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inflammatory bowel diseases ( ibd ) , including ulcerative colitis ( uc ) and crohn s disease ( cd ) , are debilitating and chronic disorders that have unpredictable courses and complicated treatment measures . similar to other chronic diseases , ibd negatively affects quality of life ( hrqol ) . the clinical spectrum ranges from an inactive or quiescent phase to low - grade active disease to fulminant disease . common symptoms include diarrhea , rectal bleeding , passage of mucus , tenesmus , urgency and abdominal pain . in more severe cases the currently held paradigm involves a complex interaction of three elements including genetic susceptibility , host immunity and environmental factors . uc is most commonly diagnosed between the third and fourth decades of life , with no difference between males and females . anti - inflammatory medications , corticosteroids , immunomodulators and biological agents against tumor necrosis factor- ( tnf- ) have been recommended as treatments for uc . they can serve as antigen - presenting cells , express cytokine receptors and leukocyte adhesion molecules , and secrete various cytokines and chemokines . patients with uc have an increased turnover rate of colonic epithelium and other abnormalities of epithelial cells such as a decrease in metabolism of short - chain fatty acids , particularly butyrate , abnormal membrane permeability , and altered composition of glycoprotein mucus produced by the colonic epithelium . the role of epithelial cells in the pathogenesis of ibd is supported further by animal models of colitis in which the colonic epithelium has been disrupted . in patients with ibd , especially uc , the repeated cycle of injury and repair of intestinal mucosa has been shown to increase the risk of colon cancer . the extent and severity of uc and its anatomic location affects agents used to induce remission in uc patients , including both oral and topical regimens . sulfasalazine and its aminosalicylate analogues , corticosteroids , immunomodulators , suppressive antimetabolites , anti - tumor necrosis factor - biologics including infliximab , and in some cases antibiotics have been reported as treatments of choice . identical to the initial treatment measures , maintenance therapy is usually individualized in coordination with the patient s medical team . patients with mild to moderate disease may be maintained on similar medications and dosages , with the exception of high - dose sulfasalazine . in some cases , as corticosteroids are generally ineffective for maintenance therapy , patients can be tapered and switched to 5-asa , azathioprine , or 6-mp . a small number of patients are refractory to induction or relapse soon after the start of maintenance therapy . so , a safer therapy that is more efficient seems necessary in treatment and prophylaxis of ibd . medhi et al . in an experimentally induced uc model in rats demonstrated that manuka honey and sulfasalazine showed synergic effects and enhancement of the antioxidant defense system . souza et al . noticed that enemas of budesonide and probiotics enhanced the mucosal trophism in experimental colitis in rats . t. polium ( lamiaceae ) is a wild - flowering plant , found abundantly in south - western asia , europe and north africa . t. poliumis well - known for its diuretic , antipyretic , diaphoretic , antispasmodic , tonic , anti - inflammatory , antihypertensive , anorexic , analgesic antibacterial and antidiabetic properties . it has been shown that an aqueous extract of the leaves and stems of t. poliumcould inhibit iron - induced lipid peroxidation in a rat liver homogenate at concentrations not toxic to the cultured hepatic cells . t. poliumhad effective protection against ethanol - induced gastric mucosal damage and was reported to reduce nadph - initated lipid peroxidation in rat liver microsomes . the in vitro antioxidant activity of t. polium extract was shown in another study . herein , we evaluated the healing effect of t. polium in acetic acid induced uc in an experimental dog model . from september to december 2010 , eight male ( 20 - 25 kg ) cross - bred dogs were obtained from the laboratory animal center affiliated with shiraz university of medical sciences , shiraz , iran . the animals underwent enemas that consisted of 6% acetic acid ( 10 mg / kg body weight , in distilled water ) administered with a no.18 feeding tube to induce uc . bowel preparation was performed for all animals on the day of induction with senagraph syrup ( 30 ml ; sina daru , tehran , iran ) through a nasogastric tube . one week following post - induction of uc , a rigid rectosigmoidoscope was used to evaluate the colonic mucosa . three biopsies ( 10 , 20 and 30 cm proximal to the anal verge ) were taken from the colon of each animal and transferred into formalin for histological analyses as described by mehrabani et al . ( 2009 ) . fromeach colon sample , we took 5 m tissue sections and stained them with hematoxylin and eosin ( h&e ) . all cases were evaluated for the presence of any macroscopic and microscopic mucosal ulcers as described by morris et al . one week after transrectal acetic acid administration and histological confirmation of uc in all animals , 400 mg / kg / day of t. poliumextract ( barieej essence company , tehran , iran ) was administered transrectally ( via enema ) for a one month period in six of the dogs . to prepare t. polium , 100 g of its dehydrated form was ground into a fi ne texture and extracted repeatedly with 80% ethanol . the control group consisted of two dogs that did not receive any therapy but were similarly treated for biopsies . we took multiple biopsies 7 , 14 , and 30 days after discontinuation of t. polium in the same manner as before treatment . histologically , samples were examined for the presence or absence of ulcers , mucosal cell depletion , inflammatory cysts , congestion , mucosal atrophy , submucosal edema , inflammatory cells , and vascular dilatation . for histological scoring , we scored samples from all dogs according to the criteria described by dundar et al . the study was approved by the ethics committee of shiraz university of medical sciences ( registration number : 90 - 5077 ) . all experiments were carried out under aseptic conditions in the laboratory animal center at shiraz university of medical sciences . the protocols for anesthesia , surgical procedures and postoperative care were identical for all animals . dogs were initially evaluated for any illnesses by physical examination and laboratory screening . before ulcer induction , all animals were deprived of food for 24 h but had free access to water to prevent excessive dehydration during starvation . to check for the presence of ulcers in the colon , 0.1 mg / kg of acepromazine was administered . spss software ( version 15.0 , chicago , il , usa ) was used for statistical analyses . after seven days , we observed inflammatory cells [ polymorphonuclear ( pmn ) leukocytes and lymphocytes ] in the mucosa and around the crypts . multiple ulcerations were visible that denoted the formation of a crypt abscess . in the submucosa , table 1 shows the healing effects of t. polium in the dogs . on day 7 the scoring was 3 - 8 ( p > 0.05 ) , on day 14 it was 2 - 5 ( p=0.04 ) , and on day 30 it was 0 - 1(p=0.005 ) . mucosal healing on days 14 ( p=0.04 ) and 30 ( p=0.005 ) were statistically significant compared to the control group . biopsies taken before ( figure 1 ) and after administration of acetic acid showed typical changes related to uc , e.g. , multiple ulcers and diffuse inflammation ( figure 2 ) . figure 3 shows the presence of severe inflammation , pmn infiltration in the lamina propria , glandular destruction and goblet cell depletion that denoted uc after seven days ( 400x , h&e).as figures 4 and 5 demonstrate , after treatment with t. polium an improvement in colonic ulcers as evidenced by increased numbers of healthy epithelial cells was noted . t. polium minimized the inflammatory burden and helped in reversing the damage to the surface of the epithelial cells and mucosal layer that was caused by acetic acid administration . inflammation in the lamina propria and crypt abscess mild chronic inflammation in the lamina propria with mild atrophy after t. polium administration ( h&e , 250x ) . in the two dogs from the control group , severe loss of body weight was noticed along with crypt damage , loss of epithelium , infiltration of inflammatory cells and depletion of goblet cells , these changes were severe , with no mucosal healing . the mainstay of medical therapy for uc focuses on medications that change the host response to decrease mucosal inflammation . treatment regimens targeting other aspects of the systemic inflammatory process or manipulating the enteric flora have also been developed . to determine the etiology of ibd , experimental colitis has been induced using animal models . some authors have shown that dogs can be used as an experimental model for uc . various chemicals , including dextran sodium sulfate , 2,4,6-trinitrobenzene sulfonic acid , oxazolone , indomethacin , and acetic acid , have been used to induce experimental colitis . t. polium has strong in vitro antioxidant properties , therefore this study investigated the healing effects of t. polium in the repair of acetic acid - induced uc in an experimental dog model . in this study we used 6% acetic acid , a readily available , inexpensive chemical agent , as an enema to induce uc in dogs . this resulted in the rapid development of signs of uc that included severe ulceration and inflammation of the colon , weight loss , diarrhea and hematochezia . histologically , the typical early lesions consisted of an infiltration of inflammatory cells , primarily polymorphonuclear leukocytes , into the crypts at the base of the mucosa , forming crypt abscesses . in this study , after the administration of 400 mg / kg / day t. polium for one month ( transrectally ) in dogs with induced uc , a significant improvement was visible both clinically and histologically . t. polium has long been recognized in folk medicine as a treatment for many pathophysiological conditions such as gastrointestinal disorders , inflammations , diabetes and rheumatism . most of these effects were related to the antioxidant and free radical scavenging properties of t. polium . kadifkova - panovska et al . reported that an aqueous extract of t. polium was not toxic to cultured hepatic cells since mitochondrial respiration was fully preserved and the cell membrane integrity remained intact . in their study , cells were exposed for 24 h to the plant powder at concentrations of up to 1 mg / ml . mehrabani et al . ( unpublished data ) investigated the effects of calendula officinalis as treatment for acetic acid - induced uc in dogs , as an animal model . they noted significant mucosal healing after administration of calendulaofficinalis after 30 and 45 days . the effects of corticosteroids as treatment for acetic acid - induced uc in dogs have been investigated . two methods of steroid therapy were compared for uc via appendicostomy ( antegrade ) and enema ( retrograde ) . . the difference may be due to peristaltic movement of the colon pushing materials from the proximal to the distal part of the colon . our results are in agreement with those reports that have investigated the healing effects of herbal extracts such as t. polium in peptic ulcers and uc . however , many factors may be considered in determining the optimal therapy for uc patients . the current therapeutic measures can be classified upon disease activity into those that treat active disease ( induction therapy ) and those that prevent recurrence of disease once remission is achieved ( maintenance therapy ) . the concept of induction and maintenance of remission is a basis of evaluating the efficacy of a specific therapy . the extent of disease in any given patient has an important role in determining the route of medication administration . enema preparations may be used alone or in combination with systemic therapy in patients with left - sided disease . other important factors are previous responses to or side effects from a specific medication and patient compliance the strength of our study was that we used the dog as an animal model for uc , which has been shown to be the most identical model for the human digestive system . the limitations of our study were vaccination of the animals for rabies and therapy for helminthic parasites , both of which were time consuming . dogs are more expensive to maintain and keep when compared with mice and rats . we did not attempt to identify the chemical constituents that could account for the anti - inflamatory action of the extract . therefore , t. polium may be considered as a treatment choice for uc and can broaden the current therapy options of the disease . the authors would like to thank the office of vice chancellor for research at shiraz university of medical sciences for financial support , st heydari for statistical consult and the personnel of the laboratory animal center at shiraz university of medical sciences for their laboratory assistance .

background inflammatory bowel diseases ( ibd ) , which include ulcerative colitis ( uc ) and crohn s disease ( cd ) , are debilitating and chronic disorders with unpredictable courses and complicated treatment measures . therefore , an efficient treatment protocol seems necessary as therapeutic prophylaxis for these disorders . this study aims to determine the healing effect of teucrium polium ( t. polium ) in acetic acid - induced uc in an experimental dog model . methods from september to december 2010 , eight male ( 20 - 25 kg ) crossbred dogs were used for induction of uc by 6% acetic acid , transrectally . after one week , three biopsies ( 10 , 20 and 30 cm proximal to the anal verge ) were taken from the colon of each animal for histological studies . in the presence of uc , 400 mg / kg / day of t. polium extract was administered orally and transrectally ( via enema ) for 30 days in six of the dogs . the remaining two dogs were used as controls and did not receive t. polium . multiple biopsies were taken 7 , 14 , and 30 days after discontinuation of t. polium in the same manner as before treatment . results after administration of acetic acid , we noted the presence of multiple ulcers , diffuse inflammation , pmn infiltration in the lamina propria , glandular destruction and goblet cell depletion . treatment with t. polium restored the colonic architecture with an increased number of healthy cells and a reduction in inflammatory cells . damage of the surface epithelial cells and mucosal layer of the lumen were reversed , which lead to faster ulcer healing . conclusion t. polium may be a treatment choice for uc and can broaden the current therapy options for uc .

schwannoma or neurilemmomas are firm , encapsulated neoplasms composed principally of neoplastic schwann cells from the spinal nerve root sheath . these mostly occur sporadically and solitary , but they may also be associated with neurofibromatosis-2 ( nf-2 ) , and less commonly with neurofibromatosis-1 ( nf-1 ) . these are usually small and complete excision with good neurological recovery is a rule rather than exception . however , schwannoma in lower lumbar and sacral regions can enlarge significantly and can further extend into the paravertebral space . giant schwannoma in contrast to their smaller counterparts pose difficulty in complete excision because of their paravertebral extension . moreover , they engulf spinal nerves as they enlarge in size hence making complete excision difficult . a multistage , multidisciplinary approach we report a case of giant extradural lumbosacral schwannoma in an 8-year - old male without neurofibromatosis . . neurological examination of the patient did not reveal any abnormality except for local tenderness at l4 and l5 spinous process . plain radiographs of the lumbosacral spine [ figure 1 ] revealed increased interpedicular distance at l4 , l5 , s1 levels , widening of the l4 - 5 , l5-s1 neural foramina and scalloping of the posterior surface of l4 and l5 vertebral body . magnetic resonance imaging ( mri ) of the lumbosacral spine [ figure 2a ] showed an extradural mass against l4 to s2 vertebral bodies with significant right paravertebral component . the mass was hypo to iso intense on t1-weighted images and hyper intense on t2-weighted images . patient underwent l3 to s2 laminectomy with subtotal excision ( complete excision from within the canal and partial excision of the paravertebral part ) of the mass from the posterior approach only [ figure 2b ] . plain radiographs of the lumbosacral spine showing increased interpedicular distance at l4 , l5 , s1 levels , widening of the l4 - 5 , l5-s1 neural foramina and scalloping of the posterior surface of l4 and l5 vertebral body mri of the lumbosacral spine ( a ) showed an extradural mass against l4 to s2 vertebral bodies with significant right paravertebral component . postoperative mri ( b ) showing surgical cavity after the excision of the mass histopathology examination ( hpe ) [ figures 3a and b ] of the tumor reveals antoni a and antoni b areas . antoni a tissue is cellular and consists of monomorphic spindle shaped schwann cells with poorly defined eosinophilic cytoplasm and spindle shaped basophilic nuclei . antoni b area is hypo cellular characterized by the presence of schwann cells suspended in copious myxoid matrix with microcyst formation . ( a ) antoni a tissue is cellular ( white arrow ) with nuclear palisading . reported an incidence of about 0.3 and 0.4 cases per 100 000 persons per year . classified giant schwannoma as those that extend over more than two vertebral levels ( type ii ) , those that have extra spinal extension of more than 2.5 cm ( giant dumbbell , type iv ) and those lesions that erode vertebral bodies and extend posterior and laterally into the myo - fascial planes ( giant invasive tumors , type v ) . schwannoma of the lower lumbar and sacral regions , because of the wide canal available at these locations and relatively mobile nerve roots can enlarge significantly and can extend vertically and in the paravertebral regions . this can be supported by the fact that in a study of 118 cases of spinal dumbbell tumors , only one dumbbell schwannoma was seen in the pediatric age group . initial symptoms depend upon the location of the tumor and are due to irritation of the involved sensory nerve . giant schwannoma , because of their growth in all directions , may extend : vertically to involve multiple vertebral levels , anterolaterally into extra spinal space via the foramen which they may erode and widen , posteriorly , thinning and attenuation of dura and posterior elements and occasionally may extend posterior myo - fascial planes , andanteriorly , erode the vertebral bodies to varying extents . vertically to involve multiple vertebral levels , anterolaterally into extra spinal space via the foramen which they may erode and widen , posteriorly , thinning and attenuation of dura and posterior elements and occasionally may extend posterior myo - fascial planes , and anteriorly , erode the vertebral bodies to varying extents . plain radiographs may reveal widening of the neural foramen and the spinal canal , erosion of the pedicle , and scalloping of the adjacent vertebral body . on mri , signal characteristics of a typical schwannoma are : t1w : iso to hypo intense to that of spinal cordt2w : typically hyper intense and often heterogeneous in pattern of intensityt1+contrast : shows heterogeneous enhancement with evidence of hemorrhage , calcification , or cyst formation . t1w : iso to hypo intense to that of spinal cord t2w : typically hyper intense and often heterogeneous in pattern of intensity t1+contrast : shows heterogeneous enhancement with evidence of hemorrhage , calcification , or cyst formation . mri is the gold standard investigation delineating the extent of giant schwannoma and hence deciding the approach for surgery . 3-dimensional computed tomography ( 3d ct ) can reveal positional relationship between tumor and iliac arteries in cases of giant sacral schwannoma . when the mass is predominantly involving the sacrum it is important to consider other benign ( osteoblastoma , aneurysmal bone cyst , and giant cell tumor ) and malignant(metastatic carcinoma , myeloma , chordoma , and chondrosarcoma ) sacral tumors in the differential diagnosis . it consists of preoperative planning for the approach to be taken up for surgery . in most of the cases of dumbbell tumors conventional posterior approach alone suffice the complete removal of the mass as in these cases the neural foramen is usually considerably widened . if the mass is invasive and if the lateral paravertebral extension is very large , a staged or single combined posterior and anterolateral approach can be used . in cases where intra spinal component is small as compared with the lateral portion , complete excision can be done through the anterolateral approach . stability of the spine has to be ensured by instrumentation after removal of the tumor . however , as our patient was a child we did not do instrumentation . although schwannoma arises from the nerve tissue , only in 50% cases a direct relationship with a nerve is found . it is usually possible to preserve some fascicles of the nerve root , although sometimes section of the entire nerve root is required , usually in invasive giant varieties . kim et al . reported that sacrificing an involved nerve root does not cause increase in the neurological deficits as the involved nerve root is nonfunctional . schwannoma , neurofibroma , meningioma , ependymoma , sarcoma , ganglioneuroma , connective and bone tissue , abscess , herniated disc , hematoma , spinal arteriovenous malformation ( avm ) , and spinal aneurysm , as well as metastatic disease should be under consideration . giant schwannoma are rare in children , complete excision of the tumor should be the goal of surgery . we recommend instrumentation only if the spine is unstable otherwise a wait and watch protocol be followed as spontaneous remodeling of the scalloped vertebral bodies is well known .

small spinal intradural extramedullary schwannoma are a common occurrence in the middle aged . however , giant schwannoma in pediatric age group is rare . we report one such case of giant extradural lumbosacral schwannoma in an 8-year - old child . clinical features , histopathology and management of giant schwannoma is discussed and the present literature reviewed .

cryptococcal meningitis ( cm ) is a common opportunistic infection in hiv infected patients with severe immunosuppression . in middle- and low - income countries , the mortality of cm ranges from 55% to 70% [ 1 , 2 ] . in sub - saharan africa , globally , it is estimated that approximately 957,900 cases of cm occur each year , resulting in 624,700 deaths . the world health organization ( who ) recommends two - week induction treatment with amphotericin b deoxycholate ( ambd ) and flucytosine or fluconazole , followed by eight - week consolidation treatment with oral fluconazole . however , a two - week treatment with ambd is not feasible for many resource - poor settings because it is frequently associated with nephrotoxicity and requires a prolonged admission in a health - care facility with frequent monitoring of the renal function and electrolytes . the nephrotoxicity of ambd occurs mainly during the second week of therapy , and severe renal toxicity is rare when the treatment is shortened to seven days or less [ 57 ] . previous studies have shown strong correlation between the rate of fungal clearance in cerebrospinal fluid ( csf ) and survival in cm . amb has a strong fungicidal activity against cryptococcus , but ambd and lipid formulations of amb have poor penetration into csf [ 8 , 9 ] . to achieve higher concentration in csf , intrathecal administration of amb has been used for the treatment of cm in china , and observational studies suggest that it could be associated with improved survival . however , ambd has a direct irritant effect , and intrathecal administration of ambd might be poorly tolerated because of inflammation of the meninges and nerve roots [ 11 , 12 ] . previous studies in humans and animals indicate that intrathecal administration of lipid formulations of amb is better tolerated than ambd [ 1315 ] . furthermore , data from a murine model suggest that the combination of intravenous antifungal agents with intrathecal administration of liposomal amb could be beneficial in terms of survival and reduction of fungal load in csf [ 16 , 17 ] . the aim of this study was to compare the standard two - week intravenous therapy with an induction regimen including one week of intravenous ambd and intrathecal amb lipid emulsion ( amble ) , both regimens accompanied by oral fluconazole for two weeks , in patients from a prospective hiv cohort study in india . the vicente ferrer hiv cohort study ( vfhcs ) is a prospective cohort study of hiv infected patients who have attended the rural development trust hospital in bathalapalli , anantapur district , ap , india . the hospital belongs to a nongovernmental organization and provides medical care to hiv infected people free of charge . in our setting , 72% of the population live in rural areas , and the hiv epidemic is largely driven by heterosexual transmission and it is characterized by low cd4 cell counts at presentation , poor socioeconomic conditions , and high levels of illiteracy [ 1921 ] . all hiv infected patients from the vfhcs database diagnosed with cm from 1 october 2010 to 31 january 2015 were included . patients who did not complete four weeks of follow - up since the initiation of cm treatment were excluded . the diagnosis of cm was based on the presence of cryptococcus antigens in csf by latex agglutination . fungal burden in csf was not measured . altered mental status was defined in patients with confusion , disorientation , coma , or low consciousness . all patients were admitted to the hospital . as in most low- and middle - income countries , flucytosine is not available in india , so fluconazole was used during the induction phase . before 15 june 2013 , patients were treated with the standard two - week induction treatment with intravenous ambd 0.71 mg / kg and oral fluconazole 1200 mg once daily followed by 600 mg once daily for eight weeks ( consolidation phase ) and 200 mg once daily thereafter ( maintenance phase ) . owing to the lack of disposable manometers , csf opening pressure was not measured . therapeutic lumbar punctures with removal of at least 20 ml of csf ( typically 3040 ml ) were performed on alternate days during the first six days of induction therapy , and according to the apparent opening pressure ( rapid flow of csf through the lumbar puncture needle ) and patient 's symptoms , such as blurred vision , headache , or altered mental status . the procedure for therapeutic lumbar punctures and the treatment used during the consolidation and the maintenance phases were identical in both groups . after 15 june 2013 , patients received intravenous ambd 0.7 mg / kg once daily for seven days , intrathecal amble 2.5 mg ( amphomul , bharat serums and vaccines , india ) once daily for seven days [ 22 , 23 ] , and oral fluconazole 600 mg twice daily for 14 days . lumbar punctures were performed daily and , after removing at least 20 ml of csf ( typically 3040 ml ) , a solution of 0.5 ml ( 2.5 mg ) of amble in four ml of 10% dextrose was inoculated slowly into the subarachnoid space . after removing the lumbar puncture needle , patients were asked to lay flat on the bed for one hour . to assess toxicity , patients were asked daily about symptoms related to the local irritating effect of amb such as lumbar pain , leg pain , vomiting , or retention of urine or stools after the intrathecal administration of amble . amble was presented in a vial of 50 mg/10 ml emulsion , so only one vial was used for each patient with cm . the cost of each vial was 1,080 indian rupees ( around 17 usd in march 2015 ) . while the total cost of drugs used in the two - week standard amb treatment was 3,465 indian rupees ( around 55 usd in march 2015 ) , the total cost of the one - week short - intrathecal amb treatment was 2,932 indian rupees ( around 47 usd in march 2015 ) . patients from both groups received one litre of normal saline solution with 20 mmol of potassium chloride before each infusion of intravenous ambd , and patients not taking antiretroviral therapy ( art ) were recommended to initiate art after four weeks of the initiation of cm treatment . there were no changes in the availability of art during the two periods of the study . statistical analysis was performed using stata statistical software ( stata corporation , release 12.1 ; college station , texas , usa ) . patients who did not die during the first 12 weeks of treatment were censored at week 12 or at their latest visit date , whatever occurred first . the proportional hazard assumption was assessed performing log - log survival curves based on schoenfeld residuals . in a sensitivity analysis , we also performed a multivariate analysis using flexible parametric survival analysis with three degrees of freedom . the selection of variables included in the multivariate analyses was based on the results of a large cohort study investigating determinants of mortality of hiv - associated cryptococcal meningitis and the availability of data in our cohort . two patients who received the standard amb regimen and one patient who received the short - intrathecal amb regimen did not complete four weeks of follow - up and were excluded . 123 patients were included in the final analysis , 78 patients in the standard amb regimen group , and 45 patients in the short - intrathecal amb regimen group . we did not find significant differences between groups , although the proportion of patients with altered mental status or seizures was higher in the standard amb regimen group ( 34.6% versus 22% , p value = 0.086 ) . of those not on art at the time of starting cm treatment , the median time from cm treatment to initiation of art was 35 days ( interquartile range : 2951 ) in the standard amb regimen group and 36 days ( interquartile range : 2648 ) in the short - intrathecal amb regimen group . sixty patients died during the study period , 45 in standard amb group , and 15 in the short - intrathecal group . kaplan - meier survival estimates by treatment group are shown in figure 1 . compared with patients who received the standard amb regimen , patients in the short - intrathecal amb regimen group had significant lower mortality ( p = 0.0165 ) . compared with the standard amb regimen , patients who received the short - intrathecal amb regimen had a significant lower risk of death in univariate ( hazard ratio ( hr ) 0.5 , 95% confidence interval [ ci ] , 0.280.89 , p = 0.019 ) and multivariate analyses ( adjusted hr 0.4 , 95% ci , 0.220.76 , p = 0.005 ) . we also performed a multivariate analysis using flexible parametric survival methods , showing similar results ( adjusted hr 0.4 , 95% ci , 0.210.75 , p = 0.004 ) . the use of the short - intrathecal amb regimen was associated with a 26.7% absolute risk reduction ( 95% ci , 9.943.5 ) in mortality at 12 weeks . we did not observe drug adverse reactions described in previous studies using intrathecal ambd such as lumbar pain , leg pain , vomiting , prostration , or altered mental status [ 11 , 12 ] . of 45 patients in the short - intrathecal amb regimen group , only one patient developed acute urinary retention , which resolved after one day . in this observational cohort study in a resource - limited setting , the use of a short - course intravenous ambd regimen along with intrathecal amble was well tolerated and was associated with a clinically important reduction in mortality compared with the standard of care in low- and middle - income countries . the who recommends two weeks of intravenous ambd and flucytosine or fluconazole during the intensive phase of cm treatment . however , this regimen is impractical in resource - poor settings because of the cost of medicines and hospital care . therefore , fluconazole monotherapy is the treatment most commonly used in low- and middle - income countries , albeit its lower efficacy compared with amb regimens . the short - intrathecal amb regimen was associated not only with an increased survival but also with a lower cost in terms of days of hospitalization and drugs . in addition , one week of intravenous ambd could be given safely without laboratory monitoring , as long as hydration and potassium supplements are provided [ 7 , 27 ] . unlike previous experiences with intrathecal ambd [ 11 , 12 ] , intrathecal amble was very well tolerated , and only one patient developed a transient urinary retention . this is in accordance with the case reports of patients receiving other lipid forms of amb intrathecally and with the results from animal models [ 1315 , 17 ] . to our knowledge , this is one of the first studies investigating the effectivity of a lipid form of amb administered intrathecally in cm . a previous study performed in mice showed that combination therapy including intrathecal liposomal amb and fluconazole was able to reduce mortality compared with intravenous liposomal amb monotherapy . moreover , mice treated with intrathecal liposomal amb had minimal inflammatory signs in the meninges [ 16 , 17 ] . in developed countries , disposable manometers are used to control the intracranial pressure . in our study , we did not measure the intracranial pressure of patients with cm . however , this reflects the situation in most resource - limited settings , where disposable manometers are rarely used due to cost , unavailability , and safety issues . a study performed in south africa and uganda suggests that therapeutic lumbar punctures can have a dramatic effect on survival of cm regardless of the initial intracranial pressure . although at least four therapeutic lumbar punctures were performed in the standard amb regimen group , the mortality reduction seen with the short - intrathecal amb regimen could be related to the fact that patients in this group undertook more therapeutic lumbar punctures . we speculate that the combination of therapeutic lumbar punctures and intrathecal administration of amble might have achieved a more rapid clearance of the fungal load in csf . however , new studies are needed to confirm these hypotheses . in some african countries , refusal of lumbar punctures is common due to the belief among patients and relatives that the procedure can cause death . however , in our setting , lumbar puncture refusal was rare , and patients frequently referred to improvement of their symptoms after the procedure . in our experience , the fact that spinal taps were used as means of administrating antifungal medication in a difficult - to - reach space helped improve the acceptability of therapeutic lumbar punctures among patients and doctors . new studies are needed to evaluate the acceptability of frequent lumbar punctures in settings with higher hiv prevalence in the general population such as sub - saharan africa . given the observational nature of the study , we must be cautious about the survival benefits of the new short - course induction regimen . this was an observational study using routine clinical data in a resource - poor setting . the selection of treatment was not randomized and the two regimens compared in this study were given at different periods of time , so it is possible that our results could be influenced by unknown confounders not included in the multivariate analysis . in addition , we did not measure the csf opening pressure or surrogates for fungal burden in csf such as quantitative cultures or cryptococcus antigen titres , which are important predictors of mortality . on the other hand , unlike clinical trials , no patient was excluded because of the severity of the disease , so our results could be generalized to other resource - poor setting where patients are diagnosed with cm at advanced stages . the study demonstrates that intrathecal administration of amble is well tolerated . in addition , the short induction therapy with intravenous ambd along with daily therapeutic lumbar punctures and intrathecal amble achieved a clinically important reduction in mortality compared with the standard of care in low- and middle - income countries . being an observational study , we must be cautious about the survival benefits of the new regimen . still , the mortality of cm in resource - poor setting is unacceptably high , and our findings deserve further research .

cryptococcal meningitis ( cm ) is a common cause of death among hiv infected patients in developing countries , especially in sub - saharan africa . in this observational hiv cohort study in a resource - limited setting in india , we compared the standard two - week intravenous amphotericin b deoxycholate ( ambd ) ( regimen i ) with one week of intravenous ambd along with daily therapeutic lumbar punctures and intrathecal amb lipid emulsion ( regimen ii ) during the intensive phase of cm treatment . 78 patients received regimen i and 45 patients received regimen ii . after adjustment for baseline characteristics ( gender , age , altered mental status or seizures at presentation , cd4 cell count , white blood cells , cerebrospinal fluid white cells , and haemoglobin ) , the use of regimen ii was associated with a significant relative risk reduction in mortality ( adjusted hazard ratio 0.4 , 95% confidence interval , 0.220.76 ) and 26.7% absolute risk reduction ( 95% confidence interval , 9.943.5 ) at 12 weeks . the use of regimen ii resulted in lower costs of drugs and hospital admission days . since the study is observational in nature , we should be cautious about our results . however , the good tolerability of intrathecal administration of amb lipid emulsion and the clinically important mortality reduction observed with the short - course induction treatment warrant further research , ideally through a randomized clinical trial .

the interest in understanding the genetic basis of diseases and drug regimens has increased , requiring dna isolation . however the extraction of dna from buccal cells ( bc ) is bringing a new perspective to obtaining dna8 . compared to other methods , such as blood collection , it is a noninvasive collection method and is therefore better tolerated by adults , children and handicapped individuals . this procedure has low cost and does not require medical assistance ( e.g. : nurse ) , so a wide population can be genotyped1,3,6,9 . the wet method consist in swishing liquids in the mouth and spitting them into a collecting cup2 . this procedure yields a higher amount and longer fragments of dna2,4 , requires more steps , is more cumbersome and has a higher cost8 . they are simpler , more cost effective8 and are considered less sensitive to the effect of long time storage at room temperature when compared to mouthwash , which may be crucial for multicenter studies6 . according to a recent study , the use of cytobrushes appears to be the most appropriate manner to facilitate self - collection of human genomic dna with good quality and high security when compared to the mouthwash method6 . commercial kits are available to extract dna from bc and they can provide sufficient dna for genetic analysis . nevertheless , due to logistic , financial , practical and methodological reasons , large studies often require the storage of bc samples before dna extraction7 . there is a lack of information in the literature regarding the best method to store bc after collection . therefore , the purpose of this study was to evaluate quantitatively and qualitatively the effect of the storage time of samples before the application of the cell lysis solution ( cls ) for extracting dna from bc . the research protocol was reviewed and approved by the research ethics committee of the federal university of pelotas , brazil . five volunteers were selected to participate in the study and were submitted to three bc collections . in each collection , 2 bc samples were obtained , being one from the upper and one form the lower gutter region . samples were collected using disposable special cytological brushes and the volunteers were instructed to brush and twirl each cytobrush for 30 s over the gutter region , which is the space between the gums and the inner portion of the lips and cheeks along the front and sides of the mouth . for all volunteers , the collections were performed in different anatomical regions of the oral cavity at the same time , with 5 days of interval between each collection . the collected samples were treated in three different forms . in the control group ( n=10 ) , immediately after the collection , the cytological brush containing the material was introduced in a microfuge tube that contained cls . after 3 h in this solution , the samples were submitted to laboratory processing for dna extraction . in the second group ( n=10 ) , soon after collection , the cytobrush was placed in a microfuge tube , without cls , and left undisturbed for 72 h at room temperature . thereafter , cls was applied and the samples were processed in the same way as in the control group . in the third group ( n=10 ) , the collected samples remained in the microfuge tube for 72 h at 4 c. after this period , cls was applied and the samples were processed in the same way as in the control group . all samples were processed following the manufacturer 's instructions ( puregene dna buccal cell kit ; gentra systems , inc . , minneapolis , mn ) . according to the manufacturer , 0.2 to 2.0 g / brush of dna after processing of each sample , 20 l of solution was obtained . from this amount , 10 l were placed in a tube containing 90 l of milli - q water and the amount of dna was read in a spectrophotometer ( eppendorf biophotometer , hamburg , germany ) , in which dna concentration and purity was evaluated . the average from the two collections in each individual was obtained , with samples submitted to the same storage condition and the obtained data analyzed statistically by one - way anova . in order to ascertain the presence of high molecular weight dna in the samples , the remaining 10 l of each sample were used to run 0.8% agarose gel electrophoresis at 2v / cm and were stained with ethidium bromide . the dna degradation was observed by fragmentation of the samples compared against a known molecular weight marker . the visible bands were examined by two calibrated examiners that were not involved in the study . the means and standard deviations for dna extracted under immediate , room temperature and cooling temperature conditions were 3.5 0.7 , 3.0 0.6 and 4.1 1.8 g , respectively . the statistical analysis did not show statistically significant difference regarding dna concentration among the three storage conditions ( p=0.385 ) . regarding the qualitative evaluation , differences in band patterns processed immediately after bc collection , no degradation traces were observed ( figure 1 ) . however , in the others groups with samples processed later under room and cooling temperature conditions , dna degradation or absence of bands were observed ( figure 1 ) . this study is particularly relevant for large - scale epidemiological studies , where generally the laboratory is not available to process the genetic material immediately after collection in a field study . therefore , sample storage is frequently necessary to prevent the loss of quantity or quality of the genetic material . although bc samples give a smaller amount of dna then blood samples , recently developed methods of genotyping use very small amounts of dna what makes the collection of bc a viable source of genetic material with high quality . furthermore blood collection is more invasive and not well tolerated by some patients , making easier the compliance in larger epidemiologic studies4,9 . the amount of dna material obtained from bc is dependent of the location , the force applied during collection and the patients ' individual variations6 . another factor that is capable to influence the amount of material obtained is the time of collection . in the present study , the time of collection of 30 s this time was used by several studies3,9,11 since longer times are unviable , especially in studies involving children . in order to avoid loss of material in the present study , the collections were made before volunteers had eaten or brushed their teeth , since the attrition of foods and toothbrush could reduce significantly the amount of material on the mucous membranes . the selection for the gutter region of the mouth instead of the inner cheek was based in a recent study by saftlas , et al.9 ( 2004 ) , where collection with cytobrushes in adult women from the gutter provided significantly larger amounts of dna ( 7.5 g ) than the standard method of brushing the inner cheeks ( 3.8 g ) . however , in the present study , the mean amount of dna obtained from the gutter area was 3.5 g , which is similar to the quantity obtained from the inner cheeks in saftlas ' et al . study . in addition , the value obtained in the present study is similar to that reported by mulot , et al.6 ( 2005 ) using cytobrushes that were twirled in the inner cheek during 15 s. the same author observed that there was no significant decrease of the dna yield between 2 , 5 and 7 days , while all samples were maintained at room temperature6 . these results corroborate those of the present study , with no significant difference between the three methods of storage after material collection . in addition , for all methods , the amount of dna was greater than 1 to 2 g , which is considered adequate for epidemiological studies6,9 . the qualitative evaluation was based on the 0.8% agarose gel observation . a decrease in dna quality was observed when the material was not immediately placed in cls and processed , but was rather stored at room temperature or kept refrigerated until immersion in cls and processing . this could suggest that soon after collection of genetic material , the brushes should be placed immediately in the lysis solution to preserve the material 's quality . king , et al.5 ( 2002 ) verified the dna quality using pcr amplification and observed that cytobrushes collections , contains dna fragments for short and intermediate amplification primers , and poor results for large gene fragments . according to the authors , it might have occurred due to degradation of the dna from the cytobrushes , suggesting that the period of storage is an important issue in dna quality , which was reaffirmed by the findings of present study . however , we also observed that the degradation process could be minimized by immediately placing the samples in the cls . finally , it is important to highlight that genetic material collection with cytobrushes has proved to be an effective and low cost method for the collection of genetic material for epidemiologic studies . within the limitations of this study it may be concluded that the amount of dna obtained was not influenced by the method of storage prior to cls application . however , the quality of the genetic material was more preserved when cell lysis was performed immediately after sample collection .

