature ( table 2 ) . the closest correlation was detected between the mean altitude for tbe and mean annual air temperature of the 3 preceding years . this correlation indicates that the mean altitude for tbe positively responds to climate warming , with a lag of several years . a similar phenomenon was described by zeman and bene ( 2 ) . at the beginning of the observed period of change , 19801984 , 48.6% of tbe foci were found at < 200 m ( figure 2 ) , 21.6% were found at > 300 m , and the highest with repeated reports of tbe was 550 m. during 20002004 only 23.0% of locations with repeated reports of tbe were found at < 200 m , 27.8% of all locations were found at > 400 m , and 5.6% of all tbe foci were found at > 600 m ( figure 2 ) . during this period , the highest location with tbe occurrence repeated for several years was 832 m. the total number of lowland tbe foci at < 200 m decreased from 36 during 19801984 to 29 during 20002004 . * nonparametric testing ( spearman rank correlation test ) . comparison between altitudinal distribution of tick - borne encephalitis ( tbe ) foci during 2 time periods , 19801984 ( gray bars ) and 20002004 ( white bars ) , slovakia . in contrast , the total number of tbe foci at > 400 m was only 2 during 19801984 and increased to 35 during 20002004 . the altitudinal distribution of tbe foci during 19801984 differed significantly from that during 20002004 ( log - likelihood ratio 31.302 , df = 7 , p<0.001 ) . the number of lowland tbe foci became significantly lower than in the beginning , a finding that corresponds with the predictions of randolph and rogers about the gradual disappearance of tbe from the lowlands of central europe ( 7 ) . the dramatic rise in the number of tbe foci at > 400 m between 19801984 ( 2 foci ) and 20002004 ( 35 foci ) is too great to be explained by only socioeconomic factors , such as particular changes in land use , which could increase the range of habitats suitable for tick survival at higher altitudes . if the observed trend continues , the number of tbe foci in the mountain areas > 500 m will probably increase in future decades . whether this would affect the total number of tbe cases is a matter for discussion . higher areas are less densely inhabited by local residents but often visited for leisure activities and recreation . the possibility of tbe emergence should be therefore considered by the management of recreation facilities and tourist resorts in areas with habitats suitable for tbe vectors .

increased tick - borne encephalitis ( tbe ) cases have been reported in central europe . to investigate temporal trends in the altitude at which tbe cases occur in slovakia , we analyzed the number of tbe cases during 19612004 . since 1980 , tbe cases moved from lowlands to submountainous areas , most likely because of rising temperature .

corneal perforation in the perinatal period is rare , and only a few cases are described in the literature . in most of the reported cases , low birth weight and systemic infection were associated with corneal perforation in the perinatal period,14 but there is one report of corneal perforation in relatively healthy newborns without evidence of trauma.5 anterior segment dysgenesis , such as peters anomaly , is also associated with corneal perforation.68 peters anomaly is characterized by a central corneal opacity from the time of birth and is accompanied by corresponding defects in the posterior stroma , descemet s membrane , and endothelium.9,10 we report a case of spontaneous corneal perforation in a neonate with peters anomaly treated with a conjunctival flap . a premature female infant , born after a gestational period of 33 weeks with a birth weight of 1.41 kg , underwent her first ophthalmologic examination at 4 weeks of age . she was hospitalized in the neonatal intensive care unit due to systemic abnormalities , such as a right clavicle fracture and microcephaly . slit - lamp examination of the right eye revealed a central corneal opacity , corneal thinning , and an iridocorneal adhesion ( figure 1 ) . the iris was fused with the posterior surface of the peripheral cornea , with poor formation of the anterior chamber . the parents were informed of the high risk of spontaneous corneal perforation without external pressure . at 42 days of age , examination revealed corneal perforation , iris protrusion , and a flat anterior chamber ( figure 2a ) . we performed a 360 conjunctival peritomy ( figure 2b ) under general anesthesia to create a conjunctival flap , and the flap was brought down to cover the cornea . simple interrupted sutures with 80 vicryl ( ethicon endo - surgery , inc , oh , usa ) were then used to close the incision ( figure 2c and d ) . three months after the surgery , the right eye of patient was successfully preserved , with no sign of inflammation or leakage . since peters original description in 1906,11 many others have reported the ocular abnormalities now known as peters anomaly . in 2007 , zaidman et al subdivided peters anomaly into 3 types : ( type i ) central corneal opacity with iridocorneal adhesions ; ( type ii ) central corneal opacity with cataracts or corneolenticular adhesions ; and ( type iii ) peters anomaly in association with cleft lip / palate , short stature , abnormal ears , and mental retardation.12 peters anomaly may be isolated or accompanied by other ocular malformations such as chorioretinal coloboma , a congenital defect caused by faulty closure of the embryonic fissure , and is associated with other ocular and systemic abnormalities.13 to our knowledge , however , only three reports of spontaneous corneal perforation occurring in association with peters anomaly have been reported in the literature.68 krause et al reported the first case of peters syndrome with spontaneous corneal perforation in 1969.6 traboulsi and maumenee reported clinical findings in 29 patients with peters anomaly , and one of 29 patients developed spontaneous corneal perforation.7 banning et al described two patients with corneal perforation and secondary congenital aphakia in peters anomaly . they performed penetrating keratoplasty to preserve the eyes.8 in our case , however , we had to create a conjunctival flap rather than perform penetrating keratoplasty because of the lack of a donor cornea . the conjunctival flap is a well proven , time honored treatment for numerous disparate corneal diseases that have a persistently compromised ocular surface in common.1416 the purpose of the conjunctival flap is to restore the integrity of a compromised corneal surface , typically damaged as a result of trauma , neurotrophic disease , severe dry eye , or bullous keratopathy . the flaps prevent progressive corneal ulceration and secondary infection ; they also control pain , eliminate frequent medications , and improve cosmesis . complications encountered after conjunctival flap surgery are relatively uncommon , but the most frequently reported complications include flap retraction , conjunctival buttonholes and erosions , epithelial inclusion cysts , and corneal perforations.17 in the present case , there were no complications . although the conjunctival flap does not permit good visual acuity or good visualization of the anterior chamber details , it is sufficient to preserve the eye . in our case the pax6 gene , which is expressed in the developing central nervous system , including the eye , is vital to eye development and is influential at early stages of ocular morphogenesis , acting as a master control gene.18 it is therefore believed to play an important role in ocular embryogenesis . mutations of the pax6 gene are associated with various ocular anomalies , including peters anomaly , aniridia , and chorioretinal coloboma.19 genetic studies of the patient may help to elucidate the causes of this anomaly . although rare , corneal perforation can occur in peters anomaly . to our knowledge , this is the first documented case of a spontaneous corneal perforation in peters anomaly treated with a conjunctival flap .

a premature female infant underwent her first ophthalmologic examination at the age of 4 weeks . the initial examination of the baby was requested for evaluation of a white spot on the surface of her right eye . she had been hospitalized in the neonatal intensive care unit because of systemic abnormalities , such as a right clavicle fracture and microcephaly . slit - lamp examination of the right eye showed a central corneal opacity , corneal thinning , and an iridocorneal adhesion . the lens and fundus of the right eye could not be observed . we observed no pathologic findings in the left eye . the baby s parents were informed of the high risk for spontaneous corneal perforation without external pressure . at 42 days of age , an ophthalmologic examination of the infant was again requested for evaluation of tears from her right eye 3 hours previously . examination revealed corneal perforation , iris protrusion , and a fat anterior chamber . we performed emergent conjunctival flap surgery . three months following surgery , the patient s right eye was successfully preserved with no sign of inflammation or leakage .

the reports not only were concerned with their fundamental properties , but also involved the promotion of their characteristics and real applications . the researches concerning the promotion of mnps ' properties focused on the chemical modification onto the surface of mnps in order to accommodate different aim of application . mnps have been applied extensively in various fields , for example , magnetic storage media , bioseparation [ 27 ] , drug delivery , biomolecular sensors , magnetic resonance imaging , jet printing , and so on . recently , magnetic nanoparticles coupled to magnetic carrier technology ( mct ) have also been used in solid - phase extraction ( spe ) , especially for analyzing environmental and biological samples . song et al . , zhao et al . [ 13 , 14 ] , and li et al . utilized bare fe3o4 or silicon - coated fe3o4 as extracting sorbent to enrich organic pollutants . . prepared magnetic c18 and c8 microspheres to extract polycyclic aromatic hydrocarbons ( pahs ) from water and polypeptide from serum , respectively . zhang et al . reported the application of magnetic molecularly imprinted polymers ( mip ) in solid or semisolid samples for trace analysis of triazines and tetracycline antibiotics . the magnetic mip with bisphenol a ( bpa ) as a template was also prepared and applied to extract bpa from environmental water and milk samples . the extraction can be easily achieved by dispersing the magnetic sorbents to sample solution , and the sorbents can be effortlessly isolated from the mixture by an external magnet . compared to common spe with nanomaterials , the magnetic spe not only can build a controllable rebinding process and allow magnetic separation to replace the centrifugation and filtration step in a convenient and economical way , but can also avoid troubles of packing spe column and the time - consuming process of loading large volume samples . the dispersivity and compatibility of sorbents used in magnetic spe are the key factors for their application . mnps using -cyclodextrin ( -cd ) as ligand were manufactured , and they showed superior dispersivity in water . hu et al . improved the biocompatibility of magnetic mip by combining spe with liquid - liquid extraction ( lle ) . . polyethylene glycol ( peg ) due to hydrophilic and biocompatible properties has been used as ligand to prepare various functional materials [ 1 , 26 ] . it would be a promising sorbent to simultaneously bond c8 and peg onto the surface of mnps . in the present work , magnetic nanospheres possessing hydrophilic , hydrophobic , and biocompatible properties were produced with c8 and peg as ligands . sodium acetate ( naac ) , triethylamine ( tea ) , polyethylene glycol ( peg ) , ethylene glycol , and ferric chloride ( fecl3 6h2o ) were obtained from tianjin chemicals corporation ( tianjin , china ) . tetraethoxysilane ( teos ) and octyltrimethoxysilane ( ocs ) were purchased from fluka ( switzerland ) . sulfamerazine ( smr ) was purchased from alfa aesar ( karlsruhe , germany ; > 98.5% ) . acetonitrile and methanol of chromatography grade were purchased from dima technology ( richmond hill , usa ) . all other reagents were of analytical reagent grade and the purified water by milli - q system was used throughout the experiments . ferric chloride ( 2.7 g , 10 mmol ) was dissolved in ethylene glycol ( 80 ml ) to form a clear solution , followed by the addition of naac ( 7.2 g ) and polyethylene glycol ( mw800 , 1.0 g ) . after ultrasonication for 10 min , the mixture was stirred vigorously for 30 min . then , it was sealed in a teflon - lined stainless - steel autoclave ( 100 ml capacity ) . the autoclave was maintained at 190c for 10 h and then cooled to room temperature . the black products ( fe3o4 ) were washed several times with ethanol and dried at 60c for 12 h. the obtained magnetic nanoparticles were encapsulated into silica beds as follows : 1.0 g fe3o4 was suspended in 200 ml ethanol , then ammonia ( 25% , 30 ml ) , water ( 30 ml ) , and teos ( 3 ml ) were added sequentially into the generated solution . after degassed , the mixture was stirred vigorously for 2 h at 50c under nitrogen gas protection . the magnetic particles were separated from the resulting solution by a magnet and the supernatant was discarded . the target materials were rinsed with ethanol to remove excess reactants , neutralized with hcl ( 0.1 mol l ) , and washed with water . the obtained materials ( fe3o4@sio2 ) were dried under vacuum at 80c for 12 h. one gram of fe3o4@sio2 , 60 ml of toluene , 1 ml of ocs , and 0.5 ml of tea were added successively to a flask . the mixture was refluxed under nitrogen gas protection and stirring for 10 h. after cooling , the magnetic particles were separated from the mixture by a magnet and the c8 bonded phase was rinsed with toluene . the obtained products were dispersed again to 60 ml of toluene . 1 ml of peg ( mw400 ) and 0.5 ml of tea were added successively to the mixture . after refluxing and stirring for 10 h , the c8-peg bonded materials were obtained and rinsed with toluene and ethanol . the products were dried under vacuum at 80c for 12 h. the obtained products were characterized with jem1200ex transmission electron microscope ( tem ) ( tokyo , japan ) and nicolet nexus 670 fourier transform infrared ( ftir ) ( mn , usa ) spectrometer . elementary analysis ( ea ) magnetic properties were measured using a vibrating sample magnetometer ( vsm ) ( lakeshore 7304 , usa ) . to measure adsorption capacity , 20 mg of c8-peg the mixture was shaken for 12 h at room temperature to facilitate adsorption of smr onto c8-peg phase . after the magnetic sorbents were isolated by an external magnetic field , smr of the supernate was determined by high performance liquid chromatography ( hplc ) . the chromatographic system consisted of varian 210 high performance liquid chromatographic pump ( ca , usa ) , 325 uv - vis detector , and varian star chromatographic workstation . an analytical reversed - phase c18 column ( 5 m , 4.5 250 mm , dima technology richmond hill , usa ) was used . the mobile phase was a mixture of acetonitrile and water ( 60 : 40 , v / v ) with flow rate of 0.8 ml min and the detection was carried out at 263 nm . the same procedure was performed for the c8 bonded material . the samples of calf serum with 10 g ml smr were diluted to 4 , 2 , and 1 g ml , respectively . 20 mg of c8-peg activated by methanol and water was added to 10 ml of diluted samples , after vortex and standing for 5 min , and then the sorbents were isolated by an external magnet . the sorbents were washed by water and hexane and then eluted by 3 ml of acetonitrile containing 1% acetic acid . at all products were measured by ftir spectrometry step by step , and the results are listed in figure 2 . figure 2(a ) displays the ir spectrum of the bare magnetic particles and the characteristic band of fe3o4 appeared at about 580 cm . the unique si - o absorption band was observed from 1000 to 1100 cm ( figure 2(b ) ) , indicating that silica coating was successful on the magnetite surface . in spectra of c8 and c8-peg bonded particles a typical band of c h stretch was about 2900 cm , and the adsorption bands between 1100 and 1600 cm were related closely to r elemental analysis was employed to measure the composition of c8 and c8-peg phase products , and the results are listed in table 1 . comparing c8-peg to c8 phase , the mass fraction of c and h increased , confirming that peg was successfully bonded onto the surface of magnetic nanospheres . however , it can not ensure precisely the component of c and h on the surface of magnetic nanospheres based on the data of elemental analysis . their morphological feature of all products was observed by tem in figure 3 . as can be seen , most of the obtained fe3o4 nanospheres exhibited regularly spherical shape with size distribution about 200 nm . after the modification of silica , the magnetic nanospheres showed core - shell structure , and the thickness of shell it is vitally important for mct that the sorbents should possess sufficient magnetic and superparamagnetism property . vsm was employed to characterize magnetic properties of the obtained magnetic materials , and the vsm magnetization curves are shown in figure 4 . it can be seen that the saturation magnetization value of fe3o4 , fe3o4@sio2 , c8 , and c8-peg decreased , respectively , due to the increase of nonmagnetic density . however , the saturation magnetization value of c8-peg was 50 emu g , which indicated that c8-peg phase materials possessed superior magnetic property . the dispersivity was investigated in order to evaluate the difference of c8 and c8-peg . as shown in figure 5 , 20 mg of magnetic materials was dispersed to 2 ml of water or 50% ethanol solution . from figure 5(a ) , the left photograph displays that c8 and c8-peg were dispersed to water by sonication , and the right photograph shows that the sorbents were collected by magnet after 10 s. the dispersivity of c8-peg in water was visibly better than c8 . figure 5(b ) illustrates that c8 and c8-peg were dispersed to 50% ethanol solution , and no evident differences of dispersivity were observed . the results confirmed that the magnetic material can be separated easily from solution by an external magnet and c8-peg phase presented superior property to c8 . the adsorption capability of c8 and c8-peg was researched by static tests with smr as the target compound . as shown in figure 6 , the capacity of c8-peg was about two times of c8 with the concentration of smr in the range 20100 mg l , and the differences decreased with the increase of smr concentration . the sample solution used in static tests was obtained by diluting the methanol solution of smr 1000 mg l. c8-peg was better dispersed in sample solution than c8 when the smr concentration was lower , and the differences of dispersivity between c8 and c8-peg reduced while the concentration of smr was higher . furthermore , the hydrogen bond between o or oh of peg and amine of smr also contributed to the differences . the tests revealed that c8-peg presented superior adsorption property to c8 for liquid samples . in order to study the feasibility of c8-peg in the real application , it was applied to enrich smr from calf serum and the spiked recoveries were investigated . as shown in figure 7 , the recoveries rose by 40% while the dilution ratio of the spiked samples ( smr , 10 g ml ) increased from 2.5 to 10 . under the condition of 10-times dilution , c8-peg could achieve better recovery without other pretreatments , confirming that it can reduce effectively the matrix effect , for example , the influences of protein , polypeptide , fat , and so on . the results demonstrated that c8-peg owning biocompatibility can be applied in the pretreatment of biological samples . the novel magnetic nano - spheres were prepared using c8 and polyethylene glycol as ligands . the prepared materials presented uniform sphere with size distribution about 200 nm and superparamagnetism . the results of tests proved that c8-peg owned better dispersivity in aqueous samples , adsorption capability , and biocompatible property . c8-peg was used to enrich smr from calf serum and the spiked recoveries were 80% .

the amphipathic magnetic nanospheres were synthesized using c8 and polyethylene glycol as ligands . their morphology , structure , and composition were characterized by transmission electron microscope , fourier transform infrared , and elementary analysis . the prepared materials presented uniform sphere with size distribution about 200 nm . the magnetic characteristics of magnetic nanomaterials were measured by vibrating sample magnetometer . the target products had a saturation magnetization value of 50 emu g1 and superparamagnetism . the adsorption capability was also studied by static tests , and the material was applied to enrich benzenesulfonamide from calf serum . the results exhibited that the c8-peg phase owned better adsorption capability , biocompatible property , and dispersivity in aqueous samples .

the personal and professional development ( ppd ) module was introduced as a part of the medical curriculum , in september 2006 , along with other curricular changes , to ensure that students not only grow professionally into good doctors , but also grow personally . in order to offer our students a humane and holistic experience in the medical curriculum , the personal and development module was introduced at the melaka manipal medical college ( mmmc ) , manipal , india . the module was designed with an objective to inculcate and impart in the students , a variety of fundamental skills to provide an environment that will extend their strengths , challenge their competencies , and work with their weaknesses . the module includes courses involving communication skills , ethics , working in groups and early patient contact through community visits . the course has a significant focus on the activities designed to foster collaborative practices , commitment to life - long learning , and aid understanding of ethical , scientific and philosophical principles underlying the practice of medicine . this study aimed at evaluating the ppd module that was introduced in the undergraduate medical curriculum . the mmmc is a private medical college that was flagged off in 1997 with classes commencing at manipal , india . the bachelor of medicine bachelor of surgery ( mbbs ) curriculum of the melaka manipal medical college is a 5-year academic program with the first two and half years in india and the next part of the program in malaysia . the first batch of students was admitted into the twin campus program at manipal , india , in september 1997 and the program grew in strength both in numbers as well as in academic quality and curricular innovations . feedback and suggestions from accrediting bodies led to mmmc adopting a new curriculum in september 2006 , 9 years after inception of the program . this curriculum called the six - strand integrated curriculum ( table 1 ) had horizontal strands including normal human body and its function , body s reaction to injury , and practice - based medicine and vertical strands including scientific basis of medicine , doctor , patient , health , community , and environmental module , and ppd module . this module was introduced to foster collaborative practices , inculcate life - long learning and enable students to understand the ethical and philosophical principles underlying the scientific practice of medicine . in the first year of the mbbs program , ppd classes are conducted in topics related to doctor patient relationship , professional ethics and humanities related topics . in the second year , students of the institution are required to pursue a project involving in - depth study of an area of interest and prepare a written , referenced report of scholarly substance . this helps the student to gain insight into research methodology and to encourage the development of critical thinking skills . in the first half of the third year , students are introduced to a few topics in palliative care . as a first step , 2 hours per week of ppd was incorporated in the time - table for the first year medical students . a group of faculty and a coordinator identified relevant topics such as medical humanities , leadership skills , communication skills , ethics , professional behavior and patient narratives ( table 2 ) that would be introduced to students . all faculty were requested to identify topics of their choice so that they could conduct the sessions in an engaging manner . there were also hours set aside for creative essay writing , role plays and theater by the students . in terms of students , the quality of the module such as content , presentations and engagement were evaluated by using a prevalidated module specific questionnaire with 10 items . a total of 528 students from three different batches from march 2011 to march 2013 were enrolled to give module feedback . the effectiveness of the module was studied by using a longitudinal survey using a modified course evaluation form . it was a 16-item questionnaire , with 16 closed and an option to write open comments , where students could explain about any personal / professional improvements they would attribute to the ppd experience . the same students responded to this questionnaire when they reached the clinical phase . in terms of faculty , personal interviews and focus group discussions were conducted by the coordinator , with eleven faculty members who conducted the ppd classes . continuous feedback is an important tool that helps to improve quality on an ongoing basis . the analysis of student responses showed that majority of them agreed that the module was useful and the results are as follows : a good percentage ( 67% ) of the students found the course to be relevant . they also found the teaching effective ( good , 27% ; and very good , 63% ) and well - paced ( 92% ) . the ppd workload was not a major issue and 97% of the students found that it was reasonable . the students strongly agreed that the course was well coordinated ( 65% ) , course materials were well prepared ( 55% ) , group discussions were effective ( 65% ) , and role plays helped in understanding the topics ( 85% ) . however , a few students wanted discussion on tourism in india , indian culture , art , and food . other useful tips from students included interactions with senior doctors from the hospital to share experiences and local community visits . students communicated that they were able to carry the content forward from what was taught and applied it in their day to day contexts . modules provided a range of opportunities to apply theoretical knowledge in different ways ( case studies , labs , interactive activities , and so forth ) . individual comments suggested that the courses challenged them to think about humane aspects of medicine , provided opportunities to develop self - directed learning skills , to develop skills and abilities to work as a team member , advanced skills of inquiry to pursue projects in second year and to develop professional attributes and behaviors in the clinical setting . however , they have made many positive comments about the perceptions of modules and its effectiveness . often , students have been able to share their learning with colleagues , either informally or through groups developed in ppd for collaborative / team work . students identified many benefits especially when they worked on their projects . in discussions on impact , students make comments such as enhancing study skills , empathy , team spirit , helping to change classroom practice , and participating proactively in clinical discussions . faculty found the topics new and interdisciplinary , handling such topics , and creating interest and engaging the students were a challenge . in the first year of the mbbs program , ppd classes are conducted in topics related to doctor patient relationship , professional ethics and humanities related topics . in the second year , students of the institution are required to pursue a project involving in - depth study of an area of interest and prepare a written , referenced report of scholarly substance . this helps the student to gain insight into research methodology and to encourage the development of critical thinking skills . in the first half of the third year , students are introduced to a few topics in palliative care . as a first step , 2 hours per week of ppd was incorporated in the time - table for the first year medical students . a group of faculty and a coordinator identified relevant topics such as medical humanities , leadership skills , communication skills , ethics , professional behavior and patient narratives ( table 2 ) that would be introduced to students . all faculty were requested to identify topics of their choice so that they could conduct the sessions in an engaging manner . there were also hours set aside for creative essay writing , role plays and theater by the students . in terms of students , the quality of the module such as content , presentations and engagement were evaluated by using a prevalidated module specific questionnaire with 10 items . a total of 528 students from three different batches from march 2011 to march 2013 were enrolled to give module feedback . the effectiveness of the module was studied by using a longitudinal survey using a modified course evaluation form . it was a 16-item questionnaire , with 16 closed and an option to write open comments , where students could explain about any personal / professional improvements they would attribute to the ppd experience . the same students responded to this questionnaire when they reached the clinical phase . in terms of faculty , personal interviews and focus group discussions were conducted by the coordinator , with eleven faculty members who conducted the ppd classes . in the first year of the mbbs program , ppd classes are conducted in topics related to doctor patient relationship , professional ethics and humanities related topics . in the second year , students of the institution are required to pursue a project involving in - depth study of an area of interest and prepare a written , referenced report of scholarly substance . this helps the student to gain insight into research methodology and to encourage the development of critical thinking skills . in the first half of the third year , students are introduced to a few topics in palliative care . as a first step , 2 hours per week of ppd was incorporated in the time - table for the first year medical students . a group of faculty and a coordinator identified relevant topics such as medical humanities , leadership skills , communication skills , ethics , professional behavior and patient narratives ( table 2 ) that would be introduced to students . all faculty were requested to identify topics of their choice so that they could conduct the sessions in an engaging manner . there were also hours set aside for creative essay writing , role plays and theater by the students . in terms of students , the quality of the module such as content , presentations and engagement were evaluated by using a prevalidated module specific questionnaire with 10 items . a total of 528 students from three different batches from march 2011 to march 2013 were enrolled to give module feedback . the effectiveness of the module was studied by using a longitudinal survey using a modified course evaluation form . it was a 16-item questionnaire , with 16 closed and an option to write open comments , where students could explain about any personal / professional improvements they would attribute to the ppd experience . the same students responded to this questionnaire when they reached the clinical phase . in terms of faculty , personal interviews and focus group discussions were conducted by the coordinator , with eleven faculty members who conducted the ppd classes . continuous feedback is an important tool that helps to improve quality on an ongoing basis . the analysis of student responses showed that majority of them agreed that the module was useful and the results are as follows : a good percentage ( 67% ) of the students found the course to be relevant . they also found the teaching effective ( good , 27% ; and very good , 63% ) and well - paced ( 92% ) . the ppd workload was not a major issue and 97% of the students found that it was reasonable . the students strongly agreed that the course was well coordinated ( 65% ) , course materials were well prepared ( 55% ) , group discussions were effective ( 65% ) , and role plays helped in understanding the topics ( 85% ) . however , a few students wanted discussion on tourism in india , indian culture , art , and food . other useful tips from students included interactions with senior doctors from the hospital to share experiences and local community visits . students communicated that they were able to carry the content forward from what was taught and applied it in their day to day contexts . modules provided a range of opportunities to apply theoretical knowledge in different ways ( case studies , labs , interactive activities , and so forth ) . individual comments suggested that the courses challenged them to think about humane aspects of medicine , provided opportunities to develop self - directed learning skills , to develop skills and abilities to work as a team member , advanced skills of inquiry to pursue projects in second year and to develop professional attributes and behaviors in the clinical setting . however , they have made many positive comments about the perceptions of modules and its effectiveness . often , students have been able to share their learning with colleagues , either informally or through groups developed in ppd for collaborative / team work . students identified many benefits especially when they worked on their projects . in discussions on impact , students make comments such as enhancing study skills , empathy , team spirit , helping to change classroom practice , and participating proactively in clinical discussions . faculty found the topics new and interdisciplinary , handling such topics , and creating interest and engaging the students were a challenge . with an objective to introspect and reflect upon the challenges and experiences of faculty and students with the ppd module that was introduced at the melaka manipal medical college , and identify key strategies to sustain and improve the module in the curriculum . students expression on the ppd sessions was similar to results obtained with the ppd module introduced in another indian university . systematic , future directed , continuous cycle of goal setting , planning , managing , and reviewing is essential for quality improvement of any program . analyzing student and faculty feedback is a simple , but rich and valuable source of information for quality enhancement . for any program to grow , stabilize , improve , be effective and sustainable the drawback of this module was that there was no formal assessment for each of the sessions . however , reflective summaries are now introduced and used to assess skills acquired through this module . in conclusion , implementation of ppd modules in the undergraduate medical curriculum in melaka manipal medical college , india was successful case since students could improve their affective skills .

the study aimed at evaluating the personal and professional development ( ppd ) module in the undergraduate medical curriculum in melaka manipal medical college , india . ppd hours were incorporated in the curriculum . a team of faculty members and a faculty coordinator identified relevant topics and students were introduced to topics such as medical humanities , leadership skills , communication skills , ethics , professional behavior , and patient narratives . the module was evaluated using a prevalidated course feedback questionnaire which was administered to three consecutive batches of students from march 2011 to march 2013 . to analyze faculty perspectives , one to one in - depth interviews and focus group discussions were conducted by the coordinators with faculty members who conducted the ppd classes . analysis of the course feedback form revealed that majority ( 80% ) of students agreed that the module was well prepared and was " highly relevant " to the profession . faculty found the topics new and interdisciplinary and there was a sense of sharing responsibility and workload by the faculty . ppd modules are necessary components of the curriculum and help to mould students while they are still acquiescent as they assume their roles as doctors of the future .

a 49yearold woman suspected of having a right optic neuritis was referred to the neurology department . she had been diagnosed with systemic lupus erythematosus ( sle ) 10 years earlier , and , at the time of presentation , she was receiving azathioprine 50 mg three times a day , prednisone 5 mg daily , and belimumab 640 milligrams intravenously every 4 weeks . four months earlier , during an ophthalmologist screening test for retinal toxicity , an optic coherence tomography ( oct ) had shown a reduction in the thickness of the macular and retinal nerve fiber layer in the right eye . she was recommended to stop treatment with hydroxychloroquine , which the patient had been receiving since the initial diagnosis of sle 10 years before ( 200 mg orally per day ) . an mri showed a highintensity signal in her right optic nerve at that moment ( fig . , followup showed an inferior nasal scotoma in her right eye , not present in previous examinations , and she was referred to the neurology department . a perineural contrast enhancement can be seen on the right optic nerve , suggesting inflammation of the nerve sheath . during the first visit to the neurologist , physical examination did not reveal other pathological findings , so ancillary tests ( visual evoked potentials and both orbital and cerebral mri ) were requested . before the tests could be carried out , the patient developed vertical diplopia on the primary gaze position that was accentuated when looking up . a paralysis of the right eye in upgaze position was found on physical examination then . mri showed signs of inflammation in the right orbit with affected the orbital fat and conditioned a slight proptosis of the eyeball , not visible to the naked eye on physical examination . a mild posterior perineural signal could still be seen in the optic nerve , but also , both the right superior rectus and superior oblique muscles were thickened ( fig . , we found that these alterations in the muscles were already but subtly present in the first mri , long before the diplopia appeared ( fig . visual evoked potentials demonstrated prolonged latencies after visual stimulus , consistent with a moderate demyelinating neuropathy of the right eye . extensive laboratory tests , including blood cell count , renal function , liver function , thyroid function , antiaquaporin4 antibodies , angiotensinconverting enzyme levels , and serologic tests for syphilis , hiv , herpesvirus , and borrelia burgdoferi , were negative or normal . antidsdna levels were 167 ui / ml , and serum complement levels were low , with c3 0.76 g / l and c4 0.07 g / l ; these results were similar to the results of previous blood tests . t2weighted brain and orbital mri . ( a ) coronal view of the mri performed nine months before the patient developed the symptoms . a slight thickening of the superior rectus , which appears hyperintense compared to the contralateral muscle , is patent , as well as mild infiltration of the surrounding fat . ( c ) axial cuts of the same mri showing also slight proptosis of the right eye . hydroxychloroquinerelated toxicity was ruled out due to both clinical and radiologic progression after suspension of the treatment . the patient was diagnosed with orbital inflammatory pseudotumor secondary to sle , and highdose corticosteroid therapy was initiated ( oral metilpredinsolone one gram daily for 5 days ) , followed by slowly decreasing doses of prednisone to 10 mg daily . this therapy achieved to improve the symptoms and diplopia resolved , without permanent damage to the visual field . afterward , immunosuppressive treatment with rituximab was started . the patient has remained asymptomatic ever since , and both antidsdna and complement levels have returned to normal values . neuroophthalmic manifestations , however , are less frequent , with a prevalence of 3.6% in adults ; among these , optic neuritis is the most common form of presentation and also one of the most visually compromising complications of sle 1 . the implication of orbital structures in sle and , specifically , inflammatory pseudotumor is very rare and therefore may go unnoticed 1 , 2 , 3 . it usually presents with proptosis , pain , and diplopia , due to infiltration of the ocular muscles . although increases in the titers of antidsdna antibodies and decreases in the complement levels may accompany disease relapses , this is not true for all sle patients 4 , 5 . in our case , although high levels of antidsdna and low levels of c3 and c4 were found , these results were similar to the results of previous blood tests . visual loss due to inflammatory infiltration of the optic nerve is uncommon ; however , it may be a preceding sign , as in this case . 2 , 6 . response to corticosteroid therapy is excellent in most patients , but sometimes progression of the disease could lead to major damage 2 . although sleassociated retinopathy has been associated with elevated levels of antiphospholipid antibodies 2 , this does not seem to be the case in inflammatory pseudotumor , and due to its low incidence , no risk factors that could help early diagnosis have been identified . retinopathy and maculopathy are widely known complications of hydroxychloroquine treatment , although inflammatory pseudotumor has never been described in this setting . although visual loss may be irreversible and even worsen after suspending treatment with hydroxychloroquine , this is more likely if high doses of hydroxychloroquine are used for more than 5 years or if there is impaired renal or liver function 7 , 8 . although our patient had been treated with hydroxychloroquine for 10 years , the daily doses were below 6 , 5 mg / kg , which are associated with very low risk of retinopathy . besides , she never presented impaired renal or liver function in successive blood tests . taking all this into account suspecting inflammatory pseudotumor and its relation to the sle is imperative to avoid further complications . in this case , the slow progression of the disorder , probably due to simultaneous immunosuppressive therapy and chronic treatment with low doses of oral corticosteroids , as well as the interference of confounding factors ( treatment with hydroxychloroquine ) delayed the diagnosis . however , when the patient developed diplopia a review of the previous mri showed that mild signs had been already present months before the symptoms appeared . therefore , after a new finding appears , going back to previous studies may help to put things into perspective .

key clinical messageorbital inflammatory pseudotumor is a rare complication of systemic lupus erythematosus . it may present a challenge for differential diagnosis , especially in the context of treatment with hydroxychloroquine , although dosage and duration of the treatment may guide us . although high antibody titers can be found , this is not specific .

in the united states , prostate cancer is the second cause of cancer death after lung and bronchus in all ages of men ( 1 ) . in iran , prostate cancer is reportedly the third most commonly diagnosed visceral cancer , accounting for almost 7.75% of new cancer cases , and is the seventh result of cancer death . according to iran cancer report , the incidence rate of prostate cancer in tehran is more than other provinces , about 16.65% - 26.35% ( 3 ) . for high resistance of apoptosis in the androgen - independence of prostate cancer the current therapy ( radiotherapy or cytotoxic chemotherapies ) may have influence on patient condition , but these cures have significant side effects . over 7,000 species of plants grow in iran among which 1000 are estimated to have medicinal effects . the presence of various climatic conditions and ecological factors provide an environment in which numerous varieties of plants grow in different regions of the country ( 5 ) . the psitacia atlantica sub kurdica from anacardiaceae family , with the local name of bane grows in iran ( 6 ) . cytotoxic effect on breast cancer cell line and inhibition growth in leukemia cell line have been seen in nuts of semecarpusanacardium ( 7 ) . the studies indicated , same genuses of bane have death properties and antiproliferative effect on some tumors . despite many reports that are about chemo - preventive effect of the same genus of bane , there are not any reports about the effects of atlantica sub kurdica on prostate cancer cell line , so we decided to evaluate the cytotoxic effect of ethanol bane skin extract on prostate cancer cell line . fresh unripe fruit from p. atlanticakurdica was collected from ilam province , iran . the fruits skin were dried and powdered by using the mechanical grinder . 10 g of dried plant was saturated in mixture of 50 ml h2o and 50 ml ethanol 100% for 48 hours in the absence of heat . the mixture was shaken to gain the extract and filtered through filter paper and finally the filtrate was evaporated in vacuum evaporator and stored at 4c . the 1 g powder of the bane was dissolved in 2 ml pbs and then filter sterilized . for preparing different concentration this stock was diluted with rpmi 1640 complete culture medium pc3 ( human prostate cancer cell lines ) and l929 ( mouse fibroblast cell line ) were acquired from pasture institute ( tehran , iran ) and cells were grown in rpmi 1640 supplemented with 5 ml of penicillin - streptomycin and 10% fetal bovine serum and in a humidified incubator containing 5% co2 . cytotoxic effects of the ethanol bane skin extract on pc3 cells were analyzed by colorimetric mtt assay . mosmann introduced the colorimetric mtt assay and then this method was modified . a total 5000pc-3 ( human prostate cancer cell lines ) and 5000l929 ( mouse fibroblast cell line ) from cell lines were cultured in 96-well plates . to 180 l aliquots in four replicates of the cells seeded in 96-well , 20 l aliquots of different concentrations were added to each of the wells to makeup the final bane extract concentrations of 0.78 , 1.5 , 3.13 , 6.25 , 12.5 mg / ml . plates were incubated in a humidified 5% co2 atmosphere , and after 24 hours , the growth medium was removed and washed with phosphate buffered solution ( pbs ) . after that , 180 l growths medium and 20 l of 3-(4,5-dimethyl thiazol-2-yl)-2,5diphenyl tetrazolium bromide ( mtt ) solution were added for each well , then incubated for 4 hours . after removing the growth medium and shaking microplates for 2 to 3 minutes , dissolvation of crystals in 200 l of pbs was achieved . the absorbance of formosan dye was recorded by an elisa plate reader at 570 nm . pc3 cells were cultured and incubated in 6 well plates at the situation described as noted before . the cells were faced with the ethanol bane skin extract , then they were stained with 10% giemsa and finally washed with phosphate buffered solution ( pbs ) . statistical processing of the data was performed by spss v.20 , using two - way anova . for detecting the point of difference , the post hoc test fresh unripe fruit from p. atlanticakurdica was collected from ilam province , iran . the fruits skin were dried and powdered by using the mechanical grinder . 10 g of dried plant was saturated in mixture of 50 ml h2o and 50 ml ethanol 100% for 48 hours in the absence of heat . the mixture was shaken to gain the extract and filtered through filter paper and finally the filtrate was evaporated in vacuum evaporator and stored at 4c . the 1 g powder of the bane was dissolved in 2 ml pbs and then filter sterilized . for preparing different concentration pc3 ( human prostate cancer cell lines ) and l929 ( mouse fibroblast cell line ) were acquired from pasture institute ( tehran , iran ) and cells were grown in rpmi 1640 supplemented with 5 ml of penicillin - streptomycin and 10% fetal bovine serum and in a humidified incubator containing 5% co2 . cytotoxic effects of the ethanol bane skin extract on pc3 cells were analyzed by colorimetric mtt assay . mosmann introduced the colorimetric mtt assay and then this method was modified . a total 5000pc-3 ( human prostate cancer cell lines ) and 5000l929 ( mouse fibroblast cell line ) from cell lines were cultured in 96-well plates . to 180 l aliquots in four replicates of the cells seeded in 96-well , 20 l aliquots of different concentrations were added to each of the wells to makeup the final bane extract concentrations of 0.78 , 1.5 , 3.13 , 6.25 , 12.5 mg / ml . plates were incubated in a humidified 5% co2 atmosphere , and after 24 hours , the growth medium was removed and washed with phosphate buffered solution ( pbs ) . after that , 180 l growths medium and 20 l of 3-(4,5-dimethyl thiazol-2-yl)-2,5diphenyl tetrazolium bromide ( mtt ) solution were added for each well , then incubated for 4 hours . after removing the growth medium and shaking microplates for 2 to 3 minutes , dissolvation of crystals in 200 l of pbs was achieved . the absorbance of formosan dye was recorded by an elisa plate reader at 570 nm . pc3 cells were cultured and incubated in 6 well plates at the situation described as noted before . the cells were faced with the ethanol bane skin extract , then they were stained with 10% giemsa and finally washed with phosphate buffered solution ( pbs ) . statistical processing of the data was performed by spss v.20 , using two - way anova . for detecting the point of difference , the post hoc test the efficacy of the ethanol bane skin extract on the viability of cells ( pc3 and l929 ) were measured by mtt assay after 24 , 48 , 72 hours with the ethanol bane skin extract concretions 0.78 , 1.5 , 3.13 , 6.25 , 12.5 mg / ml . data analysis showed there is a good correlation among the ethanol bane skin extract concentration and the time of exposing pc3 cells to the ethanol bane skin extract and cell viability on pc3cells during this study ( p < 0.001 ) . as shown in figure 1 , by increasing concentration of the ethanol bane skin extract and time of exposing pc3 cells to the ethanol bane skin extract , the cell viability reduced . the ic50 ( half inhibitory concentration ) for the ethanol bane skin extract on pc3 cells was 2.8 mg / ml after 48 , but a different manner was seen on l929 cells . after 24 hours , no significant difference was seen in cell population between the control group and l929 cells exposed to the ethanol bane skin extract in 0.78 , 1.5 , 3.13 mg / ml concentrations . the ic50 of the ethanol bane skin extract on l929 cells after 48 hours was 6.1 mg / ml . it means that cytotoxic of ethanol bane skin extract on pc3 cells is more than l929 cells ( figure 2 ) , and also the researchers did not see a significant difference between cytotoxic effect of the ethanol bane skin extract on l929 cells after 48 and 72 hours . the pc3 cells were exposed to the bane extract ( 0.78 , 1.5 , 3.13 , 6.25 , 12.5 mg / ml ) for 24 , 48 , 72 and cytotoxicity was determined using mtt assay . detecting delete the bane extract induction of apoptosis , morphological changes of the pc3 cells were examined . after staying pc3 cells whit giemsa , examined morphological changes of the pc3 cells under a microscope and compared whit control group . considerable morphological changes were observed in contrast with the morphology of the control cells ( such as apoptotic bodies and condensed dna ) ( figure 3 ) . a , normal control pc3 cells ; b , pc3 cells treated with 3.13 mg / ml bane extract ; c , pc3 cells treated with 6.25 mg / ml bane extract . for detecting delete the bane extract induction of apoptosis , morphological changes of the pc3 cells were examined . after staying pc3 cells whit giemsa , examined morphological changes of the pc3 cells under a microscope and compared whit control group . considerable morphological changes were observed in contrast with the morphology of the control cells ( such as apoptotic bodies and condensed dna ) ( figure 3 ) . a , normal control pc3 cells ; b , pc3 cells treated with 3.13 mg / ml bane extract ; c , pc3 cells treated with 6.25 mg / ml bane extract . according to world health organization ( who ) , 65% - 80% of the world population take traditional medicine to cure various diseases ( 8) . it is estimated increasing androgen - independent prostate cancer may be for resisting apoptosis . this issue is along with survival of cells within metastatic or primary tumors and increased proliferation ( 9 ) . researchers revealed that a major problem with cancer therapy was lack of specificity of the treatments for this kind of cells ( 10 ) . nowadays natural products and secondary metabolites act as good sources for treating coronary heart diseases , cancer , diabetes and infectious diseases in human ( 11 ) . many studies and experiments show that consumption of vegetables and fruits can reduce the risk of human cancer ( 12 ) . natural product can act as apoptosis inducer , so these products whit deleting precancerous cells can reduce cancer incidence ( 13 ) . mixture of phytochemicals can be more effective than single constituents because of synergistic interactions ( 15 ) . the pistacia have 15 species but only three species including pistaciavera l. , pistacia khinjuk stocks and pistacia atlantica desf have been seen in iran . these species have many applications in the field of folk medicine and also have been used in the therapy of throat infection , eczema , asthma and renal stone . likewise , these have many uses as anti - inflammatory , antibacterial , stimulant , antiviral , astringent , antipyretic and pectoral ( 16 ) . the efficacy of gum mastic of p. lentiscus in lncap prostate cancer cells has powerful inhibitory effect on expression and function of androgen receptor ( 7 ) . death inducing and anti - proliferative properties have been seen in human colon carcinoma when the cancer cells are exposed to p. lentiscus l. balan ( 17 ) repressed nf - kb activity , blocked cell cycle in the g1 phase , reduced expression of cyclin d1 in androgen - independent prostate cancer cells have reported as gum mastic of p. lentiscus properties ( 18 ) . iin prostate cancer cells , gum mastic of p. lentiscus has a rise in adjustment of mrna and protein levels of tumor suppressor ( 19 ) . studies showed that skin extract of bane is powerful than doxorubicin in some molecular ways and also induce apoptosis in in t47d cells ( 20 ) . it is supposed that anticancer activity of bane extract can have considerable amounts of polyphenolic compounds , flavonoids and anthocyanins ( 20 ) . another study shows that polyphenol rich extract of bane in ht29 cells has apoptosis induction , growth inhibition , and cell cycle arrest properties ( 21 ) . in the present study , for the first time , the researchers examined the cytotoxic effects of the ethanol bane skin extract on pc3 cell line . the study reported that the ethanol bane skin extract induced cytotoxicity in pc-3 cells and reduction of cell viability showed a time- and dose - dependent pattern and has less cytotoxic effect on l929 cells as normal cells than pc3 cells . based on the morphological changes from our study , it was shown that the ethanol bane skin extract induced the apoptosis in pc3 cells . bane skin maybe a good candidate for the management of prostate cancer . for definitive conclusion , in vivo studies are required .