this study evaluated quantitatively and qualitatively the effect of the storage time of samples before the application of the cell lysis solution ( cls ) for extracting dna from buccal cells ( bc ) . bc from the upper and lower gutter region were collected from 5 volunteers using special cytobrushes ( gentra ) , totaling 3 collections for each individual . in the control group ( n=10 ) , cls was applied soon after bc collection . in the other two groups , samples were stored at room temperature ( n=10 ) or at 4c ( n=10 ) . after cls application , dna was extracted according to the manufacturer 's instructions ( puregene dna buccal cell kit ; gentra systems , inc . ) . the dna obtained was evaluated by two calibrated blind examiners using spectrophotometry and analysis of dna bands ( 0.8% agarose gel electrophoresis ) . the obtained data were submitted to one - way anova . the means and standard deviations for dna extracted under immediate , room temperature and cooling temperature conditions were 3.5 0.7 , 3.0 0.6 and 4.1 1.8 g , respectively ( p=0.385 ) . no significant differences were found in relation to the amount of dna for the different storage conditions . however , in the visual analysis of the dna bands , no trace of dna degradation was detected when csl was applied soon after dna collection , while dna bands with degradation could be observed in the other groups . within the limitations of the study , it may be concluded that cls should be applied soon after dna collection in order to obtain high - quality dna from bc .

laparoscopic donor nephrectomy is rapidly becoming the standard of care for kidney retrieval during live kidney transplantation . however vascular anomalies can increase difficulty of the operation and lead to an increase in complications . we report a case of left retroperitoneoscopic donor nephrectomy in a donor with a duplicated inferior vena cava ( ivc ) . a 48-year - old woman was evaluated as a potential kidney donor for her son . blood and urine investigations were within normal limits and ultrasound revealed normal sized kidneys without any abnormality . a diethylene triamine pentaacetic acid renal scan revealed a glomerular filtration rate of 51 ml / min on the right side and 44 ml / min on the left . computed tomography ( ct ) the left renal vein inserted to the normally located right side ivc , and the left ivc was draining into the left renal vein [ figure 1 ] . both gonadal and lumbar veins were opening into the left ivc , whereas the adrenal vein was opening into the left renal vein . there were one left and two right renal arteries . due to the presence of multiple renal arteries and a better function on the right side , the left renal vein and cephalic portion of the duplicated ivc just below its confluence with the renal vein were dissected . two hem - o - loc clips were applied to control the left ivc just below its confluence with the left renal vein [ figure 2 ] . gonadal and lumbar tributaries of the left ivc were preserved to allow for collateral drainage . subsequently , the artery and renal vein were controlled and the kidney was removed . at bench surgery , the hem - o - loc clip was removed and the large opening in the left renal vein was repaired by continuous running suturing of 6/0 polypropylene . the renal allograft was uneventfully transplanted into the right iliac fossa of the recipient using external iliac vessels for revascularization . the length of the graft renal vein with segment of ivc was adequate and allowed easy anastomosis with the external iliac vein . the donor made an uneventful recovery requiring minimal analgesics and was discharged on the second postoperative day . serum creatinine achieved was 1.21 mg % on day 7 and 1.08 mg % at 1 month . venous phase of ct angiography showing confluence of the duplicated left ivc and left renal vein intraoperative view of clips on proximal portion of the left ivc . a renal artery , v renal vein , ivc - duplicated inferior vena cava , ao , the adoption of ct angiography for donor evaluation instead of conventional angiography has allowed the delineation and thus detection of venous anomalies . although a venous anomaly was present , its accurate anatomical assessment allowed us to proceed with retroperitoneoscopic donor nephrectomy . however , we have not encountered this anomaly previously in over 1000 consecutive ct renal angiographies performed in potential renal donors . anomalies of the ivc include transposition of the ivc , duplication of the ivc , circumaortic renal collar , and retroaortic renal vein . we have described previously the successful procurement of kidney by the retroperitoneoscopic approach when an anomalous renal vein was opening into the common iliac vein . three sets of paired venous channels , the posterior cardinal , supracardinal , and subcardinal veins , develop and regress , leading to the formation of the ivc , renal , adrenal , and gonadal veins . the venous phase of angiography delineates the anatomy of tributaries of the left renal vein . most bleeding during laparoscopic donor nephrectomy occurs due to injury of tributaries of the left renal vein rather than injury to the vein itself . two earlier reports describe hand - assisted laparoscopic donor nephrectomy in donors with duplicated ivc . ours is the first report of pure retroperitoneoscopic left donor nephrectomy in a donor with a duplicated ivc . we favored the retroperitoneoscopic approach because of direct access it provides to the left - sided ivc , left renal vein , and their tributaries . with suitable laparoscopic experience and adequate imaging , donors with anomalous venous anatomy may safely be offered retroperitoneoscopic donor nephrectomy . in the case of duplicated ivc , the left component of the ivc may be divided without deleterious effect to the donor .

vascular anomalies increase the difficulty during live donor nephrectomy . we herein report a left - sided retroperitoneoscopic living donor nephrectomy performed in a donor with a duplicated inferior vena cava ( ivc ) . computed tomography angiography provided accurate delineation of the venous anatomy and allowed preoperative planning . the duplicated ivc was clipped and divided just below its confluence with the left renal vein . the length of the left renal vein was sufficient for anastomosis in the recipient , and the recipient 's serum creatinine was 1.21% on day 7 . the donor made an uneventful recovery . duplicated ivc is not a contraindication for left retroperitoneoscopic donor nephrectomy .

limitations of the study include small sample size , and only subjective assessment of the scar has been taken into consideration to assess the outcome . scar formation is an inevitable result of surgery and trauma that results in full thickness epidermal loss . acne and other inflammatory , infectious conditions such as varicella , odontogenic sinus , surgery and trauma can result in atrophic scars over the face . scars over the face and other exposed parts can be cosmetically , psychologically and socially disturbing . various techniques such as subcision , microneedling , fillers , peels , autologous fat transplant , dermal graft and laser resurfacing are being practiced in the management of atrophic scars . an ideal technique which is free of allergic reaction or irritation , economical , less time - consuming and easily available , which gives a permanent correction with no rejection or resorption , is still very far from reality . this study was undertaken to evaluate the effectiveness and safety of dermal grafting technique in the management of atrophic facial scars . fifteen patients with atrophic facial scars of varied aetiology such as acne , varicella , traumatic or surgical linear scars , who had not responded to minor procedures such as subcision and microneedling and were willing for surgery , were considered for dermal grafting . proper counselling regarding the procedure , possible outcome , side effects and alternate modes of treatment was done . donor area was dermabraded with motorised dermabraders using dental burrs till there was pinpoint bleeding which ensured complete removal of epidermis [ figure 1a ] . depending on the type of scar , dermal grafts were harvested . for linear scars , a linear strip of appropriate length and breadth of dermal graft [ figure 1c and d ] was obtained and wound closed using continuous sutures with 3 - 0 vicryl . for irregular and circular scars , dermal grafts were obtained using 6 mm punches [ figure 1b ] and wound closed with simple sutures and dressed . the grafts so obtained were washed in normal saline and transferred to a petri dish containing trypsin and incubated at 37 c for 45 min . then , the grafts were again washed with normal saline and the action of trypsin neutralised with patients serum . linear and circular graft harvesting from retroauricular area ( a ) retro auricular area dermabraded till there is pinpoint bleeding ( b ) circular grafts taken with 6 mm punches ( c ) a linear dermal grafts taken from retro auricular area ( d ) linear dermal graft obtained in the recipient area , for circular or irregular scar , grafts were placed below the scar using a pocket technique [ figure 2 ] . for linear scar , grafts were inserted using railroading technique [ figure 3a d ] . in pocket technique a small nick was made on either side of the needle [ figure 2 ] . tunnelling was done beneath the scar using 18-g needle [ figure 3a d ] . a small nick on either side of needle was put to create an entry wound . from the bevelled edge , a suture was passed through the needle , the other end of which was tied to the one end of the linear graft previously prepared . then , the needle was slowly withdrawn ; at the same time , traction was given to the graft by pulling the suture and pushing the graft into the tunnel till it reached the other end of the tunnel . patients were reviewed after 3 day for donor area , dressing and suture removal of recipient area was done on the 5 day . patients were followed up again at 6 months , and results were assessed using visual analogue scale ranging from 1 ( least satisfied ) to 10 ( most satisfied ) . pocket technique of graft insertion railroad technique of graft insertion ( a ) a needle inserted just beneath the linear scar ( b ) a suture thread tied to the graft is made to pass through the bevel of the needle till it comes out of the hub ( c ) slow traction being given to the thread simultaneously pushing the graft below the scar ( d ) graft completely placed below the scar mean age of patients was 35 years . out of them , eight scars were secondary to trauma , two were post to varicella scar , three post acne scars , one due to branding and one due to healed odontogenic sinus scar . five were linear scars with width ranging between 3 and 5 mm , length 13 cm , seven were circular with diameter ranging between 413 mm and three were irregular scars . patient 's satisfaction was analysed using visual analogue scale which showed an average value of 8.4 [ table 1 ] . scar due to pilonidal sinus showed moderate improvement due to skin tethering [ figure 9 ] . however , two patients did not appreciate any difference in the scar due to altered skin texture over the scars though there was elevation of the scar . they were further subjected to q - switched nd - yag laser therapy to improve surface irregularities . tip necrosis [ figure 11 ] which healed with hyperpigmentation was observed in one patient [ figure 10 ] . patient satisfaction on visual analogue scale linear scar due to branding on the forehead ( a ) after dermal grafting with hyperpigmentation at entry points ( b ) traumatic scar on left upper cheek ( a ) and after ( b ) dermal grafting ( a and b ) varicella scar on the left cheek ( a and b ) varicella scar in the right cheek traumatic scar on the forehead ( a ) and after ( b ) dermal grafting healed odontogenic sinus scar on the right cheek ( a ) with partial improvement with dermal grafting ( b ) atrophic acne scar on left cheek ( a ) after dermal grafting ( b ) tip necrosis seen on the right after dermal grafting in a linear scar an effective , permanent therapy of broad , depressed scar has posed a real challenge for surgeons treating atrophic scars of the face . an ideal technique which is free of allergic reaction or irritation , economical , less time - consuming and easily available and which gives a permanent correction with no rejection or resorption , is still very far from reality . , surgeons have focussed on their use in ophthalmology and correction of defects in other organ systems . previous problems encountered with these grafts include persistence of the epithelium , cyst formation and unpredictable behaviour . however , with improved surgical technique , complications with dermal grafts have reduced . in our study , removal of epidermis by dermabrasion has prevented the formation of epidermal cyst as seen in earlier studies . fournier has utilised solid bits of dermis and fat , for implantations into facial rhytides . dermal grafting is the implantation of appropriately dissected deep dermis into corresponding recipient areas such as atrophic scars or other soft tissue defects . any acne scar which is prominent and soft , at least 45 mm across , can be considered for dermal grafting . at the same time , patients should also be counselled for the need for other procedures such as dermabrasion , peels or laser if they have irregular or pigmented surface . as the results may not be evident in scars with surface irregularities as in two of our case , choosing patients with normal skin texture is important while selecting the patient for dermal graft . the subcision releases fibrous anchoring of dermis and also produces trauma at microscopic level within scar tissues . newer matrix and collagen tissue are laid down and establish a well - vascularised bed of granulation tissue to accept the grafts once they are inserted one and half to 2 weeks after the undermining . therefore , all the patients were advised to undergo a procedure of undermining or subcision 2 weeks before dermal graft insertion . a commonly selected and convenient donor site is the crease behind one or both ears in an area devoid of appendages . depending on the scar shape and size , grafts are obtained and implanted as explained above . one is conventional technique and the other is enzymatic technique . in conventional technique , the donor tissue is harvested using any conventional dermatomes or using biopsy punches from the post - auricular site . alternatively , dermal tissue can also be harvested from a dermabraded area where the whole of epidermis is completely removed . the punch grafts or narrow strip of dermis is transferred to saline and then inserted into the recipient area . in enzymatic technique , similarly obtained dermal tissue is transferred into a petri dish containing 0.25% of trypsin in ethylenediaminetetraacetic acid solution . this technique makes dermal graft soft , flexible and easily mouldable as compared to grafts obtained via conventional technique . after preparing the graft , advantages of dermal grafts are it is readily available , there are no allergic or hypersensitivity reactions , its inexpensive , not susceptible to infections , can be accurately tailored for different types of atrophic scars and acts as a permanent spacer between the skin and underlying fibrous band of tissue . however , the drawbacks of dermal graft is that it may not be an ideal solution for large depressed scars where multiple sittings may be required and in scars with significant skin texture alteration where it may have to be combined with resurfacing techniques . the advantages and disadvantages of dermal graft in comparison with other modalities such as lasers , fillers and autologous fat transfer have been tabulated in table 2 . limitations of the study include small sample size , and subjective assessment of the scar to assess the outcome . to conclude dermal graft can serve as natural , permanent and inexpensive filler in the management of facial scars such as acne scars , varicella scars and linear scars of varied aetiology . however , large - scale studies are required to confirm the same . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .

background : scars over the face are cosmetically and psychologically disturbing . various techniques have been described and are being practiced in the management of these scars.aims and objectives : this study was undertaken to study the safety , effectiveness of using dermal grafts as fillers in the management of facial scars due to acne , chickenpox , trauma or any others.materials and methods : fifteen patients with atrophic facial scars of varied aetiology and willing for surgery were considered for dermal graft technique . after pre - operative workup , subcision was done 2 weeks before planned surgery . depending on the type of scar , grafts were inserted using pocket or road railing techniques . scar improvement was assessed based on patient satisfaction.results:linear scars showed excellent improvement . acne , varicella and traumatic scars also showed good improvement . however , two patients did not appreciate improvement due to marked surface irregularities as the scars were elevated . they were further subjected to laser and chemical peel resurfacing.conclusion:dermal grafting can be used in the management of any round to oval facial scar which is soft , prominent and at least 45 mm across ; linear scars at least 23 mm across and 34 cm in length . however , scars with prominent surface irregularities need further resurfacing techniques along with dermal grafting.limitations:limitations of the study include small sample size , and only subjective assessment of the scar has been taken into consideration to assess the outcome .

a 19-year - old male motorcycle rider was hit by a car and complained of pain in the left wrist . a physical examination revealed tenderness of the left wrist and hypesthesia of the 4th and 5th finger . the plain radiographs revealed an intraarticular comminuted fracture of the distal radius with posterolateral displacement of the distal fragment and an ulnar styloid process fracture ( fig . a closed reduction and percutaneous k - wires fixation with an external fixator were performed on the 2nd day after the trauma . postoperatively , the patient complained of a continuous tingling sensation at the medial 1/2 of the 4th and 5th fingers and the progressively development of a clawing deformity . at 6 weeks after surgery , the external fixator was removed and the range of motion exercise was started . at 8 weeks postoperatively , ultrasonography and electrophysiologic study were performed due to the continuous ulnar nerve palsy . the ultrasonographic findings showed that the continuity of the ulnar nerve was maintained but there was swelling of the ulnar nerve in the guyon 's canal and fibrosis of the tissues around the nerve . the electrophysiologic study revealed a decrease in the sensory and motor conduction velocity of the ulnar nerve and denervation potential in the intrinsic muscle of the hand . at 12 weeks postoperatively , ulnar nerve exploration , decompression and neurolysis was performed due to the lack of improvement in the neurological symptoms . the intraoperative findings revealed swelling of the ulnar nerve and compression by the adjacent fibrous tissues and adhesion in the guyon 's canal ( fig . a 27-year - old male complained of pain in his left wrist after a fall from a height . a physical examination revealed severe swelling and tenderness in the left wrist and hypesthesia in the 4th and 5th finger were observed . the plain radiographs revealed a severe intraarticular comminuted fracture of the left distal radius with an ulnar styloid process fracture ( fig . an open reduction was performed on the day of the trauma . a small 2 cm - incision the bone deficiency in the metaphysis was treated with an allogeneous cancellous bone graft , and an external fixator was applied . postoperatively , the patient complained of a tingling sensation in the medial 1/2 of the 4th and 5th finger and clawhand deformity . the ulnar nerve palsy was still present 6 weeks after surgery , which required ultrasonography and an electrophysiologic study . the ultrasonographic findings showed that the continuity of the ulnar nerve was maintained but there was swelling of the nerve in the guyon 's canal . the electrophysiologic study revealed a decrease in the sensory and motor conduction velocity of the ulnar nerve and the denervation potential in the intrinsic muscle of the hand . at 8 weeks postoperatively , ulner nerve exploration , decompression and neurolysis was performed due to the lack of improvement in the neurological symptoms . the intraoperative findings revealed swelling of the ulnar nerve and adhesion by the adjacent fibrous tissues ( fig . 4 ) . the neurological symptoms began to improve at the 4th week since the nerve exploration . at 1 year postoperatively , minor numbness was felt in the 4th finger and 5th finger but the clawhand deformity had disappeared . a 19-year - old male motorcycle rider was hit by a car and complained of pain in the left wrist . a physical examination revealed tenderness of the left wrist and hypesthesia of the 4th and 5th finger . the plain radiographs revealed an intraarticular comminuted fracture of the distal radius with posterolateral displacement of the distal fragment and an ulnar styloid process fracture ( fig . a closed reduction and percutaneous k - wires fixation with an external fixator were performed on the 2nd day after the trauma . postoperatively , the patient complained of a continuous tingling sensation at the medial 1/2 of the 4th and 5th fingers and the progressively development of a clawing deformity . at 6 weeks after surgery , the external fixator was removed and the range of motion exercise was started . at 8 weeks postoperatively , ultrasonography and electrophysiologic study were performed due to the continuous ulnar nerve palsy . the ultrasonographic findings showed that the continuity of the ulnar nerve was maintained but there was swelling of the ulnar nerve in the guyon 's canal and fibrosis of the tissues around the nerve . the electrophysiologic study revealed a decrease in the sensory and motor conduction velocity of the ulnar nerve and denervation potential in the intrinsic muscle of the hand . at 12 weeks postoperatively , ulnar nerve exploration , decompression and neurolysis was performed due to the lack of improvement in the neurological symptoms . the intraoperative findings revealed swelling of the ulnar nerve and compression by the adjacent fibrous tissues and adhesion in the guyon 's canal ( fig . a 27-year - old male complained of pain in his left wrist after a fall from a height . a physical examination revealed severe swelling and tenderness in the left wrist and hypesthesia in the 4th and 5th finger were observed . the plain radiographs revealed a severe intraarticular comminuted fracture of the left distal radius with an ulnar styloid process fracture ( fig . an open reduction was performed on the day of the trauma . a small 2 cm - incision the bone deficiency in the metaphysis was treated with an allogeneous cancellous bone graft , and an external fixator was applied . postoperatively , the patient complained of a tingling sensation in the medial 1/2 of the 4th and 5th finger and clawhand deformity . the ulnar nerve palsy was still present 6 weeks after surgery , which required ultrasonography and an electrophysiologic study . the ultrasonographic findings showed that the continuity of the ulnar nerve was maintained but there was swelling of the nerve in the guyon 's canal . the electrophysiologic study revealed a decrease in the sensory and motor conduction velocity of the ulnar nerve and the denervation potential in the intrinsic muscle of the hand . at 8 weeks postoperatively , ulner nerve exploration , decompression and neurolysis was performed due to the lack of improvement in the neurological symptoms . the intraoperative findings revealed swelling of the ulnar nerve and adhesion by the adjacent fibrous tissues ( fig . 4 ) . the neurological symptoms began to improve at the 4th week since the nerve exploration . at 1 year postoperatively , minor numbness was felt in the 4th finger and 5th finger but the clawhand deformity had disappeared . a median nerve injury following a fracture of the distal radius is a relatively common neurological complication that is found in 2 - 7% of cases and is associated with high energy trauma . carpal tunnel syndrome after a fracture of the distal radius is caused by an increase in pressure on the carpal tunnel due to swelling or bleeding into the carpal tunnel in most cases.1 - 3 ) in contrast , ulnar nerve injury is an extremely rare event with only 30 cases reported worldwide.2 - 10 ) according to bacorn and kurtzke4 ) an ulnar nerve injury was found in only 1 out of 2,000 patients ( 0.05% ) with a fracture of the distal radius . however , soong and ring3 ) suggested a higher frequency of ulnar nerve injuries , showing that 5 of their study population treated for a distal radial fracture within a 2 year period presented with an ulnar nerve injury . in our experience , the incidence of ulnar nerve injury was similar to that reported by soong and ring3 ) . we encountered 4 cases of ulnar nerve injury subsequent to a fracture of the distal radius . two of them were combined with a closed fracture and 2 of them were accompanied with open fracture involving severe soft tissue damage , such as a degloving injury . we postulate that the higher incidence of severe displacement , comminuted fractures , intra - articular fractures and open fractures are due to an increase in the number of high - energy injuries caused by motor vehicle accidents and industrial accidents . the cases reported thus far have also shown that an ulnar nerve injury mostly affects young people as a result of a high - energy injury caused by traffic accidents , falls from a height and sports injuries , and is common in patients with severe displacement and comminution , combined a distal ulnar fracture and open fracture . the 2 young patients in this study resulted from a high - energy injury caused by a motorcycle accident and a fall from a height . in them , the displacement or intra - articular comminution was severe and combined with an ulnar styloid process fracture . an ulnar nerve injury is caused primarily by direct contusion , traction and nerve compression due to fibrosis of the adjacent tissues or swelling , intraneural fibrosis , and rarely by laceration in a distal radial fracture.3,5 - 7 ) zoega7 ) reported from their intraoperative findings and a cadaver study that an ulnar nerve injury can occur as a result of contusion caused by a posterior and radial displacement of the distal radius fragment . clark and spencer5 ) reported that compression by thick fibrous tissues around the ulnar nerve resulted in progressive ulnar nerve palsy and demonstrated that a permanent ulnar nerve injury could be avoided even when it was displaced or extended in a fracture of the distal radius because it has a higher mobility and extensibility than the median nerve . according to soong and ring3 ) the ulnar nerve is more vulnerable to traction and contusion than to compression because the ulnar nerve is located outside the carpal tunnel and is fixed in the guyon 's canal . considering that our cases presented with swelling as a result of a contusion of the ulnar nerve as well as compression and adhesion by the adjacent tissues , it is believed that traction , contusion and compression by the adjacent fibrous tissues are the main causes of an ulnar nerve injury in a closed fracture with laceration being a rare cause . however , it is not believed that an ulnar nerve injury is caused by an open fracture involving extensive damage to the soft tissues . with regard to the treatment of an ulnar nerve injury after a distal radial fracture , there is no disagreement regarding the need for early nerve exploration when combined with an open fracture or acute carpal tunnel syndrome . however , there is some controversy regarding the treatment of an ulnar nerve injury in a closed fracture . some authors reported that careful observation can lead to recovery,3,7 ) while vance and gelberman6 ) reported that rapid recovery could be obtained with early decompression . in addition , bourrel and ferro1 ) suggested that neurolysis should be performed when there are no signs of neural recovery in the 6 months after the trauma . in our cases , the neurological symptoms did not disappear after reduction and fixation of the fracture , and no recovery was observed after 2 - 3 months of trauma . ultrasonography and an electrophysiologic study were performed , and the location and pattern of the ulnar nerve injury were observed . however , median and ulnar nerve injuries should be considered when a high - energy injury , wide displacement , or comminution is accompanied . considering that an ulnar nerve injury combined with a closed fracture of the distal radius results from a contusion or compression by the adjacent tissues in most cases , the treatment options should be chosen depending on the degree of recovery after an anatomical reduction and fixation of the fracture . when signs of recovery are not observed during the observations , nerve exploration after ultrasonography and an electrophysiologic study is recommended to identify the pattern , location and cause of the injury as well as the possibility of regeneration .

ulnar nerve palsy subsequent to a fracture of the distal radius is extremely rare compared to a median nerve injury . the lesion tends to occur in younger patents with a high - energy mechanism of injury and a severe injury pattern consisting of wide displacement , comminution , combined distal ulnar fracture and open fracture . the mechanism of injury can contribute to a direct contusion and traction , compression secondary to prolonged edema and tissue fibrosis , intraneural fibrosis and laceration . we report 2 cases of progressive ulnar nerve palsy subsequent to closed fractures of the distal radius . the neurological symptoms recovered in all cases who underwent nerve decompression and neurolysis at 2 or 3 months after the trauma . it is recommended that cases with high - energy , widely displaced or comminuted fractures of the distal radius be evaluated carefully for ulnar nerve as well as median nerve injury .

skin cancer is one of the most common cancers in the world , especially in the whites . the cancer includes two types of melanoma and non - melanoma ( basal cell carcinoma and squamous cell carcinoma ) . monitoring of skin cancer indicates an increase in the incidence of the disease . in the netherlands , the incidence of cancer has increased 80% from 2000 to 2005 , and in brazil , this rate has reached from 50 new cases in 2000 to 94 cases per 100,000 people in 2006 . in iran , about 15% of all cancer was skin cancer and this disease consider as the most common cancer . treatment cost of the cancer goes beyond the 500 million dollars per year in the united states . in australia in 2010 , it is estimated at around 511 million dollars . although deaths from this of cancer are low , what is more painful than the mortality rate of this type of cancer is emotional and physical suffering from it . the most important risk factors for skin cancer are individual , genetic , and environmental factors . factors such as skin color , eye color , hair color , aging , and sometimes immunodeficiency are considered genetic factors and individual characteristics affecting the risk of skin cancer . environmental factors are exposure to ultraviolet solar radiation , decreasing latitude , high intake of alcohol , and consumption of high - fat foods , long - term activities in the outdoors , and cover change . although skin cancer is a common cancer , it is one of the most preventable types of cancers . the primary prevention in the earlier stage , the impact will be greater . considering the high incidence of this cancer in iran as the most common cancer , and the absence of a comprehensive and systematic study on the trend of the disease , this study aimed to determine skin cancer trend and epidemiology in iran . this analytic study was done based on longitudinal program in iran that similar to many countries in the world that have national registry of cancer ( ncr ) is trying to identify all cases of cancer occurring in iran from 2004 to 2008 . data used in this study were obtained from a ncr , and disease control and prevention ( cdc ) of ministry of health and medical education in iran for 20042008 . in 2008 in iran , there are 30 provinces and 41 medical universities . deputy for the health of each university is responsible for health issues of the population and all health activities are managed by these deputies . registrar would apply the national registration software , which was developed by cdc . for pathologic centers , without software , the data are transmitted every 3 months , by electronic file and also hard copy of cancer registry data collection form ; this form is comprised of three parts : part i , regarding patient 's identity characteristics in addition to the name of biopsy - taker physician , name of hospital , location of which the biopsy is taken , clinical diagnosis and date of biopsy sent to histological laboratory and demographic information of the patients includes race and residence . the information includes the primary location of the tumor , date of cancer diagnosis , morphology , and histology and its behavior and diagnosis method . physicians fill the form of clinical data and the official personnel fill the identity and demographic information . quality control has been coordinated in five main areas by cancer office of cdc : ( i ) regarding completeness of coverage , ( ii ) completeness of details , ( iii ) accuracy of data , ( iv ) accuracy of reports , ( v ) accuracy of interpretation , and ( vi ) repeated cases are deleted from national data . surveillance of pathology is based on the cancer record in several selected provinces to compare it with the present pathology cancer record for a general and complete evaluation and also for the accuracy of the collected data . accordance of the international classification of diseases for oncology ( icd - oc : topography with icd - om : morphology ) is done manually and also by considering age and sex groups ( pathology file of fatal error has been revised by the scientific society of pathology of iran and also by two masters in pathology ) . method for deleting repeated cases : for the lack of any classified national identification numbers , the process for deleting the repeated cases was completed by a manual review of the record . after editing data of each province and considering in mind that for deleting of repeated cases , similar cases should also be the same as morphology , topography , identity , and demographic information ; deletion of the repeated cases would be done separately in each province and finally in all over country by experienced manual reviewers . in duration of study ( 20032008 ) , the number of cancer case that repetition and delegating from list of all type of cancers was 38,468 , 47,217 , 55,854 , 59,786 , 62,040 , and 76,159 , respectively . furthermore , between of 25% and 39.5% of patients have defected in coding [ diagram 1 ] . we consider skin cancer in four types : basal cell carcinoma , squamous cell carcinoma , malignant melanoma , and basosquamous carcinoma . process of data collection of cancer cause in iran crude ( all ages ) and age - specific rates per 100,000 person - year for all provinces were calculated . for each province , the average annual age - standardized incidence rate ( asr ) per 100,000 person - year was calculated by the direct method using the world standard population . findings obtained from the national registry system of cancer showed that the incidence of skin cancer had increasing trend from 2004 to 2008 [ figure 1 ] . that is , 43,694 cases of skin cancer have been registered in the country . of the incidence cases , 27,364 cases were male and sex ratio was 1.67 in these years . the highest incidence rate ( 9964 cases ) was observed in 2008 , but the lowest rate ( 7320 cases ) was recorded in 2004 [ table 1 ] . the trend of skin cancer incidence , 20042008 frequency , cir , and asr - based of sex and year the age - specific rate in men increased from 17 in 2004 to 22.62 in 2008 . the highest and lowest incidence rate in men observed in 2004 and 2008 , respectively . the trend of skin cancer incidence in man was increasing ; on an average , it grew by 07.06% annually . in women , this rate also elevated from 12.01 in 2004 to 15.77 in 2008 per 100,000 people . the maximum and minimum incidence rates were 17.77 and 12.01 per 100,000 people , respectively in 2008 and 2004 . furthermore , in women trend of skin cancer incidence was increasing ; on an average , it grew by 06.59% annually . the highest and lowest sex ratios were 1.69 and 1.63 , respectively in 2008 and 2004 [ table 1 and figure 1 ] . in this study , the age - specific rate was different in age groups so that as age rises , the incidence of skin cancer in men and women was increased , and the highest rate was observed at 8084 years but it decreased at above 85 years . furthermore , the age - specific rate in overall has rising trends from 2004 to 2008 [ table 2 ] . the asr according to age group and gender in 2008 , the age - specific rate of skin cancer was highest in males in semnan , isfahan , and hamedan provinces ( 34.9 , 30.80 , and 28.84 , respectively ) . the highest asrs were seen in females in semnan , yazd , and isfahan provinces ( 26.7 , 24.14 , and 18.97 , respectively ) . the lowest asr in male was observed in sistan and baluchestan , and in female in hormozgan provinces [ table 3 ] . trend of asr in iranian province from 2004 to 2008 basal cell carcinoma , squamous cell carcinoma , malignant melanoma , and basosquamous carcinoma in two gender have a rising trend in study duration , so in male basosquamous carcinoma has maximum rising in annually incidence average 16.75% and minimum basal cell carcinoma with 03.14% and in female squamous cell carcinoma has maximum rising in annually incidence average 08% and minimum in basal cell carcinoma with 04% [ table 4 ] . the frequency and percent of occurrence of skin cancer in iran from 2004 to 2008 the highest incidence rate of skin cancer was in males in semnan , isfahan , and hamedan provinces . the highest incidence rates were seen in females in semnan , yazd , and isfahan provinces . the lowest asr in male was observed in sistan and baluchestan , and in female in hormozgan provinces the incidence of the disease was more in all provinces in men than women . there was a direct association between skin cancer and age so that the incidence of skin cancer was increased as age rises . the results of this study showed that , during the period 2003 through 2008 , the trend of skin cancer incidence in iran was increasing ; on an average , it grew by 07.22% annually , extensive amount of this growing was certainly related to the enhancement of the registry and reporting system . in addition , the low incidence rate of cancer in 2004 was not due to the fact that few cancer cases occurred , but rather owing to the incomplete registration of cancer cases at the beginning of the cancer registry program . iranian national reports of cancer registry showed that the average annual percentage change for standardized incidence rate in all cancer was 9.6% in males and 10.6% in females during 20032008 , other studies also confirmed the increasing trend of the cancer . in addition this reason , various other factors may be effective in rising trend of incidence skin cancer in iran . these factors include climate changes , environmental factors , promoting awareness , and advances in diagnosis . the most important etiologic agent of all types of skin cancer is ultraviolet radiation . as the approach the equator , melanoma and non - melanoma cancers in other words , skin cancer is twice when latitude reduced nearly 10. it revealed the increasing incidence of skin cancer in different races . the incidence of skin cancer in people who have had excessive exposure to sunlight than other people was 4.8 times . in most seasons of the year , the intense radiation of the sun and lack of using suitable protection for outdoor in iran can probably lead to high incidence of the disease . according to rising life expectancy and the mean age of population in our country , increasing the incidence of skin cancer , especially in the older age , may be justifiable . other studies , similar our study , showed as age increases , the incidence of cancer will increase . another research also determined that high incidence of the cancer in men than women . in our study , such a result was observed in all provinces . daily activities in outdoor and sunny environments or contact with the carcinogen can be main factors cause to the high rate of the cancer in males . it recommended that in the area that age - specific rate is higher than the national average , appropriate studies to identify environmental , cultural , biological and so , designed to identify the factors affecting the occurrence of the disease in these areas . though the study well assessed incidence and age - specific rates of skin cancer based on the area , type of disease , age , and sex groups in iran from 2004 to 2008 , that given the extent of the time and place of the study , can have valuable results . however , it should be stated that the cancer registry system in iran is still not fully and equally in all area and sometimes the differences in the quality and coverage of data is observed . furthermore , in this study , despite the continued increase in the incidence of disease with rising the age , the disease in the age group 85 years , and elders is less than the previous age group , a possible reason was reduce in physician meeting in this age group for skin problem and reduce skin cancer diagnosis . in addition , we observed that provinces with the highest incidence rates in males were different from those where the highest rates of female cancers but with note to my study design ; we ca nt determent cause of this different . though the study well assessed incidence and age - specific rates of skin cancer based on the area , type of disease , age , and sex groups in iran from 2004 to 2008 , that given the extent of the time and place of the study , can have valuable results . however , it should be stated that the cancer registry system in iran is still not fully and equally in all area and sometimes the differences in the quality and coverage of data is observed . furthermore , in this study , despite the continued increase in the incidence of disease with rising the age , the disease in the age group 85 years , and elders is less than the previous age group , a possible reason was reduce in physician meeting in this age group for skin problem and reduce skin cancer diagnosis . in addition , we observed that provinces with the highest incidence rates in males were different from those where the highest rates of female cancers but with note to my study design ; we ca nt determent cause of this different . the incidence of skin cancer is increasing in the country . therefore , the plan for the control and prevention of this disease must be a high priority for health policy makers . our findings were obtained from the descriptive study on the incidence trend of the disease in recent years and it is recommended that analytical studies should be conducted to obtain a causal relationship and solve problems related to the disease .

background : one of the most common cancers is skin cancer worldwide . since incidence and cost of treatment of the cancer are increasing , it is necessary to further investigate to prevent and control this disease . this study aimed to determine skin cancer trend and epidemiology in iran.methods:this study was done based on existing data . data used in this study were obtained from a national registry of cancer cases and the disease management center of ministry of health in iran . all cases registered in the country were included during 20042008 . incidence rates were reported based on the direct method and standard population of world health organization.results:based on the results of this study , the incidence of skin cancer is rising in iran and the sex ratio was more in men than women in all provinces . the age - standardized incidence rate ( asr ) of skin cancer was highest in males in semnan , isfahan , and hamedan provinces ( 34.9 , 30.80 , and 28.84 , respectively ) . the highest asrs were seen in females in semnan , yazd , and isfahan provinces ( 26.7 , 24.14 , and 18.97 , respectively ) . the lowest asr in male was observed in sistan and baluchestan , and in female in hormozgan provinces.conclusions:the incidence of skin cancer is increasing in the country . therefore , the plan for the control and prevention of this cancer must be a high priority for health policy makers .

air - blowing equipment is often used in dentistry and oral surgery , and there are many reports of subcutaneous or mediastinal emphysema with the use of these machines . furthermore , emphysema has been reported with jaw corrective surgery , injuries and alternating washes in root - canal therapy . however , there are no previous reports of subcutaneous emphysema after the maxillary sinus - lift procedure . here an 80-year - old man with a history of en bloc resection of squamous cell carcinoma of the hard palate ( t4an0m0 ) complained of mastication difficulties due to the maxillary defect , and water and air leakage into the maxillary sinus . maxillary segmentectomy included resection of the alveolar ridge from the left central incisor to the right pterygoid process of the sphenoid bone ( fig . 1 ) . the resection site was reconstructed with a forearm flap , and the maxillary sinus was completely closed . however , these teeth were not strong enough to support a large jaw prosthesis that would cover the right maxillary defect , and residual teeth were missing . however , computed tomography ( ct ) revealed that the bone mass of the left molar region was inadequate for implantation of these fixtures ( fig . 2 ) . the soft tissue from the canine region to the molar tooth region was incised and elevated to expose the underlying lateral wall of the left maxillary sinus . a 12 5 mm window was created in the bone of the maxillary sinus anterior wall with a piezoelectric instrument to expose the underlying schneiderian membrane , which is the lining of the maxillary sinus cavity . through careful instrumentation , the membrane was carefully peeled from the inner aspect of the sinus cavity ( fig . the newly formed space within the bony cavity of the sinus inferior to the intact membrane was grafted with artificial bone , and artificial bone was placed on the alveolar crest to raise the alveolar crest ( fig . figure 2:the bone mass in the left molar region was inadequate for implantation of fixtures . a 12 5 mm section of bone has been removed at the maxillary sinus anterior wall with a piezoelectric instrument . ( b ) artificial bone has been grafted in the formed sinus cavity and placed on the alveolar bone . a 12 5 mm section of bone has been removed at the maxillary sinus anterior wall with a piezoelectric instrument . ( b ) artificial bone has been grafted in the formed sinus cavity and placed on the alveolar bone . two hours after the surgery , the patient complained of sudden malar swelling ( fig . marked swelling was present from the left infraorbital region to the buccal region , and we suspected postoperative bleeding . there were a few hematomas in the wound , but an apparent bleeding point was absent . the ct images revealed that the artificial bone grafted inferior to the membrane had not leaked into the maxillary sinus , and there was no apparent damage of the maxillary sinus membrane . however , the marked malar swelling was associated with air pockets at the alar base and in the angulus oculi medialis region and subcutaneous malar tissue , and no hematoma was evident ( fig . we made a diagnosis of subcutaneous emphysema and administered an intravenous drip containing antibiotics to the patient for 3 days . we confirmed emphysematous improvement and the graft situation of the artificial bone on the ct images at 12 days postoperatively . figure 4:after sinus - lift surgery , marked swelling is obvious from the left buccal region to the angulus oculi medialis . emphysema ( indicated by arrows ) is visible from the left buccal region to the angulus oculi medialis . after sinus - lift surgery , marked swelling is obvious from the left buccal region to the angulus oculi medialis . emphysema ( indicated by arrows ) is visible from the left buccal region to the angulus oculi medialis . emphysema of the maxillofacial region caused by dental treatment , oral surgical procedures or trauma is frequently reported . therefore , the mucous membrane of the maxillary sinus might have had a small hole , and air might have entered the subcutaneous tissue via the bone window when the air pressure in the maxillary sinus increased with nose blowing . one of the complications of the sinus lift is damage of the maxillary sinus membrane , and perforation of the sinus membrane occurs in 1035% of sinus - lift procedures , although membrane perforation is reduced to 7% when osteotomy is performed using the piezoelectric technique . the thickness of the sinus membrane is < 1 mm , so the membrane is easily damaged , and a small hole may not be apparent during the operation . the maxillary sinus is sometimes perforated by the extraction of teeth in contact with the maxillary sinus floor . perforation is common with the presence of a maxillary sinus septum or a history of surgery in the sinus region . rhymes reported that if the vertical section of the attached gingiva reaches the infraversion , then , during tooth extraction , it is easy to cause emphysema because air readily invades the loose tissue . furthermore , an inflow of air from the gap is reported to occur easily because of the texture when the periosteum or fascia is torn . , surgeons should take care not to tear the periosteum during periosteum detachment in mucoperiosteal flap creation . emphysema with sinus lift has not previously been reported and may not be anticipated with this procedure . patients are usually requested not to blow their noses after extraction of teeth in contact with the maxillary sinus or palatal closure of a fistula . however , we did not consider this precaution necessary with the sinus - lift procedure . it is important to advise patients to avoid increasing the intraoral pressure , for example , by blowing the nose vigorously or playing musical instruments , as these activities could cause introduction of more air . therefore , it is important to warn patients about nose blowing , coughing , sneezing and mucous plugging during the postinjury and postoperative periods [ 8 , 9 ] . special attention should be paid to postoperative supportive care to avoid increased subcutaneous air diffusion in patients who have undergone open surgery . however , it is necessary for oral surgeons to consider the possibility of postoperative subcutaneous emphysema after a maxillary sinus lift and to inform patients accordingly .

an 80-year - old man with a history of en bloc resection of squamous cell carcinoma of the hard palate ( t4an0m0 ) was performed a lateral - window sinus lift of the edentulous area of the left maxillary molar region to facilitate future placement of dental implants.two hours after the surgery , the patient complained of sudden malar swelling . marked swelling was present from the left infraorbital region to the buccal region . the swelling was associated with air pockets at the alar base and in the angulus oculi medialis region and subcutaneous malar tissue . emphysema appeared after the patient blew his nose . therefore , the mucous membrane of the maxillary sinus might have had a small hole , and air might have entered the subcutaneous tissue via the bone window when the air pressure in the maxillary sinus increased with nose blowing . it is important to advise patients to avoid increasing the intraoral pressure after sinus - lift procedure .

neoadjuvant chemotherapy ( nact ) was initially developed as a component of combined modality treatment for locally advanced breast cancer ( labc ) that either was inoperable at presentation or required extended radical surgery . the landmark trial , national surgical adjuvant breast project ( nsabp ) b-18 , found no differences in disease - free survival ( dfs ) or overall survival ( os ) based on the timing of chemotherapy relative to surgery in operable breast cancer patients but found that pcr correlated with dfs and os . following this trial , pathologic complete response rate ( pcr ) after neoadjuvant chemotherapy differs considerably across breast cancer subtypes [ 25 ] . obtaining a pcr after neoadjuvant chemotherapy appears to have the strongest association with survival for patients with either her2 overexpressed tumors or triple negative breast cancer ( tnbc ) . the neoadjuvant herceptin ( noah ) trial demonstrated an absolute improvement in pcr of 20% with the addition of trastuzumab that translated into a 36% risk reduction in death at 5 years . a large meta - analysis of 12 international neoadjuvant clinical trials confirmed improved survival , particularly among patients with tnbc and human epidermal growth factor receptor 2 ( her2 ) positive subtypes . until recently , pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular domain of the her2 protein and blocks ligand - dependent heterodimerization of her2 with other her family members leading to cell growth arrest and apoptosis . the fda approved the use of pertuzumab in the neoadjuvant setting to be used along with trastuzumab and chemotherapy on september 30th , 2013 , thus affording the opportunity of dual her2 blockade in the neoadjuvant setting for patients with her2 overexpressing breast cancers . pertuzumab was the first fda approved drug specifically for neoadjuvant use based on a pcr endpoint in the phase ii neosphere with additional data from the tryphena . in december 2013 , results from calgb 40603 ( alliance ) and i spy 2 were released at the san antonio breast cancer symposium showing higher pcr rates among tnbc patients treated with a carboplatin - containing regimen in the neoadjuvant setting [ 11 , 12 ] . the rationale for the use of platinum in the tnbc neoadjuvant setting has been its particular sensitivity to chemotherapy in general and specifically platinum agents . we investigated our single - institution experience of obtaining a pcr after neoadjuvant chemotherapy over the last five years . we hypothesized that pcr rates have increased since the presentation of neoadjuvant dual her2 therapy and carboplatin to treat tnbc . this was a retrospective single - center analysis of stage i iii breast cancer patients who were treated with neoadjuvant chemotherapy from march 2010 until march 2015 . the institutional review board at the icahn school of medicine at the mount sinai hospital approved this study . patients were identified by the pathology department database at the icahn school of medicine at mount sinai hospital . patients were included only if their pre- and postneoadjuvant tissue specimens were available and their neoadjuvant regimens could be obtained in our hospital records . patient characteristics were obtained via retrospective hospital - based chart review and included age at diagnosis , date of diagnosis , gender , bmi , tumor size on imaging , clinical axillary lymphadenopathy ( i.e. , biopsy proven ) , histologic grade , immunohistochemistry ( ihc ) for estrogen / progesterone expression , her2 expression via ihc or fluorescent in situ hybridization ( fish ) , neoadjuvant chemotherapeutic regimen , therapy completion ( yes / no ) , and pathological determination of pcr status . pcr was defined as having no residual invasive carcinoma in the breast and no tumor in the axillary lymph nodes . ihc analyses were performed on formalin - fixed paraffin - embedded tissue sections positive er and pr status was defined as at least 5% of tumor cells with nuclear staining . one patient had er expression of 1% and was treated as a tnbc and obtained a pcr . tumors were considered her2 positive with a score of 3 + on ihc and/or a fish ratio of greater than 2.0 . for the purposes of this review , treatments were categorized based on the use of regimens containing anthracycline and/or taxane only ( group 1 ) , those regimens that included carboplatin ( group 2 ) and those that contained dual her2 blockade ( group 3 ) . carboplatin - based regimens were only used in the treatment of tnbc and therefore did not overlap with the use of dual her2 blockade . a time period variable was created based on the date of diagnosis and subsequent treatment either before or after december 1st , 2013 ( time period 1 versus time period 2 ) . all identified cases in time period 1 began their treatments prior to december 2013 and all cases in time period 2 began treatment after december 2013 . this date of distinction was chosen based on emerging data at that time for the neoadjuvant use of carboplatin for the treatment of tnbc and the use of dual her2 blockade , specifically with trastuzumab and pertuzumab , for the treatment of her2 containing breast cancers . the primary objective of this retrospective study was to assess the rate of pcr after the use of neoadjuvant chemotherapy and to explore associations between tumor characteristics ( size , receptor expression , and histology ) , patient characteristics ( age , bmi , and clinical lad ) , and treatment characteristics ( standard versus carboplatin versus dual her2 containing regimens ) . continuous variables were summarized using mean and standard deviations , and categorical variables were summarized using frequency and percentages . independent t - tests were used to assess the bivariate associations between continuous variables and the outcome dependent variable , pcr . a binomial logistic regression model was created for the dichotomous outcome pcr ( yes / no ) that incorporated statistically significant independent variables in the bivariate analysis to 0.1 . statistical procedures were performed using the spss version 22 software ( spss , chicago , il , 2013 ) and statistical tests were two - tailed with 5% significance level . the cohort is described in table 1 and was categorized as hormone receptor positive only ( n = 33 ) , her2 positive ( n = 43 ) , and tnbc ( n = 37 ) with an overall pcr of 26.5 percent ( n = 30 ) for the entire cohort . by breast cancer subtype , pcr rates were as follows : hormone receptor positive only 12.1% , her2 positive 41.9% , and tnbc 21.6% . the average age of the cohort was 51.14 ( sd 13.1 ) , body mass index ( bmi ) 27.83 ( sd 7.4 ) , and tumor size 3.35 cm ( sd 2.2 ) . sixty - five ( 57.5% ) patients had axillary lymphadenopathy found on exam or ultrasound and confirmed on biopsy . sixty patients were included in time period 1 and 53 patients were included in time period 2 . eighty - five patients ( 75.2% ) received an anthracycline and/or taxane only nact and twenty - eight patients ( 24.8% ) received other regimens , which were all delivered during time period 2 . during time period 2 , eight of 16 patients with tnbc received a carboplatin - containing regimen ( 50.0% ) and 20 of 26 her2 + breast cancer patients received a dual her2 agent regimen ( 76.9% ) . several group differences were noted between time periods 1 and 2 ( table 1 ) . the pcr rate after nact increased from 14% ( 8 out of 60 cases ) to 43.1% ( 22 out of 53 cases ) ( p = 0.001 ) . patient age dropped from 53.19 to 48.85 years ( p = 0.09 ) and tumor size dropped from 3.43 to 2.49 cm on average ( p = 0.01 ) . her2 positive cases increased from 17 to 26 ( p = 0.04 ) and hormone receptor positive only cases dropped from 22 to 11 ( p = 0.04 ) and tnbc cases dropped from 21 to 16 ( p = 0.6 ) . table 2 highlights group differences between those patients who achieved a pcr after neoadjuvant chemotherapy and those who did not achieve a pcr . overall , higher pcr rates were associated with her2 + containing breast cancers ( p = 0.003 ) , being treated during time period 2 ( p = 0.001 ) and using a nonanthracycline / taxane only regimen ( e.g. , carboplatin - containing or dual her2 blockade ) ( p = 0.004 ) . hormone receptor positive only tumors were significantly associated with not achieving a pcr ( p = 0.003 ) . anthracycline / taxane only regimens were used in 81% of cases that did not achieve a pcr and 50% of cases that did achieve a pcr . that is , the use of nonanthracycline / taxane only regimens was associated with achieving a pcr . although only 28 out of 113 cases utilized a nonstandard chemotherapy , there was a higher likelihood of obtaining a pcr . the carboplatin - containing chemotherapy obtained a pcr in five out of eight cases ( 62.5% ) and dual her2 blockade achieved a pcr in 10 out of 20 cases ( 50.0% ) . age , initial tumor size , bmi , and initial clinical lymphadenopathy were not significantly associated with pcr ( table 2 ) . the role of nact and other predictive variables for obtaining a cr is borne out more clearly by multivariate binomial logistic regression ( table 3 ) . although univariate analysis found that time period , regimen , her2 positivity , and hormone positive predicted pcr , multinomial logistic regression found that time period was the only variable significantly associated with the probability of achieving pcr . that is , nact and the other predictive variables for obtaining a pcr ( i.e. , tumor type [ her2 , hormone positive only ] ) no longer significantly predicted the probability of achieving a pcr in the multinomial logistic regression model presented in table 3 . time period 2 was the only variable significantly associated with pcr ( p = 0.03 ) . our study revealed a significant difference in rates of pcr achieved at a single institution over five years . overall , the only variable that was significantly associated with pcr was when the patient was treated ( i.e. , after december 1st , 2013 ) and not clinical characteristics ( i.e. , tumor size , age , bmi , clinical lad , and breast cancer subtype ) . however , there were significant clinical differences between time periods 1 and 2 . a greater number of her2 positive patients , fewer hormone receptor positive patients , and smaller tumors were selected for neoadjuvant therapy during time period 2 . but , these characteristics did not appear to play a role in obtaining a pcr overall . our baseline rates of pcr during time period 1 ( i.e. , 8 out of 60 cases or 13.3% of nact cases ) approximated previously obtained pcr rates using standard nact regimens . although the breast cancer subgroup numbers were relatively small , time period 2 revealed much higher rates of pcr for her2 + and tnbc subgroups ( her2 + 50% , tnbc 62.5% ) . our pcr rates after the introduction of dual her2 blockade and carboplatin for tnbc are similar to previously reported pcr rates . for example , the addition of dual her2 blockade appears to improve pcr rates by 1619% regardless of combined chemotherapy type and rates of pcr based on a meta - analysis of six included trials that used dual her2 inhibition . also , the addition of carboplatin to standard dose dense nact was shown to improve pcr rates by 1321% [ 12 , 16 , 17 ] . our study only included pcr samples that had no residual disease in the axilla or lymph nodes ; the pcr definition most strongly correlated with improvement in survival outcomes . for aggressive breast cancer subtypes that achieve a pcr , the risk of death has been shown to decrease by 84% in tnbc , 92% in her2 + , and 71% in grade 3 hormone receptor positive / her2-negative breast cancers in the ctneobc pooled analysis . our analysis will include a future analysis to determine relapse - free and overall survival . time period 2 contributory factors towards obtaining a pcr may also include a patient selection bias ( i.e. , smaller tumors , more her2 + tumors and less hormone receptor only tumors , and perhaps younger age ) that could have influence the rate at which pcr status was achieved . also , although the sample size was sufficient to describe our endpoint of pcr over time , there were relatively small patient numbers to meaningfully analyze the associations of clinical and pathological characteristics with pcr . for these reasons , the actual association between the regimen and pcr versus the time period and pcr can not be reliably determined . this study shows improved rates of pcr after nact at our single institution that was most strongly associated with when they were treated ( i.e. , time period 2 ) . improved rates of pcr coincided with several institutional changes in selecting neoadjuvant patients and the use of new regimens for her2 positive breast cancer and tnbc . although the numbers of subgroups were small , our analysis shows a large difference in rates of pcr based on breast cancer subtypes . overall , the meaning of pcr is still not entirely well defined but appears to be a meaningful endpoint , especially for aggressive her2 positive breast cancer and tnbc .

historically , neoadjuvant chemotherapy ( nact ) was extrapolated from adjuvant regimens . dual her2 blockade and the introduction of carboplatin for triple negative breast cancers ( tnbc ) emerged by december 2013 and have improved pathological complete response ( pcr ) rates . the objective of this study was to assess the pcr rates before and after the introduction of these new neoadjuvant regimens . materials and methods . stage i iii breast cancer patients who received nact were analyzed for rates of pcr by clinical characteristics ( i.e. , age , bmi , axillary lymphadenopathy , and histologic subtype ) , by time period ( 1 = 3/201011/2013 , 2 = 12/20133/2015 ) , and by type of chemotherapy ( e.g. , anthracycline / taxane only , carboplatin - containing , and her2 blockade ) . results . 113 patients received nact . overall pcr rate was 26.5 percent ( n = 30 ) . the pcr rate increased from 14% to 43.1% ( p = 0.001 ) from time period 1 to time period 2 and were associated with her2 positivity ( p = 0.003 ) , receiving treatment during time period 2 ( p = 0.001 ) and using an anthracycline / taxane plus additional agent type of regimen ( p = 0.004 ) . conclusions . our study revealed a significant difference in rates of pcr over five years . window of opportunity trials and other trials that utilize pcr analysis should be encouraged .

the vein of marshall ( vom ) is an embryonic remnant of the left superior vena cava.1 ) the ligament of marshall ( lom ) , which contains nerves , fibrous tissues , and muscle bundles ( marshall bundle ) , is adjacent to the vom.2 ) the lom is a trigger of ectopic beats initiating paroxysmal atrial fibrillation ( af)3 ) and is innervated by the arrhythmogenic autonomic nerve.4 ) moreover , the lom is connected to the neighboring left atrium ( la ) including the perimitral area and lateral ridge , and may be a part of the re - entrant circuit . therefore , the lom may play a role in the initiation and maintenance of af or atrial tachycardia ( at ) . recently , the feasibility of injection of pure ethanol into the vom was demonstrated ; the adjunctive effect to pulmonary vein isolation ( pvi ) was indicated.5 ) in addition , vom ethanol infusion assists in consisting achieving bidirectional perimitral isthmus ( pmi ) block.6 ) however , the effectiveness of the infusion in persistent atrial fibrillation ( peaf ) , which is an extensive substrate in the la , is unclear . in the present case , af was terminated by ethanol infusion adjunctive to complex fractionated atrial electrogram ( cfae ) guided ablation in a patient with peaf . a 64-year - old male presented with a 6-month history of symptomatic drug refractory peaf . the patient was admitted for catheter ablation of af . transthoracic echocardiogram revealed normal ejection fraction of 55 - 60% with mildly enlarged la of 43.8 mm in the anterior - posterior diameter . cardiac magnetic resonance ( cmr ) imaging revealed late gadolinium enhancement ( lge ) in 20% of the la surface including the anterior and posterior wall . cfaes in the la were mapped for 6 seconds using ensite navx system three - dimensional automated software ( endocardial solutions , st . the cfaes were predominantly located at perimitral , septal area and left atrial appendage base ( fig . activation pattern at the high clustering of cfae was mapped using high density 20-pole catheters ( afocus ii ; st . the activation patterns obtained from three af beats of unipolar recordings at each cfae site were classified into four categories : 1)complete reentry , 2 ) incomplete reentry , 3 ) wave collision , and 4 ) wave breakup with conduction block . we preferentially targeted cfae areas with complete or incomplete reentry pattern because these sites might play an important role as rotor . in this case , only the perimitral area had re - entrant , rotor - like electrical activity ( fig . , we assumed that the perimitral area could be the critical site for af perpetuation . therefore , we decided to infuse ethanol into the vom as an add - on to radiofrequency ablation . at first , cannulation into coronary sinus was performed by ablation catheter ( therapy coolflex ; st . paul , mn , usa ) and 8 fr sheath ( sl1 sheath ; st . paul , mn , usa ) . to confirm the existence and feasibility of vom , ( 7 fr ; cordis , miami , fl , usa ) was subselectively engaged into the vom and then a hi - torque floppy ii angioplastic guidewire 0.014 ( abbott , santa clara , ca , usa ) was advanced into the vom as far as possible . a ryujin plus otw 2.020 mm angioplasty balloon catheter ( terumo , tokyo , japan ) was advanced into the vom over the angioplastic wire and inflated at the ostium of vom . engagement of the balloon catheter into the vom was confirmed by injecting contrast medium into the vom ( fig . 2b ) , and 1 cc of 100% ethanol was injected into the vom three times ( fig . each injection was delivered over 1 minute through a balloon lumen and flushed with normal saline . within 30 seconds after the first ethanol injection la local activation time mapping demonstrated macro - reentrant at , the circuit of which involved reentry around the mitral annulus in a counterclockwise fashion ( fig . bidirectional block of pmi line was achieved after ablation within cs adjunct to pmi ablation ( fig . this case report demonstrates that ethanol infusion into the vom can effectively eliminate cfaes at pmi . in addition , we suggest that activation mapping at cfaes area during af can identify the critical cfaes that maintain the peaf . even though the underlying etiology of cfae has not been fully elucidated , cfaes are considered as slow conduction or pivot sites , which represent continuous reentry of the fibrillatory waves.7 ) based on these theories , cfae guided ablation is widely used for modifying the extensive substrate of the la and/or right atrium in patients with peaf . however , whether cfae reflects slow conduction or pivot site , or only wave collision that overlaps different wavelets at the same area is contentious . moreover , 90% of continuous cfae sites do not overlap over lge on cmr and occur at non - lge and patchy lge sites.8 ) therefore , identification of the critical pivot site perpetuating af among the continuous fractionated electrogram is necessary . in the present case , we performed unipolar activation mapping at the cfae areas using a high density circular catheter to identify critical pivots and preferentially targeted the sites with complete or incomplete reentry pattern because these areas might be crucial for the perpetuation of af . among three cfaes sites , only the pmi area had complete reentry pattern and ablation at this site easily lead to termination of af . therefore , this case suggests the usefulness of unipolar mapping to identify the true cfae sites which is related to the persistence of af . however , there is limitation of unipolar mapping , which includes difficulty in positioning the lasso catheter at the la septum , la lateral ridge and below the la appendage . the present case highlights that peaf can be terminated and organized to at by ethanol infusion into the vom . valderrbano et al.5 ) demonstrated the feasibility of ethanol infusion into vom adjunct to pvi ; ethanol infusion decreased voltage around pmi and the la lateral ridge . in addition , ethanol infusion in the vom has an adjunctive effect in perimitral flutter ablation.6 ) the proximal portion of lom has complex muscle fiber connections to cs adjacent to pmi.1 ) the mid - portion of lom is directly connected to the la lateral ridge and pulmonary veins.1 ) these muscle fiber connections can act as an anchor of re - entry . therefore , ethanol infusion into the vom can lead to substrate modification at pmi and la lateral ridge . moreover , the pmi area and la lateral ridge are too thick to achieve transmural lesion only by endocardial ablation . therefore , ethanol infusion in the vom can be an effective intervention for achieving transmural scar and facilitating durable conduction block at this area . however , in this case , bidirectional block of pmi was not achieved by only ethanol infusion , but required endocardial pmi and intra - cs ablation adjunct to ethanol infusion . the transmurality and bidirectional block could be achieved by pmi ablation in only 15% of patients.9 ) this finding suggests that ablation of pmi concurrent with endocardial or epicardial lateral ridge may be needed to achieve transmural lesion in most cases . therefore , ethanol infusion into vom can be applied to the patients with peaf , especially when cfaes clusters at pmi area and the la lateral ridge .

we report the case of a 64-year - old male with persistent atrial fibrillation ( af ) terminated by ethanol infusion into vein of marshall as add - on therapy . three - dimensional automated complex fractionated atrial electrogram ( cfae ) during af revealed clustering of cfae at perimitral isthmus ( pmi ) and its unipolar mapping showed rotor - like activation , which was suggested to be critical in the perpetuation of af . af was organized to atrial tachycardia ( at ) by 100% ethanol infusion in the vein of marshall . adjunctive radiofrequency ablation at pmi successfully terminated at and led to bidirectional block of pmi .

eyelid or periocular wounds may be only initial sign of occult deep intracranial penetrations . in these cases , the initial absence of ocular or neurologic signs contributes to a low suspicion for intracranial extension , and injuries are commonly repaired without further investigation ( guthkelch 1960 ; bard and jarrett 1964 ; duffy and bhandari 1969 ) . delay in the diagnosis of intracranial injury may lead to serious and potentially life - threatening complications ( bard and jarrett 1964 ) . we recently reviewed a series of published cases of occult transorbital penetrating injuries ( turbin et al 2006 ) . our analysis of the anatomic patterns of injury characterized patterns of intracranial extension from superficial orbital wounds . improved awareness of orbital bone and fissure anatomy , as well as common injury patterns , should increase first - line evaluator recognition of occult transorbital penetrating intracranial injury . a 50-year - old male was beaten and found unconscious , sustaining multiple minute puncture wounds to the face and periorbital area . although the attack was unwitnessed , a police report concluded that he sustained multiple facial and periorbital stabs from the sharp wire ends of a bundled metal tomato cage . he was first evaluated by the author ( ret ) in an outpatient setting six months after the attack . the patient had limited recall of the attack , but remembered falling and that he was neither able to speak nor move before becoming unconscious . further details of the event are unavailable and were not known to the physicians initially evaluating him . a review of records revealed that he was intubated in the field , hospitalized , ultimately underwent a tracheotomy , and survived a prolonged ventilator - dependant comatose state . the injury left him wheelchair bound , ataxic , and hemiparetic with radiographic evidence of resolving subarachnoid and subdural hemorrhage attributed to blunt head trauma . after his recovery and discharge from the initial hospitalization , he subsequently developed aseptic ( or occult septic ) cerebrospinal fluid pleocytosis , basilar meningitis , and further neurologic decline requiring re - hospitalization at a major university medical center . subsequent computed tomographic ( ct ) scan was reported to show residual subarachnoid and subdural hemorrhage , with enhancement of the basilar meninges . the patient was diagnosed with secondary complications of a closed - head injury and penetrating orbito - cranial injury was not considered during either of the initial hospitalizations . after the second recovery period , the patient presented for outpatient evaluation of refractory diplopia . he complained of double vision and vertigo , left - sided weakness , ataxia , and remained wheel - chair bound . his pupils were equal , round , and reactive to light without afferent pupillary defect . he had 3 mm of right upper eyelid ptosis and a puncture scar along the right medial canthus . he had a moderate right gaze paresis with underaction of abduction on the right , and abnormal adduction on the left . the patient underwent subsequent evaluation with ct and magnetic resonance imaging ( mri ) of the brain and orbit . review of both images suggested an unusual obliquely oriented linear tract of signal traversing the brain stem and left cerebellar hemisphere . the linear tract projected directly back to areas of signal abnormality in the lateral aspect of the right orbit consistent with small metallic fragments , recognized only in retrospective review of magnified images of the orbit . these subtle findings were consistent with a penetrating tract through the lateral orbit and superior orbital fissure into the brainstem , pons , and cerebellum ( figure 1a , 1b ) . at the last follow - up visit , the patient ambulated with a walker and the strength of the left upper and lower extremity was improving . the motility examination was notable for mild gaze paresis with nystagmus in left , down , and up gaze . in this case , radiologic evidence of a thin penetrating tract through the orbit , midbrain , and cerebellum suggest that the sharp end of the tomato cage pierced the orbit , leaving particulate matter ( paint fragments ? ) visualized on the ct and mri . although it is also possible that the victim was stabbed with another unidentified object ; that possibility was not supported by the forensic police report . the unrecognized orbito - cranial penetration tracked along the lateral orbital wall , and probably via the greater wing of the sphenoid or the orbital fissures , passed through the temporal lobe and pierced the tegmentum , medulla , pons , and cerebellum . the brainstem injury rendered the patient hemiplegic , ataxic , diplopic , and initially ventilator - dependant . based on the location of the radiographic location of the tract , it is likely that the patient sustained myopathic damage to the right lateral rectus also resulting in mild enophthalmos . in addition , the patient sustained a central gaze palsy with nystagmus from the damage to the central pathways governing horizontal gaze . the patient then developed a late sterile or a partially suppressed infectious basilar meningitis which lead to further neurologic decompensation . our previous analysis of the anatomic patterns of injury segregated the periocular surface into four zones ( figure 2 ) ( turbin et al 2006 ) . zone 1 injury penetrates central , lateral , and upper eyelid , or superior conjunctiva . zone 3 injuries penetrate medially , and are further divided into upper , middle , and lower entry points . this case represents a zone 4 injury , and could not be further subclassified because of the otherwise unknown origin of the entry point . penetrating transorbital injury deep enough to injure intra - axial structures is rare , and is not typically occult . the small diameter of the proposed offending object is the likely reason the patient survived the injury . in less dramatic cases , the emergency room physician is usually the first or only provider to examine and potentially identify cases of occult orbito - cranial injury . a high degree of suspicion and appropriate knowledge of recurring patterns of penetrating orbito - cranial injury is necessary to make the correct diagnosis . knowledge of the superficial wound location and corresponding patterns of orbito - cranial damage should help guide the selection of appropriate radiographic studies and neuro - radiologic consultation . in fact , penetrating tracts may only be subsequently recognized in retrospective review of initial radiographic studies or orbital studies directed by a strong suspicion of this form of injury . we hope early recognition and appropriate management of such patients will prevent the sequelae of delayed diagnosis .

eyelid or periocular wounds may be the only initial sign of occult , penetrating intracranial trauma . as in this case , the failure to recognize the injury may contribute to serious and potentially life - threatening complications . the discussion emphasizes that a high degree of suspicion and knowledge of patterns of occult penetrating orbito - cranial injury may help direct appropriate radiological imaging and lead to earlier , accurate diagnosis .

although the incidence of tracheoinnominate artery fistula ( tif ) has decreased , it is still one of the most dangerous complications after tracheostomy . almost 75% of patients die from a tif , even after surgical repair has been performed . therefore , it is doubtful whether surgical repair is an effective method for treating tif ; however , it is still considered to be the optimal treatment option for tif . recently , the endovascular intervention has become the first - line treatment modality for vascular diseases and has replaced the classical surgical approach in many areas . in some cases of tif , endovascular stent graft repair ( esgr ) was successfully used as the first - line treatment.1 as the long - term outcomes and complications of tif endovascular intervention have been rarely reported , it is still wondered that the endovascular intervention can be treated as a better modality than surgery . here , we present a rare case of recurrent tif due to stent graft fracture after esgr . a 14-year - old male patient who had been followed - up for cerebral palsy and epilepsy from birth was admitted to the emergency room with fever , increase in the cough and sputum , and fresh bloody secretion through the tracheostomy . the patient had history of tif developed in 10 days after tracheostomy and was treated with endovascular stent graft ( jo stent graft , jomed gmbh , rangendmgen , germany ; 12 mm/58 mm ) insertion of the innominate artery . on the initial chest x - ray , migrated stent fragments could be seen and stent fragmentation was presumed to be caused by stent graft fracture ( fig . hence , chest computed tomography was performed , and it revealed separate stent fragments in the innominate artery that was filled by thrombus . as the bloody secretion through the tracheostomy increased , an emergent operation was planned . ( a ) initial chest x - ray after endovascular stent graft repair ( arrow ) of the innominate artery . ( b ) chest x - ray shows the migrated stent fragments ( arrow ) that developed due to stent graft fracture under general anesthesia , the sternotomy was performed . initially , the proximal and distal portions of the innominate artery were dissected and ligated with sutures , and then the inflammatory and necrotic tissues around the tif were resected . the inflammatory lesion in the tracheal defect was excised and the end - to - end anastomosis was performed . the patient was given ventilatory support for 4 days , and he was transferred to the general ward on the 7th postoperative day ( pod ) and discharged on the 33th pod . ( a ) the endovascular stent fragments ( arrow ) could be seen through a tear in the innominate artery . ( b ) after placing the innominate artery laterally , the endotracheal tube ( arrow ) could be seen through the fistula in trachea . since deguch et al successfully performed esgr in a patient with tif , 14 tif cases , including our case , that were treated by endovascular intervention have been reported until 2012 in the world literature.1 2 3 4 5 6 7 most endovascular interventions were performed as the first - line treatment , except one case , in which endovascular intervention was performed as a bridge to surgical treatment.8 considering the fact that bleeding could be controlled in most of cases , esgr seems to be an optimal treatment option for a tif.2 3 4 5 however , based on different individual situations , esgr can not be considered to be superior to surgical repair and should be prudently considered depending on the case . to date , three cases immediately developed endoleak after stent graft insertion , and three cases were recurrent tif 's which were stent - related complications . of the three cases of endoleak , one case was recovered after operation and the other case was recovered after an additional esgr . however , the third patient died from hemorrhage even though an additional esgr was performed . of the three recurrent tif 's , two cases were developed due to aggravation of fistula by continuous pressure of the inserted stent , and one case due to stent graft fracture as mentioned in our case . first two patients died from rebleeding even though the operation was performed.4 5 6 7 8 although there were several reports of successful management in tif patient who underwent esgr,1 2 7 it is still difficult to decide whether esgr for tif is a permanent treatment of option due to critical postinterventional complications . as the long - term outcome of esgr in tif has been unclear , esgr should be prudently performed in a child or an adolescent who has a long life expectancy . in patient with life - threatening bleeding from tif , esgr could be a good treatment of option as a bridge to surgical treatment . besides , the planed surgical correction is the most ideal approach for dealing with postinterventional complications .

tracheoinnominate artery fistula ( tif ) is one of the most dangerous complications after tracheostomy , and fetal even after surgical repair . recently , endovascular stent has been introduced as an option for the treatment of tif . unfortunately , endovascular stent repair could not replace the surgery due to rare clinical reports about the long - term follow - up and complications of stent graft . more collection of clinical data are necessary for the evaluation of long - term results . we report a rare case of recurrent tif due to stent graft fracture after endovascular stent graft insertion in the treatment of tif , and reviewed the world literature .