background : it is extensively supposed that vegetarian diet could affect cancer progress and increase the influence of formal chemotherapy.objectives:the present study was designed to determine the effect of the ethanol bane skin extract against chemo resistant prostate cancer pc3 cells.materials and methods : pc3 and l929 cells were cultivated and then incubated in the ethanol bane skin extract with various concentrations of 0.78 , 1.5 , 3.13 , 6.25 , 12.5 mg / ml in 3 times 24 , 48 , 72 hours . cytotoxic effect of the ethanol bane skin extract on pc3 and l929 cells was examined by mtt assay after 24 , 48 , and 72 hours . morphology of pc3 cells was evaluated by gimsa staining.results:the ethanol bane skin extract inhibited proliferation and caused cell death with ic50 values of 2.8 mg / ml on pc3 cells and the ic50 was 6.1 mg / ml on l929 cells . morphological changes and apoptotic bodies were observed in pc3 cells faced with the ethanol bane skin extract by staining with gimsa.conclusions:the ethanol bane skin extract could repress the growth of pc3 cell line . this inhibitory effect of the bane extract depended on the dose and the time on pc3 . the result of this study shows that the ethanol bane skin extract includes photochemical and inhibitory function against proliferation and inducer of apoptosis in human prostate cancer pc3 cells and also has less cytotoxic effect on l929 than pc3 cells . the ethanol bane skin extract might be a good candidate for the new herbal anticancer drug .

orofacial pain ( ofp ) includes pains whose origin is below the orbitomeatal line , above the neck and anterior to the ears and pain within the mouth . it can be a symptom of various disorders , however the majority of ofp is due to dental causes ( for example , toothache ) and facial trauma , and in most cases it is acute . the remainder is considered chronic ofp , and temporomandibular disorders ( tmd ) represent one of the most common forms of chronic ofp . tmd is a collective term , for disorders characterized by joint pain , masticatory muscle tenderness , joint noises and restricted jaw movements . the percentage of the population presenting with tmd is estimated at 3 - 4% , however up to a quarter of the population may report the symptoms during the past month . it has been suggested that there is a relationship between the removal of third molars and the postoperative onset of temporomandibular joint pain / dysfunction . as early as 1969 , greene et al . reported that 48% of patients with tmd attributed the onset of their symptoms to a specific event , including prolonged oral surgery procedures . however there is equivocal evidence on a relationship between tmd symptoms and third molars removal : while some studies supported this finding [ 5 - 8 ] , others did not find any association [ 9 - 11 ] . these studies involved patient populations , university students , health plan enrolees and dental service enrolees . one study involved cases diagnosed in clinic and controls from dental health survey . none of the above studies were conducted in general population , i.e. they were all prone to selection bias as not all people with ofp seek treatment and not everybody enrolled in health and dental plans . the aim of the current study was to investigate whether there was a relationship between a history of third molar removal and the prevalence of orofacial pain in a sample of the general population . the study was a four year follow - up of the population survey conducted by macfarlane et al . . the original survey included randomly selected participants aged 18 - 65 years registered with a general medical practice in south east cheshire , north west england . random selection ensured that the study population could represent equally all genders , ages , ethnicities and social class . as general practice registers cover more than 99% of the population in england ( http://www.statistics.gov.uk ) and access to most health service care is through the general medical practitioner , the practice age - sex resister is a convenient frame for a general population survey . ethical approval for the study was granted by south cheshire local research ethics committee . sample size for the baseline survey was calculated using the results of a pilot study using ofp prevalence estimate of 25% . every participant in the main survey who gave permission to be contacted again was included in the follow - up survey ( only 3 participants of the baseline survey did not wish to be contacted again ) . each participant received a postal questionnaire , with follow - up of non - responders by a reminder postcard , questionnaire and , if necessary , a short questionnaire and a telephone call . ofp was defined as present if participants during the past month " had any pain in their face , mouth or jaws that has lasted for one day or longer " . body pain was defined as present if participants during the past month " had any ache or pain in the body which has lasted for one day or longer " . deprivation was measured by the townsend index , an area - based score derived from postcode sectors or wards . participants were also asked if they had their wisdom teeth removed and permission to be contacted again . in addition , participants were asked permission for their dental records to be examined , and in case of positive reply , were asked to indicate the name and address of their dentist . data were extracted in duplicate ( both clinical examiners ) from 10 records to investigate reliability . one clinical examiner repeated data extraction from 10 dental records twice to investigate reproducibility . the magnitude of association between third molar removal and ofp was described by the relative risk ( rr ) . rr here is a measure of the risk of ofp in one group compared to the risk of ofp in another ( reference ) group . a relative risk of one means there is no difference between two groups in terms of their risk of ofp . a relative risk of greater than one or of less than one means that being exposed to a factor either increases ( relative risk greater than one ) or decreases ( relative risk less than one ) the risk of ofp . the data were analysed using stata 10 for windows ( statacorp , lp , usa , 2008 ) and spss 16.0 for windows ( spss inc . , chicago , il , usa , 2008 ) statistical packages . a total of 1680 persons ( 81% adjusted participation rate after excluding those who were no longer registered with the practice , deceased or who were not able to complete the questionnaire due to illness or disability or expressed a wish at baseline not to be contacted again ) participated in the follow - up survey , and the full study questionnaire was completed by 1510 participants . the remainder completed a short version of the questionnaire which did not include question on third molar removal . adjusted participation rate was higher in women ( 83% ) compared to men ( 77% ) ( chi - square test p < 0.001 ) and in affluent areas ( 83% ) compared to deprived areas ( 59% ) ( chi - square test p < 0.001 ) . non - respondents were older ( mean age 49 years [ sd = 12 ] ) then non - respondents ( mean age 44 years [ sd = 13 ] ) ( t - test p < 0.001 ) . of those who completed the full questionnaire , 295 ( 19% ) reported ofp , 1202 ( 80% ) did not report such pain and 13 ( 1% ) did not answer this question . majority ( 60% ) of self - reported ofp was chronic , i.e. lasted for more than 3 months . the mean pain severity was 4.8 on 10-point numerical analogues scale ( sd = 2.3 ) and 62% sought advice on ofp from a health professional . over half ( 873 , 58% ) of respondents did not report a history of perceived third molar extractions , 77 ( 5% ) did not answer this question , giving 560 ( 37% ) who reported third molar removal . the majority of participants ( 1060 , 70% ) who completed the full questionnaire gave permission for their dental records to be examined , and indicated the name and address of their dentist . eight hundred and sixty ( 81% ) participants were registered with four main dental practices in the study area ; the remainder were registered with dentists in the surrounding areas . these distant practices were not visited , so only these four main practices were included , and 806 ( 94% ) patient records were found . in addition , one practice in the surrounding area with 3 patient records was used as a pilot site , giving total of 809 records . median time of registration with a dentist was 14 years ( range 1 day - 46 years ) prior to completing the questionnaire . there was an acceptable ( cohen 's kappa > 0.6 , p < 0.05 ) agreement when reliability and reproducibility of information regarding third molars extracted from dental records . the minimum cohen 's kappa value was 0.61 , maximum 1.00 , median was 0.71 , indicating at least substantial agreement , according to classification by landis and koch . to validate the answers in the questionnaire regarding perceived third molar removal , this question was cross tabulated against the extractions recorded by dentists ( table 1 ) . of those who reported at least one perceived extraction , 20 ( 37% ) had extractions recorded in dental records , while for those who did not report history of extractions in the questionnaire , this figure was 27 ( 6% ) . all four third molars were present in 113 ( 25% ) of participants who did not report extractions . only 9 ( 3% ) of participants who reported that they had third molars removed had all four third molars present . validity of self - reported third molar extractions information was missing for 33 participants . participants who reported third molar extractions in the questionnaire were more likely to report ofp ( adjusted relative risk [ rr ] 1.29 ) ; ( 95% confidence interval [ ci ] 1.01 - 1.65 ) ( table 2 ) . when only information from the dental records was used and participants with all four molars present were compared to those with at least one extraction , the rr was 1.50 ( 95% ci 0.90 - 2.49 ) . however when time since last extraction was investigated , the increase was evident only in relatively recent extractions ( rr = 1.91 , 95% ci 1.10 - 3.32 ) for people with third molar extraction less than eight and a half years ago , whilst the number of third molars remaining did not show any particular pattern . relationship between third molar extractions and orofacial pain ( ofp ) 100 months was a median time since extraction and therefore was chosen as a cut - off point . this population - based epidemiological study has provided evidence that individuals who report third molar extractions are more likely to report ofp . when extraction information was validated using dental records , this association was only found in relatively recent extractions . any dental intervention that alters the occlusion has the potential to alter the position of the mandibular condyle in the mandibular ( glenoid ) fossa and predispose to tmd symptoms . the incidence of tmd has been shown to rise after 19 years of age . it has been suggested that this could be attributed to occlusal changes as a consequence of teeth exfoliation and eruption of permanent successors , or the eruption of third molars leading to overcrowded dental arches . third molar removal could lead to tmd development as a consequence of the required surgery , which may necessitate wide mouth opening and the application of relatively large forces to the posterior mandible . traumatic arthritis has been reported after third molar removal although the occurrence is rare . tmd patients with a history of trauma or non - temporomandibular joint - related operations have reported higher prevalence , severity and frequency of ofp than controls . it has been postulated that nerve damage in hard and soft tissues can cause sensitisation of both peripheral and central neurons . hypothetically , the increased pain perception following surgical third molar removal could tip the threshold balance toward tmd . there are methodological issues which need to be considered when examining the study results . the study involves a sample of the population of one geographic area in the united kingdom and therefore may not be representative . while the overall participation rate at follow - up was high , non - participants were more likely to be male , younger and from lower socio - economic background . nevertheless , these differences would only affect the comparisons in the present study if the relationship between these factors and presence of ofp were different in those subjects who participated compared with those who did not . questionnaires were posted together with a covering letter from the general medical practitioner informing practice members of the practice participation in the study . non - respondents were followed up by a postcard reminder , a further questionnaire , and , if necessary , a short questionnaire and a telephone call . although there was a statistically significant increase in risk ( 30% ) of ofp associated with self - reported extractions , we did not find a statistically significant association between at least one third molar extraction determined from the dental records and ofp ( 50% increased risk ) . firstly , there was less statistical power when information from dental records was analysed , as not all participants who completed the questionnaire had information from dental records . however we have adjusted in the statistical analysis in both cases for other potential risk factors such as other body pain and psychological distress . thirdly , it has been shown that that there was good correspondence between subjective self - reports of well - defined oral health conditions and clinical findings , for example the number of teeth and the presence of dentures . finally , there was a statistically significant increase in risk among participants with more recent extractions , which support the findings of huang and rue , who also found elevated risk in more recent extractions . while the study has achieved high participation rate and acceptable reliability when extracting information from dental records , several problems were encountered . although participants had reported third molar removal in the original questionnaire , it may not be entirely accurate . for approximately half of all cases , third molars were marked as absent in the records but with no record of extraction . it was impossible to determine from the notes whether third molars marked as absent in this way were : 1 ) congenitally absent ; 2 ) unerupted ; 3 ) had been extracted before the origin of the notes . this problem was accentuated in the older age groups , where early dental records were not available . in rare cases it was obvious that after early extraction of first molars , third molars were being recorded . in some cases charting of the tooth could change several times throughout the notes . better recording of dental notes would help resolve some of these problems in primary dental care research . in addition , this study is a cross - sectional survey and therefore the associations we report are not necessarily causal . this research has shown that there is a weak relationship between self - reported history of third molar removal and self - reported orofacial pain , and the depth and detail of evidence is still inconclusive . the authors are grateful to staff and patients of lawton house surgery , dental practice of ar mellor & associates , canal street dental practice , moody terrace dental practice and tdu miller dental practice in congleton , cheshire , united kingdom for their help with the study . d. king , university of manchester , manchester , uk and mrs . c. mackie , manchester dental school , manchester , uk , for help with access to dental records .

abstractobjectivesthe aim of the current study was to investigate whether there was a relationship between a history of third molar removal and the prevalence of orofacial pain in a sample of the general population.material and methodsa survey was conducted in south east cheshire , united kingdom ( 81% participation rate ) . information was collected using postal questionnaires ( n = 1510 ) and dental records ( n = 809).resultsparticipants who reported third molar extractions were more likely to report orofacial pain ( rr = 1.29 ; 95% confidence interval [ ci ] 1.01 - 1.65 ) . participants with a more recent history of extractions ( < 8 years ago ) as recorded in dental records were more likely to report orofacial pain compared to those who had all third molar present ( rr = 1.91 ; 95% ci 1.10 - 3.32).conclusionsthis research suggests that self - reported third molar removal is linked to self - reported orofacial pain , however evidence from one study is not sufficient to give an unequivocal answer .

primary lymphoma of the bone ( pbl ) is a rare neoplasm accounting for less than 5% of all malignant bone tumors and almost 7% of all extranodal lymphomas.1 occasionally , it may involve the vertebrae and encroach upon the nerve root , causing claudication and radicular syndrome mimicking spinal stenosis.1 we report a case of pbl of the lumbar vertebrae and pelvis , initially presenting as back pain , lumbar radicular pain and numbness . during operation , pus - like fluid was noted and a positive bacterial culture was grown from the pus discharge and necrotic debris . to the best of our knowledge , a 71-year - old retired obstetrician was referred to our hospital due to severe pain over the lumbar region radiating to the right leg with numbness for 4 months . the patient reported that the pain had started in the proximal thigh down , moving to the lower leg after walking over 100 m , and was relieved by bending or sitting . pain and numbness of the right medial leg region and a positive straight leg raise test on the right side were found . except for an increased level of c - reactive protein ( crp ; 9.25 mg / dl ) , other laboratory tests showed normal results for complete blood count , liver function , renal function , carcinoembryonic antigen , carbohydrate antigen 19 - 9 , and electrophoresis of immunoglobulin . a plain x - ray of the lumbar spine and sacrum showed a compression fracture of the l4 vertebral body and mixed osteoblastic osteoblastic changes were noted in the sacrum , ilium , and pubic bone [ figure 1b ] . a bone scan with tc showed increased uptake by l4 , l5 , and the left - side pelvis . magnetic resonance imaging ( mri ) showed a compression fracture of l4 with an enhanced mass protruding into the spinal canal and neuroforamen [ figure 2 ] , causing compression of the nerve root and cauda equina [ figure 3 ] . positron emission tomography ( pet ) was used to further investigate the extent of the possible malignancy . increased uptake of f - labeled deoxyglucose ( fdg ) was noted over the lower lumbar region and left - side bony pelvis , consistent with the mri findings . there was no evidence of the dissemination of the malignancy from other parts of the body . ( b ) osteoblastic changes were noted in the sacrum , ileum , and pubic bone enhanced mass with heterogeneous signal intensity originating from l4 vertebral body protruded into the spinal canal and neuroforamen , causing compression of the nerve root and cauda equina magnetic resonance scans t1wi ( a ) and t2wi ( b ) of the lumbar spine , showing lytic lesion of l4 vertebrae , bone marrow edema , with erosion through endplates and narrowing of l4/5 disc space . there is an extradural obstruction at the l4/5 interspace and a paraspinal soft tissue mass anterior decompression of l3l5 and anterior fibular strut interbody fusion with right anterolateral retroperitoneal approach [ figure 4 ] were performed to relieve the patient 's aggravated back pain and neurological symptoms . specimens were taken for gram 's stain and culture . also , tumor infiltration of l4 and l5 was observed intraoperatively . a grayish tumorous mass was found to occupy the l4 vertebra , protruding into the paraspinal region and compressing the dural sac and neuroforamen . during the surgical decompression and curettage of the tumor , necrotic tissue with pus discharge because of the extent of the destruction of the l4 vertebra , a corpectomy of l4 was performed . one week later , a second - stage posterior instrumentation with pedicle screw system from l2 to s1 and posterolateral fusion were done [ figure 4 ] . a rotational table was used to assist positioning the patient in a prone position to avoid displacement of the fibula allograft . anteroposterior and lateral radiographs of lumbar spine 7 months after surgical intervention : ( a ) anterior decompression with vertebrectomy of the fourth lumbar vertebral body and interbody fusion with structural fibula allograft and autologous bone graft ; ( b ) posterior stabilization and fusion of l2s1 ; note reduction of deformity and restoration of lordotic curve pathological and immunological analyses showed large and monotonous tumor cells infiltrating the stromal tissue , which were positive for marker cd20 and negative for cd3 [ figure 5 ] . three sets of bacterial culture of the tissue fluid and tumor debris resulted in the growth of methicillin - susceptible staphylococcus aureus . also , acid - fast stain and tuberculosis polymerase chain reaction ( pcr ) were done to rule out tuberculosis of bone . these studies confirmed the diagnosis of diffuse large b - cell lymphoma with superimposed osteomyelitis . the section shows a picture of malignant lymphoma , b cell linage , characterized by dyscohesive , large , and monotonous tumor cells infiltrating within the stromal tissue with irregular nuclear membrane and focal bony erosion . the insets show that these tumor cells are immunoreactive to cd20 and negative for cd3 ( magnification 400 ) the patient had immediate relief of his radicular pain after the operation . he was treated with 2 g oxacillin intravenous injection every 4 hours for 6 weeks and switched to oral ceflexin 500 mg every 6 hours for 2 weeks . after the treatment with antibiotics , the crp level came down to 5 mg / dl on the 7 postoperative day . the value gradually came down to 2 mg / dl on the 14 postoperative day . the value stayed at a stable value of 1.5 mg / dl in the 3 and 4 postoperative weeks . with a stable surgical wound and stable crp value , the treatment was followed by six cycles of chemotherapy including rituximab , cyclophosphamide , epirubicin , vincristine , and prednisolone ( r - ceop ) . the patient resumed nearly normal life 4 months after surgery , with only slight weakness of right ankle dorsiflexion . a post - therapy assessment was made with pet / ct , 6 months after the operation . the previously noted fdg - avid region , including the l4 vertebra , sacrum , and left - side pelvis , was not detectable in the post - therapy study . pbl is defined as a lymphoma of the bone without any systemic involvement within 6 months of the first diagnosis . the incidence is less than 1% of that of primary non - hodgkin lymphoma.13 the lesion is commonly located in a short bone , such as the ilium , scapula , or vertebra.3 pbls involving a single vertebra comprise 1.7% of all pbls.4 spinal osteomyelitis is estimated to occur in approximately 1 per 100,000 persons annually.5 the predominant organism in almost all studies is s. aureus , accounting for approximately 4080% of all spinal infections.6 a distant focus of infection provides an infective nidus from which bacteria spread via the bloodstream to the spinal column . the skin and genitourinary tract are common antecedent sites.7 our patient presented with osteomyelitis , with no history of trauma or previous surgery . the hematological spread of microorganisms to areas of tumor necrosis may be the basis of the infection . both pbl and spinal osteomyelitis can present as gradually progressive back pain that increases with movement . the diagnosis of pbl relies on both radiological and pathological studies , and it can be easily missed on plain radiographs.89 in our patient , the lesions appeared osteoblastic in the pelvic and iliac bones , which can lead to a misdiagnosis of metastatic disease in the first impression . in the l4 vertebral body , the lesion of our patient appeared like most other lymphoid malignancies , which produce isointense signals on t2-weighted images.8 because most metastatic cancers or sarcomas give higher signals on t2-weighted images , this may be a way to distinguish lymphoid cancer from the other pathologies.8 the treatment for pbl , which usually consists of chemotherapy , radiotherapy , or both , is potentially curative.9 although pbl seemed to be the major medical problem of this patient , osteomyelitis , if not treated in time , can cause spinal cord infection and epidural abscess , potentially resulting in paralysis within days , especially if the patient is treated immediately with chemotherapy and radiotherapy.9 surgical decompression and stabilization can be performed to treat the mechanical compression symptoms and spinal instability due to the vertebral body destruction attributable to both pbl and osteomyelitis . daniel et al . reported an undetectable difference in the rates of recurrent infection between autografts ( 5.9% ) and allografts ( 5.3%).10 a recent literature review of the treatment of pbl recommended combined radiotherapy and chemotherapy , which produced a 95% 5-year overall survival rate compared with 70% in patients treated with radiotherapy alone and 81% in patients treated with chemotherapy alone.11 both chemotherapy and radiotherapy were important in the treatment of lymphoma . primary localized lymphoma is generally treated with debulking surgery accompanied by local radiotherapy and chemotherapy . however , in the context of superadded localized infection , combined radiotherapy and chemotherapy may further compromise the patient 's immune system and delay wound healing . considering the patient 's age , proximity of two major surgeries , and multiple instrumentations , treatment team decided to postpone the chemotherapy until good control of infection and wound healing was achieved . this case is unique in the literature because it is the first reported case of pbl with superimposed osteomyelitis , with no history of trauma , previous surgery , or biopsy . we recommend extra caution in the treatment of patients with pbl of the vertebrae to avoid overlooking potential osteomyelitis in immunocompromised patients .

primary bone lymphoma ( pbl ) comprises less than 5% of all malignant bone tumors and almost 7% of all extranodal lymphomas . only 1.7% of all pbls have been reported to involve the vertebrae . in our case , osteomyelitis was accidentally found during surgery , which might have resulted in the rapid collapse of vertebral body . this is the first report on primary lymphoma of the vertebrae with superimposed osteomyelitis in the english literature to the best of our knowledge . the patient reported here received anterior vertebrectomy and posterior interbody fusion with instrumentation for spinal instability . tumor mass and the necrotic debris were removed . after the procedure , the patient received treatment with antibiotics and six cycles of chemotherapy . this case reminds us the possibility of hematologic seeding of bacteria in the tissue , especially with tumor necrosis . we suggest percutaneous needle aspiration for pathology and culture before making a decision whether or not to proceed with surgical decompression for fear of missing the occult bacterial infection .