igg4-related systemic disease , a recently proposed clinical entity that is characterized by high serum immunoglobulin g4 ( igg4 ) level and massive tissue infiltration of igg4 positive plasma cells , has been shown to affect several organs . autoimmune pancreatitis ( aip ) is the best - documented cause of this clinical entity . aip has been reported to cause multiple extra - pancreatic lesions , sometimes with renal involvement [ 58 ] . in january 2004 , a 67-year - old man with type 2 diabetes mellitus was referred to our department due to bulky tumour - like appearance of both kidneys detected by ultrasound . ct scan demonstrated markedly enlarged kidneys with irregular contrast staining , retroperitoneal fibrosis and cervical , mediastinal and paraaortic lymph node swelling ( figure 1 ) . ( b ) a paraaortic low - density area was considered to be retroperitoneal fibrosis . in the renal tissue , light microscopic examination showed massive infiltration of lymphocytes and plasma cells with extensive fibrosis and tubular atrophy in the interstitium ( figure 2 ) . interestingly , the cellular infiltration was observed in a patchy form , and the affected area and normal parenchyma were clearly separated . marked lymphoplasmacytic infiltration with extensive fibrosis was also observed in the lymph node and the perirenal tissue . the infiltrated cells showed no dysplastic changes , and castleman 's disease was clinically excluded . ( a ) the affected area had a patchy distribution and was clearly separated from normal renal parenchyma ( periodic acid schiff staining , original magnification 40 ) . ( b ) extensive fibrosis with marked tubular atrophy and lymphoplasmacytic infiltration ( masson trichrome staining , original magnification 200 ) . ( c ) igg4 positive plasma cell infiltration ( immunohistochemistry , original magnification 1200 ) . at first , we did not initiate therapy , because the serum creatinine concentration ( cr ) at referral was 1.3 mg / dl and remained stable for several months . however , renal function deteriorated gradually from cr 1.3 mg / dl to 2.1 mg / dl over 6 months and he was re - admitted to our department . blood tests revealed elevated serum total protein of 11.2 g / dl and decreased albumin of 3.2 g / dl . serum c3 , c4 and total serum haemolytic activity ( ch50 ) were decreased to 43 mg / dl , 2 mg / dl and 12 u / dl , respectively . hypergammaglobulinaemia persisted with the elevated serum igg level of 7380 mg / dl ( igg4 of 3160 mg / dl ) , iga 145 mg / dl and igm 72 mg / dl . with these pathological and serological findings , igg4-related systemic disease was suspected , although there was no immunohistochemical confirmation . this therapy effectively improved renal function with creatinine falling to 1.1 mg / dl , reduced the renal size , lymphadenopathy , retroperitoneal fibrosis and lowered the serum igg level to the normal range . prednisolone was gradually tapered to 2 mg daily over 4 years and no recurrence was observed during the observation period . subsequent immunohistochemical examination revealed abundant igg4-positive plasma cells in the renal , perirenal and lymph tissue ( figure 2 ) , which confirmed the diagnosis of an igg4-related systemic disease . igg4-related systemic disease is characterized by ( 1 ) elevated serum igg4 concentration , ( 2 ) massive infiltration of igg4-positive plasma cells and extensive fibrosis in affected organs and ( 3 ) favourable response to corticosteroid therapy . as the nomenclature is not established , this disorder is also called igg4-related disease , igg4-related sclerosing disease , igg4-related plasmocytic disease , autoimmune multi - organ lymphoproliferative syndrome or igg4 positive plasma cell disease . recently , a new clinical entity of igg4-positive multi - organ lymphoproliferative syndrome ( igg4+molps ) has been proposed . the most well - documented form of this disorder is aip [ 13 ] , also called sclerosing pancreatitis . aip was associated with several extra - pancreatic lesions , such as sclerosing cholangitis , retroperitoneal fibrosis , sclerosing sialadenitis , swelling of lacrimal glands and lymphadenopathy . recently , renal involvement of igg4-related systemic disease was reported with or without aip [ 2,59 ] . mikulicz 's disease , a sclerosing sialadenitis , has also been considered to be involved in this entity , and a case of mikulicz 's disease complicated by tubulointerstitial nephritis with igg4-positive plasma cell infiltration has been reported . two cases of tubulointerstitial nephritis with aip were reported in 2004 . on the other hand , tumour - like focal masses have been described . moreover , retroperitoneal fibrosis with hydronephrosis has also been considered as another renal manifestation in this disorder . in microscopic examinations , the affected renal area has demonstrated focal lymphoplasmacytic sclerosing lesions with igg4-positive plasma cells , similar to aip , and often clearly separated from the normal parenchyma . this characteristic tendency of focal demarcation is observed at a microscopic level , even when the macroscopic examination shows the diffuse distribution . indeed , in the present case , the renal lesion was first recognized as tumour - like on ultrasound . histologically , a lesion demonstrating patchy distribution and a clear demarcated area of infiltration with igg4-positive plasma cells was observed . these findings suggest that focal multiple lymphoplasmacytic infiltrations might either unite or expand , and finally form a diffuse or tumour - like lesions during the progression of the disease . in addition , the understanding of these characteristics is helpful for the correct diagnosis of igg4-related systemic disease and unnecessary nephrectomy can be avoided . indeed , aip is often misdiagnosed as pancreatic carcinoma , and one previous case has been reported of the renal lesion with aip mimicking renal metastasis of pancreas carcinoma . it has been reported that corticosteroid therapy is effective in igg4-related systemic disease . in treating the nephropathy , oral prednisolone at 4060 mg daily has often been used as the initial therapy and achieved favourable responses [ 79 ] . in the present case , prednisolone was also effective , as in previous reports , and marked improvements of renal function and morphology were observed . there is no consensus as to the maintenance dose of steroid or long - term prognosis , but our case showed no recurrence of the disease with a staged reduction of prednisolone , from 60 mg to 2 mg daily over 4 years . in summary , we describe a case of renal involvement in igg4-related systemic disease with lymphadenopathy and retroperitoneal fibrosis , but without aip . patchy , clearly demarcated lymphoplasmacytic infiltrations with extensive fibrosis were observed on microscopic examination , although the radiographic imaging showed bulky enlargement of both kidneys . this case may be helpful in the diagnosis and the understanding of the pathophysiology of igg4-related systemic disease .

igg4-related systemic disease , including autoimmune pancreatitis , is a multi - organ disorder characterized by elevated serum immunoglobulin g4 ( igg4 ) concentration and igg4-positive plasma cell infiltration . we report the case of a 67-year - old man with igg4-related tubulointerstitial nephritis , presenting with markedly enlarged kidneys and renal dysfunction . the serum igg4 level was elevated with 4200 mg / dl and pathological examination revealed patchy , clearly fringed areas of igg4-positive plasma cell infiltration and advanced fibrosis in the renal parenchyma , perirenal tissue and lymph nodes . with oral prednisolone at a dose of 60 mg daily , a contraction of the kidneys and an improvement of renal function were observed . no recurrence of the disease was observed during the reduction of prednisolone to 2 mg daily over 4 years .

zinc oxide has substantive advantages including the quests for leds and laser diodes because of its wide band gap ( ~3.37 ev ) and large exciton - binding energy ( 60 mev ) . also , deep level defects ( intrinsic and extrinsic ) in zno can lead to an emission band covering the whole visible spectrum . furthermore , the optoelectronic properties of zno can be tuned by changing its morphology , composition , crystalline structure , orientation and the growth conditions . the development of zno homojunction diodes is rare due to the lack of authentic procedure to grow high - quality p - type zno . as an interesting alternate , the deposition of n - zno nanostructures on different p - type semiconductors is quite frequent to utilize the electronic and optical advantages offered by heterostructure devices . gallium nitride ( gan ) is the most suitable p - type material having wide band gap , wurtzite crystal structure and least mismatching ( ~1.8% ) in lattice constants . till date , white leds are being fabricated either by using phosphors or by mixing several coloured light . however , there are significant barriers for the large - scale applications of both processes . the former is associated with a strong reduction in device efficiency due to the problems such as low durability and requirement of relatively high fabrication temperatures for organic and inorganic phosphors , respectively . on the other hand , the latter requires the complex mixing or doping schemes , and exponential decay in emission power occurs with the increase in temperature , resulting in substantial change in colour stability [ 9 - 11 ] . recently , zno nts / au schottky led has been reported covering an emission spectrum between 400 and 600 nm . here , we report a promising route towards the fabrication of heterostructure led by exploiting the zno nts for white light emitting applications . as zno nts have excellent optoelectronic properties due to their large surface to bulk ratio with high porosity and significant amount of surface states giving rise to broadband emission covering the whole visible spectrum . this technique has several advantages , e.g. cheap , simple and environmentally benign in comparison with other techniques . zno nanorods were aqueous chemically synthesized on p - gan substrate by using low - temperature approach . one of them was used as a reference sample , while the second half was dipped in potassium chloride ( kcl ) aqueous solution for the trimming of zno nanorods into nanotubes using optimized parameters , as previously reported , except the immersion time which was shortened intentionally to reduce the etching depth of zno nts . both samples were further processed to fabricate the leds by depositing the ohmic contact on p - gan film by evaporating ni / au bilayers of thicknesses 20/40 nm , respectively . shipley-1805 photoresist film was homogeneously deposited as an insulating layer by spin coating to fill the space between the zno nts and uncovered area of the p - gan substrate . selective etching of the photoresist was carried out using a reactive ion etching in order to expose the tip of zno nts ~ few nanometres . finally , top contacts on zno were made by evaporating ti / au bilayers of thicknesses 20/30 nm , respectively . figure 1a demonstrates the schematic diagram of the fabricated n - zno nts / p - gan white led . the current voltage ( i v ) characteristics curve of the n - zno nts / p - gan heterojunction exhibits a nonlinear increase in the current under forward bias as shown in fig . literally , good rectification was obtained with a threshold voltage of ~5 v. the threshold voltage is higher than the bandgap of zno ( 3.37 ev ) , mainly owing to the high resistivity of the p - type gan layer . the dimensional and morphological evaluations of the zno nts are studied by scanning electron microscopy ( sem ) as shown in fig . it is carefully observed that the diameter of the zno nts is 100 - 150 nm with the wall thickness of 2540 nm where the average length of the nts is about 1.7 m . the structural characterization is further studied by low- and high - resolution transmission electron microscopy ( tem ) to investigate the etching depth and the crystallinity of the zno nts ( fig . the etching depth of zno nts has been intentionally kept between 700 and 900 nm to protect the p n junction of the heterostructure . a schematic 3d illustration of n - zno nts / p - gan heterostructures led device b i v characteristics of the zno nts based light - emitting diode with threshold voltage ~5 v a sem image of zno nts b low - resolution tem image of single zno nt showing the tubular structure with etching depth . the inset is a high - resolution tem showing the single - crystalline structure of the zno nts the el spectra have been measured by applying a forward bias voltage at room temperature , and emitted light has been detected from the top electrode . figure 3a shows the el spectra of zno nanotubes and nanorods - based heterostructure leds at a bias voltage of 25 v. it is clear that the emission from the zno nanotubes has higher intensity than that of zno nanorods . the emission spectrum of zno nanotubes exhibits relatively weak violet blue emission and dominating broadband emission peaks , centred at around 450 and 560 nm , respectively . the origin of the former peak ( 450 nm ) is still under debate and generally attributed to two possible sources . according to the first opinion , the emission peak is due to the transition from zinc interstitial to zinc vacancy . the radiative recombination related to deep mg acceptor levels is another possible source of the violet blue emission . zno nts offer relatively low turn - on voltage and higher current growth rate than zno nanorods . hence , there will be more injection of electrons from the conduction band of zno towards the mg - doped p - gan , which could be the reason to enhance the rate of radiative recombination to emit the higher violet blue emission peak for the zno nanotubes . the latter peak can be imputed to the injection of the holes from p - gan towards zno nts and their recombination with defect states in the zno nts , which results in the increased spectral width of the deep band emission ( 425750 nm ) . zno nts also possess a large number of surface states due to the high surface to bulk ratio and high porosity . in addition , etching process may introduce more surface states and bulk defects resulting in a wide band of visible spectrum . owing to these properties , zno nanotubes have the ability to emit more intense white light when compared to zno nanorods . figure 3b , c show lighting photographs of emission from led devices based on zno nts and zno nanorods , respectively , at the same bias value . it is clear from the images that the light emission from the n - zno nts / p - gan led is stronger when compared to the emission from n - zno nanorods / p - gan . besides the broad emission , the fabricated led reveals enhancement and stability in the el intensity of n - zno nts / gan . 4 ) can be attributed to activation of more radiative recombination centres in zno nts . no significant change either in the shape or position of the el spectrum with increasing the applied voltage has been observed . this is in contrast to recently reported zno nts / au schottky led , where the position and shape of the emission spectrum are observed to be highly dependent on the applied bias . a room temperature el spectra of zno / gan leds under forward bias from nanotubes ( blue ) and nanorods ( red ) . digital images of the led devices taken at the same applied voltage from b zno nanotubes c zno nanorods room temperature el spectra of zno nts / gan leds under forward bias voltages ( 10 , 15 , 20 , 25 , 30 and 35 v ) showing broadband emission peaks without any distinct shift in conclusion , white light emitting diode based on n - zno nts / p - gan was developed by using simple , cost - efficient and low - temperature approach . the fabricated led showed higher current density and stronger el emission peaks centred at 450 and 560 nm when compared to the led comprised of zno nanorods . the enhanced el intensity of the visible band ( 425750 nm ) emission from the zno nts is due to their high porosity , large surface area and the high density of recombination centres at the surface . the use of zno nts provided the prospects to explore the potential of white inorganic light emitting diode with superior performance . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and source are credited .

we report the fabrication of heterostructure white light emitting diode ( led ) comprised of n - zno nanotubes ( nts ) aqueous chemically synthesized on p - gan substrate . room temperature electroluminescence ( el ) of the led demonstrates strong broadband white emission spectrum consisting of predominating peak centred at 560 nm and relatively weak violet blue emission peak at 450 nm under forward bias . the broadband el emission covering the whole visible spectrum has been attributed to the large surface area and high surface states of zno nts produced during the etching process . in addition , comparison of the el emission colour quality shows that zno nanotubes have much better quality than that of the zno nanorods . the colour - rendering index of the white light obtained from the nanotubes was 87 , while the nanorods - based led emit yellowish colour .

a transconjunctival approach has been used frequently to treat fractures of the infraorbital rim and orbital floor1 , as well as other types of cosmetic and pathological situations . advantages to this approach are easy approach to the bone , rapid closure once the procedure is complete and favorable aesthetic results including minimal skin scarring2 . some complications have been associated with this approach showing it is a complex procedure . baumann and ewers3 reported 2% complications and malhotra et al.4 reported 10% complications at 2-year follow - up . this case report presents an important complication of the transconjunctival approach to treating an orbital fracture . a 30-year - old male patient was admitted to the hospital at temuco , chile , due to a high - energy trauma caused by a fall from a height of 4 m. during admission the patient 's condition was assessed and a fracture of the left orbital complex was diagnosed , in addition to fractures of the orbital rim and floor , orbital sidewall , zygomaticomaxillary pillar and ipsilateral zygomatic arch.(fig . 1 ) the patient was in intensive care for one week , at which point it was possible to provide surgical treatment . no medical history was present , including diabetes , metabolic or facial syndromes or nutritional conditions and no smoking was reported . the immediate preoperative stage showed severe left periorbital edema , ophthalmoplegia and diplopia in different fields . the surgical procedure was executed by a maxillofacial surgeon with 6 years experience in facial trauma ; an upper approach was made for the left supraorbitaral rim , a left intraoral approach and a transconjunctival approach with lateral canthotomy . the procedure was performed conventionally and routinely , without complications . according to the proposed technique , internal rigid fixation was used with 1.5 plates , and no problem in screw insertion was present ; at some stage during surgery , a forced retraction of the conjunctival flap was undertaken . the final suture to the conjunctiva was made using two stitches with a reverse knot and a 5 - 0 absorbable suture . in the initial postoperative days , increased sclera exposure was observed , with no symptoms of pain or signs of enophthalmos or dystopia . on the fourth postoperative day an acute low - level conjunctivitis associated with chemosis and a 3 mm palpebral conjunctiva exposure was seen.(fig . 2 ) the patient was discharged 1 week after surgery and during the hospital stay was kept on a course of endovenous corticoids ( 12 mg intravenous [ iv ] per day for 3 days , 24 mg iv per day during the last 4 days ; fresenius kabi ag , bad homburg , germany ) . at the first out - patient check - up 10 days after the surgery , the patient presented with severe chemosis of the left eye with 5 mm of exposure ( fig . 3 ) , slight ophthalmoplegia and ptosis of the upper eyelid , with no signs of pain or visual alterations . farma , santiago , chile ) was introduced as well as an eye patch to avoid major complications associated with lack of lubrication . the ophthalmologist 's assessment reported positive visual acuity in all fields with functional impotence in the infraversion . the condition evolved in a limited fashion over the following 8 days ( 18 days after surgery ) , at which point the chemosis began to subside . 4 ) the patient showed symptom resolution , with resolved chemosis and associated conjunctivitis , but persistence of post - traumatic strabismus , which was subsequently solved with surgical treatment to manage the extrinsic muscles of the eye involved in the anomalous position of the eyeball . after two years of follow - up , the patient had an adequate recovery from the facial trauma with a slight ptosis of the upper left eyelid , limited infraversion and no signs of alterations in visual acuity.(fig . 5 , 6 ) the written informed consent for the publication of the photographs was obtained from the patient . treatment of orbital fractures and fractures of the zygomatic orbital complex has been linked to different conditions , where variables such as the patient 's age and gender as well as the presence of other facial fractures are combined5 . in a series by manganello - souza and rodrigues de freitas6 reporting on 40 patients treated with the transconjunctival approach , only five presented with related complications such ectropion , corneal ulceration and ptosis of the lateral canthus . another series with 56 patients reported only 4 patients with complications associated with entropion and trichiasis7 . baumann and ewers ' study3 of 99 patients reported 2% complications , describing a case with entropion and another case with tarsal laceration , which were both later resolved without major limitations . malhotra et al.4 presented a series of 60 patients with 2 years of follow - up and 6 cases of complications , including chemosis . with a low incidence of complications and the advantages of the transconjunctival approach , the author 's use of these techniques in 90% of the facial trauma and reconstruction cases resulted in no chemosis ( almost 30 cases per year ) . causes for this complication may be related to extensive initial orbital edema which presented at the time of surgery , excessive traction in the conjunctival flap , inadequate dissection layer or lymphatic flow complications in the postoperative time . in this sense , chemosis defined as nonspecific swelling of the conjunctiva could be associated with bacterial or viral reactions , angioedema or trauma8 . in cosmetic blepharoplasty techniques using the transconjunctival approach , it is likely that the transconjunctival approach which is oriented to remove fat tissue produces better conditions for the development of chemosis and that the physiopathological mechanism will be similar to that observed in this case , since this is a rare complication in orbital traumatology . other conditions such as carotid - cavernous fistula have also been responsible for proptosis , ophthalmoplegia and chemosis , indicating it is a response to the volume of fluids present in the orbit10 . lymphatic flow is key for postoperative chemosis11 . for instance , retrograde flow could result in the lymphatic channel filling with blood12 or may contribute to a rise in periocular or orbital pressure , resulting in venous engorgement and a back - flow of blood into the conjunctival lymphatic system13 . on other hand , dilated arterioles increase the pressure gradient between arteriolar and venule capillaries and lead to the extravasation of intravascular fluid with resultant vasodilatory edema . in this case , the patient presented with a great deal of edema at admission , a non - controlled traction of the conjunctival flap and failure in drainage which could all be related to his chemosis . a treatment protocol for this condition has been proposed based on topical and systemic corticosteroids . oral steroids are an effective adjuvant treatment in younger patients14 and topical adrenaline could be an option15 ; surgical treatment that includes sutures has been used in other trauma cases16 . the treatment strategies used in this case were in agreement with mccord et al.17 and putterman18 , and showed good results . prevention of this complication can be achieved by respecting anatomical landmarks and gentle retraction of the orbital flap . this case was resolved with minor functional alterations , although the consequences observed after 2 years ( ptosis of the upper eyelid and limited infraversion ) were not completely satisfactory , and may call into question the results obtained by the treatment provided during initial presentation and the surgical treatment of the orbital fracture .

the aim of this report was to discuss a complication resulting from a transconjunctival approach to treating an orbital fracture . a 30-year - old male patient presented with a fracture to the zygomatic orbital complex . he was treated with transconjunctival conventional surgical treatment . two days after surgical treatment , the patient presented with secondary chemosis which was initially slight and then subsequently worsened . the clinical situation was managed with topical and systemic corticosteroids and resolved within one postoperative month . two - year follow - up showed ptosis of the upper eyelid and limited infraversion in the affected eye . this unusual complication associated with an orbital trauma was resolved with minor functional alterations , although the consequences observed after 2 years were not completely satisfactory .

normal tension glaucoma ( ntg ) is an optic neuropathy associated with glaucomatous optic nerve head damage , progressive retinal nerve fiber layer thinning , characteristic visual field defects , open anterior chamber angles on gonioscopy and maximum intraocular pressure ( iop ) below 21 mmhg . glaucoma is a major optic neuropathy characterized by significant death of retinal ganglion cells . according to global surveys , the second leading cause of blindness after cataracts is glaucoma . glaucoma affects more than 66 million people and is the second leading cause of visual loss worldwide . ntg accounted for 92% of primary open - angle glaucoma ( poag ) in a japanese population . patients with ntg tend to be older than those with primary open angle glaucoma ( poag)female subjects have a higher prevalence of the disease than male counterpartsntg is more frequent among japanese peoplethe most important risk factor for glaucoma is elevated iop . it has been established that high iop is a part of the pathogenic process of ntg ; however , the pressure theory can not sufficiently explain how ntg causes loss of vision . multicenter clinical trials have confirmed the value of reducing iop both in poag and ntg . there is yet to be a consensus regarding the specific relationship between iop and ntg . however , in many cases the progression of gon has been observed even after lowering iop . patients with ntg have wider diurnal fluctuations of iop as compared to the healthy population . iop spikes may occur at night , and thus iops measured during office hours may miss nocturnal spikes in many patients . associated changes in nocturnal orbital blood pressure and iop may affect optic nerve head blood perfusion differently in glaucomatous eyes as compared to healthy eyes , and this issue may also influence the susceptibility of the optic nerve to damagecentral corneal thickness ( cct ) in patients with ntg is lower than poag subjectsvascular dysfunction and ischemia have been considered as important factors in the progression of ntg . however , the ischemia in glaucoma is not simply insufficiency of blood flow , but also due to improper vascular autoregulation , and hypothetically episodes of transient ischemia and re - perfusion injury occurcold hands and feet , as an over - reaction to cold or stress , are suggestive of defective vasoregulation . abnormal vasoregulation such as raynaud 's phenomenon and migraine are more associated with ntg than poag . a study of peripheral vascular endothelial function in patients with ntg found impaired acetylcholine - induced peripheral endothelium - mediated vasodilation in comparison to healthy age- and sex - matched control subjects , and polymorphisms of the endothelin receptor type a gene have been associated with ntgpatients with ntg have an increased frequency of headaches with or without migraine featuresnon - iop - related cardiovascular dysregulation factors , such as systemic hypertension , systemic hypotension , nocturnal hypotension , and cardiac arrhythmia are implicated in ntgthere are reports suggesting that signs of glaucoma in certain eyes may be related to an acute ischemic episode ( shock - induced neuropathy ) , or chronic obstructive arterial disease , which may be non - progressivemojon et al suggested that patients with sleep apnea syndrome are at high risk for glaucoma . the prevalence of obstructive sleep apnea syndrome ( osas ) was higher in patients with ntg . osas may cause optic nerve head hypoperfusion and glaucomatous optic neuropathy by creating transient hypoxemia and increasing vascular resistanceabnormally low diastolic double product ( ddp = diastolic blood pressure heart rate ) may represent a state of cardiovascular autonomic dysregulation , resulting in low ocular perfusion in certain ntg patientsntg patients with lower heart - rate variability , which reflects autonomic dysfunction with sympathetic predominance , manifested a faster rate of central visual field progression as compared to patients with higher heart - rate variabilityglaucoma patients have a decrease in central retinal vein ( crv ) blood velocities . this is particularly important in ntg patientsduplication of the tank - binding kinase 1 ( tbk1 ) gene can be a rare cause of ntglifestyle factors such as smoking and high body mass index can cause progression of glaucomatous visual field defect . in the blue mountain eye study , smokers were found to have higher iop than non - smoker counterpartsout of the metabolic syndrome components , hypertension and impaired glucose tolerance ( igt ) may contribute to an increased risk of ntg . patients with ntg tend to be older than those with primary open angle glaucoma ( poag ) female subjects have a higher prevalence of the disease than male counterparts ntg is more frequent among japanese people the most important risk factor for glaucoma is elevated iop . it has been established that high iop is a part of the pathogenic process of ntg ; however , the pressure theory can not sufficiently explain how ntg causes loss of vision . multicenter clinical trials have confirmed the value of reducing iop both in poag and ntg . there is yet to be a consensus regarding the specific relationship between iop and ntg . however , in many cases the progression of gon has been observed even after lowering iop . patients with ntg have wider diurnal fluctuations of iop as compared to the healthy population . iop spikes may occur at night , and thus iops measured during office hours may miss nocturnal spikes in many patients . associated changes in nocturnal orbital blood pressure and iop may affect optic nerve head blood perfusion differently in glaucomatous eyes as compared to healthy eyes , and this issue may also influence the susceptibility of the optic nerve to damage central corneal thickness ( cct ) in patients with ntg is lower than poag subjects vascular dysfunction and ischemia have been considered as important factors in the progression of ntg . however , the ischemia in glaucoma is not simply insufficiency of blood flow , but also due to improper vascular autoregulation , and hypothetically episodes of transient ischemia and re - perfusion injury occur cold hands and feet , as an over - reaction to cold or stress , are suggestive of defective vasoregulation . abnormal vasoregulation such as raynaud 's phenomenon and migraine are more associated with ntg than poag . a study of peripheral vascular endothelial function in patients with ntg found impaired acetylcholine - induced peripheral endothelium - mediated vasodilation in comparison to healthy age- and sex - matched control subjects , and polymorphisms of the endothelin receptor type a gene have been associated with ntg patients with ntg have an increased frequency of headaches with or without migraine features non - iop - related cardiovascular dysregulation factors , such as systemic hypertension , systemic hypotension , nocturnal hypotension , and cardiac arrhythmia are implicated in ntg there are reports suggesting that signs of glaucoma in certain eyes may be related to an acute ischemic episode ( shock - induced neuropathy ) , or chronic obstructive arterial disease , which may be non - progressive mojon et al suggested that patients with sleep apnea syndrome are at high risk for glaucoma . the prevalence of obstructive sleep apnea syndrome ( osas ) was higher in patients with ntg . osas may cause optic nerve head hypoperfusion and glaucomatous optic neuropathy by creating transient hypoxemia and increasing vascular resistance abnormally low diastolic double product ( ddp = diastolic blood pressure heart rate ) may represent a state of cardiovascular autonomic dysregulation , resulting in low ocular perfusion in certain ntg patients ntg patients with lower heart - rate variability , which reflects autonomic dysfunction with sympathetic predominance , manifested a faster rate of central visual field progression as compared to patients with higher heart - rate variability glaucoma patients have a decrease in central retinal vein ( crv ) blood velocities . this is particularly important in ntg patients duplication of the tank - binding kinase 1 ( tbk1 ) gene can be a rare cause of ntg lifestyle factors such as smoking and high body mass index can cause progression of glaucomatous visual field defect . in the blue mountain eye study , smokers were found to have higher iop than non - smoker counterparts out of the metabolic syndrome components , hypertension and impaired glucose tolerance ( igt ) may contribute to an increased risk of ntg . history has to be taken regarding migraine , raynaud 's phenomenon , episodes of shock , head injury , headache and other neurological symptoms . use of medications including systemic steroids and antihypertensive agents such as beta blockers should also be taken into account . goldmann applanation tonometry , gonioscopy , stereoscopic biomicroscopy of the optic nerve head , optical coherence tomography and humphrey field analyser are the main tools of investigation for diagnosis of ntg . increased cup to disc ratio or asymmetry of cupping between the two eyes ( difference more than 0.2 ) is significant [ figure 1 ] . a region of absent retinal pigment epithelium ( rpe ) is more often seen as a crescent or halo at the disc border in ntg . the cupping is often worse in the region of absent rpe , with field loss more marked in the corresponding region . occasionally , there is a notch due to thin or absent neuro - retinal rim , referred as a this is associated with a highly localized dense arcuate field defect or even a dense hemifield defect . other discs have diffuse shallow cupping and pallor , leading to the designation senile sclerotic disc . patients with high myopia may be particularly susceptible to ntg . with a frequent temporal crescent , scotomas tend to be closer to fixation than the paracentral scotomas of non - myope cases . splinter hemorrhages are seen more commonly in ntg , but may also be found in poag . hemorrhages may simply indicate poor control . although the optic nerve head may be larger in ntg than in poag , glaucomatous cupping is comparable . normal - tension glaucoma eyes can have greater optic nerve head ( onh ) torsion as compared to poag eyes with matched axial length . the direction of the onh tilt and torsion can be related to the location of the visual field defect only in ntg eyes . as compared to normal subjects , peripapillary choroidal thickness was significantly thinner in ntg patients , at least in some locations . another revealed a difference in the progression pattern as compared to poag patients ; in poag eyes , field defects initially increased in area and later in depth , whereas in patients with ntg , the increases in area and depth remained in constant proportion . other investigations include 24-hour blood pressure monitoring to exclude nocturnal systemic hypotension ; blood tests to rule out other causes of glaucomatous optic neuropathy such as vitamin b12 and folate levels , esr / crp and serum ace . cranial mri may be necessary to rule out intracranial space occupying lesions ( sols ) ; and nail fold capillaroscopy with cold provocation may detect blood flow abnormalities . a number of congenital disorders may be confused with ntg ; these include optic nerve anomalies including coloboma , pits , oblique insertion of the optic nerve , in addition to autosomal dominant optic atrophy ( kjer type ) . acquired disorders which need to be considered in the differential diagnosis of ntg include history of steroid use by any route which may have led to prior elevated iop , prior trauma or surgery which may have caused elevated iop , hemodynamic crisis , methyl alcohol poisoning , optic neuritis , ischemic optic neuropathy ( both arteritic and non - arteritic ) , compressive lesions of the optic nerve and tract ( e.g. , meningioma , vascular lesion ) ; and wide diurnal fluctuation in iop . the early manifest glaucoma trial showed that glaucoma progression was decreased by 10% with reduction of each mmhg of iop . according to the collaborative normal tension glaucoma study group , choices for medical treatment in progressive cases include betaxolol eye drops which have a beneficial effect on optic nerve blood flow in addition to iop reduction . other beta blockers and adrenergic drugs ( such as dipivefrine ) should better be avoided because of the probability of nocturnal systemic hypotension and optic nerve hypoperfusion . . dorzolamide - timolol fixed combination ( dtfc ) is a safe and effective iop - lowering agent in patients with ntg . brimonidine significantly improved retinal vascular autoregulation in ntg patients ; however , short - term alterations in visual function could not be demonstrated . in the collaborative normal tension glaucoma study ( cntgs ) , 57% of the patients achieved 30% iop reduction with topical medications , laser trabeculoplasty or both . the remaining 43% required filtering surgery which may prevent progressive damage . a single session of selective laser trabeculoplasty ( slt ) for ntg achieved iop reduction of 20% from pre - study iop and 30% reduction from baseline iop at 6 months . deep sclerectomy seems to be effective and safe in reducing iop in patients with ntg . intraoperative use of mmc results in lower postoperative iop after 12 months without an increased rate of complications . an additional part of managing ntg is treatment of any cardiovascular abnormality such as anemia , hypotension , congestive heart failure ( chf ) , transient ischemic attacks and cardiac arrhythmias to increase optic nerve head perfusion . if significant nocturnal dips in blood pressure are detected , it may be necessary to reduce the antihypertensive medication especially at bedtime . finally treatment is aimed at neuroprotection to improve the retinal ganglion cell or optic nerve head function . nilvadipine , a calcium channel blocker , increases blood flow to the optic nerve head and fovea . there was a significant reduction in the rate of disc and field damage in ntg patients who received calcium channel blockers .

normal tension glaucoma ( ntg ) is labelled when typical glaucomatous disc changes , visual field defects and open anterior chamber angles are associated with intraocular pressure ( iop ) constantly below 21 mmhg . chronic low vascular perfusion , raynaud 's phenomenon , migraine , nocturnal systemic hypotension and over - treated systemic hypertension are the main causes of normal tension glaucoma . goldmann applanation tonometry , gonioscopy , slit lamp biomicroscopy , optical coherence tomography and visual field analysis are the main tools of investigation for the diagnosis of ntg . management follows the same principles of treatment for other chronic glaucomas : to reduce iop by a substantial amount , sufficient to prevent disabling visual loss . treatment is generally aimed to lower iop by 30% from pre - existing levels to 12 - 14 mmhg . betaxolol , brimonidine , prostaglandin analogues , trabeculectomy ( in refractory cases ) , systemic calcium channel blockers ( such as nifedipine ) and 24-hour monitoring of blood pressure are considered in the management of ntg . the present review summarises risk factors , causes , pathogenesis , diagnosis and management of ntg .