the diagnosis of occult gastrointestinal bleeding of obscure origin is one of the most vexing problems confronting physicians . despite impressive technological advances during the last 30 years , the management of bleeding from the lower gastrointestinal tract remains a diagnostic and therapeutic challenge . although a generally accepted treatment protocol for upper gastrointestinal tract hemorrhage has been established , there is no similar consensus for the management of hemorrhage originating distal to the treitz ligament . a 29-year - old white male was seen in the emergency room of the american - british hospital of mexico city , referred from a rural clinic in one of the neighbor states of mexico city with a 4-day history of severe gastrointestinal bleeding characterized at first by melena and then hematochezia . six units of packed red blood cells were transfused to the patient before his admission to the emergency room . past history was unrewarding except for a laparoscopic fundoplication nine months before for severe gastroesophageal reflux disease . an emergency esophagogastroduodenoscopy was negative for bleeding and showed a properly functioning fundoplication ; a colonoscopy performed two hours later after bowel preparation showed fresh blood in the large bowel coming from the ileum . the next morning the patient was taken to the operating room , and , under general anesthesia , a 10 mm trocar was placed in the umbilicus . the abdominal cavity was inspected and immediately a 6 5 cm ileal cystic dark mass was identified in the pelvic area ( figure 1 ) . another 10 mm trocar was placed in the right flank and a 5 mm one in the left flank . the whole small bowel was inspected from the ligament of treitz to the ileocecal valve and the tumor was located at 50 cm proximal to the latter . the umbilical incision was extended 3 cm downwards , the wound protected , the tumor exteriorized ( figure 2 ) , and a 20 cm ileal resection was performed , followed by a termino - terminal stapler anastomosis . the postoperative course was uneventful : a liquid diet was tolerated the following day , a normal bowel movement occurred on postoperative day 2 , and the patient was discharged on postoperative day 4 and remains asymptomatic 18 months later . the specimen was a segment of small intestine which measured 17 2.5 cm . on its outer surface , it had a reddish - brown hue , bosselated surface with areas of recent hemorrhage and measured 6 5.5 4 cm . on sectioning , it had a firm consistency , and the surface was trabeculated , gray - pink and with focal hemorrhage at the periphery . the base of implantation was 3 cm wide , and part of the neoplasia protruded through the bowel wall , creating a dumbbell shape ( figure 3 ) . microscopically , the tumor was hypercellular and made up of bundles of fusiform cells with bland nuclei , homogeneous chromatin pattern , occasional small , inconspicuous and usually single nucleolus . there were 2 mitotic figures in a 150 hpf count , no necrotic foci , no pleomorphic cells nor skeinoid fibers , and only scattered hemorrhagic areas ( figure 4 ) . the immunohistochemical profile showed focal positivity for ps-100 , cd34 ( qbend/10 ) ; actin antigen ( pcna ) was strongly positive in 4.1% of neoplastic cells . dna analysis ( cas-200 ) showed a hypodiploid population ( dna index : 0.4 , s - phase : 3.3 ) . low risk small bowel stromal tumor ( gist ) , based on size ( 6 5.5 cm ) , no necrosis , 2 mitotic figures in hpfs and pcna index lower than 10% . low risk small bowel stromal tumor ( gist ) , based on size ( 6 5.5 cm ) , no necrosis , 2 mitotic figures in hpfs and pcna index lower than 10% . etiology of acute lower gastrointestinal bleeding is closely associated with the patient 's age . in adolescents and young adults , meckel 's diverticulum , inflammatory bowel disease and polyps account for the majority of cases . in adult patients up to 60 years of age , diverticulosis , inflammatory bowel disease , and polyps are the most common cause , whereas in patients older than 60 years angiodysplasia , diverticulosis and cancer are the most common etiologies . most acute lower gastrointestinal bleeding episodes arise from the colon ; however , 15% to 20% originate in the small intestine . it must be mentioned that the yield of small bowel series performed to evaluate patients with obscure gastrointestinal bleeding is 2% to 3% for small bowel tumors ; use of enteroclysis , or double - contrast small bowel series , may increase the yield 6% to 10% . push enteroscopy should be the next step in the evaluation of all cases of gastrointestinal bleeding of obscure origin because diagnostic yield has been reported to be that of 5% to 20% for small bowel masses . other tests such as ct scan and endoscopic ultrasound have occasionally showed good results . in this case , the colonoscopy was of great importance because it gave us the information that the bleeding site was located within the limits of the jejunum and the ileum . following the endoscopic procedures , it was decided that the patient should be explored in the operative room given the negligible morbidity of a diagnostic laparoscopy . the rationale was that arteriography has a relatively high complication rate ( up to 9% ) that includes arterial thrombosis , embolization , and renal failure and success rates vary widely ( 14% to 72% ) ; that radionuclide scanning is time consuming , and several reports in the literature are not encouraging ; that the bleeding site was located somewhere between the proximal jejunum and the ileum and given the patient 's age the likelihood of an etiologic factor that could be readily identified by laparoscopy . primary benign and malignant as well as metastatic neoplasms of the small bowel are rare entities , comprising less than 5% of all gastrointestinal tumors and 0.35% of all malignancies . gastrointestinal stromal tumors ( gists ) have been the subject of considerable debate since their earliest descriptions , with controversy centering on the cell of origin , line of cellular differentiation and the prediction of clinical behavior . it is hard to estimate the exact incidence of gist from previous reports in the literature . both benign and malignant stromal tumors may occur at any age and either sex . whereas most of them are asymptomatic , the most common presenting symptom is gastrointestinal bleeding ; other manifestations are obstruction , intussusception or , rarely , perforation . despite advances in technology , preoperative diagnosis of gist - specially of those in the small bowel most of these tumors are located in the stomach ( 47% ) , small bowel and rectum ( 11% ) , colon ( 7% ) , duodenum ( 5% ) and esophagus ( 5% ) . both benign and malignant tumors can share a similar appearance , even when the latter tend to be bigger than the former . from a microscopic standpoint , there is not , however , a single immunohistochemical profile that allows one to predict the neoplasm 's biological behavior . generally accepted malignancy criteria include a diameter of more than 5 cm , invasion to nearby structures , necrosis , hypercellularity , increased nucleus / cytoplasm ratio , mitotic rate greater than 1 - 5 per 10 hpf , and infiltration of the overlying mucosa . sometimes , the term the greatest value of tests using proliferative markers is the possibility to re - classify with more precision tumors that were considered as borderline or of unknown biological conduct into high or low - risk groups . lymph nodes are affected in 7%-10% of cases , and rarely are extra - abdominal structures invaded : lung , subcutaneous tissue , brain , thyroid , bone , kidney , adrenals , heart , larynx , skin and spermatic cord . as gists are usually radio - resistant and insensitive to chemotherapeutic agents , the only curative therapy is surgical excision . it is likely that this tumor was present during the previous laparoscopic surgery , but a careful review of the video a posteriori did not reveal any abnormality during the abdominal inspection ( although an examination of the small bowel was not done ) , and the patient did not have any evidence of anemia and/or any other gastrointestinal symptoms . laparoscopic surgery for small bowel obstruction , perforated diverticulitis , and for benign and malignant tumors of the small and large intestine has produced excellent results in experienced hands , although in some cases may require conversion to laparotomy and/or an assisted procedure . in the case herein presented , the tumor was localized immediately with the aid of a simple diagnostic laparoscopy , which allowed a successful assisted resection . it is recommended that in some selected , well - evaluated patients with lower gastrointestinal bleeding of unknown origin and stable vital signs , laparoscopy may provide a precise diagnosis and adequate treatment within the same procedure , avoiding the need for time - consuming studies with substantial morbidity and expense .

the authors report a case of a 29-year - old male patient with a severe lower gastrointestinal hemorrhage in whom a successful laparoscopic diagnosis and resection ( assisted ) of an ileal gastrointestinal stromal tumor ( gist ) was performed . laparoscopy can be very useful in the diagnosis and treatment of selected cases of lower gastrointestinal bleeding .

lung cancer is the leading cause of cancer deaths in japan , with 45 927 men and 17 307 women dying from lung cancer in 2006 . to date , increase in the incidence rates of lung adenocarcinoma ( adc ) and decrease in the incidence rates of squamous cell carcinoma ( sqcc ) and small cell carcinoma ( smcc ) have been reported in japan ( 1,2 ) . some previous studies reported that there was a trough of lung cancer incidence or mortality in japanese male 193539 birth - cohorts because of the limited cigarette supply just after world war ii ( 610 ) . ( 7 ) reported the birth - cohort analysis by histological type using nagasaki cancer registry in 2000 . however , this study was based on the small number of registered lung cancer cases and excluded the cases without histological diagnoses . in the present study , we updated the recent trends in lung cancer incidence by histological type and tried to clarify their characteristics by birth - cohort , using the data from osaka cancer registry ( ocr ) with the large number of lung cancer incidence . ocr , which started in 1962 , is the population - based cancer registry covering osaka prefecture ( population : 8.8 million , 2005 census ) . using ocr data on lung cancer incidence ( international classification of diseases 10th revision c33c34 ) diagnosed between 1975 and 2003 , we calculated the number of lung cancer incidence per year , age - adjusted rates and age - specific rates by birth - cohort according to histological type . histological types were categorized into three major types : adc ( icd - o : 8140 , 8141 , 8200 , 8211 , 8250 , 8251 , 8260 , 8310 , 8323 , 8440 , 8470 , 8480 , 8481 and 8490 ) , sqcc ( icd - o : 8050 , 8052 and 80708076 ) , smcc ( icd - o : 80418045 ) and the others . incident years are divided into 5-year periods : 197578 , 197983 , 198993 , 199498 and 19992003 . the population data by age group in osaka prefecture were obtained from the data of population census . for age - standardization , the data from ocr included the cases without specific histological diagnosis : a maximum of 60.4% in 197578 and a minimum of 31.4% in 199498 . based on the assumption that distributions of histological types in the same sex and age group were the same between those with and without a specific histological type , we compensated for the proportion of cases without a specific histological type . the detailed procedure was followed to the previous study ( 1 ) ; first , the sex- , age ( 5-year)- and incident year ( or birth - cohort)-specific numbers of incidence were calculated for all histological types including the cases without histological diagnosis . second , the sex- , age ( 10-year)- and incident year ( or birth - cohort)-specific proportion of each histological type among the cases with histological diagnosis were calculated for three major histological types . finally , the sex- , age ( 5-year)- , incident year ( or birth - cohort)-specific number of incidence were multiplied by the corresponding sex- , age- and incident year ( or birth - cohort)-specific proportion to approximate the number of incidence by histological type . table 1 shows the trends in the number of lung cancer incidence per year according to histological type . lung cancer incidence per year for all histological types among men and women increased consistently ; from 1086 in 197578 to 3487 in 19992003 among men and from 395 in 197578 to 1482 in 19992003 among women . as for histological type , the number of adc incidence has increased remarkably among men and women . the shift in main histological type among men occurred in the 1990s . trends in the number of lung cancer incidence per year according to histological type table 2 shows the trends in the age - adjusted rates according to the histological type . the age - adjusted rates for all histological types peaked in 199498 and recently leveled off among men , while those consistently increased among women . in contrast , the rates for sqcc and smcc peaked in 198993 among men , and decreased subsequently . those rates for sqcc and smcc peaked in 198488 and 198993 , respectively , among women , and decreased subsequently . trends in age - adjusted lung cancer incidence rates per 100 000 person - years according to histological type fig . 1 shows the trends in the age - specific lung cancer incidence rates with 95% confidence interval by birth - cohort for all histological types . among men , there was a trough in rates for all age groups in 193539 birth - cohorts , which was consistent with the previous findings ( 7,10 ) . in the subsequent birth - cohorts , the rates increased for all age groups , but the declining tendency appeared in 195559 birth - cohorts . among women , the rates for aged 50 years increased gradually , while it seemed that the rates for aged < 50 years turned to decrease or level off after 195054 birth - cohorts : however , these trends were unstable because of the wide confidence intervals due to the small number of incidence . trends in age - group - specific lung cancer incidence rates with 95% confidence interval by birth - cohort for all histological types . figs 24 show the trends in the age - specific incidence rates with 95% confidence interval by birth - cohort for adc , sqcc and smcc , respectively . the rates for adc among men increased gradually for all age groups , but the declining tendency appeared in 195559 birth - cohorts . furthermore , it seemed that there was a slight trough in rates in 193539 birth - cohorts , as well as findings in all histological types . the trends in adc among women were almost similar with those in all histological types . the rates for sqcc among men peaked in 191014 birth - cohorts and decreased in the subsequent birth - cohorts . the trough in rates during 193539 birth - cohorts was not clear for sqcc among men . trends in the rates for sqcc among women aged 65 years were similar with those among men . the trends in aged < 65 years were , however , unclear because of the wide confidence interval . the rates for smcc among men peaked around 1920s birth - cohorts and turned to slightly decrease or level off in the subsequent birth - cohorts . trends in age - group - specific incidence rates with 95% confidence interval by birth - cohort for adenocarcinoma . trends in age - group - specific incidence rates with 95% confidence interval by birth - cohort for squamous cell carcinoma . trends in age - group - specific incidence rates with 95% confidence interval by birth - cohort for small cell carcinoma . in the present study , we reported the population - based trends in lung cancer incidence including birth - cohort analyses according to histological type using ocr . the number of lung cancer incidence per year increased continuously because of the population aging . the main histological type of lung cancer switched from sqcc to adc among men in 1990s . smoking prevalence by birth - cohort among japanese men was reported to have two peaks : around the 1925 birth - cohort and around the 1950 birth - cohort ( 11 ) . in addition , there was a trough of smoking prevalence in 193040 birth - cohorts because of the limited cigarette supply just after world war ii ( 11 ) . in general , the trends in lung cancer incidence or mortality by birth - cohort were parallel to the trends in the smoking prevalence . our results were consistent with the findings from previous studies , showing that lung cancer mortality and incidence rates among men in 193539 birth - cohorts were lower than the subsequent birth - cohorts ( 610 ) . since the smoking prevalence among japanese men was declining after 1950s birth - cohorts , the appearance of declining trends of lung cancer incidence among men in 195559 birth - cohorts was an expected result . classically , smoking behavior was considered to be more strongly associated with sqcc than with adc . however , sqcc incidence rates by birth - cohort among men were not parallel to the smoking prevalence by birth - cohort . sqcc incidence rates among men after 194044 birth - cohorts leveled off , whereas the smoking prevalence among men after 194044 birth - cohorts increased . filtered cigarettes were considered to be associated with peripheral adc because of the deep inhalation ( 3,12,13 ) . according to the information from japan tobacco inc . , the switching from non - filtered cigarettes to filtered cigarettes occurred in the 1960s in japan ( 14 ) . the shift from sqcc to adc among men in 1990s observed in the present study might have been the result of this shift in cigarette types . the smoking prevalence by birth - cohort among women is continuously increasing after 1930s birth - cohorts ( 11 ) . however , lung cancer incidence among women in 1950s birth - cohorts , particularly for adc , seemed to be leveling off or decreasing . 15 ) also reported the trends in lung cancer mortality by birth - cohort using the national vital statistics . in that study , lung cancer mortality trends appeared to be decreasing for female birth - cohorts born after 1960 . although our results were unstable because of the wide confidence intervals , those were not contradictory to this previous study . there would be some factors other than active smoking for lung cancer incidence among them . the proportion of death certificate only for lung cancer in ocr was 19.3% in 19982002 ( 16 ) . secondly , the trends by histological type among young women were unstable because of the small number of incidence ; the number of lung cancer incidence among women aged < 50 years per year was 80 cases in 2003 . finally , the data from ocr included many lung cancer cases without specific histological diagnoses . we had to use assumption in order to calculate the number of incidence according to histological type . the proportions of lung cancer cases without histological diagnoses for aged < 80 years decreased between 197578 and 19992003 ; from 49.7 to 16.4% among aged 4049 years , from 47.4 to 17.6% among aged 5059 years , from 55.9 to 22.7% among aged 6069 years and from 70.8 to 31.6% among aged 7079 years , respectively . however , those for aged 80 years were still high : from 78.9 to 64.1% . therefore , we require carefulness to interpret the findings , particularly for elderly . in conclusion , we reported recent trends in lung cancer incidence according to histological type . the increase in adc incidence and the decrease in sqcc and smcc incidence the trends in lung cancer incidence among young women in 1950s birth - cohorts , particularly for adc , were not parallel to the smoking prevalence . we need careful monitoring of the trends in lung cancer incidence , particularly for adc among young women . funding to pay the open access publication charges for this article was provided by the third - term comprehensive 10-year strategy for cancer control , ministry of health , labour and welfare , japan .

backgroundin japan , an increase in age - adjusted incidence rates of lung adenocarcinoma ( adc ) and a decrease in lung squamous cell carcinoma ( sqcc ) have been reported.methodsthe number of lung cancer incidence , age - adjusted rates , and age - specific rates by birth - cohort according to histological type were examined using the data from osaka cancer registry.resultsthe numbers of lung cancer incidence among men and women have increased , particularly in adc . the age - adjusted incidence rates of adc among men and women have continuously increased , while those of sqcc and small cell carcinoma ( smcc ) turned to decrease since 1990s . a trough of lung cancer incidence rates was observed among men in 193539 birth - cohorts . the declining trend appeared in 195559 birth - cohorts . lung cancer incidence rates among women have increased since 189599 birth - cohorts , but those rates leveled off or decreased in 1950s birth - cohorts . trends of adc by birth - cohort were almost the same as those of all histological types . the sqcc among men peaked in 191519 birth - cohorts , and decreased in the subsequent birth - cohorts . the smcc among men peaked in 1920s birth - cohorts , and decreased or leveled off in the subsequent birth-cohorts.conclusionslung cancer incidence rates by birth - cohorts were almost parallel to the smoking prevalence . however , those for adc among young women in 1950s birth - cohorts were not parallel to the smoking prevalence , which requires careful monitoring to confirm such findings .

a 15-year - old adolescent ( weight , 46 kg ; height , 162 cm ) had a medical history of hypertension , cyclic headache , and vomiting for 10 years without an awareness of his medical condition . thereafter , he demonstrated a seizure with subcortical ich in the left frontal area 6 weeks before the surgery . he was diagnosed with pheochromocytoma as confirmed by excessive catecholamine production in his serum and urine . the computed tomography scan revealed two masses ( dimension , 4.0 3.5 cm , and 1.6 1.2 cm ) in the left adrenal gland . preoperative preparation consisted of terazosin 1 mg , losartan 1.25 mg , atenolol 25 mg , and levetiracetam 1 g daily for 2 weeks , which resulted in symptomatic improvement , normotension and prevention of seizure . before entering the operating room , 2 mg of midazolam was infused and dexmedetomidine was given 1 g / kg over 10 min at the waiting area , followed by a continuous intravenous infusion at 0.5 g / kg / hr . on arrival to the operating room , the intraoperative monitoring consisted of electrocardiogram ( lead ii ) , hr , pulse oximeter , end - tidal co2 , bispectral index , esophageal temperature , invasive measurement of bp with cardiac index , central venous pressure , central venous oxygen saturation , and urine output . arterial blood gases , electrolytes , glucose , and serum catecholamines were planned to check before induction and after intubation , tumor manipulation , and removal of tumors . general anesthesia was induced with propofol 100 mg , continuous infusion of dexmedetomidine , remifentanil 0.2 g / kg / min and sevoflurane 2.0 vol% by mask . anesthesia was maintained with a 2.5% end - tidal concentration of sevoflurane in an oxygen - air mixture ( fio2 = 0.50 ) and infusion of remifentanil 0.1 g / kg / min and dexmedetomidine however , when the surgeon began to manipulate it , bp and hr were abruptly increased ( fig . those changes were controlled with bolus injection of remifentanil , nicardipine , esmolol , and sodium nitroprusside . remifentanil , nicardipine , and sodium nitroprusside were also used to put back his vitals to baseline . after tumor removal , bp decreased rapidly , which responded to ephedrine and phenylephrine to produce an increase in systolic bp of 80 - 100 mmhg . dexmedetomidine and remifentanil were stopped at closure of peritoneum and at end of skin closure , respectively . after extubation , the patient was mildly sedated but had good respiration and possible purposeful movement . the total operation time was 200 min , and the total period of anesthesia was 285 min . estimated blood loss was about 200 ml and the total dose of infused dexmedetomidine was 144 g . after the surgery , he stayed at the intensive care unit for 1 day and was discharged 10 days after the surgery with no noticeable complications and events . the anesthetic management for maintaining stable cardiovascular response during the resection of pheochromocytoma is still an unsolved assignment to the anesthetist . during the operation , catecholamine level increase of up to 200,000 - 1,000,000 pg / ml ( normal catecholamine levels under stressful events : 200 - 2,000 pg / ml ) , because our patient had an episode of seizure and ich only 6 weeks before the surgery , we had to concentrate on keeping his bp under our control to avoid neurologic complications . dexmedetomidine is a highly selective alpha-2 adrenoceptor agonist compared with clonidine , especially for the 2a subtype . they are located on blood vessels , where they mediate vasoconstriction , and on sympathetic terminals , where they inhibit noradrenaline release . alpha-2 adrenoceptors are also located within the central nervous system , and their activation leads to sedation , a 60 - 80% reduction of tonic levels of sympathetic outflow and catecholamines , and an augmentation of cardiac - vagal activity . dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and surgical stimuli and has a significant anesthetic and analgesic sparing effect when used intraoperatively . additionally , dexmedetomidine has recently been investigated for its potential in many other clinical scenarios , including neuroprotection , cardioprotection and renoprotection , with promising results . the pharmacokinetics of remifentanil is characterized by small volume of distribution , rapid clearance , and short context - sensitive half - time . prompt onset and short duration of action make remifentanil a useful selection for the suppression of the transient sympathetic nervous system response to tracheal intubation and noxious stimuli in at risk patients . although remifentanil is effective for blunting the sympathetic response , there were reports that even if remifentanil was being infused in pheochromocytoma excision to control intraoperative hemodynamic instability , the use of vasodilators was required during tumor manipulations . although our anesthetic team assumed that the combination of dexmedetomidine and remifentanil might produce additional hypotensive agents to be unnecessary , we actually infused low dose of esmolol , sodium nitroprusside and nicardipine when bp surges came up during tumor manipulation . because one of masses was placed difficult to dissect , the surgeon had a hard time manipulating the tumors before ligation of the adrenal vein . there are some reports on serum plasma catecholamine levels during the resection of pheochromocytoma , which show wide variation depending on what stimuli had been done to the patient . in comparison , our patient 's levels of catecholamine ( table 1 ) represented persistent decreasing trend except with epinephrine , which means that infusion of dexmedetomidine and remifentanil might interrupt the release of norepinephrine effectively during the procedure . russell et al . , in a retrospective analysis of a group of adult patients , found a significant correlation between intraoperative cardiovascular instability and peak serum catecholamine levels measured at the time . . also showed a significant correlation between plasma norepinephrine concentration and mean arterial pressure during surgery . bryskin and weldon reported that the infusion of dexmedetomidine and magnesium sulfate in their case was effective for stable hemodynamics , with the pattern of steadily decreasing catecholamine levels following intubation . therefore , we presume that the decreasing trend of catecholamine levels could help to diminish sudden fluctuating changes of hemodynamics . in conclusion , the levels of perioperative catecholamines demonstrate that the combination of dexmedetomidine and remifentanil was an effective manner to achieve safe anesthesia in our patient . the optimal intra - operative dosing and timing of dexmedetomidine and remifentanil remain to be determined , and a further study in this setting is needed .

a 15-year - old adolescent with unilateral multiple adrenal pheochromocytoma had an episode of subcortical intracerebral hemorrhage and seizure 6 weeks before the surgery . he was pretreated with terazosin , losartan , atenolol and levetiracetam for 2 weeks . dexmedetomidine was started in the preoperative waiting area , and a combination of dexmedetomidine and remifentanil was continuously infused for most of anesthetic time . to control blood pressure , bolus injection of remifentanil and low - dose infusion of sodium nitroprusside , nicardipine , and esmolol were administered during three adrenergic crises . there was minimal post - resection hypotension , and his trachea was extubated safely 20 min after the surgery . he was discharged without noticeable complication . his catecholamine levels showed the steadily decreasing pattern during the operation in this case . though a combination of dexmedetomidine and remifentanil may not prevent the hemodynamic instability impeccably during the tumor manipulation , this combination seems to be the way of interrupting release of catecholamines and minimizing hemodynamic fluctuations .

the subject patient of this case report was diagnosed with mild ap and underwent conservative medical management . since the patient was stable and fetal well - being was confirmed with bpp and nst , the termination of pregnancy was out of question at that time . the occurrence of unexpected fetal death despite assuring parameters led us reconsider the approach to the pregnant women with mild ap . acute pancreatitis ( ap ) is a potentially life threatening inflammatory condition of the pancreas with a high mortality and morbidity rates . while the annual incidence of ap is 580 per 100,000 of the general population , the incidence of ap in pregnancy varies between 1 in 1000 and 3 in 10,000 births . the spectrum of ap in pregnancy ranges from a mild self - limiting condition to severe rapidly progressive disease associated with pancreatic abscesses , necrosis , multiple organ dysfunction as well as poor fetal and maternal outcomes . herein we report a complicated case of mild acute pancreatitis induced by gallbladder sludge in a pregnant woman whose pregnancy ended up with unexpected fetal demise at 34 weeks of her gestation , despite the fact that she had reactive nonstress test ( nst ) described in the guideline 3 h prior to fetal death , and we discuss the management of this condition during pregnancy . a 29-year - old primigravida was admitted to emergency department at the 34th gestational week complaining of upper abdominal pain lasting more than a week , radiating to the right flank and back . her blood analysis showed white blood cell count : 7.12 k/l ( reference interval ( ri ) 4.31.3 k/l ) , hemoglobin : 14.5 g / dl ( ri : 13.617.2 g / dl ) , platelet : 249 k/l(ri : 156373 k/l ) , aspartate transaminase : 86 u / l ( ri : 032 u / l ) , alanine transaminase : 108 u / l ( ri : 032 u / l ) , total bilirubin : 0.7 mg / dl ( ri : 01.1 mg / dl ) , direct bilirubin : 0.437 mg / dl ( ri : 00.3 mg / dl ) , potassium 2.87 mmol / l ( ri : 3.35.4 mmol / l ) , calcium : 9 mmol / l ( ri : 8.610.2 mmol / l ) , gamma - glutamil transferase : 47 u / l ( ri : 851 u / l ) , amilase : 188 u / l ( ri : 25100 u / l ) , lipase : 291 u / l ( ri : 1350 u / l ) , c - reactive protein ( crp ) : 7.98 mg / dl ( 00.8 mg / dl ) . the patient was hospitalized by the department of general surgery with the diagnosis of mild acute pancreatitis according to the ranson criteria . at the time of hospitalization , vital signs of the patient obstetrical assessment of the patient revealed 34 weeks pregnancy with excellent biophysical profile ( bpp : 10 ) , reactive fetal nonstress test ( nst ) . nst was planned to be performed three times a day and assessment of the test was made by obstetrics clinics . the regular follow - up procedures were maintained for 3 days with no observed deterioration in general conditions and laboratory results of the patient . three hours after her daily assessment on the third day of her hospitalization , the condition of the patient suddenly started to deteriorate . an emergency cesarean section was performed due to continuing deterioration of her clinical and biochemical parameters . the 2300 g male fetus was delivered dead with conspicuous generalized peeling skin lesions ( picture 1 ) which were especially located on his neck . the accumulation of 3000 cc of intra - abdominal yellowish green ascitic fluid was drained during the surgery . intestines , ovaries and the uterus were observed as edematous and congested with scattered necrotic lesions on them . the patient was transferred to the intensive care unit ( icu ) for postoperative follow up . postmortem assessment of the fetus did not reveal any major congenital anomalies and signs of infection related demise . pathological investigation of the fetus confirmed that skin lesions were occurred as a result of pancreatic lytic enzymes released into the circulation . no signs of infection related to fetal demise were detected during the post - mortem examination of fetus . the patient stayed in the icu for 36 days and later she was discharged 40 days after admission to the hospital . despite the excellent biophysical profile performed 3 days ago , and the reactive nst maximum 3 h prior to intrauterine fetal death , unexpected antepartum stillbirth occurred at 34 weeks of gestation . the patient was diagnosed as having mild pancreatitis and treatment was made accordingly by department of general surgery . acute pancreatitis in pregnancy is first described in 1818 , and the management of this disease during the pregnancy has been the subject of obstetrics care of high risk pregnancies due to challenging nature of the disease , and maternal and fetal considerations . cholelithiasis is the most common cause of ap during pregnancy , with an incidence of 2.54.2% . while 4066% of acute pancreatitis in pregnancy occurs as a result of gallstone or biliary sludge which was considered as having better prognosis than the non - biliary pancreatitis , 1050% of ap in pregnancy is related to hypertriglyceridemia . in this group hypertriglyceridemia induced ap in pregnancy is tend to be more severe with an increased risk of concomitant complications ( multiple organ failure , shock , infections ) . idiopathic reasons , alcohol consumption , pre - eclampsia , and the use of certain drugs such as tetracycline , thiazides ( not common in pregnancy ) are responsible for the rest of the ap cases in pregnancy . clinical manifestations of ap include , anorexia , nausea , vomiting , and midepigastric pain , left upper quadrant pain radiating to the back , decreased bowel sounds , fever , and associated pulmonary findings . diagnosis of ap is supported by increased serum amylase and lipase , as well as triglyceride levels , calcium levels , and a complete blood count . serum amylase level is usually considered as a reliable marker of ap in pregnant women . however , patients with necrotic pancreatitis , or hypertriglyceridemia induced ap may have normal serum levels of serum amylase , and this result can be interpreted as not having ap in pregnancy . after diagnosing of ap in pregnancy , certain tests such as blood tests , urine tests , and imaging methods should be performed in order to determine the severity of the diseases which will totally change the way of approaching to the patient . the goal of the treatment in ap is to maintain both maternal and fetal well - being . conservative medical management of pancreatitis can be summarized as intravenous fluids , fat restriction with total parenteral nutrition , total parenteral nutrition if necessary , nasogastric suctioning , bowel rest , use of analgesics , antispasmodics , and antibiotics , management of underlying cause . in this current case report , amylase and lipase levels were mildly increased , and serum triglyceride , calcium levels were in normal ranges . the patient did not give any history of any kind of disease which predisposed ap . the mechanism for biliary sludge causing acute pancreatitis can be explained as biliary and pancreatic sphincter dysfunction by mechanical irritation of microcrystals and subsequent inflammation . the patient subject to this case report , was classified as having mild ap and conservative medical management was made subsequently . since the patient was stable and fetal well - being was confirmed with bpp and nst , the termination of pregnancy was out of question at that time . this unexpected event what fetal death was occurred , despite those assurance parameters , let us reconsider the approach to the pregnant woman with mild ap . the most widely cited causes of fetal demise in ap are severe metabolic disturbance , acidosis and placental abruption . however furthermore , the male fetus demonstrated generalized ecchymotic lesions on his skin , and scattered skin peeling especially located on his neck . these skin lesions were considered as a sign of affected fetus , despite having mild ap . the majority of cases with mild ap in pregnancy can be cured by the conventional therapy with a good prognosis . severe ap is considered as having pancreatic abscess , necrosis , infection , or deterioration of biochemical and clinical parameters despite the effective conservative medical treatment of 4872 h. severe ap usually occurs in the third trimester of pregnancy , and pregnant women are more prone to developing serious condition that results in a higher risk of intrauterine fetal death . in this group , pregnancy must be terminated in order to prevent further damage to the mother and the fetus . another study demonstrated that mild ap in pregnancy is not absolutely a sign for neither pregnancy termination nor cesarean section but deteriorating severe ap is . however , in this chinese study they reported early pregnancy termination in pregnant woman with mild ap , since couples decided to terminate the pregnancies , due to china 's national single child per couple policy . in this study induced abortion was performed in 5 cases of 22 mild ap patients during 1234 weeks . cesarean section was performed in another 4 mild ap cases during 3337 weeks due to developing severe ap . they report only one case of fetal death due to severe ap . in the study of vilallonga et al . they concluded that ap in pregnant women usually has a benign course with proper treatment . based on the research , we can conclude that ap in pregnancy should be managed with conservative medical treatment except in pancreatic abscess , necrosis , infection , large intra - abdominal exudates , infected effusion ; associated with other serious complications such as gastrointestinal perforation ; the situation deteriorates after active treatment of 4872 h. however , obstetricians should always keep in mind that even in the presence of reassuring nst and biophysical profile assessment , an unpredictable fetal loss may occur during the medical management of the pregnancies complicated with mild acute pancreatitis . ap in pregnancy should be managed carefully in order to prevent further damage to the mother and the fetus . written informed consent was obtained from the patient for publication of this case report and accompanying images . all authors contributed to the intellectual context and approved the final version.key learning pointsdealing with acute pancreatitis in pregnancy is a challenging problem due to unexpected nature of the disease . obstetricians should keep in mind that even in the presence of reassuring nst and biophysical profile assessment , an unpredictable fetal loss can occur during the medical management of the pregnancies complicated with mild acute pancreatitis . dealing with acute pancreatitis in pregnancy obstetricians should keep in mind that even in the presence of reassuring nst and biophysical profile assessment , an unpredictable fetal loss can occur during the medical management of the pregnancies complicated with mild acute pancreatitis . dealing with acute pancreatitis in pregnancy obstetricians should keep in mind that even in the presence of reassuring nst and biophysical profile assessment , an unpredictable fetal loss can occur during the medical management of the pregnancies complicated with mild acute pancreatitis .

highlightsdealing with acute pancreatitis in pregnancy is a challenging problem.even in the presence of reassuring nst and biophysical profile assessment , an unpredictable fetal loss can occur during the medical management of the pregnancies complicated with mild acute pancreatitis.acute pancreatitis ( ap ) is a potentially life threatening inflammatory condition of the pancreas with a high mortality and morbidity rates.we report a complicated case of mild acute pancreatitis induced by gallbladder sludge in a pregnant woman whose pregnancy ended up with unexpected fetal demise at 34 weeks of her gestation .

dabigatran ( pradaxa , boehringer - ingelheim ) is a direct thrombin inhibitor that is often substituted for warfarin because monitoring of anticoagulation is not required . in the re - ly study ( randomized evaluation of long - term anticoagulation therapy ) , dabigatran was non - inferior to warfarin in reducing incidence of stroke with atrial fibrillation . bleeding risk was less than that of warfarin with dabigatran dosed at 110 mg twice daily , but equivalent at 150 mg twice daily . we present a case of acute kidney injury ( aki ) in the setting of conversion from warfarin to dabigatran that reveals a pathophysiological mechanism of injury that likely has relevance to warfarin nephropathy . a 67-year - old caucasian male , with previously normal kidney function [ serum creatinine concentration ( scr ) 1.0 mg / dl ( 88 mol / l ) , egfr 78 ml / min/1.73 m using the ckd - epi equation , and no proteinuria on urinalysis ] , presented with aki and 1 week of gross hematuria . he denied family history of kidney disease , but did have one previous episode of dark - colored urine 2 months prior that resolved spontaneously . medications included aspirin 81 mg daily , sotalol , omeprazole , lisinopril and dabigatran 150 mg twice daily . one week prior to presentation , warfarin had been held for 3 days and then dabigatran initiated , at request of the patient . scr was 5.5 mg / dl ( 420 mol / l ) with no evidence for systemic hemolysis . the international normalized ratio ( inr ) was 1.6 with a prothromboplastin time of 62 s. he was initially managed with i.v . fluids , and anticoagulants were held . a serological workup , including antineutrophilic cytoplasmic antibody ( anca ) , cryoglobulins , c3/c4 , serum / urine protein electrophoresis , and viral serologies , was negative . because hematuria persisted and creatinine continued to rise , he underwent kidney biopsy . the biopsy showed extensive , diffuse tubular injury with nuclear dropout , sloughing of brush border membrane and cytoplasmic reabsorption droplets containing eosinophilic proteinaceous material ( figure 1a ) . the glomeruli showed capillary congestion and mesangial matrix expansion and hypercellularity ( figure 1b ) . the vessels were unremarkable and a prussian - blue stain showed focal positivity in 12% of tubular profiles . immunofluorescence studies showed 23 + mesangial positivity for iga ( figure 1c ) and 1 + mesangial positivity for c3 . ultrastructural evaluation showed segmental foot process effacement and large mesangial immune complex deposits ( figure 1d ) . the proximal tubular epithelial cells showed cytoplasmic reabsorption droplets containing heme - proteins and intratubular granular casts ( figure 1e ) . 1.(a ) diffuse acute tubular injury with rbc casts and cytoplasmic reabsorption droplets ( arrow ) ( h&e 400 ) . ( c ) if stain for iga with strong mesangial staining pattern ( 200 ) ; ( d ) em with mesangial immune complex deposits ( arrow ; 8000 ) . basement membranes with normal thickness of 230 60 nm ; ( e ) em of tubular epithelium with cytoplasmic reabsorption droplets containing heme proteins ( arrow ; 13 000 ) . ( f ) immunohistochemistry stain for cd163 ( 400 ) . ( a ) diffuse acute tubular injury with rbc casts and cytoplasmic reabsorption droplets ( arrow ) ( h&e 400 ) . ( b ) glomerulus with increased mesangial cellularity ( h&e 400 ) . ( c ) if stain for iga with strong mesangial staining pattern ( 200 ) ; ( d ) em with mesangial immune complex deposits ( arrow ; 8000 ) . basement membranes with normal thickness of 230 60 nm ; ( e ) em of tubular epithelium with cytoplasmic reabsorption droplets containing heme proteins ( arrow ; 13 000 ) . the patient had previously had mild undiagnosed iga nephropathy that was found on biopsy but in the setting of a high dose of dabigatran and aspirin he developed massive hematuria ( likely predisposed by iga nephropathy ) and acute tubular necrosis from the direct toxic effect of heme pigment in the proximal tubular cells . the patient 's creatinine stabilized at 6.0 mg / dl ( 530 mol / l ) , and he was treated with normal saline to encourage diuresis . he was discharged home and his creatinine improved over a 3-month period to 1.8 mg / dl ( 160 mol / l ) . aki in the setting of iga nephropathy may result from immune - mediated proliferative glomerulonephritis , glomerular bleeding leading to tubular injury or a process completely unrelated to the disease . previous case reports have shown that hematuria itself may lead to an acute decline in renal function . warfarin - related nephropathy ( wrn ) is seen in patients with or without chronic kidney disease on anticoagulation with inrs over three . aki during warfarin therapy is usually hemodynamic due to hemorrhage , interstitial nephritis or occlusive rbc casts [ 46 ] . these rbc casts form as a consequence of enhanced glomerular hemorrhage that might be augmented by drugs that increase glomerular filtration pressure . kidney disorders associated with hematuria , such as iga nephropathy , may predispose the patient to warfarin - induced glomerular hemorrhage . however , < 1.5% of patients with iga nephropathy and gross hematuria present with aki . therefore , the reason for the development of aki in wrn is still unknown . moreover , the kidney biopsies in patients with wrn show that the percentage of tubules with rbc casts is low ( < 20% ) as reported in the previous cases . these observations raise the question whether other additional mechanisms might be involved in the pathogenesis of tubular injury in wrn . this patient 's biopsy showed large rbc casts , extensive acute tubular injury and cytoplasmic protein reabsorption droplets in proximal tubular cells . our patient did have underlying iga nephropathy , discovered at the time of kidney biopsy , but the conversion to dabigatran in association with aspirin precipitated aki . the iga nephropathy was largely quiescent with normal kidney function and only one previous episode of dark urine. moderate iga staining on kidney biopsy , previous high egfr and low - level proteinuria suggest mild pre - existing disease . our patient 's biopsy showed rbc casts in only 10% of tubules , but extensive , diffuse cytoplasmic protein reabsorption droplets in most proximal tubular cells . there was focally positive iron staining and heme aggregates in both the proximal tubular lumens and in the cytoplasm of proximal tubular cells . high hemoglobin concentrations in the urine and tubular rbc casts lead to increased uptake of hemoglobin in the proximal tubule cells . cubulin receptors and internalization through apical vacuoles that become protein absorption droplets [ 9 , 10 ] . the heme molecule in its free form is tubulo - toxic through lysosomal overload , inflammation , apoptosis and oxygen - radical formation [ 11 , 12 ] . studies in isolated tubular segments have shown significant toxicity of heme proteins through oxidative damage . heme further induces significant mitochondrial damage and augments ischemia - induced lipid peroxidation , augmented by fe2 + . exposure of tubular cells to high concentrations of heme proteins may increase synthesis of the vasoconstrictor peptide endothelin-1 , leading to ischemic injury or monocyte migration . a possible mechanism through which dabigatran might enhance heme - induced tubulotoxicity is by heme oxygenase-1 inhibition , thus preventing the breakdown of heme to biliverdin and iron . the expression of cd-163 positive macrophages suggests an immune role in the presence of direct tubular and interstitial damage through the scavenging of toxic heme compounds . however , it is quite possible that the underlying hematuria and subsequent injury overwhelmed this compensatory mechanism . this patient did have underlying iga nephropathy , with mesangial immune complexes , but minimal proteinuria , suggesting mild disease . the aki present on biopsy was not directly caused by the iga nephropathy , but rather a result of significant anticoagulation with dabigatran and aspirin . it is quite possible that the combination of warfarin , dabigatran and aspirin during the transition period resulted in excessive anticoagulation . the inr was mildly elevated at 1.6 possibly suggesting persistent vitamin k antagonism and thereby anticoagulation from warfarin in addition to the direct thrombin inhibition of dabigatran . the progression of aki most likely exacerbated the effects by elevating serum levels of dabigatran further ( although levels were not measured ) . all anticoagulants , such as dabigatran or warfarin , may cause severe hematuria , leading to acute tubular injury . in summary , excessive glomerular hemorrhage may lead to aki via several pathological mechanisms ( see figure 2 ) . red blood cells may be endocytosed by proximal tubular cells , resulting in heme protein induced necrosis . the burden of these different injury mechanisms overcomes the regenerative capacity of the tubular cells perpetuating injury . we propose that the mechanism of injury in this patient was similar to wrn , but the patient was not taking warfarin . the results presented in this paper have not been published previously in whole or part , except in abstract format . g.w.m . : nothing to disclose .

dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long - term anticoagulation . we describe a patient who developed acute kidney injury ( aki ) in the setting of warfarin conversion to dabigatran , and a renal biopsy demonstrating acute tubular injury . although the patient had undiagnosed iga nephropathy that may have predisposed him to bleeding , aki was due to heme - associated tubular injury . we propose that severe hematuria in patients with underlying glomerular pathology treated with either dabigatran or warfarin may lead to toxic tubular injury through the accumulation of heme - proteins .