lacosamide ( lcm ) is a novel antiepileptic drug ( aed ) approved by the u.s . food and drug administration ( fda ) for the adjunct treatment of partial epilepsy with and without secondary generalization . lacosamide selectively modulates voltage - gated sodium channels by enhancing slow inactivation without affecting fast inactivation to exert its antiepileptic activity [ 13 ] . lacosamide has linear pharmacokinetics , reaches maximum concentration within 14 h following oral administration , and has a half - life of 13 h . lacosamide is a potent antiepileptic agent with superior efficacy compared to placebo in patients with partial seizures . the choice of aed is related to both its efficacy in treating seizures and its side - effect profile . dose - dependent lcm - induced cardiac dysrhythmias have been reported in recent literature [ 4,69 ] . high - dose lcm ( 600 mg total daily dose ) has been associated with atrial fibrillation / flutter . the authors report a case believed to represent the first instance of low - dose lcm - induced atrial fibrillation . a 67-year - old right - handed woman with history of epilepsy , migraines , and recently diagnosed plasma cell multiple myeloma with lambda - free light chains and with swollen tongue presented to our institution for autologous bone marrow transplant . there was no known history of structural heart disease or conduction abnormalities though a family history ( mother / brother ) of atrial fibrillation was later determined . one week following the bone marrow transplant , frequent episodes of staring associated with oral and facial automatisms ( lip smacking and head shaking ) were noted which prompted neurology consultation . medications at time of consultation included primidone 250 mg daily , fluconazole 400 mg daily , acyclovir 400 mg every 12 h , filgrastim 300 g daily , methyl - prednisolone 40 mg iv daily , pantoprazole 40 mg daily , potassium chloride , and clotrimazole mouthwash 10 mg five times a day which she did not receive that day due to epigastric discomfort . the patient had received loperamide 10 mg 3 times in the last 2 days and ondansetron 8 mg iv on the day prior to consultation . comprehensive metabolic panel and complete blood count were normal on the day of consultation excluding sodium 134 meq / l , fasting glucose 108 mg / dl , hemoglobin 8.5 g / dl , and hematocrit 24.5% . phenobarbital level was 3.6 g / ml . her ecg revealed a sinus rhythm at 96 bpm with premature ventricular contractions with qtc of 437 ms and pr of 156 ms . during this consultation , the patient revealed a history of three generalized tonic - clonic ( gtc ) seizures at age 21 associated with an aura described as tinnitus . the convulsive seizure activity responded to primidone 250 mg total daily dose ; however , the patient reported ongoing tinnitus occurring once monthly and had been told by her family that she would have brief periods of behavioral arrest with staring , which she minimized by stating that she was thinking of a response . initial routine eeg revealed 1 ) disorganized background characterized by diffuse slowing with frontally predominant theta and delta activities and intermittent semi - rhythmic delta activity ; 2 ) intermittent left fronto - temporal polymorphic delta activity ; and 3 ) few left fronto - temporal high - amplitude sharp waves ( fig . 1 ) . clinical presentation and eeg following initial evaluation by the neurology team , levetiracetam 250 mg iv twice daily was initiated without significant change in clinical status . intravenous administration was required as the patient was not tolerating oral medications and had vomited her primidone . her episodes increased in frequency with descriptive features including continuous tinnitus , staring , facial automatisms , limited verbal responses and lethargy . levetiracetam was titrated to 500 mg iv twice daily with primidone 300 mg daily , and the patient was placed on continuous video - eeg ( veeg ) to better characterize seizure activity and to monitor treatment response . during a four - hour period on continuous veeg , greater than 30 episodes were recorded with electrographic correlation including seizures with and without secondary generalization ( fig . 2 ) . the patient had continued lethargy with altered mental status between episodes consistent with complex partial status epilepticus . levetiracetam was increased to 1000 mg twice daily , and the patient received a loading dose of lacosamide 200 mg iv given over 60 min . the patient was noted to have an irregular cardiac rhythm on the veeg telemetry lead at the end of the lacosamide infusion ( fig . a 12-lead ecg confirmed atrial fibrillation with rapid ventricular response ( 132 bpm ) . cardiology was consulted for this new - onset atrial fibrillation . at time of cardiac consultation , the patient 's comprehensive metabolic panel and complete blood count were normal excluding sodium 128 meq / l , potassium 3.4 meq / l , glucose 142 mg / dl , phosphorus 2.1 mg / dl , white blood cell count 0.1 thousand/l , red blood cell count 2.4 million/l , hemoglobin 7.3 g / dl , hematocrit 21% , and platelet count 45 thousand/l . pertinent normal laboratories included troponin i < 0.03 ng / ml , magnesium 1.8 mg / dl , and tsh 1.56 lacosamide was discontinued following the infusion and the atrial fibrillation , which did not respond to metoprolol 2.5 mg iv , spontaneously resolved within 8 h. a trans - thoracic echocardiogram ( tte ) was performed on the following day and revealed a normal left ventricular size and systolic function with an estimated ejection fraction of 55% , a normal right ventricular size and systolic function , normal bi - atrial size , mild aortic insufficiency , and mild tricuspid regurgitation with moderate pulmonary hypertension ( right ventricular systolic pressure of 59 mm hg ) . cardiology concluded that the atrial fibrillation was induced by the lacosamide infusion as there were no structural or motion abnormalities . anticonvulsant regimen was changed to levetiracetam 1500 mg iv twice daily and , following two boluses of phenobarbital 600 mg iv , phenobarbital 60 mg iv every 8 h without significant change in seizure frequency . video - eeg showed a seizure frequency of 6 to 8 events per hour , each lasting approximately 60 s in duration , consisting of left temporal rhythmic sharp waves with staring . the patient received phenytoin 1200 mg iv loading dose following which the veeg recorded a three - hour seizure - free period without epileptiform activity ; thereafter , the patient remained seizure - free though intermittent sharp waves were noted . levetiracetam was discontinued , and seizure freedom persisted with phenobarbital 60 mg iv every eight hours and phenytoin 100 mg iv every eight hours with respective anticonvulsant blood levels of 23.9 g / ml and 2.1 g / ml ( free ) . ninety - six hours after the initial atrial fibrillation , the patient had another brief period of atrial fibrillation that lasted several minutes without any clinical complication . a full 48 h without seizure activity was recorded , and veeg was discontinued . the patient remained on cardiac telemetry during the remaining two weeks of her admission during which time there were no further episodes of atrial fibrillation . upon discharge this unique case of apparent low - dose lacosamide - induced atrial fibrillation in a patient with refractory epilepsy and nonconvulsive complex partial status epilepticus allows the discussion of several key points both specific to this patient and to the lcm treatment of patients considered to be at high risk for cardiac dysrhythmias . first , patients often minimize their symptoms in acute and chronic medical conditions as well as adverse drug reactions which may lead to increased morbidity and mortality [ 1012 ] . in this instance , minimizing symptoms led to untreated complex partial seizures ; for though her tonic - clonic seizures were controlled with primidone , the patient had ongoing periods of tinnitus with behavioral arrest and staring . minimizing these epileptic symptoms led to an unnecessary treatment gap . events include dose - dependent pr - interval prolongation , first- , second- and third - degree av blocks , and atrial fibrillation / atrial flutter with high - dose lcm ( 600 mg / day ) [ 4,69,13,14 ] . third , current clinical practice and recent literature suggest that lcm may be used in older and critically ill patients [ 1517 ] . this patient population is at greater risk for atrial fibrillation as the reported risk factors for atrial fibrillation include , but are not limited to , older age , male gender , hypertension , diabetes , congestive heart failure , myocardial infarction , cardiac surgery , valvular disease , severe sepsis , hyperthyroidism , obesity , and smoking [ 1821 ] . though the echocardiogram was normal , a cardiac biopsy was not performed , and as such , early cardiac amyloidosis could not be excluded . fifth , analysis of the framingham offspring study noted that parental atrial fibrillation is associated with a 1.85 odds ratio for atrial fibrillation in the offspring . in this case , both the patient 's mother and brother had atrial fibrillation . genetic predisposition was a risk factor in this case . sixth , the patient 's second period of atrial fibrillation , lasting several minutes 96 h after the lcm - associated atrial fibrillation , may imply unknown cardiac pathology as a predisposing risk factor . seventh , atrial fibrillation occurred at the end of the lcm iv infusion , consistent with the theoretical maximum blood concentration . lacosamide has linear ( first - order ) pharmacokinetics with an elimination half - life of 13 h . the spontaneous resolution of atrial fibrillation within 8 h following the lcm infusion suggests a concentration - dependent effect . eighth , the patient had multiple potential risk factors ( older age , possible cardiac amyloidosis , genetic predisposition , and possible unknown cardiac pathology ) for cardiac arrhythmias . in the context of additive risk factors , the probability of lcm inducing the initial episode of atrial fibrillation was determined by the naranjo 's adverse reaction probability scale as probable ( scored as 5 ) . ninth , as lcm may cause ( or precipitate ) cardiac dysrhythmias including atrial fibrillation in susceptible patients , recommendations prior to the initiation of lcm may include 1 ) obtaining baseline 12-lead ecg , 2 ) obtaining careful cardiac history verifying potential risk factors including family history of atrial fibrillation or other dysrhythmias , 3 ) obtaining comprehensive metabolic panel with magnesium , 4 ) normalizing electrolyte levels , and 5 ) adjusting lcm dose based on renal and hepatic functions . further , as this paper suggests that lcm - induced atrial fibrillation may occur at low doses cardiac monitoring during both initial lcm administration and titration should be considered . there are specific limitations to this paper . as a case report ( n = 1 ) , the findings can not be generalized . in this case , and other studies of atrial fibrillation , pre - existing asymptomatic atrial fibrillation can not be excluded . lacosamide blood level was not measured . cardiac biopsy to confirm amyloidosis impacting the heart was not obtained . though the patient had a family history of atrial fibrillation , no genetic assessment was performed to confirm familial atrial fibrillation . finally , the patient could not be re - challenged with lacosamide for ethical reasons . low - dose lacosamide may induce atrial fibrillation , especially in patients at risk for cardiac arrhythmias . clinicians need to be aware of this potential adverse drug effect and to evaluate and monitor at - risk patients appropriately .

lacosamide ( lcm ) is a novel antiepileptic drug ( aed ) approved by the fda for adjunctive treatment of partial epilepsy with and without secondary generalization . lacosamide dose - dependent dysrhythmias ( pr - interval prolongation , av block , and atrial fibrillation / flutter ) have been reported . this case represents the first instance of lcm - induced atrial fibrillation following a low loading dose ( 200 mg ) . risk factors for atrial fibrillation are addressed and discussed in the context of this case . full cardiac history is recommended prior to patients being initiated on lcm . cardiac monitoring may be required for at - risk patients on lcm . clinicians need to be cognizant of this potential adverse effect .

bone is a common site for metastatic spread of solid tumors , particularly for patients with metastatic breast and prostate cancers . here , we specifically focus on the factors impacting the bone microenvironment that thereby influence bone metastasis , which is the cause of significant patient mortality and morbidity and is currently incurable . at present , very little is known about systemic processes that influence bone metastasis . increasingly , efforts are being directed toward this area of investigation with the notion that a better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone . results from studies using pre - clinical metastasis models have revealed that primary tumor - derived circulating factors can affect various tissue microenvironments , even in the absence of observable metastases to those tissues , to make them a more hospitable environment for seeding and colonization of tumor cells that eventually disseminate from the primary tumor , . pre - metastatic niche formation and most of what is known in this regard was gleaned from pre - clinical studies of lung metastasis . much less is known about cancer - derived circulating factors that establish pre - metastatic niches in the bone . on one hand , the paucity of information may be due to the fact that there are very few bone metastasis models currently available to researchers . on the other hand , the bone microenvironment may inherently provide a favorable environment for disseminated tumor cells , thus eliminating the need for pre - metastatic modulation . the fact that disseminated tumor cells are frequently detected in bone marrow aspirates of cancer patients who are tested in this manner favors the idea that disseminating tumor cells find a ready - made niche in the bone microenvironment . traditionally , bone metastatic niches have been defined as microdomains within the bone that support tumor cell seeding and outgrowth via paracrine interactions , and can be comprised of hematopoietic cells , a variety of mesenchymal stromal cells , osteoblasts , osteoclasts , and/or vascular cells ( fig . 1 ) . within these microdomains , a number of chemokines and integrins that are endogenously expressed by various bone stromal cells to regulate mobilization and homing of hematopoietic cells for example , bone stroma derived cxcl12 ( sdf-1 ) has been demonstrated to recruit cxcr4-expressing neuroblastoma cells . likewise , differentiating osteoclasts secrete ccl22 , which was shown to promote bone metastasis of ccr4-expressing breast cancer cells . additionally , osteoblasts express a number of factors , including ccl12 , which has been correlated with increased tropism of ccr7-expressing metastatic breast cancer cells . more recently , primary tumor driven generation of a bone pre - metastatic niche was observed in a mouse model of estrogen receptor - negative breast cancer metastasis . specifically , lysyl oxidase ( lox ) secreted into the circulation from hypoxic primary breast tumors disrupted bone homeostasis , thereby inducing osteolysis . the osteolytic microdomains within the bone served as niches for subsequent metastatic tumor cells , and bisphosphonate administration in the pre - metastatic setting prevented development of metastatic disease . this work is the first reported observation of breast cancer induced osteolytic action - at - a - distance ( breast cancers frequently induce osteolysis following their dissemination to bone , as we discuss later ) . these findings , if further supported , have important clinical implications and should prompt further investigation into systemic modulation of bone - specific pre - metastatic niches . interestingly , bone is a conduit during pre - metastatic niche formation in visceral tissues in nearly all reported studies to date . in other words , pre - metastatic niche formation in extra - osseous organs involves mobilization , modification , and recruitment of bone marrow derived cells ( bmdcs ) that help create the niche . even before the discovery of pre - metastatic niches , investigation into the role of bmdcs in primary tumor progression and metastasis was an active area of research , as it still is today . numerous studies have shown that tumor - derived systemically acting factors impact the bone microenvironment to expand and mobilize bone marrow cells ( bmcs ) into the circulation that are subsequently recruited to tumor sites where they instigate various processes that support tumor progression , ( table 1 ) . for example , tumor - derived granulocyte colony - stimulating factor ( g - csf ) and interleukin-1 ( il1 ) mobilize tumor - supportive cd11b+/gr1 + myeloid cells from the bone marrow into circulation , while vascular endothelial growth factor - a ( vegf - a ) and placental growth factor ( pigf ) release hemangiogenic bmcs ( vegfr1 + cells ) from the bone marrow into circulation . breast cancer - associated fibroblasts ( cafs ) have been demonstrated to secrete cxcl12 , which induces the release of pro - angiogenic hematopoietic progenitor cells into the circulation . membrane - bound particles released from a primary tumor that carry lipids , proteins , mrnas and mirnas could also modulate cells in the bone microenvironment . more recently , opn carried through the circulation by murine mammary carcinoma - derived microparticles in response to chemotherapy , was necessary for mobilizing pro - angiogenic cells from the bone marrow . it is becoming increasingly apparent that tumor - derived factors can also alter certain bmcs by affecting their gene expression even prior to their mobilization into the circulation ( table 1 ) . murine cancer models revealed that a subset of myeloid cells upregulated pro - angiogenic factors in response to tumor - derived g - csf . in studies of mouse xenograft models , tumor - derived soluble opn , which functions as an inflammatory cytokine , rendered sca1+/ckit-/cd45 + hematopoietic bmcs pro - tumorigenic by modulating gene expression prior to their mobilization into circulation . based on the seemingly intimate relationship between primary cancers and the bone microenvironment , and given that certain tumors can act in an endocrine fashion to generate pro - tumorigenic hematopoietic bmcs , it stands to reason that these same bmcs would provide support to tumor cells that land in the bone . however , this hypothesis remains to be tested , thus representing an area where additional research is necessary . in this context , it is likely that many more tumor - derived systemic factors that modify bmcs remain to be identified . despite the frequency with which disseminated tumor cells ( dtcs ) are found in the bone marrow of cancer patients , the significance of these cells is unknown , as a considerable number of these patients never develop overt metastatic disease . such findings support the concepts of metastatic inefficiency and tumor dormancy and suggest that while the bone microenvironment may be conducive to initial dissemination and survival of tumor cells , other processes are required to promote disease progression . certainly , dynamic interactions between dtcs and stromal cells within the bone microenvironment disrupt bone homeostasis , which is normally tightly controlled , to fuel metastatic progression ( table 1 ) . for example , it is well established that osteolytic breast cancer dtc - derived factors , such as matrix metalloproteinases , cause the release of latent tgf- from the bone microenvironment . this , in turn , induces dtc production of a variety of cytokines , most notably parathyroid hormone - related protein ( pthrp ) , which either promotes osteoclast maturation or stimulates osteoblast secretion of il-6 and rankl thus propagating a vicious cycle of tumor outgrowth and osteolytic bone breakdown . tumor cells can also directly secrete interleukins ( specifically il-6 , il-8 , and il-11 ) to increase osteoclastogenesis , and thus fuel the vicious cycle of tumor progression . likewise , osteoblastic dtcs , such as those that metastasize from prostate cancers , initiate paracrine interactions within the bone microenvironment that serve to promote their growth . the fact that many of the same tumor - supportive cytokines that are secreted by dtcs within the bone microenvironment are also secreted by the primary tumors that spawned them begs the question of how much influence the primary tumor has on dtcs in the bone . the answer may have clinical relevance , considering that patients who develop metastatic disease after surgery and treatment of their primary cancer clearly had dtcs in the periphery at the time of their initial diagnosis . indeed , pre - clinical models of the early phases of metastatic disease , when patients harbor indolent dtcs at a time when their primary tumor is present , have provided important insights into systemic cross talk between distantly located tumors . for example , early studies of chemically - induced cancers revealed that some tumors establish an immune - permissive environment for the outgrowth of otherwise immunogenic tumors at distant sites . in a process that was termed , certain primary tumors promote the outgrowth of otherwise indolent lung metastases by secreting factors that cause mobilization and recruitment of bmdcs that aid metastatic outgrowth . in the case of systemic instigation by triple - negative breast cancer , primary tumors secrete opn into the circulation , which is necessary for rendering bmcs pro - tumorigenic . in systemic instigation models of luminal breast cancer , tumor - derived cytokines and growth factors are taken up by circulating platelets that cooperate with bmdcs to promote angiogenesis in the distant tumors . in addition to tumor cells , cells in the primary tumor microenvironment can impact distant metastasis . for example , cancer activated fibroblasts secrete growth / differentiation factor 15 ( gdf15 , also known as macrophage inhibitory cytokine-1 , mic-1 , a member of the tgf- family of growth factors ) to promote metastatic outgrowth in the lung . although it stands to reason that primary tumor derived systemic factors that render bmcs pro - tumorigenic would almost certainly impact tumor cells that had metastasized to bone , systemic instigation of bone metastasis has not been reported . research in this area seems crucial for identifying therapeutic avenues designed to restrict growth of dtcs in the bone . the past decade has seen a significant expansion in our knowledge about the intimate , yet long - distance relationship between various cancers and the bone microenvironment ( fig . 1 ) . nevertheless , surprisingly little is known about whether or how such systemic endocrinal interactions impact bone metastases . development of better pre - clinical models of bone metastasis , with validation in clinical studies , should help guide interventions aimed at inhibiting underlying systemic signaling cascades , if they exist , and could offer clinical benefit for cancer patients . hence , some critical questions in this active area of research remain unanswered:does the bone environment need to be modified in order to establish a hospitable niche for disseminating tumor cells?what systemic factors , if any , are necessary and/or sufficient to generate tumor - supportive or tumor - inhibitory niches in the bone marrow?how do modulation of osteoblast / osteoclast , hematopoietic , vascular , and/or bone stromal compartments affect bone metastasis?what lessons can be learned from studying metastatic niches in other visceral organs to inform bone metastasis?are there primary tumor - derived systemic instigation factors that promote outgrowth of dormant dtcs in the bone?are factors secreted by bone dtcs to influence the bone microenvironment also secreted by primary tumors from a distance to influence bone metastasis?do physiological conditions that impact the bone microenvironment , such as pregnancy , wound healing , bone remodeling , and aging , also influence bone metastases?what is the impact of systemic regulation of immune function on metastatic colonization in the bone?do bone - modulating drugs ( denosumab , bisphosphonates , filgrastim , plerixafor , etc . ) also influence bone metastases?what therapeutic interventions could be developed to inhibit systemic signaling mechanisms of cancer metastasis to the bone?what patient biomarkers may be used to indicate the tumor - specific systemic environment in the bone , and subsequent response to adjuvant therapies ? does the bone environment need to be modified in order to establish a hospitable niche for disseminating tumor cells ? what systemic factors , if any , are necessary and/or sufficient to generate tumor - supportive or tumor - inhibitory niches in the bone marrow ? how do modulation of osteoblast / osteoclast , hematopoietic , vascular , and/or bone stromal compartments affect bone metastasis ? what lessons can be learned from studying metastatic niches in other visceral organs to inform bone metastasis ? are there primary tumor - derived systemic instigation factors that promote outgrowth of dormant dtcs in the bone ? are factors secreted by bone dtcs to influence the bone microenvironment also secreted by primary tumors from a distance to influence bone metastasis ? do physiological conditions that impact the bone microenvironment , such as pregnancy , wound healing , bone remodeling , and aging , also influence bone metastases ? what is the impact of systemic regulation of immune function on metastatic colonization in the bone ? do bone - modulating drugs ( denosumab , bisphosphonates , filgrastim , plerixafor , etc . ) also influence bone metastases ? what therapeutic interventions could be developed to inhibit systemic signaling mechanisms of cancer metastasis to the bone ? what patient biomarkers may be used to indicate the tumor - specific systemic environment in the bone , and subsequent response to adjuvant therapies ?

systemic factors including cytokines , cell - free nucleic acids , microvesicles , and platelets are appreciated as important regulators of adenocarcinoma progression . research findings using pre - clinical mouse models have revealed that many such systemically acting factors are either secreted by or responsive to peripheral tumors and impact bone and bone marrow ( collectively referred to as the bone microenvironment ) to initiate processes that ultimately govern disease progression , even in the absence of detectable bone metastases . in some cases , cancer - driven modulation of the bone microenvironment involves mobilization of bone marrow hematopoietic and mesenchymal cells into the circulation that are subsequently recruited into peripheral tissues and tumors . in other cases , systemic factors alter bone marrow cell ( bmc ) differentiation and/or gene expression to render the bmcs pro - tumorigenic even prior to their mobilization into the circulation . given their effect on the bone microenvironment , it stands to reason that such systemic factors might also influence metastases in the bone ; however , this hypothesis remains to be comprehensively tested . here , we briefly review what is known , and not known , about systemic factors that regulate the bone microenvironment and thereby influence bone metastases . we also pose a number of currently unanswered questions in this active area of research . a better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone , which is the cause of significant patient mortality and morbidity and is currently incurable .

ceftriaxone is a third - generation cephalosporin , commonly used in the treatment of serious gram - negative infections due to its broad antimicrobial spectrum , long half - life , and easy penetration into the cerebrospinal fluid ( 1 , 2 ) . contrary to other cephalosporins , a dose adjustment is not required for ceftriaxone even in the presence of renal insufficiency , thus it is prescribed conveniently for patients with chronic kidney disease ( ckd ) ( 3 ) . neurologic adverse effects of ceftriaxone are infrequent , however , encephalopathy , myoclonus , and seizures may occur as exemplified in other cephalosporins ( 4 - 6 ) . here , we describe a case of ceftriaxone - induced nonconvulsive status epilepticus ( ncse ) with characteristic electroencephalogram ( eeg ) findings and discuss with literature review . a 65-yr - old woman with ckd was admitted to our hospital because of abdominal pain and poor oral intake on november 18 , 2010 . she had been diagnosed with idiopathic membranous glomerulonephropathy on renal biopsy six months prior to admission . her abdominal discomfort began two weeks earlier and was located predominantly in the right lower quadrant , and was associated with lower back discomfort . she described a constant pressure unrelated to food intake that was associated with intermittent nausea and vomiting . her symptoms were not relieved by the administration of antacid , acetaminophen , or defecation . laboratory data at patient admission were as follows : serum creatinine 3.2 mg / dl ( 1.7 mg / dl , 8 weeks before admission ) , albumin 1.8 g / dl ( 2.7 g / dl , 8 weeks before admission ) , and random urine protein - to - creatinine ratio 10.4 g / g ( 3.3 g / g , 8 weeks before admission ) , which demonstrated the deterioration of renal function and increase in urinary protein excretion . gastroscopy exhibited superficial gastritis and the colonoscopy revealed no observable mucosal lesions . to identify other potential causes of abdominal pain and exacerbation of renal insufficiency , such as renal vein thrombosis , computed tomography ( ct ) scan of abdomen and pelvis was recommended , however she refused further work up being afraid of hemodialysis following ct scan . on day 15 of the hospitalization , she developed a chill , and her temperature rose to 38.5. because she complained of vague urinary symptoms and urinalysis demonstrated pyuria and bacteriuria , ceftriaxone ( 2 g / day ) was administered intravenously for empirical treatment of urinary tract infection . her temperature returned to normal after three days . on day 20 of the patient 's hospitalization , there was no history of seizures , and no other relevant neurological features observed upon neurological examination . the patient exhibited no fever and the c - reactive protein was 3.2 mg / dl ( normal range < 0.3 ) . the serum creatinine level rose to 6.7 mg / dl and the daily urine amount decreased to 300 ml , therefore an emergent hemodialysis was initiated for progressive uremia . an eeg recording on the next day showed generalized slowing with superimposed almost continuous or periodic bursts of sharp waves or sharp and slow wave activity ( fig . , ceftriaxone was discontinued on day 22 of the hospitalization , and she returned to a completely alert , cooperative , and oriented state within two days of cessation of the drug . the eeg on day 24 showed slowing of the background without epileptiform discharges ( fig . in addition , the abdomen / pelvis ct revealed extensive thrombosis at the inferior vena cava , both renal veins , right ovarian vein , and both external iliac veins ( fig . in this report , we described a case of ncse following the administration of ceftriaxone in a patient with progressive renal impairment . the temporal relationship between the start of ceftriaxone therapy and the manifestation of ncse as well as the withdrawal of ceftriaxone and the disappearance of the symptom strongly indicated that ceftriaxone was a causative agent . moreover , hemodialysis did not improve her mental status , and we could not find any other factors that could explain the neurologic symptom observed . neurotoxicity has been reported with both third - generation and fourth - generation cephalosporins ( 7 - 9 ) . epileptogenic activity of -lactam antibiotics was first shown in 1945 , when seizures were reported in experimental animals following intraventricular injection of penicillin ( 10 ) , particularly in the settings of renal failure and excessive dosage ( 11 ) . the exact mechanism is not fully understood , but it has been proposed to be mediated by competitive antagonism of brain -aminobutyric acid ( gaba ) , which is the principal inhibitory neurotransmitter in the brain ( 12 ) . other authors ( 13 ) have proposed that cephalosporins might induce the release of cytokines including tumor necrosis factor- , which could cause direct cerebral toxicity . cephalosporin - induced neurotoxicity may manifest in a variety of clinical presentations , such as encephalopathy or mental status changes , myoclonus , asterixis , and seizures ( 4 - 8 ) . the latency of neurotoxicity , the period between the start of cephalosporin treatment and the resulting neurologic manifestations , varied between one and ten days . all reported neurologic symptoms typically resolved within two to seven days after discontinuation of the drug . the ceftriaxone - associated neurologic syndrome observed in our patients was similar to studies previously described in the literature ( 6 - 8 ) . predisposing factors for cephalosporins - induced neurotoxicity include excessive dosage , renal insufficiency , pre - existing central nervous system ( cns ) abnormalities , and increased cerebral penetration of the drug ( 12 , 14 , 15 ) . eeg findings include diffuse slow - wave delta activity , semi - periodic triphasic sharp wave activity , or frank periodic discharges ( 7 ) . given that the majority of patients using cephaloporins have co - morbidity associated with mental alteration , eeg could be of benefit in the diagnosis and management of antibiotics - associated neurotoxicity . the prevention of cephalosporin - induced neurotoxicity in high risk patients , as discussed above , is of the utmost importance . the careful monitoring of medication dosages and serum levels may be helpful in the minimization of this risk ( 7 ) . as seen in this case report , many symptoms resolved completely only with discontinuation of the drug . anticonvulsants such as phenytoin or valproate were administered in two previously reported cases , and their symptoms improved five days after stopping ceftriaxone ( 4 ) . besides , we did not use any anticonvulsants because of the rapid ( < 2 days ) clinical improvement after discontinuation of ceftriaxone . data are still lacking as to whether patients with cephalosporin - induced ncse require antiepileptic drug therapy or simple cessation of drugs results in improvement . however , some authors recommend that anticonvulsant therapy including lorazepam and/or phenytoin might be considered in ncse until the patient 's mental status returns to normal and periodic discharges or ncse shown on eeg resolve ( 7 ) . since neurotoxicity related to cephalosporins is reversible , it is unlikely that patients would need long - term anticonvulsant therapy . while most of cephalosporins are highly dialyzable ( 70% of a given dose over a 3-hr hemodialysis session ) , ceftriaxone is not dialyzed during hemodialysis ( 3 , 7 ) . moreover , the pharmacokinetics of ceftriaxone in patients with renal insufficiency differ markedly from those of other cephalosporins . compared to values in healthy subjects , the half - life of other cephalosporins is prolonged 6- to 8-fold in patients with end - stage renal disease . however , the half - life of ceftriaxone is not greatly affected by a progressive decrease in the renal function ( 3 ) . accordingly , dose adjustment of ceftriaxone is not required for ckd patients . only seven cases of ceftriaxone - induced neurotoxicity have been reported to date ( table 1 ) . all the previous cases had renal impairment and 4 cases of those cases were on hemodialysis . there were 4 cases of choreoathetosis , 2 cases of ncse , and one case of encephalopathy . notably , there was no case of which the observed neurologic symptoms and signs were improved by dialysis . these findings are compatible with the pharmacokinetic property of ceftriaxone that is not removable by dialysis . moreover , given that no dose adjustment is required for ceftriaxone in the patient with renal impairment , overdose did not seem to play a role in ceftriaxone - associated neurotoxicity . in the previous reports , the elimination half - life of ceftriaxone was markedly prolonged in some dialysis patients , it might be due to an impaired biliary excretion process that is the alternative pathway of elimination for ceftriaxone in ckd patients ( 7,16 ) . these might contribute to the development of infrequent ceftriaxone neurotoxicity in patients with renal insufficiency . this neurotoxicity should be considered carefully in patients with reduced renal function or prior cns abnormalities . in addition , eeg should be performed when a patient receiving ceftriaxone develops neurological symptoms . early recognition is of the utmost importance because the discontinuation of ceftriaxone reverts the symptoms completely .

ceftriaxone is widely used in patients for the treatment of serious gram - negative infections . ceftriaxone can induce some potential side effects , including neurotoxicity , however , nonconvulsive status epilepticus has rarely been reported . we report a case of acute reversible neurotoxicity associated with ceftriaxone . a 65-yr - old woman with chronic kidney disease developed altered consciousness during ceftriaxone treatment for urinary tract infection . the electroencephalogram demonstrated continuous bursts of generalized , high - voltage , 1 to 2 hz sharp wave activity . neurologic symptoms disappeared following withdrawal of ceftriaxone . the possibility of ceftriaxone - induced neurotoxicity should be considered in patients developing neurological impairment during ceftriaxone use , and the discontinuation of the drug could lead to complete neurological improvement .

incomplete seating of crowns after cementation is a well - known phenomenon and the ensuing complications have been described9 . an ill - fitting margin may contribute to increase plaque retention and compromise gingival health by causing alterations in gingival microbiota11 , also leading to cement washout and loss of retention2 . this phenomenon has been mainly related to the entrapment of cement between the tooth and the restoration , followed by hydrodynamic intracoronal pressure during cementation , preventing complete seating of the restoration6 . therefore , the more accurately the restoration fits the prepared tooth , the more difficult it is for cement excess to escape from the inner crown surface3,12 . it has been shown that a 25-m - thick film may produce a marginal gap of 50 m in well - fitting casts8 . several methods have been suggested to improve the seating of crowns after cementation based on the release of hydrodynamic pressure of cementation . nevertheless , few studies have reported the influence of the amount of cement or of the application site on the marginal adaptation of cemented crowns2,5,11 . therefore , the aim of this study was to evaluate the influence of the application site of provisional cement on the marginal adaptation of provisional crowns and on cement flow to the internal surfaces of restoration . forty phantom maxillary premolars ( prodens produtos odontolgicos ltda , niteri , rj , brazil ) were selected for this study . the region corresponding to the roots of the teeth were embedded in type iii gypsum ( jon , so paulo , sp , brazil ) in cylindrical tubes , and the long axes were aligned parallel to tube walls . for standardization of a 6-degree taper , ltda , barueri , sp , brazil ) on a straight high - speed turbine coupled to a surveyor with articulated rod ( bioart 1000 ; bioart equipamentos odontolgicos ltda , so carlos , sp , brazil ) ( figure 1 ) . in order to standardize the surface roughness , a new diamond bur was used for each preparation . the height of preparations was determined at 4 mm with aid of a digital caliper ( starret indstria e comrcio ltda , itu , sp , brazil ) . the provisional crowns were prepared directly on the teeth by application of self - curing acrylic resin ( duralay ; reliance dental mfg co , wort , il , usa ) with a brush . the occlusal surface was finished thick , flat and parallel to the inferior surface of the cylinder tube . two aligned circular marks were made with self - curing red acrylic resin ( duralay ; reliance dental mfg co , wort , il , usa ) in each specimen , one on the provisional crown and other apical to the tooth preparation margin , in areas corresponding to buccal , lingual , mesial and distal surfaces ( figure 2 ) . this procedure maintained the relation of the crown to the tooth by indicating its correct seating position ( the marks on the crown should be aligned to the marks on the tooth ) , in addition to allowing measurement of marginal opening before and after cementation . after fabrication of provisional crowns , a 5-kg static load was applied to the occlusal surfaces to allow adequate seating of the restorations . a comparison microscope ( mitutoyo america corporation , il , usa ) was used to measure the distances between the internal tangents of the two circular marks , determining the pre - cementation marginal opening with 0.0001-mm accuracy ( figure 2 ) . three measurements were made for each specimen at each tooth surface ( buccal , lingual , mesial and distal ) and the mean value of these measurements was calculated . the 40 prepared teeth were randomly assigned to 4 groups ( n=10 ) ( figure 3 ) . a provisional cement ( temp bond ne ; kerr corporation , orange , ca , usa ) , mixed according to the manufacturer 's instructions , was used for cementation of crowns . an amount of 0.2 ml of the provisional cement ( controlled with aid of an insulin syringe ) was applied to each crown with a brush . the crowns were seated on the prepared teeth under finger pressure followed by a 5-kg static load until cement setting . the cement was applied to the inner surface of the crown , comprehending all axial walls and the occlusal surface . the same sites received the cement in group ca , except for the occlusal surface . in group cm , the cement was applied only to the cervical crown margin , and in group tm the cement was applied to the cervical margin of the prepared teeth . the same procedures adopted for pre - cementation measurements were accomplished to determine postcementation marginal opening . again , three measurements were made for each specimen in all tooth surfaces ( buccal , lingual , mesial and distal ) and the mean values were calculated . after post - cementation measurement , the crowns were removed to allow visual evaluation of cement flow on the internal surfaces of restorations . the marginal discrepancies produced by cementation procedures were determined by the difference between pre- and post - cementation measurements . data were analyzed statistically by anova and tukey 's tests at the 5% significance level . mean values for marginal opening were as follows : cao : 144.8 m ( sd = 72.6 ) ; ca : 67.2 m ( sd = 21.0 ) ; cm : 45.9 m ( sd = 27.0 ) ; tm : 34.3 m ( sd = 29.2 ) ( table 1 ) . cm and tm presented significantly lower marginal openings compared to cao and ca ( p<0.05 ) . no statistically significant difference was found between ca , cm and tm ( p>0.05 ) ( table 2 ) . groups connected by a vertical line were not statistically different ( =0.05 ) . during visual evaluation of cement flow , it was found that only in group tm the cement did not reach the internal occlusal surface of the restoration , and this occurred in 100% of the specimens in this group . in the other groups , several techniques have been described in order to improve the marginal fit of complete crowns after cementation . yet , it may generate undesirable consequences , such as problems in restoring the vent or loss of retention . in this study , different application sites of the cement were tested , seeking for the best marginal adaptation after cementation , without the need for venting or restoration internal relief . according to the american dental association1 , the maximum film thickness for class i cements is 25 m . within the limits of this in vitro study , it was found that when the provisional cement was applied only to the cervical margins of the prepared tooth , lower marginal discrepancies were obtained ( 34.3 m ) . on the other hand , considerably larger marginal discrepancies were observed when the cement was applied to the internal surfaces of the crown , including the occlusal surfaces ( 144.8 m ) , with a high standard deviation , which might be due to the amount of cement applied , as reported elsewhere5,11 . the results of this study are also in accordance with the findings of assif , et al.2 , who evaluated the effect of the site of application of zinc phosphate cement on the marginal adaptation of crowns and found that the preferred method is to apply the cement to the margin of the prepared tooth . these authors also observed that , if applied to the crown , the cement layer should be limited to the crown margin . despite the good results obtained in this study with application of cement only to the margin of the prepared tooth , it should be mentioned that this was the only technique in which the cement did not flow to all internal surfaces of the restoration , which could reduce crown retention . the marginal discrepancy values obtained when the cement was applied to the internal surfaces of the crown except for the occlusal surface , or only to the cervical crown margin , were not statistically different from those obtained by cement application to tooth margin alone . moreover , with ca and cm techniques , the cement flowed to all internal surfaces of the restoration , including the occlusal surface . therefore , the technique of cement application to the crown margin seems to be a good technique from a clinical standpoint , since it provides adequate fit with complete filling of spaces between the internal crown walls and the prepared tooth , with a thinner cement film , as proposed by ishikiriama , et al.5 . within the limitations of this study , the following conclusion may be drawn : 1 . better marginal fit was achieved after cementation of provisional crown restorations when the cement was applied to the cervical margin of the prepared tooth , to the cervical crown margin or to the internal surfaces of the provisional crown , except for the occlusal surface ; 2 . visual inspection of cement flow , showed that all crowns were completely filled with cement , except for those of group tm ( cement applied to the cervical tooth margins ) , in which the cement did not reach the internal occlusal surface of the restoration .

introduction : marginal discrepancies may lead to cement washout and marginal leakage , damaging periodontal and pulp tissues or causing premature loss of the restoration . purpose : this study evaluated the influence of application site of provisional cement on the marginal adaptation of provisional crowns . material and methods : four different application sites of provisional cement ( temp bond ne , kerr corporation ) were used for cementation of provisional crowns on phantom teeth prepared for full crown restorations , performing 4 experimental groups ( n=10 ) : cement applied to all internal surfaces of the crown ( cao ) ; cement applied to all internal surfaces of the crown , except for the occlusal surface ( ca ) ; cement applied to the cervical crown margin ( cm ) ; and cement applied to the cervical tooth margin ( tm ) . a comparison microscope ( mitutoyo america corporation ) was used to measure the distances between the internal tangents of two circular marks , one made on the provisional crown and one made apical to the tooth preparation margin , in areas corresponding to buccal , lingual , mesial and distal surfaces . marginal adaptation was determined before and after cementation , with 0.0001-mm accuracy . data were analyzed statistically by anova and tukey 's test at 5% significance level . results : mean values of marginal opening obtained for each group were : cao : 145 m ; ca : 67 m ; cm : 46 m ; tm : 34 m . ca , cm and tm presented significantly lower marginal openings than cao ( p<0.05 ) . conclusion : complete filling of the crown with provisional cement , including the occlusal surface , provided grater marginal discrepancies when compared to the other methods evaluated .