marijuana is the most commonly used illicit drug in the us , particularly among young adults , with marijuana use prevalence increasing in recent years . chronic marijuana use is associated with cognitive impairment and addiction . while marijuana can be used in various forms ( e.g. , vaporized and edible ) , the most common mode of use is smoking , which is implicated in long - term effects on lung function [ 46 ] , chronic bronchitis and respiratory irritation [ 2 , 4 ] , and impaired immunological competence of respiratory systems . marijuana smoke includes nitric oxide , nitrogen oxide , hydrogen cyanide , and aromatic amine ( which is responsible for the mutagenic and carcinogenic activity of cigarette condensates ) and includes more chemicals than tobacco smoke . in addition , risk factors of adolescent marijuana use include peer influence , home environment , and parental monitoring . thus , marijuana use in the home may impact health of nonusers and increase the likelihood of youth initiation . recent efforts regarding legalization and decriminalization of marijuana use in the us restricts use to personal residential environments . thus , we must understand how marijuana use is being voluntarily regulated in these settings ; moreover , it is critical to understand correlates of having fewer restrictions on marijuana use in these settings to potentially inform interventions aimed at increasing certain restrictions . the theory of planned behavior ( tpb ) , with its focus on the impact of attitudes , subjective norms , and perceived behavioral control on behavior , has been applied to adopting home restrictions for cigarette smoking and thus may be an appropriate framework for this issue . notably , research has shown that attitudes about marijuana use and expectations of family members and close friends ( i.e. , subjective norms ) are influential in predicting the adoption of smoke - free rules in residential settings [ 12 , 13 ] . given the importance of this emerging and complex public health issue , our research aims were to ( 1 ) characterize rules regarding marijuana and its use in households among young adult population recruited via an online social networking site and ( 2 ) document correlates of having less restrictive rules including sociodemographic factors , personal marijuana use , social factors , and perceptions of marijuana risk . we recruited participants aged 1834 years via advertisements on facebook , a social networking website , targeting tobacco and marijuana users and nonusers . we advertised to facebook users who liked certain tobacco- or marijuana - related pages ( e.g. , major cigarette brands and magazines focusing on marijuana ) or had identified related interests ( e.g. , advertisements included images of tobacco products , marijuana - related images , and other benign images intended to recruit nonusers . individuals who clicked on the advertisement were directed to a page describing the survey and the consent statement . consenting individuals were screened for eligibility ( i.e. , age ) ; those eligible were forwarded to the online survey , administered via http://www.surveygizmo.com/. to limit duplicate responses , one response per ip address was permitted . 2251 did not complete the entire survey ( 52.6% of whom did not move past the information and consent ) ; 699 were disqualified , including 482 who were outside the age range , 77 who declined consent , and 140 who provided invalid responses . thus , 1,567 had complete and valid responses . in our sample , 648 ( 41.6% ) the average number of days of use in the past 30 days was 17.86 ( sd = 11.29 ; not shown in table 1 ) . this high prevalence of marijuana use in this sample was intentional , per our recruitment approach targeting tobacco and marijuana users . we intended to ensure that the phenomenon of interest was relevant to the sample , particularly given that the vast majority of the us population does not face issues related to marijuana use in their home . marijuana users implicitly make decisions about use in the home , and tobacco users are more likely to affiliate with marijuana users , suggesting that they may also face decisions about marijuana use in their home . this sample allowed us to explore this phenomenon within a sample where this topic was relevant , including both marijuana users and marijuana nonusers . the survey assessed standard sociodemographic factors and health - related factors ; health - related factors included in the current analyses are detailed below . participants were asked , in the past 30 days , on how many days did you use marijuana ( pot , weed , hashish , hash oil ) ? . participants were asked if any parental figures , anyone living in their home , or their significant other uses marijuana and , out of his / her five closest friends , the number who use marijuana . participants were asked to rate on a scale of 1 = not at all to 7 = extremely the extent to which they perceived marijuana to be socially acceptable among peers , harmful to health , addictive , and harmful to those exposed to its byproducts . always true , or does not apply . to quantify the relative restrictions within the sample , an aggregate score of the household marijuana rules ( hmr ) index was derived by assigning a score of 0 for never true , 1 for sometimes true , and 2 for always true or does not apply . does not apply scored 2 because participants reporting this response were not allowing certain behaviors in those contexts by default . in addition , items skipped because of inclusive or restrictive rules leading to a skip pattern were treated as 2 's as well . bivariate analyses were conducted comparing marijuana users versus nonusers and associations with hmr index scores . a multivariable regression model was then developed to identify correlates of hmr , employing backwards stepwise entry at p < .10 . table 1 presents data indicating that marijuana users versus nonusers were younger ( m = 24.49 5.09 versus m = 25.67 5.03 , p < .001 ) , were less educated ( > hs = 63.0% versus 70.7% , p < .001 ) , and were more likely to be married or living with a partner ( 62.3% versus 54.5% , p = .001 ) . in terms of social factors , they were more likely to be living with friends / relatives ( 26.9% versus 20.9% ) , have parental figures who use marijuana ( 29.9% versus 8.3% , p < .001 ) , have people who live with them use marijuana ( 48.0% versus 14.0% , p < .001 ) , and have a partner who uses marijuana ( 36.1% versus 6.5% , p < .001 ) but less likely to have children ( 23.9% versus 32.0% , p < .001 ) . users also had more friends who used marijuana ( m = 3.85 1.36 versus m = 1.42 1.55 , p < .001 ) . in terms of other attitudes about marijuana use , marijuana users versus nonusers perceived marijuana to be more socially acceptable ( m = 6.11 1.48 versus m = 4.34 2.26 , p < .001 ) , less harmful ( m = 2.18 1.49 versus m = 3.57 2.42 , p < .001 ) , and less addictive ( m = 2.54 1.79 versus m = 3.40 2.34 , p < .001 ) and perceived exposure to marijuana byproducts to be less harmful ( m = 2.30 1.66 versus m = 3.75 2.28 , p < .001 ) . overall , 46.0% ( 24.8% of users ; 61.1% of nonusers ) reported that marijuana of any type is not allowed on their property ( table 2 ) . in addition to those not allowing it on the property , 6.4% ( 5.5% of users , 7.7% of nonusers ) prohibited marijuana use on their property . of those that allowed some level of marijuana use on their property , 29.2% prohibited marijuana smoking in their home , 11.0% prohibited vaping , eating , or drinking marijuana , and 8.4% prohibited its use in outdoor areas . ( n = 30/1560 ) allowed marijuana use in the presence of children , with little variability depending on how it was used ( e.g. , smoked or vaped ) . marijuana users versus nonusers had higher hmr index scores ( m = 24.54 8.15 versus m = 29.29 5.59 , resp . , other factors associated with higher hmr scores ( table 1 ) included younger age ( p = .006 ) ; being female ( p = .029 ) ; lower parental educational background ( p = .002 ) ; being heterosexual ( p = .035 ) ; living with parents or on campus versus other situations ( p = .001 ) ; not having parents , others in the home , or a partner who uses marijuana ( p 's < .001 ) ; having fewer friends who use ( p < .001 ) ; perceiving marijuana use to be less socially acceptable , more harmful , and more addictive ( p 's < .001 ) ; and perceiving marijuana byproducts to be more harmful ( p 's < .001 ) . prior to constructing the multivariable model predicting hmr index scores , we explored collinearity among the predictors of interest . we found that number of friends who smoke was collinear with perceived social acceptability and personal use and that perceptions of harm of marijuana byproducts was collinear with perceived harm of marijuana . thus , we excluded these two variables and entered all other factors associated with hmr index scores at the p < .10 . predictors of higher hmr index scores included younger age ( beta = 0.16 , ci 0.22 , 0.09 ) , being female ( beta = 0.69 , ci 1.31 , 0.07 ) , having a bachelor 's degree or higher education ( beta = 0.57 , ci 1.06 , 0.08 ) , not having a parent ( beta = 2.00 , ci 2.88 , 1.11 ) or people living in their home who used / uses marijuana ( beta = 3.40 , ci 4.18 , 2.63 ) , perceiving marijuana use to be less socially acceptable ( beta = 0.43 , ci 0.60 , 0.26 ) and more harmful ( beta = 0.31 , ci 0.14 , 0.47 ) , and less likelihood of being a marijuana user ( beta = 2.16 , ci 2.94 , 1.39 ; adjusted r = 0.206 ) . as expected , the newly developed index correlated with theoretical factors per the tpb , such as attitudes toward marijuana ( e.g. , perceptions of harm and addictiveness ) and social factors ( e.g. , important others ' marijuana use ) ; these findings are in line with those derived from the home smoking restrictions literature [ 12 , 13 ] . there was an association between more restrictions and sociodemographics including younger age , gender , and education , which warrant further examination . in this sample of young adults , nearly half ( 46.0% ) prohibited marijuana on their property , the majority of whom were nonusers . additionally , a quarter of users prohibited marijuana on their property , implying use outside of the home . there were also some differences in the restriction of smoked marijuana versus noncombustible marijuana in the home , which might suggest that some young adults feel that covert ( i.e. , noncombustible ) use is more acceptable . in addition , a small percentage had rules about use in outdoor areas , which might impact neighbors , be observable by individuals off the property ( i.e. , on sidewalks ) , and be subject to legal restrictions , particularly in multiunit housing . this is favorable , as substance use by parents and other adults may normalize use and encourage youth initiation . this index might inform research regarding risks related to marijuana in residential environments , which is critical in a rapidly evolving context of marijuana regulations and the need to intervene to circumvent the potential harms of marijuana secondhand smoke and the impact on youth initiation . future research should also qualitatively examine how rules are voluntarily adopted and communicated within one 's social system and identify other possible rules used in these and other settings . it would also be useful to determine how well individuals understand legal restrictions on use in residential location and whether the rules as they express them are consistent with these laws . furthermore , more research is needed to inform the appropriate public health outcome , particularly given the limited research regarding the impact of secondhand marijuana smoke exposure . if so , where should use be allowed , since use in public is precluded by legalization policies and may have other public health consequences ? alternatively , is the objective to ban smoked forms of marijuana in the home or prevent use in the presence of youth ? if so , should noncombustible marijuana use and/or proper storage be encouraged ? even in a time of uncertainty regarding desired outcomes , surveillance regarding how people approach limitations include limited generalizability given that the sample was focused on young adults and specifically targeted marijuana and tobacco users in order to ensure that the phenomenon of interest was relevant to the sample obtained . also , this sample was mainly drawn from north america and thus is unlikely to represent the attitudes and values of people worldwide . we also had a relatively low response rate , which is open to selection bias . future research should examine these and other related phenomena among a more representative national sample . specifically , research might explore other dimensions of how people regulate marijuana use in other settings ( e.g. , cars ) . additionally , the online survey format does not allow us to explore the reasons why individuals might have reported does not apply for certain items . finally , the cross - sectional nature of this study limits the ability to make causal attributions . attitudes about marijuana use and subjective norms related to use are important correlates of allowing marijuana and its use in residential settings . these findings have implications for future research aimed at objectively examining areas of risk regarding household marijuana rules and informing intervention efforts aimed at reducing exposure to marijuana byproducts and youth exposure to marijuana use .

recent changes in policy and social norms related to marijuana use have increased its use and concern about how / where marijuana should be used . we aimed to characterize rules regarding marijuana and its use in homes . we recruited 1,567 us adults aged 1834 years through facebook advertisements to complete an online survey assessing marijuana use , social factors , perceptions of marijuana , and rules regarding marijuana and its use in the home , targeting tobacco and marijuana users to ensure the relevance of this topic . overall , 648 ( 41.6% ) were current marijuana users ; 46.0% of participants reported that marijuana of any type is not allowed in their home or on their property . of those allowing marijuana on their property , 6.4% prohibited use of marijuana in their home . of the remainder , 29.2% prohibited smoking marijuana , and 11.0% prohibited vaping , eating , or drinking marijuana . correlates of more restrictive rules included younger age , being female , having < bachelor 's degree , not having parents or people living with them who use marijuana , perceiving use to be less socially acceptable and more harmful , and being a nonuser ( p 's < .05 ) . attitudes and subjective norms regarding marijuana are correlates of allowing marijuana in residential settings . future work should examine areas of risk regarding household marijuana rules .

a 55-year - old female presented with 6-month history of progressively worsening right posterior calf pain . on physical exam , the right posterior calf appeared erythematous and warm with decreased range of motion . core needle biopsy of the right calf mass demonstrated diffuse - type giant cell tumor [ also known as diffuse - type tenosynovial giant cell tumor ( tgct ) ] and the patient underwent surgical resection . approximately 7 weeks after surgery , the patient noticed swelling and warmth of the right lower extremity with associated slow growth of friable red soft tissue , approximately 1 cm lateral to the incision . the patient returned to the operating room for resection of suspected recurrent tgct and debridement of devitalized tissue , ultimately followed by amputation . the slowing of disease was short - lived and , despite multiple subsequent systemic therapies first with imatinib , followed by adriamycin ifosfamide , the patient developed extensive metastatic disease with significant tumor burden in the chest and right inguinal region . radiographs taken on presentation revealed mild osteoarthritis in bilateral knees , with fullness posterior to the right knee [ figure 1 ] . post - operative ultrasound performed 7 weeks after initial resection showed a complex cystic and solid mass with hypervascular solid components [ figure 2 ] . mri demonstrated a large , well - circumscribed , mixed - density soft tissue 20-cm mass , with both solid and cystic components extending from the popliteal fossa to the mid - calf [ figure 3 ] . ct of the chest , abdomen , and pelvis showed no evidence of metastatic disease . 55-year - old female with right posterior calf pain diagnosed with tenosynovial giant cell tumor . lateral radiograph of the knee reveals soft tissue fullness in the popliteal fossa ( arrow ) . 55-year - old female with right posterior calf pain diagnosed with tenosynovial giant cell tumor . doppler ultrasound shows prominent vascularity within the solid , echogenic components of the lesion ( arrow ) . 55-year - old female with right posterior calf pain diagnosed with tenosynovial giant cell tumor . sagittal t1-weighted mr post - contrast imaging reveals enhancement of solid areas ( arrow ) . mri done 7 weeks after initial resection showed a heterogeneous lobulated lesion with enhancement of the solid components , centered within the gastrocnemius and extending 7 cm superior to the tibiofemoral joint [ figure 4 ] . low - volume lymph nodes in the right inguinal region were unchanged . given the aggressive appearance of the lesion , the patient underwent a below the knee amputation . 55-year - old female 7 weeks post - resection of tenosynovial giant cell tumor with complaints of pain and friable tissue growth at the incision site . ( a ) coronal t1-weighted post - contrast mri of the right knee shows a heterogeneous lobulated lesion extending to the mid - calf . margins of soft tissue components of the lesion are ill - defined and somewhat infiltrative in some areas ( arrowhead ) . ( b ) sagittal t2-weighted mr of the right knee shows both cystic ( thick arrow ) and solid ( thin arrow ) areas within the heterogeneous lesion . core needle biopsy of the right calf mass demonstrated diffuse - type giant cell tumor ( also known as diffuse - type tgct ) with a heterogeneous cell population consisting of sheets of larger , epithelioid cells with round nuclei and discrete cell borders in a background of histocytes , lymphocytes , and scattered hemosiderin [ figure 5a ] , the characteristic appearance of diffuse - type tgct . numerous giant cells and focal necrosis were also present . although the cytology of the tumor was atypical with a high mitotic rate of 27 per 10 high - power fields ( hpfs ) , a diagnosis of malignant diffuse - type tgct was not warranted in this limited sample as the sample did not meet five out of the eight criteria needed for a diagnosis of malignancy ( see discussion ) . immunohistochemical stains were negative for smooth muscle actin ( sma ) , desmin , cd34 ( cluster of differentiation protein ) , pan - k , and s100 protein in the small amount of tissue present . 55-year - old female with right posterior calf pain initially diagnosed with tenosynovial giant cell tumor with subsequent resection demonstrating malignant tenosynovial giant cell tumor . ( a ) core biopsy sample of the mass stained with hematoxylin and eosin , 400 , shows epithelioid cells with round nuclei and a background of lymphocytes , histiocytes , several multinucleated giant cells ( thick arrows ) , and scattered mitoses ( thin arrow ) . ( b ) although the majority of the resection specimen appears similar to the core biopsy , select areas of the resection stained with hematoxylin and eosin ( 400 ) , display pleomorphic cytology with large , highly atypical cells ( arrow ) and atypical mitoses ( arrowhead ) , consistent with the diagnosis of malignant diffuse - type tgct . the right lower extremity amputation specimen , which was received 7 weeks after the initial resection , revealed a large , cystic and solid mass extending from the popliteal fossa to the mid - calf [ figure 6 ] . microscopic examination showed areas of large , bizarre , and anaplastic epithelioid cells , warranting a diagnosis of malignant tgct . atypical mitoses were also present , and the tumor showed an infiltrative pattern , with invasion of the skin , associated ulceration and necrosis , and a mitotic rate of 23 per 10 hpfs [ figure 5b ] . hemosiderin deposition and characteristic cleft - like spaces were readily apparent , along with widespread areas with relatively bland cytology , the characteristic appearance of benign diffuse - type tgct . 55-year - old female who initially presented with progressive right posterior calf pain now status post right leg amputation for malignant tenosynovial giant cell tumor . gross pathology of the amputated right lower extremity reveals a heterogeneous tumor with cystic ( thick arrow ) and solid ( thin arrow ) components extending from the popliteal fossa to the mid - calf . immunohistochemical stains for sma , d2 - 40 ( focal ) , and desmin ( rare ) were positive in lesional cells , with cd163-positive histiocytes , while s100 , pan - k , cd34 , and leukocyte common antigen ( lca or cd45 ) immunostains were negative . these differences from the original immunoprofile were minor and also likely due to tumor heterogeneity . core needle biopsy of the right calf mass demonstrated diffuse - type giant cell tumor ( also known as diffuse - type tgct ) with a heterogeneous cell population consisting of sheets of larger , epithelioid cells with round nuclei and discrete cell borders in a background of histocytes , lymphocytes , and scattered hemosiderin [ figure 5a ] , the characteristic appearance of diffuse - type tgct . numerous giant cells and focal necrosis were also present . although the cytology of the tumor was atypical with a high mitotic rate of 27 per 10 high - power fields ( hpfs ) , a diagnosis of malignant diffuse - type tgct was not warranted in this limited sample as the sample did not meet five out of the eight criteria needed for a diagnosis of malignancy ( see discussion ) . immunohistochemical stains were negative for smooth muscle actin ( sma ) , desmin , cd34 ( cluster of differentiation protein ) , pan - k , and s100 protein in the small amount of tissue present . 55-year - old female with right posterior calf pain initially diagnosed with tenosynovial giant cell tumor with subsequent resection demonstrating malignant tenosynovial giant cell tumor . ( a ) core biopsy sample of the mass stained with hematoxylin and eosin , 400 , shows epithelioid cells with round nuclei and a background of lymphocytes , histiocytes , several multinucleated giant cells ( thick arrows ) , and scattered mitoses ( thin arrow ) . ( b ) although the majority of the resection specimen appears similar to the core biopsy , select areas of the resection stained with hematoxylin and eosin ( 400 ) , display pleomorphic cytology with large , highly atypical cells ( arrow ) and atypical mitoses ( arrowhead ) , consistent with the diagnosis of malignant diffuse - type tgct . the right lower extremity amputation specimen , which was received 7 weeks after the initial resection , revealed a large , cystic and solid mass extending from the popliteal fossa to the mid - calf [ figure 6 ] . microscopic examination showed areas of large , bizarre , and anaplastic epithelioid cells , warranting a diagnosis of malignant tgct . atypical mitoses were also present , and the tumor showed an infiltrative pattern , with invasion of the skin , associated ulceration and necrosis , and a mitotic rate of 23 per 10 hpfs [ figure 5b ] . hemosiderin deposition and characteristic cleft - like spaces were readily apparent , along with widespread areas with relatively bland cytology , the characteristic appearance of benign diffuse - type tgct . 55-year - old female who initially presented with progressive right posterior calf pain now status post right leg amputation for malignant tenosynovial giant cell tumor . gross pathology of the amputated right lower extremity reveals a heterogeneous tumor with cystic ( thick arrow ) and solid ( thin arrow ) components extending from the popliteal fossa to the mid - calf . immunohistochemical stains for sma , d2 - 40 ( focal ) , and desmin ( rare ) were positive in lesional cells , with cd163-positive histiocytes , while s100 , pan - k , cd34 , and leukocyte common antigen ( lca or cd45 ) immunostains were negative . these differences from the original immunoprofile were minor and also likely due to tumor heterogeneity . tgct was first described in 1852 by chassaignac as synovial membrane proliferation involving the flexor tendons of the fingers and was later redefined by jafee et al . , to encompass lesions involving the synovium , tendon sheath , bursa , and joint . the most common type of localized tgct is also referred to as giant cell tumor of the tendon sheath , which typically occurs as a localized nodule on the tendon sheaths of the fingers or toes . on the contrary , the diffuse type tends to infiltrate the joint , and more frequently involves large joints , most commonly the knee , followed by the hip . diffuse - type tgct tends to be more aggressive , often recurring locally ( 856% ) , and is capable of malignant transformation . enzinger et al . , first described malignant tgct as uncontrolled growth within a benign lesion or as the recurrence of a previously benign lesion . despite aggressive management , including surgical resection , chemotherapy , and radiation , prognosis in malignant tgct is poor . lesions most commonly metastasize to regional lymph nodes and lungs , with a median survival of 22.5 months after diagnosis . time to metastatic disease ranges from 4 months to 5 years , with a median of 11 months . li et al . , and bertoni et al . , described the following histologic characteristics as suggestive of malignancy : nodular and/or solid infiltrative growth pattern , large round or oval cells , cells with large nuclei and nucleoli , areas of necrosis , and atypical mitoses . criteria for malignant tgct were also developed at the armed forces institute of pathology ( afip ) to include five out of eight characteristics including diffuse pleomorphism , prominent nucleoli , high cytoplasmic to nuclear ratios , mitotic ratio greater than 10 per 10 hpfs , necrosis , discohesion of tumor cells , paucity of giant cells , and a diffuse growth pattern . our case demonstrated features described by both bertoni et al . , and the afip to be classified as malignant [ figure 5b ] and the initial biopsy of the lesion was atypical including a mitotic rate greater than 10 per 10 hpfs as well as necrosis ; however , it did not fulfill enough of the criteria to be classified as malignant tgct . radiographic appearance of tgct is non - specific , ranging from soft tissue swelling to soft tissue mass and bony involvement . radiographs of tgct lesions most commonly demonstrate joint effusion , soft tissue swelling , bony erosion , and lack of calcification in the context of normal bone mineralization and preservation of the joint space . similarly , ultrasound is non - specific ; however , it is useful for characterizing its solid and cystic components . mri is superior due to its better delineation of soft tissues and its ability to more accurately determine the extent of synovial proliferation , joint effusion , bone erosion , and deposits of hemosiderin . tgct lesions generally have hemosiderin deposits , which will appear as dark , low - signal regions on t1-weighted and t2-weighted images , with associated susceptibility artifact on gradient echo sequences . the presence of hemosiderin is characteristic of tgct lesions ; however , it can also be seen in other lesions such as synovial hemangioma or hemophiliac arthropathy and does not correlate with malignant potential . regions of enhancement can be seen in tgct in the regions of synovial proliferation , but do not predict the aggressiveness of the lesion . imaging of malignant tgct is rarely reported , and the only description of the mri characteristics suggestive of malignant tgct is reported in the pathology and rheumatology literature and includes frequent lobulation , infiltrative lesions with poorly defined margins , and close association with tenosynovial structures and/or joint spaces . murphey et al . , suggest that findings most consistent with a malignant lesion are bony invasion and presence of metastases . our patient 's first post - resection mri included multiple areas of lobulation and close association with the joint ; however , these findings are also often seen in benign disease . the most concerning feature of the post - resection mri was diffuse involvement of the medial and lateral gastrocnemius muscles with an infiltrative appearance and loss of clear tissue planes , a finding that was not seen on the initial mri . in all reported cases , the diagnosis of malignant tgct was not made until after histopathologic examination of the biopsied lesion , most likely because of the low incidence of the lesion and the paucity of imaging of malignant tgct in the literature . this case highlights the appearance of malignant tgct on multiple imaging modalities . while no single clinical , histopathologic , or radiographic feature separates benign from malignant lesions , a compilation of findings including rapid recurrence , and infiltrative appearance on imaging with invasion of adjacent soft tissues suggest malignancy . therefore , the current standard of practice remains local wide resection of tgct lesions with close follow - up and tissue sampling when clinically indicated .

malignant tenosynovial giant cell tumor ( tgct ) is a rare clinical entity that can arise as a recurrent lesion or can co - exist with a benign tgct lesion . malignant tgct most commonly arises in the lower extremity and tends to be clinically aggressive , with most patients developing recurrent lesions or dying . much of the literature describes the histopathologic features and classifies this broad group of tumors , with little description of the imaging characteristics of this disease . we present the multimodality appearance of a case of malignant diffuse - type tgct that recurred 2 months after resection with subsequent rapid clinical progression .