the effect of the physical activity on the brain and cognition has grown in interest in recent years , with an increasing number of reports indicating that chronic participation and single , acute bouts of exercise , benefit a host of cognitive processes . coe and colleagues administered a three - day physical activity recall questionnaire to sixth grade children and observed their academic performance in four core classes ( i.e. , mathematics , science , english , world studies ) and terra nova standardized test scores . they found an increased performance in the core academic classes for those children who reported vigorous physical activity outside of the school relative , to those who reported no physical activity . several other studies have appeared in literature as well , indicating positive relations between physical activity and the aspects of academic performance.[35 ] although , several studies have also observed no relation between physical activity and academic performance . cognitive control is a term used to describe a subset of goal - directed , self - regulatory operations involved in the selection , scheduling , and coordination of computational processes underlying perception , memory , and action . core cognitive processes collectively termed cognitive control or executive control include inhibition , working memory , and cognitive flexibility . of these core processes , inhibition has been the most studied in the acute exercise literature and relates to the ability to act on the basis of choice rather than impulse.[810 ] event - related potentials ( erps ) reflect invariant changes in the ongoing electroencephalographic ( eeg ) activity evoked by the stimulus . the most prominent erp components observed in the studies of selective attention , using the auditory oddball paradigm are , n100 , p200 , n200 , and p300 , with peak latencies at about 100 , 150 , 200 , and 300 ms after the stimulus onset , respectively . the long - latency potentials of the auditory evoked potentials ( aep ) comprise of the n1 ( n100 ) and p2 ( p200 ) peaks , the so - called vertex potentials . the vertex potentials do not represent the first volley of sensory information into the primary auditory cortex , which occurs on the order of tens of milliseconds rather than hundreds . in addition , these vertex potentials represent several components with different brain generators , some of which are not purely sensory , but are modulated by subjective mental operations . for example , attention to the tones can lead to an increase in the amplitudes of n1 and p2 , and hence , there is some endogenous aspect to the vertex potentials . the n1-p2 deflection has also been considered as an indicator for the cortical arousal response . thus , the n1 and p2 are probably the best considered event - related potentials ( erps ) encompassing both exogenous and endogenous potentials . the n200 ( n2 ) component is usually assumed to reflect the classification or categorization of deviant stimuli . this reflects processes of transient arousal triggered by unattended discrimination processes , which in turn trigger a target reaction . typically evoked between 180 to 325 ms following the presentation of a specific visual or auditory stimulus , the n2 is a negativity resulting from a deviation in the form or context of a prevailing stimulus . n2 is typically evoked before the motor response , suggesting its link to the cognitive processes of stimulus identification and distinction . showed that by using the evaluation of the p300 interpeak latency ( ipl ) , we can assess the disturbed steps in the cognitive process in schizophrenic patients . very few studies have been found in literature to access the role of acute exercise on cognition using event - related potentials ( n1 , p2 , and n2 ) and inter - peak latencies of erp , that is the reason for our having designed this study , to see if there is any effect of an acute bout of exercise on the erp of people having sedentary lifestyles . sixty right - handed participants ( 34 males , 26 females ) of age group 1530 years , having a sedentary lifestyle , were recruited from undergraduate and postgraduate students and staff members of a medical college . all the participants reported no adverse health conditions , such as , previous history of stroke , diabetes , depression , hypertension , osteoarthritis , chronic obstructive lung disease , visual or auditory impairment , or smoking habits . basic anthropometric measurements such as age , sex , height , and weight were recorded and the body mass index ( bmi ) was calculated [ table 1 ] . the demographic pattern of the study group before taking part in the experiment , all the participants signed written consent forms and were fully informed about the protocol . the participants visited the laboratory at the same time of the day , between 9 to 11 a.m. the basal recording of the event - related potential ( erp ) was recorded using recorders and medicare systems - electromyography ( rms - emg ) , ep mark - ii ( chandigarh ) in a sound proof room , and then the subjects were asked to do moderate exercise for five minutes on an electronic bicycle ergometer ( magcycle ) . the severity of the exercise was moderate ( 6080% of maximum load of effort during exercise , where 100%=200-age ) . immediately after doing the exercise , the erp was recorded again . an ag - agcl electrode was placed at cz actively , according to the international 1020 system , referenced to earlobe electrodes , and with a forehead electrode as a ground electrode . impedances were maintained below 5 k and were measured from each lead at the beginning and end of each session . the target tones were presented with a probability of 20% , whereas , the non - target tones were presented with a probability of 80% binaurally over headphones , at a sound level intensity of 80 db . the tone bursts were presented with an inter - stimulus interval of one second , randomly . at the end of each session , each participant 's count was compared with the actual number of target tones given , to assess the accuracy of the task performance . the principal peaks and their identification were made according to the standard recommendations for long latency auditory event - related potentials of the international federation of clinical neurophysiology using the principal component analysis technique . waveforms from each electrode and stimulus condition were analyzed with the p300 component defined as the largest positive going peak occurring for all electrode sites after the n100-p200-n200 complex , within the latency window , between 250 and 500 ms . data thus collected was subjected to statistical analysis using the paired student 's t test , comparing the before and after exercise values . an ag - agcl electrode was placed at cz actively , according to the international 1020 system , referenced to earlobe electrodes , and with a forehead electrode as a ground electrode . impedances were maintained below 5 k and were measured from each lead at the beginning and end of each session . the target tones were presented with a probability of 20% , whereas , the non - target tones were presented with a probability of 80% binaurally over headphones , at a sound level intensity of 80 db . the tone bursts were presented with an inter - stimulus interval of one second , randomly . at the end of each session , each participant 's count was compared with the actual number of target tones given , to assess the accuracy of the task performance . the principal peaks and their identification were made according to the standard recommendations for long latency auditory event - related potentials of the international federation of clinical neurophysiology using the principal component analysis technique . waveforms from each electrode and stimulus condition were analyzed with the p300 component defined as the largest positive going peak occurring for all electrode sites after the n100-p200-n200 complex , within the latency window , between 250 and 500 ms . data thus collected was subjected to statistical analysis using the paired student 's t test , comparing the before and after exercise values . table 2 shows that on doing an acute bout of moderate exercise there was a significant ( p<0.01 ) decrease in the latency of wave n1 of all females , for both frequent and rare stimuli , while there was no significant change in males . also there was a significant decrease in the latency of wave p2 in females , for both frequent ( p<0.001 ) and rare ( p<0.05 ) stimuli . a significant decrease in latency was seen in wave n2 , with rare stimulus in both females ( p<0.01 ) and males ( p<0.001 ) , while for frequent stimulus , a significant ( p<0.05 ) decrease was seen only in females . means.d . of latencies ( ms ) of different erp waves before and after doing exercise table 3 shows that in total there was a significant decrease in n2-p3 interpeak latency for both target ( p<0.001 ) and non - target ( p<0.05 ) stimuli . n2-p3 interpeak latency significantly decreased in males , while there was no significant decrease in females . also there was a significant ( p<0.05 ) decrease in p2-n2 interpeak latency for the target stimuli in total , although there was no significant decrease when males and females were compared separately . means.d . of interpeak latencies ( ms ) between different erp waves before and after doing exercise there is evidence that aerobic exercise produces its effect on event - related potentials by increasing arousal . yagi et al . examined the auditory and visual p3 and reaction times in young volunteers before and after exercise on a cycle ergometer . two basic mechanisms have been suggested to explain the effect of aerobic fitness on cognitive processes : the cerebral circulation hypothesis and the neurotrophic - stimulation hypothesis , which predicts a beneficial effect of neuromuscular activity on higher brain centers ; both mechanisms may contribute simultaneously . event - related potentials offer the requisite temporal precision to gain insight into covert cognitive operations that occur between stimulus engagement and response selection , which may be more sensitive to these processes than overt behavioral measures of task performance . erps refer to patterns of neuroelectric activation that occur in response to , or in preparation for , a stimulus or response . previous studies have examined the p3 component of the stimulus - locked erp , to understand the alterations in stimulus engagement . in our study , an acute bout of moderate exercise led to a significant decrease in the latency of wave n1 and p2 of females for both frequent and rare stimuli . significant decrease in latency was seen in wave n2 with rare stimulus in both females and males , while for frequent stimulus , a significant decrease was seen only in females . in a study by ozkaya , the latencies of the p2 and n2 components at the fz and cz sites , decreased significantly in the strength training ( st ) group compared to the endurance training ( et ) group , and after training , the latencies of the n1 , n2 , and p2 components shortened significantly in the st group compared to the control group . also the latencies of the n2 and p2 components shortened significantly in the et group compared to the control group . in contrast pontifex et al . observed longer n2 and p3 latencies during exercise ( cycling at 60% of maximal , in their study , suggested that physical fitness , but not an acute bout of aerobic exercise , enhanced cognitive processing by increasing attention allocation to stimulus encoding , during task preparation . in our study , we found that the n2-p3 interpeak latency significantly decreased in males , while there was no significant decrease in females , suggesting that males had a specific effect on information processing between the generation of the p2 and p3 waves . no study was found in the literature regarding exercise and interpeak latencies of event - related potentials . we conclude that there is a definite role of exercise in enhancing the cognitive functions as evidenced by its effect on event - related potentials . males feel its effect on the later parts of information processing , as suggested by the interpeak latencies . extensive research is needed in this field to assess the role of exercise at a molecular level .

background : effect of acute moderate exercise on cognition has been studied recently , although there are controversial reports in this context . this is the reason we performed this study , to observe the effect of acute moderate exercise on the cognitive functions of persons having a sedentary lifestyle , by measuring the latencies of event - related potentials n100 , p200 , n200 , and the inter - peak latencies n100-p200 , p200-n200 , and n200-p300.materials and methods : sixty right - handed participants ( 34 males , 26 females ) of age group 15 30 years , having a sedentary lifestyle , were recruited for the study . a baseline recording of event - related potentials was conducted and then they were subjected to acute moderate exercise ( 60 80% of the maximum load of effort during exercise , where 100%=200 - age ) , again the recording was carried out using the paired student 's t test , to compare the present values with the initial values.results:after performing the exercise there was a significant decrease in the latency of wave n1 and p2 of females for both frequent and rare stimuli . a significant decrease in the latency was seen in wave n2 with rare stimulus in both females and males . while , for frequent stimulus a significant decrease was seen only in females . also the n2-p3 interpeak latency significantly decreased in males , while there was no significant decrease in females.conclusion:there was a definite role of exercise in enhancing the cognitive functions as evidenced by its effect on the latencies of event - related potentials n100 , p200 , n200 , and interpeak latencies .

bilioenteric anastomosis strictures may be caused by benign conditions such as postoperative fibrotic change and scarring , or malignant conditions such as tumor recurrence [ 1 - 3 ] . they are a serious complication of biliary surgery , and may result in recurrent cholangitis , choledocholithiasis , biliary cirrhosis , and hepatic failure . bilioenteric reconstructive surgery is performed for patients with bilioenteric anastomosis stricture complications . however , this surgery is difficult to perform , and its success rate decreases with each successive surgery [ 2,4 - 7 ] . the percutaneous transhepatic cholagioscopy ( ptcs ) or peroral endoscopy - guided intervention is less invasive procedure that has become an increasingly popular alternative for managing bilioenteric anastomostic strictures . with the increase in the number of liver transplantations especially living - donor transplantations over the last few decades , ptcs - guided interventions are laborious procedures , which require multi - step preparation before cholangioscopic intervention can be performed . first , percutaneous transhepatic biliary drainage ( ptbd ) is performed with an 8.5-fr catheter inserted under fluoroscopic guidance into the right posterior branch or left peripheral branch of the intrahepatic duct , based on a planned anatomical approach to the stricture . two or 3 days after ptbd , the percutaneous tract is dilated to allow for the passage of the cholangioscope . this is usually done by one - stage dilation ( e.g. , from 8.5 to 16 or 18 fr ) or stepwise dilation in two sessions . for sinus tract maturation , a 16- or 18-fr ptc catheter procedure - related complications tend to occur during ptbd insertion ( 12.9% ) , tract dilation ( 12.8% ) , and tract maturation ( 6.9% ) . the incidence of complications for therapeutic cholangioscopies has been reported to be 6.7% , of which cholangitis and bile duct injuries are the commonest complications . it is essential to be able to diagnose a bilioenteric anastomosis stricture accurately , because the choice of treatment depends on whether the cause is benign or malignant . however , in bilioenteric anastomosis strictures , access is limited by the surgically altered anatomy and the limited visualization of the stricture site via a retrograde approach . as such , it is almost impossible to obtain a tissue sample with endoscopic retrograde cholangiopancreatography or single ( or double ) balloon enteroscopy . instead , ptcs can play an important diagnostic role by allowing the direct visual inspection of a bilioenteric anastomotic lesion in an antegrade approach . the typical cholangioscopic findings of a benign biliary stricture include the following : smooth mucosal surface , tapered luminal narrowing , short stricture segment ( accompanying stones ) , and the absence of definite neovascularization ( tumor vessel ) . a tumor vessel is an abnormally proliferating and tortuous vascular structure on the bile duct mucosa , and is one of the defining characteristics of biliary malignancy ( fig . they had a sensitivity of 96% , specificity of 100% , positive predictive value of 100% , and negative predictive value of 91% . ptcs has several advantages over percutaneous cholangiography - guided interventions in treating bilioenteric anastomosis strictures . due to the presence of bile stasis and remnant suture materials , postoperative large stones proximal to the stricture site can be easily fragmented with electrohydraulic shock - wave lithotripsy or laser lithotripsy , and then removed during stricture dilation . in addition , since remnant suture materials or surgical clips can act as niduses for stone formation , it is essential to remove any foreign bodies present at the bilioenteric anastomosis stricture site . the main role of ptcs in bilioenteric anastomosis strictures is the recanalization and dilation of the strictures . due to postoperative fibrosis and scarring , 2 ) . ptcs guides the targeted recanalization with a guidewire or needle - knife . the initial technical success rate was reported as 100% ; however , the recurrence rate was 38% at a mean of 17 months . the overall success rate after repeated dilation was 82% after a mean follow - up period of 33 months , and the 5-year cumulative patency rate was 48% . there were no significant correlations between recurrence rate and the duration of catheter maintenance or number of sessions required . one drawback of ptcs is that the working channel has a small diameter , and as such , a self - expandable metal stent can not be placed through it . one study compared the temporary percutaneous placement of retrievable fully - covered metal stents with percutaneous balloon dilation in patients with benign biliary strictures . it found that the patency rates were significantly better in the metal stent group than in the balloon dilation group at 3 years ( 87% vs. 44% , p=0.022 ) . the indwelling period of the ptbd catheter after the initial procedure was also shorter in the metal stent group ( 2.5 months vs. 4.5 months , p=0.001 ) . although the evidence is limited to case reports , steroids ( triamcinolone ) can be injected directly into strictures refractory to treatment with balloon dilation and indwelling catheters . for cases in which conventional methods for recanalization and/or dilation fail , ptcs can be used to guide the correct placement of magnets into the stricture site . magnetic compression anastomosis was reported to be successful in 15 of 19 patients who had treatment - refractory benign biliary strictures or duct - to - duct anastomosis strictures after liver transplantation . it is essential to be able to diagnose a bilioenteric anastomosis stricture accurately , because the choice of treatment depends on whether the cause is benign or malignant . however , in bilioenteric anastomosis strictures , access is limited by the surgically altered anatomy and the limited visualization of the stricture site via a retrograde approach . as such , it is almost impossible to obtain a tissue sample with endoscopic retrograde cholangiopancreatography or single ( or double ) balloon enteroscopy . instead , ptcs can play an important diagnostic role by allowing the direct visual inspection of a bilioenteric anastomotic lesion in an antegrade approach . the typical cholangioscopic findings of a benign biliary stricture include the following : smooth mucosal surface , tapered luminal narrowing , short stricture segment ( accompanying stones ) , and the absence of definite neovascularization ( tumor vessel ) . a tumor vessel is an abnormally proliferating and tortuous vascular structure on the bile duct mucosa , and is one of the defining characteristics of biliary malignancy ( fig . they had a sensitivity of 96% , specificity of 100% , positive predictive value of 100% , and negative predictive value of 91% . ptcs has several advantages over percutaneous cholangiography - guided interventions in treating bilioenteric anastomosis strictures . due to the presence of bile stasis and remnant suture materials , postoperative large stones proximal to the stricture site can be easily fragmented with electrohydraulic shock - wave lithotripsy or laser lithotripsy , and then removed during stricture dilation . in addition , since remnant suture materials or surgical clips can act as niduses for stone formation , it is essential to remove any foreign bodies present at the bilioenteric anastomosis stricture site . the main role of ptcs in bilioenteric anastomosis strictures is the recanalization and dilation of the strictures . due to postoperative fibrosis and scarring , the initial technical success rate was reported as 100% ; however , the recurrence rate was 38% at a mean of 17 months . the overall success rate after repeated dilation was 82% after a mean follow - up period of 33 months , and the 5-year cumulative patency rate was 48% . there were no significant correlations between recurrence rate and the duration of catheter maintenance or number of sessions required . one drawback of ptcs is that the working channel has a small diameter , and as such , a self - expandable metal stent can not be placed through it . one study compared the temporary percutaneous placement of retrievable fully - covered metal stents with percutaneous balloon dilation in patients with benign biliary strictures . it found that the patency rates were significantly better in the metal stent group than in the balloon dilation group at 3 years ( 87% vs. 44% , p=0.022 ) . the indwelling period of the ptbd catheter after the initial procedure was also shorter in the metal stent group ( 2.5 months vs. 4.5 months , p=0.001 ) . although the evidence is limited to case reports , steroids ( triamcinolone ) can be injected directly into strictures refractory to treatment with balloon dilation and indwelling catheters . for cases in which conventional methods for recanalization and/or dilation fail , ptcs can be used to guide the correct placement of magnets into the stricture site . magnetic compression anastomosis was reported to be successful in 15 of 19 patients who had treatment - refractory benign biliary strictures or duct - to - duct anastomosis strictures after liver transplantation . despite the laborious preparations required , ptcs has an important role to play in the management of bilioenteric anastomosis strictures .

bilioenteric anastomosis strictures are a serious complication of biliary surgery , and often result in recurrent cholangitis , choledocholithiasis , biliary cirrhosis , and hepatic failure . bilioenteric reconstructive surgery is the standard treatment of choice for such complications . however , percutaneous transhepatic cholangioscopy ( ptcs ) , also known as per - oral endoscopic - guided intervention , is a less invasive procedure that is becoming an increasingly popular alternative . this review describes the ptcs procedure ( including the preparation process ) , as well as the diagnostic and therapeutic role of ptcs in bilioenteric anastomosis strictures .

diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion , insulin action , or both . a consequence of this is chronic hyperglycemia with disturbances in carbohydrate , fat , and protein metabolism . diabetes mellitus ( dm ) is a common disorder of carbohydrate , fat , and protein metabolism reflected by inappropriate high fasting and postprandial glucose levels ( hyperglycemia ) . this ailment results from the absence or scantiness of insulin secretion with or without concurrent impairment of insulin action . consequently , the disease was classified into two types known as type i ( insulin dependent , iddm ) and ii ( non - insulin dependent , niddm ) according to the degree of pancreatic defect . this classification has been even recognized since the time of ibn sinaa , who mentioned it in his book the canon of medicine . dm is not confined to abnormal blood glucose levels but progresses to affect other body systems . this fact has been confirmed by several epidemiological studies and clinical trials that have linked hyperglycemia to several complications at the macrovascular ( coronary artery disease and cerebrovascular disease ) and microvascular levels ( renal failure , blindness , limb amputation , neurological complications and premature death)1 . endocrine and metabolic alterations in diabetes mellitus can trigger disorders of calcium homeostasis , skeletal metabolism , and bone mass1 . it is reported that more than of 50% type 1 diabetes patients have osteoporosis ( op ) , which is called diabetic osteoporosis ( do ) , a reduced bone mass and an increased fracture risk shown to occur in type 1 diabetes mellitus2 . on the other hand , in type 2 diabetes , several but not all cross - sectional studies have found normal3 or elevated4 bone mass , and these results are surprising given the increased fracture risk associated with type 2 diabetes5 . in type 2 dm patients complicated with op , there is a larger decrease in bone formation than bone resorption in compared with the case of postmenopausol op , and this mainly influences the indexes of bone formation and may be a lower turnover ratio type . we investigated whether there is any difference among dm patients and a control group in terms of lumbar and femur bmd ( bone mineral density ) and standard deviation scores ( z score and t score ) . this randomized , prospective , controlled , single - blind study was conducted in physical medicine and rehabilitation department faculty of medicine , bezm - i alem vakf university . in addition to their demographic characteristics ( age , gender , weight , height , body mass index [ bmi ] ) , waist circumference , hip circumference , waist / hip proportion , used medicines , body muscle masses , fat masses , and fat percentages were obtained . the patients included in this study were between the ages of 40 and 65 . all the recruited subjects signed informed consent forms before participating in the study , and approval of a local ethics committee was obtained . the exclusion characteristics were early menopause , hormone replacement therapy , usage of medicines able to affect bmd ( thiazide diuretics , statins , anticoagulants , antiepileptics ) , diseases affecting bone metabolism ( hypo / hyperthyroid , cushing syndrome , primary hiperparathyroidism , renal failure , liver disease , inflammatory bowel disease , malabsorption ) , alcoholism , osteoporotic breakage history , scoliosis . data about the presence of diabetic complications ( retinopathy , ischemic cardiac disease , hypertension , neuropathy , nephropathy ) were regularly recorded in during follow - up . the whole blood count , fasting blood glucose , urea , creatine , c - reactive protein , hba1c ( glycolysed hemoglobin ) , alkaline phosphatase ( alp ) , calcium ( ca ) , phosphor ( p ) levels , and erythrocyte sedimentation rate ( esr ) were examined , and a 24-h urinalysis was carried out . through dual - energy x - ray absorptiometry ( dexa , dpx - lunar ) , bmd measurements of the lumbar spine ( anteroposterior projection of l1-l4 ) and left proximal femur ( total score ) were executed . the bmd data are presented in g / cm and standard deviation scores ( z and t scores ) . t scores between 1 and 2.5 were considered to indicate osteopenia , and those equal or below 2.5 were considered to indicate osteoporosis ( who study group , 1994 ) . the calculations were performed using the statistical package for social sciences for windows software version 16.0 ( spss inc . , the kolmogorov - smirnov test was used to confirm that data within the ranges of the normal distribution in both groups . the comparison of the data between the groups was carried out with the mann - whitney u - test . the wilcoxon signed - rank test was used to examine the pre- and post- exercise differences within groups . statistical significance was based on a value of p < 0.05 with a 95% confidence interval . a total of 126 patients completed the study ( 63 in the study group , 63 in the control group ) . the clinical and demographic characteristics of the patients and the healthy controls are listed in table 1table 1.clinical and demographic characteristics of patient and control groups ( mean sd or n , % ) dm group(n=63)control group(n=63)age60.18.558.47.8male patients ( n , % ) 29 ( 46%)30 ( 47%)bmi ( cm / kg)32.44.828.45.5 dm : diabetes mellitus ; sd : standard deviation . there was no significant difference in the result of the laboratory examinations of the cases ( table 2table 2.clinical and demographic characteristics of patient and control groups ( mean sd or n , % ) dm group(n=63)control group(n=63)ca ( mg / dl)8.80.28.50.2p ( mg / dl)4.20.84.30.8alp ( u / l)85.9 + 26.784.4 + 32.3fasting blood glucose ( mg / dl)162.444.898.415.524-h urea ca143.881.1133.855.4urea ( mg / dl)4811.2428.2creatine ( mg / dl)0.90.30.70.2esr15.68.218.17.5crp0.20.40.10.5 dm : diabetes mellitus ; sd : standard deviation . p < 0.05 is significant ) . the bone mineral densities of the cases are presented in table 3table 3.bmd , z and t scores of patient and control groups ( mean sd or n , % ) dm group(n=63)control group(n=63)plumbar ( l14 ) bmd46.6205.41.10.1lumbar ( l14 ) t score0.91.10.011.7lumbar ( l14 ) z score0.011.10.11.2total femur bmd14.9110.61.00.1total femur t score0.21.00.01.2total femur z score0.50.90.11.3 dm : diabetes mellitus ; sd : standard deviation . p < 0.05 is significant .. regarding the medications taken by the diabetic patients , 48 patients were using oral antidiabetic , and 8 patients were using insulin , and 7 patients were using both of them . with regard to the disease durations , there were 23 patients in the 05 year group ( 36.5% ) , 17 patients in the 610 year group ( 27% ) , 14 patients in the 1115 year group ( 22.2% ) , 4 patients in the 1620 year group ( 6.3% ) , 1 patient in the 2125 year group ( 1.6% ) , and 4 patients in the 2630 year group ( 6.3% ) . no significant correlation was detected when comparing disease durations and the bone marrow densities of the type 2 dm patients by the medicines taken ( p>0.050 ) ( table 4table 4.bmd , z and t scores of drug usages of diabetic patients ( mean sd or n , % ) oral antidiabetic(n=48)insulin(n=15)lumbar ( l14 ) bmd53.6195.442.3180.1lumbar ( l14 ) t score0.61.10.81.7lumbar ( l14 ) z score0.041.00.01.3total femur bmd14.9110.613.0100.1total femur t score0.21.10.11.2total femur z score0.50.90.51.2 dm : diabetes mellitus ; sd : standard deviation . the most important aim of our study was to compare the bone mineral densities of type 2 diabetes mellitus patients with those of a normal , healthy population . in our examinations , we determined that there was a significant decrease in the lumbar region t score in compared with the normal population . although osteoporosis is one of the complications of type 1 diabetes , the effect of type 2 dm on bone mineral density is controversial . in different studies , the bmd values in type 2 dm have increased6 , decreased7 , or stayed normal8 . in general , the type 2 dm patients with low bmd values have been observed to have long - term diabetes and menopause , to have poor glucose control , and to have disordered renal functions9 . furthermore , in some studies , it has been concluded that diabetic women are protected from osteopenia10 . this can be explained in type 2 dm , unlike the case of type 1 dm , by the frequent observation of obesity due to increased insulin resistance and the higher of osteoarthritis in dm patients11 . in the study of sosa et al . , 47 female type 2 dm patients and 252 nondiabetic women were compared in terms of bmd through dexa and quantitative computerized tomography , and no significant difference was detected12 . in the literature , it has been found that type 2 dm patients , individuals using a dietary and oral antidiabetic , and individuals taking insulin have lower bmd values13 . it has been asserted that better glysemic control , exercise , diet , and medical therapy can decrease the complications in dm14 . but in our study , no difference could be determined in bmd in relation to medicine usage . in measurements from the calcaneal region , a previous study reported higher bmd values in postmenapousal women and similar values to those of a control group in diabetic men , and it has been determined that there was no difference between women and men15 . one of them is that it can lead to diabetic osteopenia due to deficiency in anabolic activation of insulin13 . another mechanism asserted in diabetic osteopenia is suppression of osteoblastic bone formation16 . in previous studies , it has been shown that decreases in osteoblastic functions occurred in diabetic ostopenia17 . previous studies have also shown that the bone cycle speed in type 2 dm is much slower than that in healthy postmenopausal patients18 . in another study on type 1 and type 2 diabetes patients , it has been underlined that the decrease in bone mass can be related with decrease in bone formation and microangiopathy in bone tissue19 . in histopathologic examination of type 2 dm patients , the osteoblast surface , cortical thickness , osteoid thickness , osteoid volume , and bone volume have been found to be lower in diabetic patients . it has been concluded that the mechanism laying behind the diabetic osteopenia can be the decrease of quantitative osteoid , the decrease of osteoblasts , and finally the decrease of bone cycle17 . in dm patients , estradiol has a direct stimulatory effect on osteoblasts , and this may contribute to osteoporosis20 . as a result , the bmd measurements the postmenopausal women with type 2 diabetes mellitus in the present study did not show any difference in proportion to those of the control group .

[ purpose ] diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion , insulin action , or both . a consequence of this is chronic hyperglycemia with disturbances in carbohydrate , fat and protein metabolism . we investigated whether there is any difference among dm patients and a control group in terms of lumbar and femur bmd ( bone mineral density ) , and standard deviation scores ( z score and t score ) . [ subjects and methods ] this randomized , prospective , controlled , single - blind study was conducted in the physical medicine and rehabilitation department faculty of medicine , bezm - i alem vakf university . patients with type 2 diabetes mellitus were included in the patient groups . healthy individuals were included in the control group . [ results ] a total of 126 patients completed the study ( 63 in the study group , 63 in the control group ) . there was no significant difference in the results of the laboratory examinations of the cases . the bone mineral densities of the cases were found to be significantly low in terms of the lumbar ( l14 ) t scores in the type 2 diabetes group . [ conclusion ] although osteoporosis is one of the potential complications of type 1 diabetes , its effect on bone mineral density in type 2 dm is controversial . in different studies , the bone mineral density values have increased , decreased or remained normal . with the exception of the lumbar ( l14 ) t score , similar results were obtained in this study .

immunoglobulin gg4-related disease ( igg4-rd ) is a recently described disease entity characterized by tumefactive lesions , abundant tissue lymphoplasmacytic and igg4-positive plasma cell infiltration , storiform fibrosis and elevated serum igg4 concentrations ( 1 ) . since autoimmune pancreatitis , associated with high serum igg4 expression levels , was first reported in 2001 ( 2 ) , igg4-rd has been described in various organ systems , including the pancreas , kidney , biliary tree , salivary glands and the nervous system ( 1,35 ) . the disease is more common in middle - aged and elderly males ( 6 ) . the incidence rate of igg4-rd has not been established because of the relative rarity of this diagnosis ( 6 ) . igg4-rd typically responds significantly to treatment with immunosuppressants ( 7 ) ; treatment with systemic steroids is recommended , and a longer duration of treatment with steroids may decrease the rate of recurrence ( 79 ) . while optic nerve involvement is rare , a series of recent studies have reported the presence of a mass around the orbit ( 1013 ) . in the present study , a serologically and histopathologically documented igg4-rd case is reported , which presented with rapid progressive optic neuropathy with no mass around the orbit . the current case also responded to glucocorticoid treatment , providing new insights into this form of igg4-rd . a 79-year - old woman was admitted at the china - japan friendship hospital ( beijing , china ) in october 2013 , complaining of rapid loss of vision in the left eye that persisted for two months . the study was approved by the institutional review board of the china - japan friendship hospital , and written informed consent was obtained from the patient . approximately 30 years earlier , the patient presented with symmetrical spot - like vitiligo of the skin around the two ankles , which has spread upward on both legs and lower abdomen . the patient was diagnosed with pancreatic neoplasm and diabetes 4 years before admission for vision loss , and treatment with oral hypoglycemic agents ( 30 mg acarbose , thrice daily for 4 years ; bayer ag , leverkusen , germany ) was initiated to maintain normal blood glucose levels . in addition , the patient developed enlarged right cervical and double subaxillary painless lymph nodes 3.5 years before admission , and a right upper palpebral mass 3 years ago . additional features of the patient 's medical history were coronary artery disease for the past 8 years and hypertension for the past 7 years , which were treated with oral agents ( 30 mg adalat daily for 7 years ; bayer ) . furthermore , the patient had undergone bilateral cataract surgery 7 years prior to admission ; thereafter , visual acuity , as measured with a standard logarithmic letter chart ~6 months after cataract surgery , was maintained at 0.60.8/1.5 in both eyes . during the initial evaluation in october 2013 , the patient was awake , alert and oriented to time , place and persons . the results of a neurological examination ( cranial nerve , motor and sensor system examinations ) were normal , with the exception of vision loss on the left eye . at this point in time , visual acuity was 0.03/1.5 ( left eye ) and 0.6/1.5 ( right eye ) . dilated fundus examination by direct ophthalmoscopy revealed optic atrophy in the left eye and arteriosclerosis in both eyes . immunoglobulin g ( igg ) and igg4 serum levels were elevated to 3,150 and 2,440 mg / dl on admission , respectively ( igg reference range , 6941,620 mg / dl ; igg4 reference range , 3.0201 mg / dl ) . the erythrocyte sedimentation rate of the patient was 53 mm / h ( reference range , 020 mm / h ) . visual evoked potentials ( veps ; medtronic , minneapolis , mn , usa ) were obtained to a 26-degree square pattern of 1-degree high contrast black and white checks that reversed at 1 hz . vep implicit times were prolonged when the left eye was stimulated , but not when the right eye was tested ( fig . cranial magnetic resonance imaging ( mri ; gyroscan 1.5 t ; philips healthcare , da best , the netherlands ) showed atrophy of the left optic nerve with a focal hyperintense lesion , as shown in a t2-weighted image ( fig . the mri analysis revealed the absence of any mass surrounding the optic nerve or any other orbital areas . furthermore , a thoracic computed tomography ( ct ; aquilion ; toshiba , tokyo , japan ) scan showed diffused interstitial pneumonia . no abnormalities were detected on fundus fluorescein angiography , electromyography , abdominal - pelvic ct , specific autoimmune testing , hematological examination , serum angiotensin - converting enzyme ( ace ) and other immunoglobulin ( iga , igm and ige ) levels . clinicopathological examination of cervical lymph node by needle biopsy revealed diffuse lymphoplasmacytic infiltration and storiform fibrosis . an immunohistochemical stain against igg4 demonstrated that the number of igg4-positive plasma cells were elevated to > 50 cells per high - power field ( fig . 3a ) , as compared to the 020 cells per high - power field observed in normal biopsy specimens ( 14,15 ) . in addition , an igg4/igg plasma cell ratio of > 40% was observed ( fig . 3b ) , which was much higher compared with the 6% ratio typically observed in normal subjects . a labial gland biopsy revealed lymphoplasmacytic focal infiltration in the salivary gland stroma with mild changes in the acinus and ducts , but was negative for igg4 . upon analysis of the skin biopsy , igg4-positive plasma cells were absent from the dermis and epidermis . the patient was diagnosed with igg4-rd and began oral administration of methylprednisolone ( pfizer , inc . , new york , ny , usa ) at 40 mg / day ( 1 mg / kg / day ) , followed by gradual reduction of the dose ( ~1 pill per month reduction ) within a period of 24 weeks , maintaining a dose of 4 mg / day for ~1 year . this treatment resulted in a decrease in serum igg and igg4 levels to 732 mg / dl and 259 mg / dl , respectively . the visual acuity in the left eye was stabilized and improved to 0.3/1.5 , which persisted over a 1-year post - treatment period . after 4 months of therapy , the left optic nerve had a normal appearance on an mri scan ( fig . the present study reported the case of a woman with unilateral vision loss in addition to involvement of salivary gland , lymph node , lung , pancreas , eyelid and skin . other systemic diseases that may cause similar vision loss include the vogt - koyanagi - harada syndrome , sarcoidosis , sjgren 's syndrome and systemic vasculitis . in the present case , these conditions were excluded by normal fundus fluorescein angiography , negative serum ace , specific autoantibody testing and labial biopsy . the diagnosis of the patient conformed to the 2011 diagnostic criteria for igg4-rd based on organs affected , enriched igg4-positive plasma cells in involved tissues and high serum igg4 concentration ( 7 ) . orbital involvement in igg4-rd has been previously reported to affect nearly every orbital structure , including lacrimal glands , extra - ocular muscles and the trigeminal nerve ( 16,17 ) . the term igg4-related ophthalmic disease ( igg4-rod ) has been suggested for igg4-rd with ophthalmic involvement ( 18 ) . according to kashii ( 18 ) , igg4-rod is characterized by bilateral lacrimal gland enlargement accompanied by three distinctive features , including infraorbital nerve enlargement , extraocular myositis and compressive optic neuropathy . comparing the characteristics of the patient of the current study to this classification , we note that an upper eyelid mass was present , which was consistent with lacrimal gland enlargement ; however , this disappeared spontaneously and prior to methylprednisolone treatment . cranial mri scans documented the presence of optic nerve atrophy with focal lesion , but did not identify any masses infiltrating the optic nerve or orbit , distinguishing this case from previous cases ( summarized in table i ) . we hypothesize that the underlying pathophysiologic mechanism may involve inflammatory demyelination of the optic nerve based on the findings of mri , vep implicit time delays and positive response to glucocorticoid treatment . although this mechanism was not confirmed through optic nerve biopsy , this hypothesis raises a novel pathogenic feature that should be addressed in future cases of igg4-related optic neuropathy . a recent case has shown evident improvement to normal vision after a 3-month course of steroid treatment ( 10 ) . by contrast , the vision of the current patient did not reach normal levels within the 1-year follow - up period . this may reflect the presence of an irreversible optic atrophy or reflect more severe fundus arteriosclerosis in the left eye of the patient . in conclusion , the current study presented a case of igg4-rd with ocular symptoms that were rapidly improved by glucocorticoid treatment . the current case did not involve focal mass infiltration of any orbital structure . by broadening the spectrum of igg4-rod , the present case provides new information regarding the underlying pathogenic mechanisms of igg4-related optic neuropathy .

the present study reports the case of a 79-year - old woman manifesting skin changes , a pancreatic neoplasm , enlarged lymph nodes , an eyelid mass and interstitial pneumonia over a 30-year period . at 2 months before admission to our hospital , the patient presented rapid vision loss in the left eye . left optic nerve atrophy with a focal hyperintense lesion was documented on a t2-weighted magnetic resonance imaging ( mri ) scan , and visual evoked potential implicit times were prolonged . elevated serum immunoglobulin g4 ( igg4 ) concentrations and the presence of enriched igg4-positive plasma cells in the lymph nodes established the diagnosis of igg4-related optic neuropathy . following oral treatment with methylprednisolone , the serum igg4 levels fell to normal levels , and the left eye visual acuity improved to a level that remained stable over a 1-year follow - up period . after 4 months of methylprednisolone administration , the optic nerve appeared to be normal on an mri scan . prior reports on igg4-related optic neuropathy involved an infiltrating mass , which was not observed in the present case . similarly to the current study , previous cases have responded to treatment with glucocorticoids , indicating that the underlying mechanism of the disease may be common .