a 19-year - old girl with rett syndrome was scheduled for elective phacoemulsification with intraocular lens insertion for immature cataracts . we did not know about her family history and other medical history because she was an orphan and she could not communicate with our medical team . but there was some description on the consultation paper from her orphanage . according to the paper , her physical disability had steadily progressed although her developmental milestones had been normal until the age of ten months , and she was known to have diffuse brain atrophy with mental retardation , including typical autistic disorder and convulsions . she also had untreated scoliosis and she had been bedridden for 5 years . on examination , her weight was 23 kg ( below the 5th percentile ) , her body temperature and blood pressure were normal and she was not distressed . the thyromental distance was 3.5 cm and the airway was normal except for trismus and excessive secretions . the preoperative hemoglobin level was 11.0 ( g / dl ) and the other lab tests were normal . on chest x - ray , the heart and lungs were unremarkable , although severe scoliosis of the t / l - spine and diffuse osteoporosis were observed . a head ct scan revealed diffuse brain atrophy , and the background was slow on the eeg . the patient was quiet on arrival to the operating room without premedication . in the operating room , her pulse oximetry was 99% on room air and her blood pressure was 110/75 mmhg . after loss of consciousness , mask ventilation was started with 2 vol% of sevoflurane . because we expected her trismus would be improved after injection of rocuronium , direct laryngoscopy was attempted . so , the fiberoptic - guided nasotracheal technique was initially chosen considering the extremely limited mouth opening , but this was unsuccessful because her nostrils were too small to intubate with a tube with an internal diameter of 5.0 mm . before an attempt was made with a 4.5 mm tube , we realized that the small space due to the malocclusion was large enough to handle a 480-sized oral airway ( diameter : 0.48 mm ) . fiberoptic - guided orotracheal intubation through this space was then successfully performed with suction ( fig . the trachea was intubated with a 5.0 mm oral tracheal tube and it was fixed at 18 cm . anesthesia was maintained with n2o 2 l / min , o2 2 l / min , sevoflurane 1.0 - 2.0 vol% , a tidal volume of 200 ml and a rr of 18/min . after the completion of surgery , which lasted 1 hour and there were no complications , the nitrous oxide and sevoflurane were discontinued , and the muscle relaxant was reversed with glycopyrrolate 0.2 mg and pyridostigmine 10 mg . we tried to wean her from the ventilator , but her recovery was slow and complicated by episodes of shaking . the patient was then transferred to the pacu after her respiration was found to be adequate . she remained drowsy in the pacu and it took a full day for her to regain full consciousness . rett syndrome is characterized by a devastating deterioration of the central nervous system in young females and it is accompanied by neurological problems that are associated with failure to thrive . there is a lack of sufficient data to make reliable estimates about the life expectancy beyond the age of 40 , although the average life expectancy of a girl with rett syndrome may be in the mid-40s . microcephaly due to growth retardation , diminished muscle tone , decreased eye contact and inattentive behavior develop during this period . immobility , respiratory dysrhythmia ( hyperventilation , periodic apnea ) , gastrointestinal dysfunctions ( peristalsis , esophageal atony , obstipation , etc . ) , spasticity , joint contraction and arrhythmias due to cardiac transduction defects also appear with disease progression . so , there are several points to consider for the anesthetic management of rett syndrome patients . the presence of scoliosis and muscular tonicity and the breathing abnormalities that range from centrally mediated hyperventilation to apnea make it necessary to evaluate the respiratory status using oxygen saturation to predict the outcomes before surgery . there is also a great risk of aspiration pneumonia during anesthetic induction or emergence due to esophageal atony . there are no reports about anesthetic experiences in patients with rett syndrome and who have limited mouth opening . but it can cause difficulties to correctly position the patient and if it involves the tm joint like our case , the anesthesiologist can be confronted with problems during orotracheal intubation or airway management . antegrade fiberoptic - guided orotracheal or nasotracheal intubation , retrograde guidewire - assisted fiberoptic intubation and blind nasal intubation can be considered . fortunately for us , antegrade fiberoptic - guided orotracheal intubation was possible to perform by an experienced anesthesiologist . yet we also prepared a tracheostomy set to secure the airway in the event of severe difficulty when securing the airway . we should check the breathing patterns , the preoperative arterial blood gases , the presence of gastrointestinal reflux and autonomic disturbances , the seizure history , the ecg and the musculoskeletal system . we should carefully interview the patient and the guardians for obtain proper information about the patient . however they thought that patients with rett syndrome may be unduly sensitive to sedative drugs and they exhibit slow recovery from anesthesia . so , the anesthesiologist should have great concern about the choice of anesthetics and maintaining the proper depth of anesthesia . in conclusion , we experienced great difficulty securing the airway in an adult female patient with rett syndrome during minor surgery , and this is the first report about the anesthetic management of a patient with rett syndrome . the patient with rett syndrome has many difficulties and points to be considered for anesthetic management , as described above . anesthesiologists should have proper knowledge about the disease and the patients to avoid the complications and problems that can be encountered during the perioperative and postoperative periods .

rett syndrome is a neurological disease that occurs only in females and it manifests with mental retardation , seizures , movement disorders , autistic behavior and abnormal breathing . a 19-year - old female with rett syndrome underwent ophthalmologic surgery under general anesthesia at our institution . airway control was difficult due to her limited mouth opening . we recommend that anesthesiologists should have proper knowledge about this disease and the patients to avoid the complications and problems that can be encountered during the perioperative period .

pituitary apoplexy is a well - known clinical syndrome characterized by headache , meningeal irritation , visual loss , ophthalmoplegia , and alterations in consciousness ( 1 ) . , we report a rare case of a 43-yr - old man with pituitary apoplexy presenting with hemiplegia . a 43-yr - old man presented with a sudden onset of severe headache , visual disturbance and left hemiplegia . the initial neurological examination showed an impaired direct / indirect light reflex of the right eye and a right third nerve palsy , accompanied by anisocoria and ptosis . his motor power was grade ii on the left side . computed tomography ( ct ) scans of the brain showed an enlarged pituitary fossa containing a hemorrhagic pituitary tumor ( fig . 1a ) . magnetic resonance imaging ( mri ) revealed a nodular mass , approximately 323 cm in size , located in the sella and suprasellar portion , accompanied by compression of the optic chiasm ( fig . the mass compressed the bilateral cavernous sinuses , resulting in the obliteration of the cavernous portion of the right internal carotid artery ( fig . a border zone infarct in the right fronto - parietal region was also found ( fig . although the patient 's level of consciousness improved during the next 24 hr , the focal neurological signs persisted . the patient 's vision improved immediately after the decompression , but the left hemiplegia persisted . 3 ) . a conventional cerebral angiography performed one week after the operation and mr angiography demonstrated the restoration of flow within the right internal carotid artery ( fig . his left side motor power improved to grade iv within six months after the operation . the occurrence of cerebral ischemia , or infarct , in patients with pituitary apoplexy is rare , with only 13 cases reported thus far . the ischemic events were attributed to cerebral vasospasm in six cases ( 2 - 6 ) and to mechanical compression by tumor in seven cases ( 7 - 13 ) . however , several hypotheses have been proposed to account for vasospasm following surgery for pituitary adenoma and other parasellar tumors ( 14 , 15 ) , such as the presence of subarachnoidblood , the release of vasoactive chemical substances from the tumor , hypothalamic damage and dysfunction , and intraoperative manipulation . bilateral involvement of the intracerebral arteries was common in cases of cerebral vasospasm . in our case , the restoration of cerebral blood flow following the decompression of the apoplexy was confirmed angiographically . the characteristics of patients whose ischemic events were attributed to the mechanical compression of the cerebral arteries by a pituitary apoplexy are summarized in table 1 . pituitary apoplexy was associated with both a cerebral angiography and a triple bolus test with the intravenous injection of luteinizing hormone - releasing hormone , thyrotropin - releasing hormone and regular insulin ( 7 , 11 ) . the occlusion sites of the compromised vessels were primarily located in the supraclinoid or cavernous portions of the internal carotid artery . theoretically , the pressure of the pituitary apoplexy should be stronger than the intraarterial pressure for the mechanical compression . intrasellar pressure measurements in patients with pituitary apoplexy were conducted in a previous study ( 16 ) . the measurements ranged from 25 - 58 mmhg , with a median pressure of 47 mmhg . moreover , the tight dural attachment of the cavernous and clinoid segments in addition to the surrounding bony structures could create additional pressure and a barrier that occludes the compensatory space of the compromised vessels , resulting in further mechanical compression . emergent decompression was performed in two cases ( 9 , 11 ) of pituitary apoplexy associated with cerebral infarction . the decompression of the internal carotid artery resulted in a patent vessel , but the procedure was also likely to result in the hemorrhagic transformation of the infarct area . the combined effect of the infarct and the brain edema was usually the cause of mortality in patients who underwent emergent decompression . on the other hand , delayed decompression following conservative therapy with steroids was associated with better outcomes in patients with cerebral infarct . we performed delayed surgery following steroid administration in our patient , which resulted in the immediate improvement of the patient 's vision . the patient 's motor weakness steadily recovered with physiotherapy , and the patient is now capable of walking without assistance . if the pituitary apoplexy is associated with cerebral ischemia rather than infarct , as in the case described by bernstein et al . ( 7 ) , early operative management to restore the flow in the carotid artery may result in the resolution of the neurological deficits . motor weakness following pituitary apoplexy is rare , but clinicians should pay close attention to the initial images in order to differentiate between infarct and ischemia in cases of pituitary apoplexy .

we report a case of pituitary apoplexy resulting in right internal carotid artery occlusion accompanied by hemiplegia and lethargy . a 43-yr - old man presented with a sudden onset of severe headache , visual disturbance and left hemiplegia . investigations revealed a nodular mass , located in the sella and suprasellar portion and accompanied by compression of the optic chiasm . the mass compressed the bilateral cavernous sinuses , resulting in the obliteration of the cavernous portion of the right internal carotid artery . a border zone infarct in the right fronto - parietal region was found . transsphenoidal tumor decompression following conservative therapy with fluid replacement and steroids was performed . pathological examination revealed an almost completely infarcted pituitary adenoma . the patient 's vision improved immediately after the decompression , and the motor weakness improved to grade iv+ within six months after the operation . pituitary apoplexy resulting in internal carotid artery occlusion is rare . however , clinicians should be aware of the possibility and the appropriate management of such an occurrence .

implantable cardioverter - defibrillator ( icd ) implantation is performed at many centers in korea,1)2 ) however , icd lead extraction has not yet been reported . we report our experience of icd lead extraction using locking stylet and polypropylene dilator sheath in a patient with recurrent inappropriate shocks due to lead fracture . a 46-year - old man presented to our institution for evaluation of repeated , inappropriate , icd shocks . icd ( single chamber , dual coils , vitruso dr d164awg , medtronic inc . , minneapolis , mn , usa ) was implanted for sustained monomorphic ventricular tachycardia associated with unstable hemodynamics and underlying systolic left ventricular dysfunction . the ejection fraction of 30% was recorded two years ago at another hospital . during icd implantation , ventricular fibrillation was induced by t - shock and successfully terminated by biphasic shock at 10 j icd interrogation revealed 33 episodes of shock delivery due to noise sensing . however , a definite break point of icd lead was not detected on chest x - ray . icd therapy was switched off based on a clinical diagnosis of icd lead fracture , and the patient was transferred to our hospital . the icd lead ( sprint quattro 6944 , medtronic inc . , minneapolis , mn , usa ) was tined , and the diameter of lead tip and shaft ( comprising shock coil ) was 2.7 mm . icd lead extraction was performed with support from the cardiac surgery team . following routine preparation for generator removal the disconnected lead was tested again to exclude connection problem between icd lead and the generator , which showed high impedance over 2,500 ohms . lead extraction was performed after confirming icd lead fracture . a locking stylet ( liberator locking stylet 016 - 032 , cook vascular inc . , vandergrift , pa , usa ) was inserted into the central core of the icd lead to prevent lead disruption . a 12 fr ( 4 mm ) polypropylene dilator sheath ( byrd dilator sheath sets , cook vascular inc . , vandergrift , pa , usa ) was inserted over the icd lead for counter - traction . mild traction force was applied to the locking stylet to straighten the alignment of the icd lead and the dilating sheath . the dilator sheath was advanced with bidirectional ( clockwise and counter - clockwise ) rotation to dissect adhesive fibrous bands formed around the icd lead . when the dilator sheath was placed 1 - 2 cm below the tip of rv - lead , the locking stylet was pulled gently with gradually increasing traction forces . the icd lead and dilator sheath were successfully removed without evidence of lead fragments remaining in the right ventricle ( rv ) ( fig . there was no evidence of major complications , such as hemopericardium , hemothorax , and myocardial inversion . after confirming successful icd lead extraction , a new icd lead was inserted into rv followed by skin closure . pacemaker or icd rv - lead extraction is a high risk procedure with a morbidity of 1.4 - 2.5%.3)4 ) fibrous tissues encapsulate implanted leads and cause adhesion to major veins , the right atrial or the ventricular wall.5 ) major complications such as hemopericardium , hemothorax and death occur during fibrous tissues dissection around the implanted leads.6 ) incomplete lead removal or procedure failure is another clinical problem that occurs in 7 - 13.2% of cases.3)4 ) if an infected lead is retained , the risk of treatment failure with antibiotics will be very high.7 ) even non - infected lead fragment may cause embolic complications.8)9 ) therefore , various extraction techniques have been tried to improve the success rate of complete lead removal . they include direct traction with rotational forces,10 ) traction with locking stylet,11 ) counter - traction with dilating sheath,3)4 ) femoral workstation,12 ) laser sheath,13 ) and electrosurgical sheath.14 ) traction and counter - traction using locking stylet and dilating sheath is a conventional technique for pacemaker and icd lead extraction . it has been proven to be effective and safe in clinical trials.3)4 ) although newly developed techniques such as electrosurgical or laser sheath are in clinical use , they have not been introduced in korea , and the conventional technique using locking stylet and dilator sheath is still useful if performed by experienced operators.14 ) the authors tried 25 pacemaker and one icd lead extractions associated with lead malfunction or infection since 2004 . of the 26 cases , 24 cases were successfully managed with the conventional traction and counter - traction technique using locking stylet and dilator sheath . in the two failed attempts , the operators could not advance the dilator sheath to the icd lead tip due to severe fibrous adhesion at the subclavian vein and in the superior vena cava . of the 24 successful cases , open heart surgery was performed in one case due to cardiac tamponade following complete pacemaker ventricular lead extraction . icd lead extraction is known to have higher complication rate than pacemaker lead extraction.6 ) however , it can be removed successfully with the same techniques . to our knowledge , this is the first icd lead extraction case reported in korea .

a 46-year - old man presented to our institution with inappropriate implantable cardioverter - defibrillator ( icd ) shock delivery . the icd ( single chamber , dual shock coils ) was implanted for sustained monomorphic ventricular tachycardia with unstable hemodynamics and underlying systolic left ventricular dysfunction . icd interrogation revealed recurrent episodes of icd shock due to noise sensing and increased impedance of right ventricular ( rv)-lead . with the impression of lead fracture , icd lead extraction was performed . the fractured icd lead was completely removed by traction of locking stylet and counter - traction of polypropylene dilator sheath . a new lead was inserted and the patient was discharged without complications after 2 days . to our knowledge , this is the first report on icd lead extraction by conventional traction and counter - traction technique in korea .

the patient had received medical treatment due to a mild fever , cough , and yellowish sputum that developed 10 days prior , but the symptoms had not improved . furthermore , his oral intake had become worse 5 days before and hemoptysis started 2 days before admission to our hospital . at first , about a 10 ml of bloody sputum developed , but the amount progressively increased and eventually approximately 100 ml of bloody sputum was produced per hour . the patient was a white - collar worker , who had smoked 1 pack of cigarettes per day for 40 years and had consumed 1 alcoholic drink per day , 4 times a week , for 40 years . he had been diagnosed with diabetes mellitus at a regional hospital 3 years earlier and was still on medication . he was also diagnosed with bronchiectasis at a regional hospital 3 years earlier , and received medical treatment for the bronchiectasis 1 year earlier . at the time of that treatment , he did not undergo a bronchial artery embolization , but continued to receive drug therapy . the three months prior to admission at our hospital , episodic chest tightness developed , which became aggravated especially after intensive exercise . he reported that a reevaluation of his chest tightness and dyspnea at a regional hospital had not revealed any specific findings other than bronchiectasis . when admitted to our hospital , his blood pressure was 117/59 mmhg , heart rate was 87 beats / min , respiratory rate was 19 breaths / min , and body temperature was 37.6. the laboratory test results were within normal limits except the wbc ( 12,400/l ) and crp ( 10.08 ) . the electrocardiogram on admission showed a normal sinus rhythm and a chest radiograph showed a bronchiectatic change in the left lower lung ( fig . 1 ) . contrast - enhanced multidetector chest computed tomography ( mdct ) revealed a severe cylindrical bronchiectatic change in the left lower lung field , and tortuous and anomalous communicating vascular crowding around the left hilum that was communicating with the right coronary artery ( rca ) ( fig . 2 ) . since the transthoracic echocardiography revealed decreased wall motion in the rca territory , a coronary angiography was performed to rule out coronary vascular disease . coronary angiography via the radial artery revealed a coronary - bronchial artery fistula originating from the rca and extending to the bronchial artery . however , we performed surgical treatment in an attempt to treat the underlying bronchiectasis . under general anesthesia , a posterolateral thoracic incision was made . a left lower lung lobectomy was performed and the coronary - bronchial artery fistula was removed . his clinical symptoms including chest tightness and dyspnea improved , and he was discharged from the hospital . at a 24-month follow - up , his postoperative course was found to be uneventful without any recurrence . a coronary - bronchial artery fistula is a rare congenital anomaly that occurs at the coronary artery . it has been reported that this anomaly is detected in 0.18% of patients who undergo coronary angiography . with advances in diagnostic technologies such as mdct , many cases of coronary - bronchial artery fistula have recently been reported . however , its pathogenesis has not yet been elucidated . most cases of coronary - bronchial artery fistula have no clinical implications because they are asymptomatic , whereas some cases are related to the tetralogy of fallot , a supraventricular aortic stenosis , aortitis syndrome . several previous reports have proposed that patients with a coronary - bronchial artery fistula need aggressive treatment , including embolization , in order to prevent lethal complications such as infective endocarditis or an aneurysmal rupture . a comprehensive physical examination and thorough review of a patient 's history are extremely important for determining the diagnosis of this fistula . contrast - enhanced mdct with retrospective electrocardiogram gating is an accurate and non - invasive screening test , which allows for more acceptable diagnostic outcomes with advances in ct resolution . echocardiography is essential to the evaluation of concurrent cardiac anomalies and left - to - right shunts . in our patient , shin et al . have demonstrated that functional tests including the myocardial perfusion scanning are helpful in the diagnosis of coronary - bronchial artery fistula . a great variety of clinical features have been reported in patients who has coronary - bronchial artery fistula . hackett and hallidie - smith reported a case of spontaneous closure of a coronary artery fistula secondary to thrombosis . the severity of the clinical features of a coronary - bronchial artery fistula depends on the degree of the left - to - right shunt . as the degree of the left - to - right shunt increases , complications such as pulmonary hypertension or congestive heart failure . a few cases of rupture or thrombosis of coronary artery fistulas have been reported in association with arterial aneurysms or coronary steal phenomena . our patient presented with only chest pain and hemoptysis , and the diagnosis of a coronary - bronchial fistula was established by mdct , which was performed to assess massive hemoptysis . it seems likely that recurrent life - threatening hemoptysis may be attributed to coronary - bronchial artery fistula associated with bronchiectasis , and that patients with such fistulas can be treated surgically . however , since a standard treatment method for coronary fistulas has not yet been determined , most patients have been managed in light of anecdotal case reports or small series of cases . further studies with a larger number of cases are needed to understand the clinical features and to establish a standard treatment modality . closure of coronary - bronchial artery fistula is mainly indicated for patients with heart failure , myocardial ischemia , or high - flow shunting . shin et al . have proposed prophylactic and therapeutic embolization of coronary - bronchial artery fistula in patients with bronchiectasis . however , patients with such fistulas should be treated based on the presence of concurrent cardiac anomalies as well as the clinical evaluation of other organs . embolization can be safely performed after the anatomical relationships between the fistula and the surrounding structures are completely assessed . kang et al . have indicated that contrast - enhanced mdct coronary angiography is helpful in the identification of the course of a coronary - bronchial artery fistula . we reported the case of a patient with a coronary - bronchial artery fistula who presented with angina symptoms and bronchiectasis and was successfully treated . further studies are needed to understand the precise pathogenesis of the fistula and the relationship between the fistula and bronchiectasis .

a coronary - bronchial artery fistula is a very rare congenital anomaly of the coronary artery whose etiology and pathogenesis have not yet been clarified . most patients with coronary - bronchial fistulas are asymptomatic ; however , some patients present with congestive heart failure , infective endocarditis , myocardial ischemia induced by a coronary steal phenomenon , or rupture of an aneurysmal fistula . furthermore , patients with a coronary - bronchial artery fistula rarely manifest life - threatening hemoptysis due to the associated bronchiectasis . we report herein the case of a patient with a coronary - bronchial artery fistula who had bronchiectasis and a history of massive hemoptysis and myocardial ischemia .

abnormal variation of the posterior corneal curvature may occur in two forms : the generalized posterior keratoconus , characterized by an regular increase of the curvature of the entire posterior corneal surface has , and the circumscribed posterior keratoconus , in which a localized paracentral or central posterior corneal indentation is seen . in the generalized form , the corneal stroma typically remains clear . in contrast , the circumscribed posterior keratoconus shows stromal opacities overlying the localized anterior ectasia of the posterior surface , which may occupy the full stromal thickness . circumscribed posterior keratoconus is usually bilateral and sporadic , but familial cases have been also documented . despite the anterior protrusion in some cases , the 60-year - old white male of mediterranean origin presented for a cataract extraction on his left eye . visual acuity was 20/25 in the right eye and light perception in the left eye due to cataract formation . the patient denied history of injury , reporting only a bilateral ocular infection in childhood was reported . slitlamp examination revealed a bilateral paracentrally localized depression of the posterior curvature measuring 3 mm in diameter . there was scarring in the overlying corneal stroma ( figures 1 , 2 , and 3 ) . the posterior depression was clearly detectable using ultrasound biomicroscopy ( humphrey , zeiss , oberkochen ) ( figure 5 ) and slit - scanning topography analysis ( orbscan , bausch and lomb ) ( figure 6 ) . corneal thickness measured 450 m within the lesion and 540 m in the adjacent healthy cornea using the orbscan system . the refractive power of both the posterior and anterior corneal curvature was 50 to 56 diopters within the paracentral area . following phacoemulsification and posterior chamber lens implantation visual acuity increased to 20/50 in the left eye . the clinical and topographic findings in this patient are consistent with the paracentral keratoconus posterior circumscriptus . this is the first report on ultrasound biomicroscopy to visualise the local anterior bulging of the posterior corneal surface with concomitant thinning of the stroma . light microscopy of this abnormality has shown focal disorganization of basal epithelium and basement membrane , a replacement of bowman 's layer by fibrous tissue , a thinned stroma with an irregular arrangement of the central collagen lamellae , and a variable appearance of descemet 's membrane with posterior excrescences indentating the vacuolated endothelium correspond to the corneal guttae seen in specular reflection . iron deposits are present in the basal and suprabasal epithelium , corresponding to the brownish epithelial line observed clinically , indicating an irregularity of the anterior corneal surface . visualisation of the posterior keratoconus using corneal topography analysis has been reported so far in a few cases [ 7 , 8 ] . the light microscopy findings suggest an early pathogenic mechanism probably originated in the fifth or sixth month of gestation . it is classified as one of the anterior chamber cleavage anomalies ( mesenchymal dysgenesis ) , as there are other anterior segment and systemic developmental abnormalities , as well as melanin depositions surrounding the posterior depression and iridocorneal adhesions . however , not all cases share this phenomenon . acquired cases occur and are usually associated with trauma [ 9 , 10 ] . the mechanism in such cases involves an oblique penetrating injury with splitting of the inner corneal layers . differential diagnosis also includes congenital disorders as peter 's anomaly and congenital hereditary endothelial dystrophy but they are usually found in new borns . inflammation process as perforated corneal ulcer may also be taken into consideration , but it is usually unilateral . in most of the cases of posterior keratoconus the vision is not affected , rarely it may be associated with other ocular abnormalities as polar cataract , lenticonus , and ectopia lentis .

this paper documents a rare nonprogressive developmental disorder bilateral circumscribed posterior keratoconus in a 60-year - old man referred for a cataract surgery . for the first time ultrasound biomicroscopy was used to visualise the local anterior bulging of the posterior corneal surface with concomitant thinning of the stroma . the amount of localized posterior depression , corneal thickness and the refractive power of both the posterior and anterior corneal curvature were measured using slit - scanning topography analysis ( orbscan ) .

despite the improvement in both patient and short - term renal allograft survival in the last decade , probably because of newer and more specific immunosuppressive agents in addition to improved surgical and medical cares , long - term graft failure continues to plague kidney allografts with both immune - dependent and -independent factors which continue to contribute to failure . even the morbidity and mortality remain much higher than in the general population , mainly due to the complications of immunosuppressive therapy . a number of promising observations made in human kidney recipients suggest unique protein and genetic signatures that may identify biomarkers of injury , as well as potential targets of therapy . some of these may be obtained through noninvasive methods and may thus be extremely useful in the clinical realm [ 1 , 2 ] . nonspecific etiopathogenic graft parenchymal lesions in allograft biopsies , graft function evolution using surrogate markers of graft dysfunction such as serum creatinine or proteinuria , and indirect measurements of the alloimmune response using blood trough levels of immunosuppressants are the current markers used worldwide in the clinic in renal transplantation . huge effort is being made among the transplant community investigating novel biomarkers at different biological levels that enable transplant clinicians to identify patients at risk for allograft rejection or , conversely , patients in whom immunosuppression could be safely minimized or even ideally withdrawn because of their biological suitability to accept the renal allograft . the search for biomarkers of tolerance or rejection has been focusing at different biological levels , including analysis of sera looking for alloantibodies , peripheral blood mononuclear cells ( pbmcs ) using different techniques ( flow cytometry , microarrays , and reverse transcription pcr ) , analysis of the urine at the protein , peptide or transcriptomic level , histological assessment of transplant biopsies , and , finally , functional assays measuring alloreactive or antiviral pbmc responses . because of the relatively easy induction of permanent renal allograft acceptance in mice with minimal amount of immunosuppression , some groups have assessed the expression of certain genes during either rejection or permanent graft acceptance both in peripheral blood and within the graft tissue . interestingly , the assessment of two particular gene fragments such as tolerance - associated gene-1 , a mitochondrial protein t - cell apoptosis ( toag-1 ) , and a-1,2-mannosidase ( relevant gene for the n - glycosylation of membrane bound and secreted proteins ) in a model of kidney and cardiac rat transplantation was shown to be downregulated both in peripheral blood and within the kidney graft prior and during acute and chronic rejection and highly expressed during induction and maintenance of graft acceptance with high specificity and reproducibility . both clinical and experimental observations suggest that allograft rejection is a complex process with multiple components that are , at least partially , functionally redundant . studies using graft recipients which are deficient in certain genes including chemokines , cytokines , and other immune - associated genes frequently produce a phenotype of delayed , but not indefinitely prevented , rejection . only a small subset of genetic deletions ( e.g. , tcr _ or _ , mhc i and ii , b7 - 1 and b7 - 2 , and recombinase - activating gene ) permit permanent graft acceptance suggesting that rejection is orchestrated by a complex network of interrelated inflammatory and immune responses . to investigate this complex process , oligonucleotide microarrays have been used to generate quantitative mrna expression profiles following transplantation genes upregulated during the early phase included genes with prior biological functions associated with ischemia , injury , and ag - independent innate immunity , whereas genes upregulated in the late phase were enriched for genes associated with adaptive immunity . there are several stages to perform a microarray analysis : preparation of the microarray ; generation of fluorescent targets from the rna of the samples , hybridization to the probes , data acquisition : scanning of the signal intensity emanating from the hybridized labeled probes , and then data analysis which is often the most challenging component of gep . in general , cdna microarray experiments require more than 50 micrograms of total rna from target tissues , while 5 micrograms may be sufficient for an oligo array experiment . moreover , in a cdna microarray , a control sample ( e.g. , normal as compared to diseased tissue ) is simultaneously analyzed along with the test sample on the same chip . the development of high microarray technology by assessing changes in expression of multiple genes and quantitation of proteins within human cells , plasma , or tissues will provide the opportunity for novel insight into molecular pathways of tissue injury and disease processes [ 712 ] . recently , the diagnostic sensitivity , specificity , and accuracy of histological diagnosis using this technology have been improved [ 13 , 14 ] and both biomarker panels and individual biomarkers have been identified within the allograft to improve the diagnostic , prognostic , and potentially therapeutic categorization of acute rejection [ 1518 ] . noninvasive sources such as peripheral blood have increasingly been targeted to provide information in the field of organ transplantation [ 1922 ] . the biological function of the expressed genes encompasses major biological categories of cellular processes related to immune signal transduction , cytoskeletal reorganization , and apoptosis and emphasizes the participation of the cytokine - activated jak - stat pathway and interferon signaling in lymphocyte activation proliferation , chemotaxis , and adhesion . 2010 , have observed that the characteristic changes in the plasma proteome were paralleled to plasma proteins changes that encompassed processes related to inflammation , complement activation , blood coagulation , and wound repair which were significantly different between patient cohorts with and without biopsy - confirmed acute rejection . , 2008 reported that measurement of the expression levels of a small set of genes in peripheral blood could be useful to accurately identify liver recipients who are able to accept their grafts in the absence of pharmacological immunosuppression . validation of such findings in prospective immunosuppression weaning trials would open the door to the possibility of withdrawing immunosuppressive drugs in transplant recipients with high likelihood of being tolerant . further , functional analysis of expression patterns suggests that molecular pathways involved in the activation and function of innate immunity cell types ( nk and tcr+ t cells ) are central to the maintenance of operational tolerance following liver transplantation . all these findings explain the value of peripheral blood transcriptional profiling in the immune monitoring of liver transplant recipients and provide insight into the pathogenesis of human allograft tolerance . in this direction , different expression patterns of selected genes have been reported to be upregulated or downregulated during allograft rejection ( both t cell or antibody mediated ) , in nonimmune - mediated allograft dysfunction or in stable functioning allografts . preliminary reports , from two large consortia , showed that similar observations in tolerant patients were observed , in terms of increased expression of b - cell genes as compared with patients under conventional immunosuppression [ 26 , 27 ] . interestingly and in such direction , low expression of the mrna b - cell marker cd20 has been observed within grafts that failed as a consequence of either t - cell or antibody - mediated rejection as compared with those that had a favorable course . furthermore , the nantes group has shown increased mrna levels of two interesting markers ( granzyme b and tribbles-1 ) that were assessed in peripheral blood and in graft tissue in patients undergoing chronic antibody - mediated rejection as compared with patients with a nonimmune - mediated chronic graft dysfunction [ 29 , 30 ] . matsui et al . identified two genes ( h2-ea and frzb ) that were highly expressed in long - term surviving heart allografts . moreover , another group has recently reported an interesting upregulation of specific set of genes ( tgf - b2 , ppenk , gm2a , gitr , and il-1r2 ) in regulatory t cells ( tregs ) associated with tolerance of skin allografts [ 32 , 33 ] . some reports have assessed the gene expression profile ( gep ) in different settings during renal transplantation . the use of dna microarrays , which allow detailed measurements of gene expression in a global scale , both in graft tissue samples and in peripheral blood , has been extensively used . investigated the molecular basis of acute rejection analyzing the gene expression patterns in 67 allograft biopsies using dna microarrays . interestingly , extensive differences in the gene expression in patients with the same histological pattern of acute rejection were observed . such differences were associated with different immunologic and cellular features as well as with a different clinical outcome . the molecular characterization using affymetrix dna microarrays ( http://affymetrix.com ) has been assessed by flechner et al . , using both peripheral blood and graft tissue samples at the same time . they were able to show a unique expression signature with upregulation of certain immune / inflammatory and profibrotic / fibrotic - associated genes in patients with high banff score lesions , in patients under calcineurin inhibitors ( cni ) , and in patients with well - functioning transplant allografts . in the same direction , mas et al . , using affymetrix microarrays in 17 renal tissue samples from 18 renal transplant patients , identified a 728-probe set genes related to immune response ( cytokine , chemokine , and receptor genes ) and to fibrosis and extracellular matrix deposition , differentially expressed between 11 kidneys with histological proven lesions of chronic rejection and seven transplant controls . on the other hand , brouard et al . reported a potential tolerance gene signature using pan - genomic cdna microarrays and real - time ( rt)-pcr in pbmcs . interestingly , they were able to screen 17 kidney transplant patients with operational tolerance and compared with patients undergoing acute or chronic rejection , others with well - functioning grafts and healthy volunteers . a tolerance footprint of 49 genes was able to correctly separate the tolerance and chronic rejection phenotypes with high specificity ( 100% ) and sensitivity ( 90% ) . also , they could identify this gene signature in six of 22 patients under immunosuppression . tolerant fingerprint , suggesting that it is not only a gene signature for being off of immunosuppression . expression of costimulatory genes and markers of early and late t - cell activation was reduced in tolerant patients and many transforming growth - factor - beta - regulated genes were interestingly upregulated . , using microarray analyses followed by rt - pcr , were able to describe a tolerance gene expression signature in an initial set of 17 tolerant and 21 nontolerant liver transplant recipients initially containing 68 genes , which comprised a large number of transcripts associated with natural killer and gdt cells . among lung transplant recipients , xu et al . 2005 , utilized this highly sensitive method using small , bronchoscopically acquired biopsy specimens of allografts . transcript signatures obtained by this approach suggested that airway and alveolar responses to rejection differ and that endobronchial biopsy specimens assess lymphocytic bronchitis and chronic rejection but are not proxies for transbronchial biopsy specimens . moreover , they reveal changes in airway expression of the specific genes involved in host defense and remodeling and suggested that measurement of transcripts correlating with lymphocytic bronchitis may be diagnostic adjuncts to histopathology . 2006 reported that gene expression testing can detect absence of moderate / severe rejection although this need additional clinical experience thus avoiding biopsy in certain clinical settings as cardiac transplant recipients . 2010 , had demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short - term posttransplantation clinical outcomes . moreover , they theorized that targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post - transplantation clinical outcomes . it is important to note that the reproducibility of differently expressed genes might be affected by many factors such as gene ranking and selection methods , inherent differences between types , and the choice of thresholds . however , because microarray analyses are expensive and time - consuming and their statistical evaluation is often very difficult , gene expression analysis using the rtpcr method is nowadays recommended . in the field of organ transplantation , gene - expression - based decision might help in improving patient and graft outcome and there are a multitude of studies showing that gene - expression profiling is feasible .

aim of review . huge effort is being made among the transplant community investigating novel biomarkers that enable transplant clinicians to identify patients at risk for allograft rejection or those who will develop tolerance so that immunosuppression could be safely minimized or even ideally withdrawn . despite the important advances achieved in the identification of several potential biomarkers of tolerance , rejection , or both , validation and demonstration of their clinical utility still needs to be tested , which will need international cooperative networks . it is important to note that the reproducibility of differently expressed genes might be affected by many factors such as gene ranking and selection methods , inherent differences between types , and the choice of thresholds . however , because microarray analyses are expensive and time consuming and their statistical evaluation is often very difficult , gene expression analysis using the rtpcr method is nowadays recommended . conclusions . in the field of organ transplantation , gene - expression - based decision might help in improving patient and graft outcome and there are a multitude of studies showing that gene - expression profiling is feasible .

pharmacopuncture refers to be in the limelight acupuncture therapy that treat diseases by using techniques such as warming ( chunghwa ) , alcohol extraction or pressing to extract drugs from one or more oriental medicines and then injecting them into specific acupoints related to the disease and adjusting meridian functions . cathami semen is the seed of the safflower and is composed of 20%-30% fatty oil ( acids ) , whose main constituents are glycerides , linoleic acid , and oleic acid , as well as serotonin , serotonin conjugate , and serotobenin . carthamus tinctorious l. contains safflower - yellow cathamin , which reportedly extends blood vessels , excites the uterus , and reduces blood cholesterol . in oriental medicine , carthamus tinctorious l. has warmness , which can affect detoxification , pain relief and blood circulation . carthmi - flos herbal acupuncture ( cf ) , a representative meridian pharmacopuncture medicine , is an oriental medicine made by extracting and refining oil from cathami semen . cf was prepared in a sterile laborotary at the korean pharmacopuncture institute ( kpi ) . after the seeds had been cleaned , ground and peeled , they were screw pressed on a prepared mat . water soluble carthmi - flos herbal acupuncture ( wcf ) was prepared by homogenizing cf , water for injection ( wfi ) and an emulsifier . pharmacopuncture with carthamus tinctorious l. is a representative pharmacopuncture method whose efficacy was demonstrated by many studies . various studies on the effects of pharmacopuncture with carthamus tinctorious l. in treating painful diseases , such as anti - pain effects in an arthritis model on experimental animals , pain - relief effects in degenerative knee arthritis patients , and effects in reducing backache according to the oswestry disability index , were conducted , as were studies on immune - function and blood - vessel effects , including its anti - carcinogenic activity and its effect on suppressing blood clots induced by endotoxin . other studies addressed hematological diseases ( the treatment of alopecia areata by using pharmacopuncture with carthamus tinctorious l. ) , and gynecological diseases ( the treatment of oligomenorrhea with pharmacopuncture and carthamus tinctorious l. ) . thus , the effects of pharmacopuncture combined with carthamus tinctorious l. have been demonstrated in a variety of different fields . studied the safety of pharmacopuncture with carthamus tinctorious l. against skin irritation and eye irritation , and an et al . verified its safety through acute and subacute toxicity experiments . because pharmacopuncture with carthamus tinctorious l. is expected to show gradual diversification of clinical use as an oriental medicine , studies on toxicity , dose , and side effects must be pursued because pharmacopuncture inserts foreign substances into the human body . in this study , single intramuscular- dose toxicity tests were performed on rats to verify the safety and to identify any side effects of wcf prepared using carthamus tinctorious l. preliminary study was performed at biotoxtech by non - good laboratory practices ( glp ) . these tests were performed by biotoxtech according to glp and the standards of the ministry of food and drug safety as requested by the kpi . wcf was developed to increase the treatment effects by increasing absorptivity and to reduce the side effects by reducing residue of existing cf . wcf was prepared in three steps : in step 1 , cf , wfi and primary emulsifier were mixed together and homogenized for 30 minutes by using a high - speed homogenizer . emulsifier was added in step 2 and homogenized at 30 - 80. in step 3 , the temperature was reduced , and the mixture was homogenized to yield wcf . the rats , 24 males and 24 females , were 5-weeks old with body weights of 111.8 - 135.8 g and 107.4 - 127.9 g , respectively . general symptoms and body weights were observed to verify that no problems existed with the animals . during the grace period , individual subjects were marked , and at the end of the grace period , 20 males and 20 females closest to the standard body weight were selected and randomly divided into 4 groups of 5 male rats and 5 female rats so that the mean weights of the four groups were uniform . solid feed ( teklad certified irradiated global 18% protein rodent diet 2918c ) and filtered tap water ( cheongju tap water filtered using a filter water sterilizer and irradiated with ultraviolet rays ) were freely available . the breeding environment was as follows : a temperature of 20.0- 22.8 , relative humidity of 48.5%-65.8% , 10- to 15-hour ventilation , 12-hour / day lighting cycle , and illuminesence of 150 - 300 lux . the clinical dose of wcf was 1.0 ml per application , as no fatalities had been observed at doses up to this value in preliminary tests ( biotoxtech study no . : thus , under consultation with the test s requester , 1.0-ml/ animal was configured as the high dose . medium and low doses were 0.5- and 0.1-ml / animal ; the same amount of saline solution , 1.0-ml / animal , was injected into the control group . ( table 1 ) injection was performed using a disposable syringe ( 1 ml , 26 g ) . single doses were injected into the left femoral muscle for the low - dose and the medium - dose groups . for the control and the high - dose groups , single injections , 0.5 ml / site , were done into the left and the right femoral muscles . on the day of injection ( day 0 ) , clinical symptoms and fatalities were observed at 30 minutes and at 1 , 2 , 4 and 6 hours after injection . from day 1 to day 14 , general symptoms were observed once a day . body weights were measured ( cp3202s scale ) on days of injection ( before injection ) and on days 3 , 7 and 14 . for the hematology test , blood was collected from the abdominal aorta on day 15 after applying anesthesia by isoflurane . hematological analyses were carried out by placing 1 ml of collected blood into a tube containing ethylenediaminetetraacetic acid , which was then analyzed using a blood corpuscle analyzer ( advia 120 , siemens , germany ) . for the coagulation test , about 2 ml of collected blood was placed in a tube containing 3.2% sodium citrate and centrifuged for 10 minutes at 3,000 rpm , after which the blood plasma was collected . measurement was done using a coagulation time analyzer ( coapresta 2000 , sekisui , japan ) . the prothrombin time and the activated partial thromboplastin time ( aptt ) were measured . after completing the hematology tests , for the clinical chemistry test , we centrifuged the remaining blood for 10 minutes at 3,000 rpm and collected the blood serum . a clinical chemistry analyzer ( 7180 , hitachi , japan ) and an electrolyte analyzer ( avl9181 , roche , germany ) were used . visual inspection of all body organs and tissues was performed on all animals after necropsy . body organs and tissues were extracted and fixed in 10% neutral buffered formalin , and histopathological observations were carried out . body - weight , hematology and clinical chemistry results were tested using sas ( version 9.3 , sas institute inc . bartlett tests were performed for homo - scedasticity ( significance level : 0.05 ) . for homo - scedasticity , one - way analysis of variance tests were performed to yield the significance ( significance level : 0.05 ) , and multiple dunnett s t - tests were carried out ( significance level : 0.05 on both sides and 0.01 ) . for hetero - scedasticity , significance ( significance level : 0.05 ) was checked using the kruskal - wallis test . accordingly , computation of the ld50 was impossible ; however , a single intramuscular dose of wcf at 1.0 ml / animal caused no mortalities . ( table 2 ) no abnormal clinical symptoms ( type of toxicity symptom , time of expression , time of recovery , etc . ) were observed on the day of injection ( day 0 ) at 30 minutes and at 1 , 2 , 4 and 6 hours after injection , as was the case for days 1 to 14 after injection . all groups showed a continued increase in body weight , but the differences among the groups were not significant . tables 3 , 4 , 5 ) hematological analyses on the ratsblood showed wcf to have no effect . however , aptt ( sec ) mean of the g3 female group showed a statistically significant change ( p < 0.01),but it was a miscellaneous change with no dose dependence , clinical meaning or toxicological meaning . clinical chemistry analyses showed no significant differences for any of the measured items between the normal saline and the wcf groups . in no male or female experimental group were visual abnormalities observed . ( tables 6 , 7 , 8) on the histopathological tests , one female in the highdose group showed infiltration of mononuclear cells and a multi - nucleated giant cell around eosinophilic materials caused by wcf in an area similar to a cross section of muscular fiber , and 8 eosinophilic materials were clustered at a local part . wcf is prepared by homogenizing a mixture of cf , wfi and emulsifier and increases the treatment efficacy while maintaining the characteristics of existing cf . the effects of cf have been demonstrated by various studies ; i.e. , cf can be used for pain relief , is effective for a variety of different pains , increases regional cerebral blood flow significantly , and can be used in a variety of different fields with different effects such as anti - carcinogenic [ 7 , 12 ] and anti - oxidative effects . in this experiment , an intramuscular - dose toxicity test of wcf was performed by biotoxtech to evaluate the safety of wcf manufactured by the kpi according to the glp . no mortalities occurred in any group . also , observations taken after injection of wcf showed no abnormalities in the clinical symptoms of the four groups . hematologically , a change in the aptt ( sec ) mean value of the g3 female group was observed , but had no clinical or toxicological meaning . finally , histopathological observation showed that wcf caused a change in one female in the high - dose group . visual examination showed the subject to have suffered infiltration of mononuclear cell and to have had a multi - nucleated giant cell around eosinophilic material . studies on the side effects and the safety of cf are continuously being conducted . according to , pain , flare and edema after 4 days , side effects , such as flare and edema , mostly disappeared . they were thought to have occurred due to a mixture of highly - toxic drugs in the oil press during cf during preparation . suppuration and pain appeared in the surgical parts in 1 patient who received cf therapy of 0.1 ml/1 time / week for 8 months and 1 patient who received cf therapy of 0.1 ml/1 - 3 times / week for 3 months . grade - minimal unlike in , the side effects were deemed to be due to an accumulation of cf in the human body from long - term therapy . the safety of cf was reported in based on a toxicity test of cf , but this was only a short - term study on acute and subacute toxicity . chronic toxicity tests on cf must be carried out in the future . although histological abnormalities caused by wcf were found in a subject of the high - dose group in this experiment , according to , no histological abnormalities were observed in sprague - dawley rats treated with cf 3 times a week for 1 - 2 weeks . however , the group with 4 weeks of therapy showed histological ambiguity regarding the boundary of muscular tissues , observation of flares , and induction of inflammations . a histological study with a greater number of subjects and a longer period is deemed necessary to examine long - term or high - dose effects of cf or wcf . the safety of cf was demonstrated , but its side effects were presented in several studies . thus , the toxicity and the safety of wcf must be investigated , and long - term histological studies based on large numbers of subjects are deemed necessary . the results of single intramuscular - dose toxicity tests with wcf on 4 groups of sprague - dawley rats , 3 experimental groups ( 0.1 ml / animal , 0.5 ml / animal and 1.0 ml / animal ) and 1 control group ( 1.0 ml / animal of saline solution ) , are as follows : in all groups no mortalities occurred . there was no abnormalities in clinical symptoms , body - weight , hematology tests , clinical chemistry tests , necropsy , histopathological tests . in 1.0 ml / animal dose of wcf , this study do not show wcf s safety of human body . to examine the safety of wcf , we need to carry out testing to check whether or not the toxicity would have negative effects on human body .

objectives : this experiment was conducted to examine the toxicity of water soluble carthmi - flos herbal acupuncture ( wcf ) by administering a single intramuscular dose of wcf in 6-week - old , male and female sprague - dawley rats and to find the lethality dose for wcf.methods:the experiment was conducted at biotoxtech according to good laboratory practices under a request by the korean pharmacopuncture institute . this experiment was performed based on the testing standards of toxicity test standards for drugs by the ministry of food and drug safety . subjects were divided into 4 groups : 1 control group in which normal saline was administered and 3 test groups in which 0.1 , 0.5 or 1.0 ml of wcf was administered ; a single intramuscular dose was injected into 5 males and 5 females in each group . general symptoms and body weights were observed / measured for 14 days after injection . at the end of the observation period , hematological and clinical chemistry tests were performed , followed by necropsy and histopathological examinations of the injected sections.results:no mortalities were observed in any group . also , symptoms , body weight , hematology , clinical chemistry and necropsy were not affected . however , histopathological examination of the injected part in one female in the 1.0-ml group showed infiltration of mononuclear cells and a multi - nucleated giant cell around eosinophilic material.conclusion:administration of single intramuscular doses of wcf in 3 groups of rats showed that the approximate lethal dose of wcf for all rats was in excess of 1.0 ml , as no mortalities were observed for injections up to and including 1.0 ml .