various modalities , such as percutaneous nephrolithotomy ( pcnl ) , extracorporeal shock wave lithotripsy , and retrograde intrarenal surgery , are used to manage renal stone disease [ 1 - 3 ] . however , pcnl is regarded as the treatment of choice for most renal stones , especially for patients with a large renal stone ( > 2 cm ) , an infected stone , or a cystine stone and for those with a history of failed shock wave lithotripsy . general anesthesia during pcnl has many advantages , for example , it enables breathing control and improves patient comfort . however , associated complications and cost are higher for general anesthesia than for regional anesthesia . for example , endotracheal tube migration and neurologic problems , particularly at the time of position transition , may arise during pcnl under general anesthesia . unfortunately , few research studies have been conducted to compare regional and general anesthesia with respect to operative parameters . in the present study , therefore , to determine whether pcnl under regional anesthesia is a better alternative than pcnl under general anesthesia , we examined surgical outcomes after these two procedures . one hundred and one consecutive patients who underwent pcnl as a first - line management for renal stones , including staghorn , pelvic , and calyceal stones , from june 2004 to june 2013 at inje university sanggye paik hospital were included in this retrospective study . the patients were classified into two groups by anesthesia method : a regional anesthesia group ( n=77 ) and a general anesthesia group ( n=24 ) . decisions regarding anesthesia method were mainly based on considerations of medical status , such as cardiac problems and the presence of respiratory illness or coagulopathy . in the absence of such factors , the contraindications for pcnl were uncorrected coagulopathy , congenital renal anomaly , and metastatic malignancy . in addition to history taking , we performed a physical examination , preoperative laboratory tests , and a radiological evaluation , which included plain radiography of the kidney - ureter - bladder ( kub ) region and abdominopelvic computed tomography ( ct ) . stone size was defined as the sum of the maximal lengths of renal stones on ct images . patients with a urinary tract infection were treated preoperatively in accordance with urine culture sensitivity . the clinical and stone parameters compared were age , gender , body mass index , stone laterality , stone size , and stone number , respectively . regional anesthesia was induced with 0.5% heavy bupivacaine ( marcaine , astrazeneca korea , seoul , korea ) 12 ml , and a spinal epidural set ( portex , smiths medical , kent , uk ) was injected intrathecally into the l3 - 4 or l4 - 5 interspaces . the level of anesthesia was checked for 5 minutes after injection with the patient in the trendelenburg position . if surgery was prolonged , levobupivacaine ( chirocaine , abbott korea , seoul , korea ) was administered by an anesthesiologist to maintain adequate anesthesia . general anesthesia was carried out by using intravenous propofol ( pofol , dongkook pharmaceutical co. , seoul , korea ) and rocuronium ( esmeron , msd korea , seoul , korea ) . following the induction of anesthesia an occlusion ureteral catheter was then inserted into the renal pelvis and ballooning ( 1 ml ) was performed to prevent stone fragments from descending into the proximal ureter . patients were then rotated to the prone position and percutaneous nephrostomy was performed under ultrasonographic guidance . the access tract was dilated with an amplatz and a balloon dilator , and stone fragmentation was performed by using a combination of ultrasonic and pneumatic lithotripsy . stone fragments were removed by using grasping forceps under a 24-fr nephroscope . a 20-fr nephrostomy tube was left and a fluoroscopic nephrostogram was routinely obtained to assess status at the end of the procedure . patients in both groups were radiologically followed up at 1 day ( initial ) and 1 month ( overall ) after surgery to assess status . stone - free status was defined as the absence of any fragment greater than 4 mm by kub . operative outcomes , surgical times , hospital stays , stone - free rates , perioperative complications , and changes in hemoglobin and white blood cell counts were compared by using the modified clavien grading system , which was proposed to grade perioperative complications of general surgery and has been validated in a cohort of 6,336 patients . fever was defined as a temperature exceeding 37.7 at 1,600 on the first postoperative day . postoperative antipyretics ( arthagyl , ilyang pharmaceutical co. , seoul , korea ) , analgesics ( tridol , yuhan co. , seoul , korea ) , antiemetics ( mexolon , donga pharm , seoul , korea ) , and diuretics ( lasix , handok inc . , seoul , korea ) were injected intravenously when symptoms appeared during the operative or first postoperative day . blood transfusions were done in the operating room on the basis of decisions made by anesthesiologists . chicago , il , usa ) . because the number of patients in the general anesthesia group was small ( n=24 ) , continuous variables were assessed by using the mann - whitney test , and categorical variables were analyzed by using the chi - square test . clinical parameters are expressed as meanstandard deviations , and statistical significance was accepted for p - values < 0.05 . patient and stone characteristics in the regional and general anesthesia groups are compared in table 1 . mean ages in these groups were 54.812.2 years and 50.817.8 years , respectively ( p=0.338 ) . gender and body mass index were nonsignificantly different , and mean stone sizes ( 34.524.0 mm and 42.336.1 mm , respectively ; p=0.309 ) , mean stone numbers ( 2.02.4 and 2.95.1 , respectively ; p=0.648 ) , and the distributions of renal stones were similar ( p=0.254 ) . intergroup differences between initial stone - free rates ( 68.8% and 41.7% , respectively ; p=0.246 ) and overall stone - free rates ( 80.5% and 66.7% , respectively ; p=0.371 ) were nonsignificantly different . no significant intergroup differences were found between mean surgical times ( 14372 minutes and 151112 minutes , respectively ; p=0.185 ) or changes in hemoglobin levels ( -1.61.2 g / dl and -1.71.3 g / dl , respectively ; p=0.734 ) in the regional and general anesthesia groups . furthermore , white blood cell levels were not significantly changed in the two groups ( 3,8833,110/l and 3,9103,509/l , respectively ; p=0.480 ) . however , mean hospital stay was significantly shorter in the regional anesthesia group ( 8.93.2 days vs. 11.56.9 days , respectively ; p=0.025 ) . perioperative complications were investigated by using the modified clavien grading system , and the results are summarized in table 2 . a smaller proportion of patients in the regional anesthesia group experienced postoperative fever ( p=0.007 ) . however , mean dosages of antipyretics ( p=0.397 ) , analgesics ( p=0.800 ) , antiemetics ( p=0.179 ) , and diuretics ( p=0.737 ) administered were not significantly different . furthermore , the mean number of pints of blood transfused per patient was similar in the two groups ( 0.30.9 vs. 0.30.7 , respectively ; p=0.811 ) . no patient experienced a grade iii or iv complication according to the modified clavien grading system . pcnl remains the first - line treatment of choice for managing renal stone disease , although minimally invasive modalities , such as retrograde intrarenal surgery , have been introduced . furthermore , most urologists prefer general anesthesia for pcnl owing to the high level of anesthesia achieved , the ability to control the patient 's breathing , and because it is more comfortable for patients . however , general anesthesia is more likely to cause severe morbidities , such as drug - induced anaphylaxis , complications associated with endotracheal tube insertion , and cardiovascular , pulmonary , and neurologic complications , than is regional anesthesia . studies have been conducted to demonstrate the benefits of regional anesthesia in other types of surgery , such as radical retropubic prostatectomy and total hip arthroplasty . salonia et al . asserted that regional anesthesia permits fine muscle relaxation and achieves excellent surgical outcomes after radical retropubic prostatectomy . furthermore , regional anesthesia has been reported to reduce the risk of intraoperative hemorrhage , to be associated with less postoperative pain , and to allow earlier restoration than general anesthesia [ 18 - 20 ] . in addition , gonano et al . reported that the cost of regional anesthesia is 40% less than that of general anesthesia during orthopedic surgeries . several comparative studies on anesthesia methods in pcnl have demonstrated various benefits for pcnl under regional anesthesia compared with general anesthesia . in a retrospective comparative study of 37 patients who underwent regional anesthesia and 45 who underwent general anesthesia , it was concluded that the results were comparable in terms of general profiles , operative times , and stone - free rates . in another study of 50 patients who underwent pcnl , regional anesthesia was found to be associated with greater patient satisfaction , less early postoperative pain , and fewer adverse events than general anesthesia . furthermore , in a prospective randomized study on pcnl in 64 patients ( 32 general and 32 regional anesthesia ) , patients in the regional anesthesia group were found to have significantly lower postoperative analgesic demands and shorter hospitalization periods . reported that general anesthesia increases the probabilities of fluid absorption and electrolyte imbalance , and other authors have recommended regional anesthesia for patients with an electrolyte imbalance , especially for morbidly obese patients . despite the opinion held by some that regional anesthesia is unsuitable for pcnl of calculi in the upper pole of the kidney , regional anesthesia ( bupivacaine [ marcaine ] , 12 - 15 mg ) can be used to anesthetize up to the t4 level ( level of axilla ) according to an anesthesiology textbook . general anesthesia is associated with significant changes in the shape of the chest and alveolar gas contents . outside of that , these changes result in continued elevation of the risk for reintubation , mechanical ventilation , and nosocomial pneumonia , all of which prolong the hospital stay . regarding hospital stay , it was previously reported that average hospital stay is approximately 5 to 7 days regardless of anesthesia type . however , in the present study , hospital stays were 8.93.2 days and 11.56.9 days , respectively , which could have been due to the exclusion of time spent at the hospital before surgery and the procedure used to determine the discharge date . in addition , according to a large - scale study , initial and overall stone - free rates were 69.9% and 88.8% , respectively , and another study conducted on 610 patients found corresponding rates of 57.6% and 84.9% , respectively . in the present study , values were 68.8% and 80.5% in the regional anesthesia group and 42.9% and 71.4% in the general anesthesia group , which were relatively low and did not represent a significant intergroup difference . we attribute these differences to the different definitions used for the stone - free rate and patient descriptive features . in brief , this retrospective study showed that despite similar patient characteristics in the two groups , postoperative fever rates and hospital stays were significantly greater in the general anesthesia group . thus , it may be more helpful for patients to implement pcnl under regional anesthesia than general anesthesia in matters of fever control and cost of hospitalization . the present study had some limitations that deserve mention . first , it was inherently limited by its retrospective design ; as such , lack of control of basic patient factors may have introduced bias . second , the study was performed at a single center , and the general anesthesia group was appreciably smaller than the regional anesthesia group . the present study showed that in terms of general characteristics and procedural success , the outcomes of pcnl conducted by use of regional or general anesthesia are similar . nevertheless , pcnl with regional anesthesia required fewer hospital days and was associated with a lower postoperative fever rate . accordingly , we conclude that pcnl under regional anesthesia is at least as advantageous as pcnl under general anesthesia in patients with kidney calculi .

purposeto compare surgical outcomes and complications after percutaneous nephrolithotomy ( pcnl ) under regional or general anesthesia.materials and methodsone hundred and one patients who underwent pcnl as a first - line treatment for kidney calculi between june 2004 and june 2013 were enrolled in this retrospective study . patients were classified into two groups by anesthetic method : 77 were allocated to the regional anesthesia group and 24 to the general anesthesia group . patient general characteristics , stone features , surgical outcomes , and complications were compared between the two groups.resultsthe two groups were similar in terms of mean age and stone size , number , and type . furthermore , they did not differ significantly in terms of general characteristics , treatment outcomes , or complications excluding postoperative fever . however , mean hospital stay was significantly shorter in the regional anesthesia group than in the general anesthesia group ( 8.93.2 days vs. 11.56.9 days , respectively , p=0.025 ) . also , the postoperative fever rate was significantly higher in the general anesthesia group ( 53.2% vs. 83.3% , respectively , p=0.007).conclusionsregional anesthesia is as effective as general anesthesia during percutaneous nephrolithotomy and is associated with shorter hospital stays and lower rates of postoperative fever .

ehlers - danlos syndrome ( eds ) is a heritary disorder of connective tissue characterized by fragility of skin and blood vessels , hyperextensibility of the skin and joint laxity . milder variants of the classical mitis form of the eds are common in the population and can be identified by a well - defined clinical scoring system . a 17-year - old female born out of nonconsaguineous marriage attended the dermatology out - patient department with a history of laxity of skin and joints . a history of bruising of the skin and gaping wounds with even very trivial trauma could be easily ascertained , but no episode of a major hemorrhagic accident had ever occurred in the past . the patient was an outcome of a full term normal delivery with no neonatal or perinatal morbidity . the family history revealed no such complaints in parents and siblings . on physical examination , the skin was soft , velvety and hyperextensible [ figure 3 ] but with normal recoil . atrophic cigarette paper scars [ figure 1 ] were seen on forehead , cheeks , forearms , elbows , knees and both shin . joints were hypermobile [ figure 2 ] with genu recurvatum of the knee and hallux valgus deformity of both great toes . there was no evidence of ecchymosis , cyanosis , digital clubbing , jaundice and lymphadenopathy . the fundus , routine blood test , urine , coagulogram , blood urea , sugar and echocardiogram were within the normal limits . x - ray of the spine and knee joints was normal except for feet which showed hallux valgus deformity . histopathology with special stain for collagen and elastic fibers showed a decrease in collagen fibers with the relative increase in elastic fibers consistent with the diagnosis of eds [ figures 5 and 6 ] . cigarette paper scarring on forehead and lower limbs hyperelastic skin and palms touching the floor gorlin 's sign and reverse namaskar sign van giesons stain for collagen fibers under 10 showing decrease in collagen bundles acid orcein giemsa stain for elastic fibres under 10 showing relative increase in elastic fibres eds cases have been reported in previous literature . it 's a heterogenous group of inherited disorder of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity . ehler noticed the easy bruisability of the skin whereas ; danlos noted the peculiar cigarette paper scars and pseudotumour formation of the skin . danlos also put forth four diagnostic criteria , namely , hyperelasticity of skin [ figure 3 ] , fragility of skin , hypermobility of joints [ figure 4 ] and subcutaneous molluscus pseudotumour formation . more than ten clinical types have been described based on clinical , genetic and biochemical information . in a recent consensus in villefranche , in 1997 , the classification of eds was reorganized into six major subtypes . the diagnostic skin signs described in eds includes gorlins sign [ figure 4](ability to touch the tip of the nose with the tongue ) , metenier sign ( easy eversion of upper eyelid ) and atrophic cigarette paper scarring [ figure 1 ] . these are subcutaneous nodules due to herniation of subcutaneous fatty tissue and resemble lipomas histologically . the reverse namaskar sign [ figure 4 ] , a valuable diagnostic sign has been described by premalatha in patients with eds . absence of ocular lesions , ecchymosis , large joint dislocations and periodontitis led us to classify our patient as eds type ii ( mitis ) . we report this case because of the classical clinical signs present , which are depicted in the figures which will be helpful to diagnose the case of eds in clinical practice .

ehlers - danlos syndrome ( eds ) is a generalized disorder of one element of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity . it is a hereditary disorder , the inheritance being usually autosomal dominant with low penetrance . autosomal recessive and x - linked recessive varieties are also known . first described by hippocrates in 4th century b.c . , the various clinical types with variable penetrance have been described lately . the number of cases eds reported in the literature is very meagre . with the available information only about six publications of classic eds in siblings had been reported in indian literature .

drosophila melanogaster is one of the most well - studied model organisms due to its short generation time and ease of genetic manipulation . hence , it is continuously providing major insights into biological processes which are conserved in multicellular organisms . single nucleotide polymorphisms ( snps ) are widely used as genetic markers in mapping experiments , quantitative trait loci ( qtl ) analyses , population genetic or evolutionary studies , since they are frequent , mostly phenotypically neutral and molecularly defined . flysnpdb contains data of a polymorphism map with an unprecedented resolution of 50 kb between snp markers , which is significantly higher than the density of previous drosophila snp maps ( 14 ) . polymorphisms > 1 nt were also counted , including indels , which are particularly useful for genotyping assays based on pcr - product length polymorphisms [ plp ; ( 2 ) ] or denaturing high performance liquid chromatography [ dhplc ; ( 5 ) ] or also for evolutionary analyses ( 6,7 ) . the map comprises snps from five different d. melanogaster stocks ( supplementary table 1 ) . since polymorphisms in drosophila are generally bi - allelic and randomly distributed among the utilized strains , we anticipate that most of our snp markers can be used to discriminate almost any other pair of drosophila stocks . flysnpdb is part of the flysnp website ( http://flysnp.imp.ac.at/ ) , which provides detailed information on the practical aspects of snp mapping and genotyping in drosophila ( 8) as well as a user guide for the database , a glossary and protocols . with this database , we want to provide a versatile snp data resource , which is easy to use and has a user - friendly web interface . for snp identification , we designed primer pairs to amplify fragments which are 1 kb long ( 9 ) , equally distributed along each major chromosome arm ( x , 2l , 2r , 3l and 3r ) , and which preferentially lie in unique , non - protein coding regions ( figure 1 ) . genomic dna of up to five standard laboratory stocks per amplicon served as template : besides the wild - type stocks canton s and oregon r , we selected for each chromosome arm one strain that carries visible recessive markers , one stock with a flp recombinase target ( frt ) element ( 10 ) close to the centromere , and one stock with an enhancer - promoter p- ( ep ) element at the chromosome tip and a visible white marker ( 11 ) ( see also supplementary table 1 ) . the wild - type and frt stocks are commonly utilized in mutagenesis screens , and the recessive marker as well as ep stocks are useful for identification of recombination events in defined chromosomal regions ( 2,4 ) . pcr products were sequenced in both orientations , each using one of the amplification primers as sequencing primer . in total , > 2.3 mb ( 1.7% ) of the 117 mb long euchromatic region of the d. melanogaster genome were resequenced and analysed . after sequencing the pcr fragments , the phred / cross_match / polybayes software package ( 1214 ) was used for trace quality assessment , alignment to the reference genome ( strain y ; cn bw sp ) ( 15,16 ) , and automated snp discovery . in order to obtain high - quality data , snps at the first and last 75 bases of an amplicon or below phred in addition , 27% of the alignments were visually inspected [ with the help of consed 11.0 ( 17 ) ] , which was particularly necessary for detection of long indels ( > 6 bases ) . if multiple sequence reads from the same stock were available at one site , the allele with the highest phred score was selected . moreover , snps located at adjacent loci were considered as a single polymorphic site . of the analysed amplicons , the snp positions were updated to release 5 ( fb2006_01 ) of the d. melanogaster genome by aligning 40 bp of the sequences ( from release 3 or 4 ) flanking each snp site to the new reference sequence using blastn ( 18 ) . prediction of restriction fragment length polymorphism ( rflp ) sites was accomplished with the help of remap [ emboss software suite ( 19,20 ) ] and the rebase list of commercially available restriction enzymes with cut sites 4 bp ( 21,22 ) . figure 1.data source pipeline for snp identification , data retrieval and curation . software tools are displayed below each task ( for references please see text ) ; if not otherwise stated , costum - made scripts were used . software tools are displayed below each task ( for references please see text ) ; if not otherwise stated , costum - made scripts were used . the flysnpdb data set currently comprises > 81 700 snp alleles at 27 367 sites in 2238 amplicons of about 1 kb length ( table 1 ) . one snp marker contains in average 12 polymorphisms , the maximal snp count per marker is 73 . the average distance between snp markers is 50.3 kb , a region in which one can find in average 6.6 genes [ according to the flybase release 5.10 , fb2008_07 annotation ( 23 ) ] . the biggest gap between markers is 360 kb long and lies at the tip of chromosome arm 3r , between cytological region 82a1 and 82c3 . only 169 polymorphic loci ( 0.6% of total snps ) are tri - allelic , the rest is bi - allelic . a total of 13.7% ( 3743 ) of the snps are indels , which are up to 360 bp long , but predominantly ( 96.4% ) < 10 bp ( 46.6% of the indels are 1 nt long ) . for any given stock - pair , the average percentage of snp markers with a sequence divergence between these two stocks is 76.6% , ranging from 35.3% to 92.0% . furthermore , the database provides information on the molecular and cytological snp locations for three genome assembly versions [ release 35 ; ( 15 ) ] , together with the 30 bp flanking sequences as additional site identification feature . for data quality assessment , polybayes probability scores ( 14 ) , phred trace quality scores ( 12 ) , as well as the number of sequence reads per alignment are available , and manually curated snps are indicated . since non - coding regions are more polymorphic , we have put our focus on non - exonic regions . if snps lie within an intron or exon ( according to flybase release 5.10 ) , the corresponding gene name is also retrievable . in addition , information on snp marker amplification primers is available for genotyping assays which are based on sequencing . polymorphisms that are suitable for rflp assays ( snps which result in differential restriction enzyme sites ) or for which verified plp or tag - array mini - sequencing ( tams ) assays ( 8) are available , are also indicated , including further information like verified primers or suitable restriction enzymes . table 1.number of snps in flysnpdb , per chromosome arm and in totalchromosome armx2l2r3l3rtotalsnp markers4834434074174882238snp sites4720584954025993540327 367indels6857557488097463743alleles15 96616 50015 71417 48316 12381 786snp sites are locations where a differential base has been identified in at least one of the stocks compared to the reference sequence or to another stock . allele counts reflect called bases in each of the sequenced drosophila stocks , without the alleles of the reference sequence ( which are also available in flysnpdb ) . number of snps in flysnpdb , per chromosome arm and in total snp sites are locations where a differential base has been identified in at least one of the stocks compared to the reference sequence or to another stock . allele counts reflect called bases in each of the sequenced drosophila stocks , without the alleles of the reference sequence ( which are also available in flysnpdb ) . all data are organized and stored in a relational database . for increasing the speed of web queries , several summarizing tables were precomputed and put into a mysql database which is accessed through php scripts . the form on the first page asks the user to specify the chromosomal region and two stocks for which data on differential polymorphisms will be retrieved ( figure 2 ) . the region can be indicated as molecular coordinates ( position 1 position 2 or position 1 + length ) or as cytological segment ( region 1 region 2 ) . furthermore , it is possible to select whole chromosome arms by leaving the location field blank , or getting all data by selecting the browse all option . snp data can be viewed as list of snp markers ( including snp count , amplification primer sequences ) or as table of snp sites ( with alleles , flanking sequences , etc . ) . additional information concerning quality scores , genotyping assay suitability or coding information ( genic , intronic or exonic ) can be optionally selected . for users of the previous flysnp database version , old identifiers ( ids ) are retrievable and a link to this version is provided . on each query result page , sub - selections can be made by clicking on the checkboxes at the left side of each row , or by entering search parameters in the fields below each column ( figure 2 ) . the tables are downloadable , e.g. as tab - separated text files which can be easily imported into commonly used databases or excel spreadsheets , or as track files which can be uploaded to the flybase genome viewer [ gbrowse ; ( 24 ) ] . as an additional feature , a link to flybase gbrowse is provided for the graphical display of the region previously specified by the user . , the user selects chromosomal region and stocks as well as different view options . on the search result page , further features such as table download or sub - queries are available . the user selects chromosomal region and stocks as well as different view options . on the search result page , the flysnpdb data were recently submitted to dbsnp ( ncbi , release 129 ; http://www.ncbi.nlm.nih.gov/projects/snp/ ) so that direct linkage to the flybase data repository is feasible . furthermore , sequence traces and alignments will be provided for users who would like to see the raw data for detailed quality assessment . we are open to help users with their individual needs and will implement suggestions of common use . european union fifth framework programme ( qlri - ct-2001 - 00004);boehringer ingelheim gmbh ; japan society for the promotion of science .

flysnpdb provides high - resolution single nucleotide polymorphism ( snp ) data of drosophila melanogaster . the database currently contains 27 367 polymorphisms , including > 3700 indels ( insertions / deletions ) , covering all major chromsomes . these snps are clustered into 2238 markers , which are evenly distributed with an average density of one marker every 50.3 kb or 6.6 genes . snps were identified automatically , filtered for high quality and partly manually curated . the database provides detailed information on the snp data including molecular and cytological locations ( genome releases 35 ) , alleles of up to five commonly used laboratory stocks , flanking sequences , snp marker amplification primers , quality scores and genotyping assays . data specific for a certain region , particular stocks or a certain genome assembly version are easily retrievable through the interface of a publicly accessible website ( http://flysnp.imp.ac.at/flysnpdb.php ) .

pulmonary arterial hypertension ( pah ) is a cardiovascular complication that causes death in thalassemic patients . pah in thalassemia was reported with a high incidence in several studies.14 there was evidence that pah in thalassemia is associated with platelet activation.57 acetylsalicylic acid ( asa ) lowers the thromboxane a previous cohort study found that the rise of arterial partial pressure of oxygen ( pao2 ) in ten out of the 12 -thalassemic patients after asa ten grains or persantin administration for 24 weeks indicates that the observed hypoxemia is due to reversible platelet aggregation.9 a recent study showed that asa decreased pulmonary artery pressure , reduced right ventricular hypertrophy , and improved survival in the monocrotaline animal model of pah.10 the erythrocytes and platelets of thalassemic patients contained higher levels of reactive oxygen and lower levels of intracellular glutathione than normal erythrocytes and platelets11 that play a role in oxidative stress , thereby leading to the proper therapy . studies of antiplatelet therapy are required before there are conclusive treatment guidelines for thalassemic patients with pah . in clinical practice the aim of the research was to compare after 1 year of follow - up the pulmonary artery systolic pressure ( pasp ) of patients with thalassemia and pah to whom asa was and was not prescribed . a retrospective cohort study was conducted at the hematological outpatient clinic at chiang rai hospital , chiang rai , thailand . all new adult ( aged 15 years ) cases of thalassemia with pah defined as pasp > 35 mmhg by doppler echocardiography ( echo ) from january 2007 to january 2012 were evaluated and followed from the first month to 12 months later . 81 mg was prescribed daily for 1 year , and in another group , no asa was prescribed , due to contraindications for asa ( including bleeding , gastrointestinal side effects , and thrombocytopenia [ platelets < 10010/l ] ) . pasp , functional class status , clinical right heart failure , and oxygen saturation were measured at baseline and at the end of 12 months . the functional class status was defined by the new york heart association ( nyha ) classification.12 patients with other causes of pah or who used other antiplatelets and/or anticoagulants were excluded . the study protocol was approved by the institutional research ethics committee and was carried out in accordance with the declaration of helsinki . complete two - dimensional , m - mode , and doppler ( pulsed wave , continuous wave , and color ) echo was performed at rest . in the study patients , a tricuspid regurgitation jet was sought from all available midprecordial and apical positions until a flow signal with the maximum spectral representation of the highest velocities was obtained . peak velocity was recorded from a holosystolic regurgitant jet . from the maximum velocity ( v ) of the regurgitant jet , the systolic pressure gradient ( p ) between the right ventricle and the right atrium was calculated by modified bernoulli equation ( p = 4v2).13 right atrial pressure was estimated by the response of the inferior vena cava diameter to inspiration . right atrial pressure was assumed to be 5 mmhg if the inferior vena cava completely collapsed with inspiration , 10 mmhg if the inferior vena cava dia meter decreased > 50% during inspiration , and 15 mmhg if it decreased < 50% . if the inferior vena cava diameter was > 2.5 cm and reduced by < 50% during inspiration , right atrial pressure was assumed to be 20 mmhg.14 adding the transtricuspid gradient to the mean right atrial pressure provided the right ventricular systolic pressure or peak systolic pulmonary arterial pressure in the absence of right ventricular outflow tract obstruction . pah was defined as pasp > 35 mmhg.15 in cases with an absence of tricuspid regurgitation , at the end of the diastolic pulmonic regurgitant the velocity was calculated using the pressure gradient between the pulmonary artery and right ventricular end diastolic pressure : pulmonary artery pressure = 4 ( vpr)2 + right atrial pressure . the baseline characteristics were compared using exact probability tests for categorical variables ; student s t - test or wilcoxon rank - sum test was used to compare the mean difference of continuous variables . propensity scores for prescribing asa versus no asa were calculated from a logistic regression model that estimated the likelihood of prescribing asa based on the observed patient characteristics . data are presented by frequency , percentage , mean , standard deviation ( sd ) , beta coefficient , 95% confidence interval [ ci ] , and p - value . all statistical analyses were two - tailed . a p - value of < 0.05 was considered statistically significant . complete two - dimensional , m - mode , and doppler ( pulsed wave , continuous wave , and color ) echo was performed at rest . in the study patients , a tricuspid regurgitation jet was sought from all available midprecordial and apical positions until a flow signal with the maximum spectral representation of the highest velocities was obtained . peak velocity was recorded from a holosystolic regurgitant jet . from the maximum velocity ( v ) of the regurgitant jet , the systolic pressure gradient ( p ) between the right ventricle and the right atrium was calculated by modified bernoulli equation ( p = 4v2).13 right atrial pressure was estimated by the response of the inferior vena cava diameter to inspiration . right atrial pressure was assumed to be 5 mmhg if the inferior vena cava completely collapsed with inspiration , 10 mmhg if the inferior vena cava dia meter decreased > 50% during inspiration , and 15 mmhg if it decreased < 50% . if the inferior vena cava diameter was > 2.5 cm and reduced by < 50% during inspiration , right atrial pressure was assumed to be 20 mmhg.14 adding the transtricuspid gradient to the mean right atrial pressure provided the right ventricular systolic pressure or peak systolic pulmonary arterial pressure in the absence of right ventricular outflow tract obstruction . pah was defined as pasp > 35 mmhg.15 in cases with an absence of tricuspid regurgitation , at the end of the diastolic pulmonic regurgitant the velocity was calculated using the pressure gradient between the pulmonary artery and right ventricular end diastolic pressure : pulmonary artery pressure = 4 ( vpr)2 + right atrial pressure . the baseline characteristics were compared using exact probability tests for categorical variables ; student s t - test or wilcoxon rank - sum test was used to compare the mean difference of continuous variables . propensity scores for prescribing asa versus no asa were calculated from a logistic regression model that estimated the likelihood of prescribing asa based on the observed patient characteristics . data are presented by frequency , percentage , mean , standard deviation ( sd ) , beta coefficient , 95% confidence interval [ ci ] , and p - value . a total of 63 thalassemia patients with pah , 53 with e/-thal , six with homozygous -thal , and four with hb h disease were evaluated . there were 47 ( 74.6% ) in the asa group and 16 ( 25.4% ) in the no asa group . patients in the second group had the following contraindications for asa : seven ( 43.7% ) bleeding , seven ( 43.7% ) gastrointestinal side effects , and two ( 12.5% ) thrombocytopenia . the mean age was 35.916.8 years and 28.314.1 years , and the mean pasp was 51.913.7 mmhg and 45.69.9 mmhg in the asa group and the no asa group . the baseline characteristics of the patients did not differ significantly except for red cell transfusion and right ventricular diameter ( table 1 ) . the patients in the asa group received fewer blood transfusions during the follow - up time of 12 months than those without asa ( 6.24.8 vs 11.04.6 units , p=0.002 ) , and the asa group had wider right ventricular diameter than the no asa group ( 29.55.8 vs 25.54.2 mm , p=0.016 ) . during the follow - up period of 12 months , pasp increased in 12 of 47 ( 25.5% ) patients in the asa group and in three of 16 ( 18.7% ) in the no asa group . echo findings showed that the patients in the asa group had a higher mean pasp than the no asa group , but there was no statistical difference . after adjusting for propensity score ( based on type of thalassemia , splenectomy , o2 saturation , nyha classification , red cell transfusion , clinical right heart failure , hemoglobin level , platelet count , nucleated red cell , serum ferritin level , baseline pasp , left ventricular ejection fraction , main pulmonary artery diameter , right ventricular diameter , right ventricular systolic function , and diastolic function ) , there were no statistically significant differences in the functional class status , clinical right heart failure , and oxygen saturation between the two groups ( table 3 ) . asa , as compared with no asa , did not significantly reduce pasp ( adjusted difference 0.95 ; 95% ci 16.99 to 15.10 ; p=0.906 ) . in the present study , asa did not improve the functional class status , clinical right heart failure , and oxygen saturation and did not have a significant effect on pasp after 12 months . both the asa and the no asa groups had reduced pasp by 4.711.0 mmhg and 4.37.1 mmhg with no clinical or statistical significance . the results of this study were similar to those of a randomized clinical trial of asa and simvastatin for pah , which concluded that the results did not support the routine treatment of patients with pah with these medications.16 and thalassemia patients who experienced a thromboembolic event and received asa afterwards had a lower recurrence of thromboembolic event compared with those who were not taking asa , although these differences were not statistically significant.17 subgroup analysis of e/-thal ; asa , as compared with no asa , did not significantly reduce the pasp ( adjusted difference 3.62 ; 95% ci 11.84 to 4.60 ; p=0.225 ) . for the transfusion- and nontransfusion - dependent patients , in contrast to the previous study that reported that there was a rise of arterial pao2 after high - dose asa administration in thalassemia patients with pah,9 we found that oxygen saturation rose in the patients who had received low - dose asa but without statistical significance ( adjusted difference 0.31 ; 95% ci 1.71 to 2.33 ; p=0.757 ) . pah developed in thalassemic patients because of platelet activation and hypercoagulable state.18,19 therefore , it was reasonable that antiplatelet therapy alone may be less effective for pah in thalassemia . further studies of pah management will be required before conclusive recommendations can be made for anti - platelet or anticoagulant therapy or prevention for high risk of pah in thalassemia ( postsplenectomy status3 ) . the present study may have some limitations , as it was not a randomized controlled trial , the duration of treatment was only 12 months , and the 6-minute walk test was not used as a clinical outcome due to its retrospective nature . the lack of cardiac catheterization to confirm pasp is a limitation for a therapeutic trial of pah.20 however , echo is more sensitive and is a commonly used noninvasive tool to screen pah . more evidence from observational studies or preferably randomized clinical trials may be required before it can be concluded that asa would offer any beneficial effects to these patients . the current therapies for pah in thalassemia include the use of sildenafil21,22 and bosentan.23 however , a large cohort of patients on the topic are needed before definite recommendations can be made . the present findings suggested that low - dose asa may not have a beneficial effect on pasp after 1-year treatment of pah in thalassemia .

objectiveto compare pulmonary artery systolic pressure ( pasp ) between thalassemic patients with pulmonary arterial hypertension ( pah ) for whom acetylsalicylic acid ( asa ) was and was not prescribed after 1 year.methodsa retrospective cohort study was conducted at the hematological outpatient clinic at chiang rai hospital , chiang rai , thailand . all new cases of thalassemia with pah from january 2007 to january 2012 were studied at the first month and at 12 months . the patients were classified into two groups . in one group , asa 81 mg daily was prescribed for 1 year , whereas in another group no asa was prescribed , due to its contraindications , which included bleeding , gastrointestinal side effects , and thrombocytopenia . pasp , estimated by a doppler echocardiography , was measured by the same cardiologist . propensity score adjustment was used to control confounding variables by indication and contraindication . multivariable regression analysis was used to evaluate the effects of asa.resultsof the 63 thalassemia patients with pah , there were 47 ( 74.6% ) in the asa group and 16 ( 25.4% ) in the no asa group . asa , as compared with no asa , did not significantly reduce pasp ( adjusted difference 0.95 ; 95% confidence interval 16.99 to 15.10 ; p=0.906).conclusionlow - dose asa may not have a beneficial effect on pasp after 1 year of treatment of pah in thalassemia .

bacterial artificial chromosome ( bac ) libraries play a critical role in determination of genome organization and chromosome walking . in addition , we have utilized bac libraries for linkage analysis and physical mapping of lepidoptera , butterflies and moths . we reported construction of the first lepidopteran bac library from the silkworm , bombyx mori , which was used for characterization of the hox gene cluster . bac clones isolated with monomorphic sequence tagged sites ( stss ) were utilized for finding polymorphisms from flanking regions of the original stss and construction of bac contigs covering 22% of the b. mori genome , enabling us to localize genes which could not be mapped genetically . we showed that bac clones could be used effectively as probes for fluorescence in situ hybridization ( fish ) in this species despite the limited cytological differentiation of individual chromosomes [ 24 ] and defined a karyotype for b. mori using this technique . bac libraries have since been constructed for several other lepidopteran species [ 59 ] and used to reveal longer range genome organization [ 811 ] . we previously showed that the gene order is well conserved between b. mori and the tobacco horn worm , manduca sexta , by mapping m. sexta orthologs of 124 conserved and putative single - copy genes using bac - fish technology , which is suitable for genetically uncharacterized species . however , b. mori and m. sexta belong to the same superfamily , bombycoidea , and analysis of other major lepidopteran groups is necessary to determine to what extent synteny exists at the chromosomal level among a wide range of lepidoptera . noctuoidea is the largest family of lepidoptera and includes many serious and globally distributed agricultural pests . therefore , we selected the tobacco budworm , heliothis virescens , as a target for our studies since a bac library and more than 60,000 expressed sequenced tags ( ests ) [ 1315 ] were available . the european corn borer , ostrinia nubilalis , was also appropriate for this analysis due to the availability of a bac library ( http://www.genome.clemson.edu/services ) and ests [ 16 , 17 ] . o. nubilalis belongs to the superfamily , pyraloidea , which forms a different clade from bombycoidea and noctuidae but is closer to them than butterflies ( figure 1 ) . another species with available bacs was the diamondback moth , plutella xylostella , which is well known to develop resistance rapidly to a wide variety of insecticides [ 1921 ] . p. xylostella belongs to the superfamily , yponomeutoidea , which is primitive compared with macrolepidoptera , which contains the other two species , but all belong to the same major group of advanced lepidoptera , ditrysia ( figure 1 ) . here , we describe isolation of bac clones containing conserved genes from these three distantly related species , h. virescens , o. nubilalis , and p. xylostella . a total of 458 clones were isolated by pcr - based screening of bac libraries . total rna was isolated from tissues and whole bodies of embryos , larvae , pharate pupae , pupae , and adults . cdna was synthesized using a super smart pcr cdna synthesis kit ( clontech ) and cloned into a pgem - t easy plasmid vector ( promega ) . a total of twelve cdna libraries were constructed , and nucleotide sequences of randomly selected clones were determined using an abi3730 dna sequencer ( applied biosystems ) ( table s1 ) . the dna sequences were analyzed using a blastx program ( http://blast.ncbi.nlm.nih.gov/blast.cgi ) to estimate their function . single - step or nested pcr amplifications were performed using degenerate primers designed from conserved genes previously mapped in b. mori . single - step pcr amplification was performed using genomic dna as template except for the small heat shock protein genes ( table s2 ) , for which rt - pcr and 3'-race analyses were performed ( table s2 ) . pcr products were then cloned into a pgem - t easy plasmid vector ( promega ) and sequenced with an abi3730 dna sequencer . sequences of h. virescens , o. nubilalis , and p. xylostella genes and ests were obtained from public databases or by est sequencing as described above and used as queries for tblastn ( sequences with cds ) or tblastx ( sequences without cds ) searches against assembled genome sequences of b. mori using the blast tool ( http://kaikoblast.dna.affrc.go.jp/ ) associated with a database of the silkworm genome , kaikobase . genes and ests showing significant similarity to putative single - copy b. mori genome sequences were selected and checked for localization of their b. mori orthologs in our previous studies by inheritance - based gene mapping and analysis of bac contigs [ 2 , 12 , 23 ] . we performed pcr - based linkage analysis of unmapped orthologs with newly designed primers for sequence - tagged sites ( stss ) ( see in supplementary material available online at doi : 10.1155/2011/165894 table s3 ) using 22166 f2 individuals of b. mori from a single pair - mating of a strain c108 female by a strain p50 male , as reported previously , for the confirmation of chromosomal locations obtained from kaikobase . when pcr products amplified from b. mori orthologs were monomorphic in our mapping population , pcr - based screening of a b. mori p50 bac library was performed in the same manner as described elsewhere to confirm whether unmapped b. mori orthologs were localized on previously mapped bac contigs . bac libraries used in this study were an h. virescens library , hvb , ( average insert size 171 kb ) , obtained from the gene finder genomic resources ( texas a&m university , college station , tx , usa ) , an o. nubilalis library , on_ba , ( average insert size 125 kb ) and a p. xylostella library , pxcdba , ( average insert size 109.4 kb ) obtained from the clemson university genomics institute ( clemson , sc , usa ) . primer sets used for pcr - based screening of h. virescens ( table s5 ) , o. nubilalis ( table s6 ) , and p. xylostella ( table s7 ) were designed from genes and ests whose b. mori orthologs were mapped or localized on mapped bac contigs as noted above ( table s4 ) . the first screening was performed against dna pools derived from 48 ( h. virescens ) , 96 ( o. nubilalis ) , and 62 ( p. xylostella ) plates , using a mixture of 384 bac - dnas for each plate . when a large number of the plate pools generated positive signals , new primers were designed to improve the specificity for the targeted sequences . the second screening was carried out only in positive plates by amplifying pcr products , using as templates dna pools for 24 columns and 16 rows , each composed of mixtures of bac - dnas located in the same column or rows . finally , an overnight liquid culture of candidates identified by the preceding two steps was amplified individually to confirm the presence of target sequences . we constructed twelve cdna libraries from various tissues and stages and determined the sequences of 625 clones randomly selected from them ( table s1 ) . we also attempted to clone o. nubilalis orthologs of b. mori single - copy genes which we had previously mapped ( table s2 ) [ 2 , 12 , 23 ] . however , larger - scale est analyses of o. nubilalis were published later [ 16 , 17 ] , which provided a sufficient number of candidate genes . the strategy we used for the selection of genes used for bac isolation is summarized in figure 2 . dna sequences of known genes and ests of h. virescens , o. nubilalis , and p. xylostella were used to find orthologs in b. mori by tblastn / tblastx search against genome sequences in kaikobase . ests of h. virescens [ 14 , 15 ] and o. nubilalis were published after the first selection of candidate genes and yielded too many for a manual similarity search using kaikobase . instead , tblastx search against ests in the dna data bank of japan ( http://www.ddbj.nig.ac.jp/search/top-e.html ) was performed to find h. virescens or o. nubilalis orthologs when no candidates were found in the first search or ests were too short to design pcr primers . in the previous study , we found some incorrect mapping information in kaikobase and subsequently had to carry out experimental confirmation of the chromosomal location of b. mori orthologs to avoid being misled by false gene translocations . to minimize additional mapping efforts in b. mori , we gave priority to finding orthologs of b. mori genes which had been confirmed in the previous reports [ 2 , 12 , 23 ] . putting this limitation on genes for this type of study also leads to the isolation of orthologous bacs from different species , which facilitates comparison among multiple genomes . more than 800 candidates were identified , which showed significant similarity and seemed to be single - copy in the genome of b. mori . two hundred thirty - six of them had been mapped genetically onto a linkage map of b. mori or localized to the mapped bac contigs in our previous reports [ 2 , 12 , 23 ] ( table s4 ) . to improve the resolution for comparing genomes , we designed 246 additional pairs of new primers for b. mori orthologs to select and clone bac probes where the interval between markers was relatively long . in all , we identified 482 putative single - copy conserved genes in b. mori which were orthologous to known genes and ests of the three species ( table s4 ) . to isolate bac clones of h. virescens , o. nubilalis , and p. xylostella using pcr - based screening , we designed primer sets to avoid including putative exon - intron junctions predicted from the alignment of cdna sequences with genome sequences of b. mori . ultimately , 181 , 150 , and 101 primer pairs could be used to screen h. virescens , o. nubilalis , and p. xylostella bac libraries ( tables s57 ) and yielded 188 , 163 , and 108 bacs for 332 orthologous genes , respectively ( table s8 ) . we found 24 pairs and two sets of three genes for which orthologs closely spaced in b. mori were positive for identical clones in the three screened species ( table s8 ) . similar colocalization on bac clones was also observed between m. sexta and b. mori , suggesting microsynteny , that is , conserved fine scale gene order exists among these species , which was recently confirmed by sequence determination of bac clones [ 10 , 11 ] . figure 3 shows a venn diagram with the correspondence of genes isolated for each species . for 84 genes , clones were isolated from more than two species , which will be useful as universal markers in bac - fish analysis . in addition , these clones can be used as a resource for sequence comparison across multiple genomes including b. mori which might reveal conserved or specific regulatory elements . bac libraries are highly useful for identifying detailed genome organization across relatively long chromosomal distances and are now available for several species of lepidoptera [ 1 , 79 ] . however , few studies using lepidopteran bac libraries have been published , especially for species other than b. mori [ 812 ] . one reason for this lack is that the technique described here to isolate clones of interest from bac libraries is not commonly used . for sequenced model organisms like b. mori , bac clones can be easily anchored to ordered genome sequences by their bac - end sequences , which enables selection of candidate clones in silico . in contrast , bac - end sequencing of nonmodel organisms is not an efficient strategy since it is not suitable for recently developed non - sanger sequencing technologies , and it takes much cost and labor to ensure sufficient coverage to find sequences of interest . the use of pcr - based screening for rapid isolation of bac clones was a major factor that improved efficiency in this study . in situ hybridization using high - density replica ( hdr ) filters is the most commonly used method to screen bac libraries . however , hdr filters are usually designed with sufficient redundancy to avoid failures in screening and are too large for the isolation of a minimum number of clones used in studies like ours . pcr - based screening can be carried out using standard thermal cyclers without any special skills , and stepwise changes in the scale of screening using a pooling strategy reduce time and labor . in addition , pcr - based screening can be easily performed for gene sequences downloaded from public databases , whereas dna probes for in situ hybridization either have to be obtained from the original investigators or prepared independently . thus , we could carefully eliminate genes which were likely to be duplicated in the b. mori genome including putative pseudogenes from the candidates for bac isolation . on the other hand , preparation of dna pools for pcr - based screening is laborious , and high efficiency is not accomplished in a small - scale analysis . ideally , a catalogue linking bacs with located genes should be constructed and published , which will release inexperienced researchers of nonsequenced species from the technical labor of bac isolation and let them concentrate on functional analysis . the species used in this study , h. virescens , o. nubilalis , and p. xylostella , are not closely related to each other ( figure 1 ) , but share a haploid karyotype of n = 31 . this karyotype is considered the basal number in lepidoptera since a survey of more than 1,000 species revealed that more than half from many independent lineages carry this chromosome number . the four lepidopteran species for which their chromosome organization has been characterized in detail are either n = 28 ( b. mori , m. sexta , bicyclus anynana ) or n = 21 ( heliconius melpomene ) , indicating that several chromosomal fusions occurred in their lineages . we are now analyzing the chromosomal organization of the tobacco bollworm , helicoverpa armigera , a noctuid species closely related to h. virescens using bac probes from h. virescens in parallel with the analysis of o. nubilalis . the identification of the karyotypes of the three species used in this experiment will reveal the ancestral karyotype and chromosome rearrangements which have occurred in each of these representative lepidopteran lineages .

lepidoptera , butterflies and moths , is the second largest animal order and includes numerous agricultural pests . to facilitate comparative genomics in lepidoptera , we isolated bac clones containing conserved and putative single - copy genes from libraries of three pests , heliothis virescens , ostrinia nubilalis , and plutella xylostella , harboring the haploid chromosome number , n = 31 , which are not closely related with each other or with the silkworm , bombyx mori , ( n = 28 ) , the sequenced model lepidopteran . a total of 108184 clones representing 101182 conserved genes were isolated for each species . for 79 genes , clones were isolated from more than two species , which will be useful as common markers for analysis using fluorescence in situ hybridization ( fish ) , as well as for comparison of genome sequence among multiple species . the pcr - based clone isolation method presented here is applicable to species which lack a sequenced genome but have a significant collection of cdna or est sequences .

leishmaniasis is a vector - borne disease caused by obligate intramacrophage protozoan parasites of the genus leishmania [ 1 , 2 ] . the infecting leishmania species determines the clinical presentation of disease , of which there are three dominant clinical forms : cutaneous leishmaniasis ( cl ) , mucocutaneous leishmaniasis ( mcl ) , and visceral leishmaniasis [ 1 , 2 ] . in bolivia , the etiological agent of both , cl and mcl is leishmania ( viannia ) braziliensis , formerly known as the l. braziliensis complex . while cl is characterized by single or multiple ulcerated dermal lesions , mcl which develops as a complication of l. ( v. ) braziliensis cl in 5%20% of patients from parasite dissemination to the upper respiratory tract mucosa , involving the nasal , pharyngeal , and laryngeal mucosa , leads to extensive tissue destruction [ 5 , 6 ] . cl either heals spontaneously or promptly responds to antimonial therapy but mcl usually evolves chronically and is difficult to treat . then , amphotericin b ( amb ) is an alternative for patients who fail to respond to pentavalent antimonial therapy . it has been known that amb potentiates the antimicrobial and tumoricidal activities of macrophages , either directly or via induction of cytokines such as tumor necrosis factor- ( tnf- ) and interleukin-1 ( il-1 ) , as well as generation of a respiratory burst [ 10 , 11 ] . apart from these effects , little is known about the mechanisms associated with the efficacy of this compound in the treatment of mcl . therefore , it was of interest to determine the participation of other soluble factors , apart from tnf- , in amb - treated mucocutaneous leishmaniasis , keeping in mind that activation of the infected macrophages to kill intracellular parasites is carried out through a cell - mediated response that requires the classic features of antigen presentation and production of il-12 by macrophages and activation of th1 lymphocytes with production of interferon- ( ifn- ) to activate the macrophages . the present study was aimed at elucidating the participation of critical soluble factors associated with amb treatment that could alleviate , in future , the collateral effects of this arduous treatment by combining immunochemotherapy with lower doses of drug . in the present investigation , we present evidence for an exacerbated th1 immune response in mcl treated with amb , manifested by an elevated synthesis of ifn- which directly relates to a great increase in il-12 production . twenty four leishmaniasis patients were included in this study , 12 with cl and 12 with mcl , including male and female , average age 30 years old . all of them acquired the disease in the yungas valley of la paz department , an endemic area for l ( v. ) braziliensis infection . patients included in the study presented clinical features compatible with cl or mcl , were positive in both the montenegro skin test and the serology for l. ( v. ) braziliensis antibodies ( indirect immunofluorescence ) . at the moment of taking the blood samples , mcl patients were being treated with amphotericin b , at a dose of 1 mg / kg / day by infusion till a total dose of 1 to 3 grams , and had received mean doses of 7.5 ( 510 doses ) . the parasite lysate ( alb ) utilized for cytokine production was obtained from an l. ( v. ) braziliensis strain ( mhom / br/75/2903 ) . the promastigotes were resuspended in phosphate - buffered saline ( pbs ) ph 7.2 , at a concentration of 1 10 parasites per ml , and soluble antigens were prepared through seven cycles of freezing ( 70c ) and thawing ( 37c ) the parasite suspension . this material was assayed for protein content , aliquoted , and stored at 70c until used . pbmcs were purified by centrifugation ( 400 g , 20c , 45 minute ) over a mixture of ficoll hypaque at a density of 1.077 ( sigma , st . after washings with serum free medium , the cells were resuspended at the desired concentration in rpmi medium containing 10% heat - inactivated human ab serum ( sigma ) , 100 iu of penicillin per ml , and 100 g of streptomycin per ml ( complete medium ) . fresh pbmcs were cultured in duplicate in 24 well plates at a final concentration of 1.25 10 cells / ml in 2 ml complete medium for 3days ( 37c , 5% co2 ) , in the absence or presence of alb , at a final protein concentration of 15 g / ml . aliquots of cell - free supernatants from alb in vitro - stimulated pbmc cultures were assayed for tnf- , ifn- , and il-12 by means of solid phase sandwich enzyme linked immunosorbent assays ( elisas ) ( biosource europe , belgium ) . all samples were tested in duplicate and cytokine concentrations were determined by comparison to standard curves . the sensitivity of each assay was as follows : tnf- , 3 pg / ml ; ifn- , 0.03 iu / ml ; and il-12 , 1.5 pg / ml . statistical analysis was performed by the wilcoxon nonparametric test using the systat software , version 10.2 ( systat software inc . , the course of mcl has been associated with an unmodulated high production of the proinflammatory cytokines ifn- and tnf- . considering the high activity of amb in the treatment of mcl , we decided to compare specific cytokine production between pbmc from cl and mcl patients , through an in vitro cell culture approach with alb , that would recreate the status of patients ' immune response . cytokine production by pbmcs from cl and mcl patients the response of pbmc induced by alb stimulation was evaluated in terms of tnf- , ifn- , and il-12 production , at 3 days of culture . while a 72-hour culture period has proven sufficient to stimulate production of tnf- and ifn- in patients ' pbmcs stimulated with leishmanial antigens , il-12 production is specifically stimulated as early as 24 hours of pbmc culture from mcl patients . whatever the patient group , tnf- , ifn- , and il-12 were released at similar background levels . therefore , in this study , the levels of cytokine released in unstimulated pbmc cultures did not reflect an activated state from contact in vivo with parasite antigens . figure 1 reveals a nonsignificant slight increase in the production of tnf- in mcl ( 1104 732 pg / ml ) , comparing with cl ( 760 307 pg / ml ) patients ( p = .1 ) . the reduced liberation of tnf- in the supernatants of mcl patients is surprising considering that amb has been associated with its production but it also reflects the beneficial effect of this drug in mcl as it has been reported that refractory mucosal leishmaniasis can be successfully treated through a combination of pentavalent antimony plus pentoxifylline , an inhibitor of tnf- production . alternatively to the activation of macrophage microbicidal capacity through the induction of proinflammatory cytokines , amb can also exert its effect intracellularly . intracellular accumulation of the drug in monocytes augmented the capacity of the cells to kill ingested candida albicans . however , whether this mechanism of action is in fact operating in mcl treatment remains to be confirmed . contrary to the production of tnf- , samples from mcl patients had the capacity to significantly augment synthesis of ifn- with regard patients with cl ( 17.1 11.5 versus 4.2 3.2 iu / m ) [ p < .05 ] ( figure 2 ) . furthermore , the observation of background levels of il-4 despite stimulation with alb ( not shown ) evokes a th1-type immune response . additionally , and in direct correlation to the increased production of ifn- , there was a much higher concentration of il-12 when comparing mcl ( 175.7 164.8 pg / ml ) and cl ( 26.8 28.2 pg / ml ) patient cytokine responses ( p < .05 ) ( figure 3 ) . future studies in vitro with amb will seek to verify the cellular source of il-12 considering that , in human , peripheral blood monocyte / macrophages are the main producers of il-12 . a previous study reporting suppression of il-12 production by murine macrophages infected with l. mexicana amastigotes on interaction with th1 cells is of particular interest in the context of this study as it adds incentive to unveil through the present experimental system ( alb stimulation ) the intracellular signals , likely set in motion by amb treatment , to increase production of il-12 , one of the two cytokines most clearly needed for protection in leishmaniasis . in general , the present results are reminiscent of a previous investigation on the use of a recombinant leishmanial antigen from leishmania braziliensis . apart from the production of il-2 , this antigen elicited also the production of ifn- dependent on il-12 , from pbmcs of patients with mucosal and cutaneous leishmaniasis . by analogy to our observations , it could be postulated that amb treatment would favor , preferentially , processing of antigens inducing th1-type immune responses , whereby stimulation of antigen - presenting cells by ifn- leads to il-12 production , potentiating in this manner , a positive feedback loop . even though amb killing of leishmania parasites does not require a host immune response , we reason that similar targeting of the th1-cell mechanism might increase its efficacy and permit lower doses to be used with compatible activities . an important aspect to consider in the present study is that cytokines are being compared in two patients groups differing by two parameters , mcl versus cl and treated versus untreated patients . hence , there would be the possibility that the increase in ifn- and il-12 relates to the different clinical forms rather than to amb treatment . however , it is interesting to note that samples from three mcl patients , not under treatment and excluded from this study , had the capacity to produce lower levels of ifn- compared with treated patients , and this production was not associated with an increased release of il-12 . therefore , manipulation of the host 's immune response in favor of the th1-cell - associated mechanism may provide the opportunity to use amb - sparing regimens with lower doses of drug , fewer injections , and/or a shorter treatment duration , avoiding toxicity associated with the cumulative dose . future studies will seek to improve understanding on the mechanisms of action of amb at the cellular level , particularly those associated with increased il-12 production .

in an attempt to investigate the effects of treatment of human leishmaniasis , the cytokines produced by peripheral blood mononuclear cells ( pbmcs ) of patients with cutaneous leishmaniasis ( cl ) and mucocutaneous leishmaniasis ( mcl ) under treatment with amphotericin b were determined during the active disease from cocultures of cells and leishmania ( viannia ) braziliensis antigens . pbmc of these patients exhibited a nonsignificant marginal increased production of tnf- upon antigen stimulation . however , under the same antigenic stimulus , patients with active mcl presented higher ifn- production compared to patients with cl . this increased ifn- production was accompanied by a drastically augmented il-12 synthesis from cells of mcl patients . the highlighted t cell responses could be relevant for sound control measures of protozoan infections with emphasis on the combined usage of immunoenhancing agents and antiprotozoal drugs .

posterior inferior cerebellar artery ( pica ) aneurysms comprise 1% of all intracranial aneurysms , which are usually located at the vertebral artery ( va)-pica junction or just distal to it . the pica is well known for its varied anatomical origin and course , originating below the foramen magnum in 18% normal arteriograms . extracranially located pica aneurysms are rare ; only 21 cases have been reported till date . we report an unusual case of extracranially originating saccular pica aneurysm , presenting with hemorrhage into the fourth and lateral ventricles . the patient underwent microsurgical clipping of the aneurysm and showed good recovery . in this report , we highlight the diagnostic pitfalls that may befall clinicians managing such patients . a 16-year - old female presented with sudden onset severe headache followed by transient loss of consciousness but no neurological deficits . she developed vasospasm on post - ictus day 9 with paraparesis , which improved gradually . computed tomography ( ct ) , magnetic resonance imaging ( mri ) , and magnetic resonance angiography ( mra ) of the brain performed at a regional center revealed intraventicular hemorrhage ( ivh ) in the lateral and fourth ventricles but did not reveal any aneurysm or arteriovenous malformation [ figure 1 ] . the patient was referred to us after one month with severe headache and improving paraparesis . repeat ct showed non - communicating hydrocephalus , and a four - vessel digital subtraction angiography ( dsa ) showed extracranially originating right pica harbouring a 9.5 3.6 5.2 mm saccular aneurysm directed posteriorly with a neck measuring 2 mm at the level of c1 , which was missed on the initial brain mri ; as the aneurysm was extracranial [ figure 2 ] . in view of the raised intracranial pressure because of the hydrocephalus , the patient underwent a right ventriculo - peritoneal shunt followed by right far lateral sub - occipital craniectomy with c1-c2 right hemi - laminectomy for clipping the extracranially placed pica aneurysm . ( a and b ) plain axial ct showing presence of supratentorial ivh alongwith fourth ventricle ivh . ( c and d ) 3d - time of flight mr angiography images do not show any obvious vascular pathology . note the non inclusion of the origin of the right pica in the mra slab ( arrow ) which was noted retrospectively , subsequent to the dsa result ( a , b , c ) dsa shows the lobulated tubular aneurysm arising from the right pica origin directed posteriorly and inferiomedially . ( d ) volume rendered reconstruction of the 3d rotational angiography better depicts the aneurysm location and morphology picas usually arise from the va , approximately 14 - 17 mm proximal to the vertebrabasilar junction , but they may be absent ( 10 - 15% cases ) , situated below the foramen magnum ( 18 - 35% cases ) , and may not uncommonly have an extracranial extradural origin from the va . they arise either from the proximal part ( medullary ) of the extracranially originating pica or from the caudal loop ( the loop of the tonsillomedullary segment passing near the lower part of the tonsil ) when it dips below the foramen magnum . the etiology of extracranial aneurysms arising from the pica may involve the tortuous course of the pica and va , resulting in hemodynamic stress in the proximal segment ( where the pica branches from the va ) and at the top of the caudal loop . an additional factor that may play a role is the chronic flexion - extension or rotator stress at the craniovertebral junction , causing an interaction between the c1 lamina and the pica , which results in vessel wall damage . literature reflects a female preponderance ( 2.2:1 ) for extracranial pica aneurysms , with a high occurrence in younger patients . the clinical presentation of ruptured extracranial pica aneurysms is that of a typical subarachnoid hemorrhage ( sah ) with severe headache and nuchal rigidity . the radiological picture usually reveals ivh in the fourth ventricle alongwith sah in the posterior fossa . it is rare to have ivh in the lateral ventricles ; only one case has been reported till date . in our case , a brain mri with mra failed to detect the aneurysm because of its extracranial location [ figure 1 ] as the vertebral artery was not imaged below the foramen magnum . also , the blood in the lateral ventricles acted as a decoy and prevented further investigations at the regional center once the mra was negative . our patient had an extracranial pica aneurysm directed posteriorly and medially at the level of the first cervical vertebra , which must have ruptured into the cistern magna and the spurt was hence carried from the fourth ventricles into the supratentorial ventricular system . the initial ct performed on post - ictus day 6 shows blood only in the fourth ventricle and the occipital horns of the lateral ventricles where the clot would have settled after 5 days of rupture . thus , hemorrhage was not observed in the cistern magna because of csf circulation , which washed off the blood . extracranial pica aneurysms presenting with isolated ivh have been reported and this should be borne in mind while investigating such patients . as pointed out by dammers et al . , extracranial pica aneursyms should definitively be ruled out in case of ictus with ivh ( especially in the fourth ventricle ) with a four vessel angiography ( ct or dsa ) . such aneurysms have been missed even on three vessel angiograms , thus further reiterating our stand that a four vessel angiography is a must . if mr or ct angiography is used primarily to evaluate these patients , it is essential to image them upwards from the aortic arch to avoid missing an extracranial pica aneurysm . for proximal segment pica aneurysms , an inferiorly extended standard paramedian suboccipital approach with drilling of the superomedial part of the condyle has been suggested . we performed a far lateral suboccipital craniectomy along with hemilaminectomy at the c1 and c2 , levels to delineate the course of the extracranial va for proximal control for the aneurysm , if required . although , till date , only 22 cases ( including our case ) of extracranial pica aneurysms have been reported , it should be noted that in 25% of these cases ( including our case ) , clinicians missed such an extracranial aneurysm during the initial diagnosis , either because a four vessel dsa was not undertaken or the upper cervical region was not included when ct or mr angiography was performed . this emphasizes the need for clinicians to keep this rare possibility in mindto avoid any diagnostic pitfalllike the one encountered in our caseand ask for a dedicated four vessel angiography when dealing with patients presenting with an ictus and fourth intra - ventricular bleeding , even when supratentorial ivh exists .

extracranially located posterior inferior cerebellar artery ( pica ) aneurysms are rare with only 21 cases reported till date . they may arise either from the proximal segment of an extracranially originating pica or from the tip of its caudal loop when it dips below the foramen magnum . a 16-year - old female presenting with sudden onset severe headache and intraventricular hemorrhage ( ivh ) in the occipital horns of the lateral ventricle and the fourth ventricles , was diagnosed to have an extracranial proximal segment pica aneurysm on a four vessel digital subtraction angiography ( dsa ) , after initially missing it on the brain magnetic resonance imaging ( mri ) with angiogram ( mra ) because of its extracranial location . during surgery , the aneurysm was clipped following a far lateral suboccipital craniectomy with c1-c2 hemilaminectomy . the patient showed good recovery . thus , we emphasize the need for a dedicated four vessel angiography to diagnose such lesions .

autoimmune bullous skin diseases ( abds ) represent a heterogeneous group of disorders of the skin and mucosa ; these disorders are commonly associated with deposits of immunoglobulins , complement , and fibrinogen , usually directed against distinct adhesion molecules . the resultant loss of adhesion between the epidermis / mucosa and dermis results in blister formation and erosions . a large number of cellular events induced in target keratinocytes by abd autoantibodies have been described , and suggest that abd autoantibodies bind to their target antigens and trigger a complex cascade of intracellular signaling and regulatory events . several intracellular signaling pathways , such as p38mapk activation and rhoa inhibition , pemphigus igg activation - translocation of protein kinase c , and imbalances in both akt / mtor and cyclic adenosine 5- monophosphate signaling have been demonstrated to be altered following autoantibody binding and to be causally involved in loss of keratinocyte cohesion . in our study , we evaluated potential , additional intracellular signaling by studying the presence of the phosphorylated ribosomal protein s6-ps240 in multiple abds . specifically , we performed a pilot study to search for the presence of this phosphorylated enzyme in the in situ immune response of abds by performing immunohistochemistry ( ihc ) staining on lesional skin biopsies . we tested 30 biopsies from patients affected by endemic pemphigus foliaceus ( epf ) in el bagre , colombia , south america ( el bagre - epf ) and 15 skin biopsies from normal controls from the el bagre - epf endemic area ( ncea ) . we also utilized 30 control skin biopsies from healthy plastic surgery reduction patients in the usa , taken from the chest and/or abdomen normal human skin ( nhs ) . biopsies were fixed in 10% buffered formalin , then embedded in paraffin and cut at 4 micron thicknesses . the tissue was then submitted for hematoxylin and eosin ( h and e ) and immunohistochemical ( ihc ) staining . in addition , we tested biopsies from the archival files of two private , board certified dermatopathology laboratories in the usa ; these patients underwent primary diagnostic biopsies , and were not taking immunosuppressive therapeutic medications at the time of biopsy . we evaluated 20 biopsies from bullous pemphigoid ( bp ) patients , 20 from patients with pemphigus vulgaris ( pv ) , eight patient biopsies with pemphigus foliaceus ( pf ) , and 12 from patients with dermatitis herpetiformis ( dh ) . for all of the el bagre area patients and controls , we obtained written consent , as well as institutional review board ( irb ) permission from the local hospital . the archival biopsies were irb exempt due to the lack of patient identifiers . in both dermatopathology laboratories , each biopsy also was sent also for direct immunofluorescence ( dif ) for correlation with the h and e diagnoses . we performed our ihc studies to assist in differentiation between specific pathologic autoreactivity , and nonspecific intrinsic autofluorescence ( produced by the physiological presence of autofluorescent molecules ) . specifically , our antibody was conjugated with horseradish peroxidase ( hrp ) labeled secondary antibodies . for all our ihc testing , we used a dual endogenous peroxidase blockage , with the addition of an envision dual link to assist in chromogen attachment . the samples were run in a dako ( carpinteria , california , usa ) autostainer universal staining system . we utilized monoclonal mouse antihuman ribosomal protein antibody s6-ps240 ; phosphorilation site specific , clone dak - s6 - 240 , dako catalog no . the nonparametric mann - whitney u - test was used to calculate significant levels for all measurements . we tested 30 biopsies from patients affected by endemic pemphigus foliaceus ( epf ) in el bagre , colombia , south america ( el bagre - epf ) and 15 skin biopsies from normal controls from the el bagre - epf endemic area ( ncea ) . we also utilized 30 control skin biopsies from healthy plastic surgery reduction patients in the usa , taken from the chest and/or abdomen normal human skin ( nhs ) . biopsies were fixed in 10% buffered formalin , then embedded in paraffin and cut at 4 micron thicknesses . the tissue was then submitted for hematoxylin and eosin ( h and e ) and immunohistochemical ( ihc ) staining . in addition , we tested biopsies from the archival files of two private , board certified dermatopathology laboratories in the usa ; these patients underwent primary diagnostic biopsies , and were not taking immunosuppressive therapeutic medications at the time of biopsy . we evaluated 20 biopsies from bullous pemphigoid ( bp ) patients , 20 from patients with pemphigus vulgaris ( pv ) , eight patient biopsies with pemphigus foliaceus ( pf ) , and 12 from patients with dermatitis herpetiformis ( dh ) . for all of the el bagre area patients and controls , we obtained written consent , as well as institutional review board ( irb ) permission from the local hospital . the archival biopsies were irb exempt due to the lack of patient identifiers . in both dermatopathology laboratories , each biopsy also was sent also for direct immunofluorescence ( dif ) for correlation with the h and e diagnoses . we performed our ihc studies to assist in differentiation between specific pathologic autoreactivity , and nonspecific intrinsic autofluorescence ( produced by the physiological presence of autofluorescent molecules ) . specifically , our antibody was conjugated with horseradish peroxidase ( hrp ) labeled secondary antibodies . for all our ihc testing , we used a dual endogenous peroxidase blockage , with the addition of an envision dual link to assist in chromogen attachment . the samples were run in a dako ( carpinteria , california , usa ) autostainer universal staining system . we utilized monoclonal mouse antihuman ribosomal protein antibody s6-ps240 ; phosphorilation site specific , clone dak - s6 - 240 , dako catalog no . for statistical analysis , the nonparametric mann - whitney u - test was used to calculate significant levels for all measurements among patients with el bagre epf , 23/30 exhibited positive staining in spotty areas of the epidermal corneal layer , and around neurovascular supply structures of dermal eccrine glands and hair follicles . very active clinical cases were strongly positive at within the epidermal stratum granulosum ( including the middle layers of hair follicles ) , sebaceous glands , and especially in their base membranes . only two controls from the endemic area displayed positive staining , specifically with focal corneal reactivity ( p < 0.05 ) ; controls from the usa stained uniformly negative ( p < 0.05 ) . among bp patients , 17/20 stained positive for s6-ps240 in dermal eccrine glands , subjacent to disease blisters , along the bases of the blisters , and within dermal endothelial - mesenchymal cell junction - like structures ( p < 0.05 ) [ table 1 ] . in patients with pv , 15/20 stained positive within upper dermal inflammatory infiltrates , and both inside and around epidermal disease blisters ( p < 0.05 ) . in patient biopsies with pf , 5/8 stained positive within the epidermal stratum granulosum and in one very active clinical case was also positive at the middle layers of hair follicles ) , sebaceous glands and especially in their base membranes , and around dermal eccrine glands and hair follicles . among patients with dh , 8/12 exhibited positive staining , primarily subjacent to the base membrane zone where the majority of the inflammatory infiltrate was present ( p < 0.05 ) . figure 1 documents our most commonly observed patterns of s6-ps240 staining positivity in patients with abds . the majority of the normal skin controls and the controls from the endemic area of pemphigus were negative for s6-ps240 staining ( p < 0.05 ) . our percent expressions of s6-ps240 and respective patterns of positivity are summarized in table 1 . percentages and patterns of positive ihc staining in abds with s6-ps240 positive staining of s6-ps240 immunohistochemistry ( ihc ) in multiple autoimmune blistering diseases . ( a ) a representative case of pemphigus foliaceus ( pf ) , showing reactivity in a dermal eccrine sweat duct ( brown staining , black arrow ) and in the epidermal stratum granulosum and corneal layer ( brown staining ; red arrow ) . ( b ) a representative case of pv , demonstrating reactivity in the epidermis in proximity to a pathogenic blister , as well as on the blister roof ( brown staining ; black arrows ) and in a mesenchymal / endothelial cell junction - like structure in the dermis ( brown staining ; red arrow ) . ( c ) a bp case , displaying positivity in a subepidermal blister area ( brown staining ; red arrow ) and in a dermal mesenchymal / endothelial cell junction - like structure ( brown staining ; black arrow ) . ( d and e ) two different cases of el bagre - endemic pemphigus foliaceus ( epf ) , demonstrating reactivity in dermal piloerector muscles ( brown staining ; red arrows ) . ( f ) a dh case , highlighting positivity in a dermal endothelial - mesenchymal cell junction - like structure ( brown staining ; red arrow ) . ( g and h ) two cases of el bagre epf , demonstrating reactivity within a dermal eccrine gland coil and a hair follicle , respectively ( brown staining ; red arrows ) . ( i ) a case of bp , displaying positivity to a dermal mesenchymal - endothelial cell junction - like structure ( brown staining ; red arrow ) we found that s6-ps240 is strongly expressed in most abs especially in what seem to be anatomical areas where active cellular processes are happening ( either for immune response , cell signaling , and or for unknown reasons ) . this indicates the complex immune regulation and their cells signaling network . in the pathophysiology of these diseases , complex intracellular signaling networks monitor diverse environmental inputs to evoke appropriate and coordinated effectors responses . in general , defective signal transduction underlies the pathophysiology of many disorders , including autoimmune diseases . several pathways of intracellular signaling have been previously shown in abds , possibly triggered by the disease autoantibodies . the major components of intracellular signaling and complex metabolic interactions between the multiple networks including protein kinases and protein phosphatases , which catalyze the reversible phosphorylation of proteins . s6-ps240 specifically represents an intracellular enzyme directly involved in protein synthesis , cell growth , and phosphorylation . s6-ps240 has been demonstrated to be present in subcorneal pustular dermatosis , as well as in psoriasis where mtor and s6-ps240 represent downstream signaling components . in our study , we document the presence of s6-ps240 in areas where the autoimmune blistering processes occur , as well as in dermal inflammatory immune response areas . since we present a pilot study , we only can speculate that s6-ps240 may be involved in influencing protein synthesis and/or with the inflammatory / anti - inflammatory immune response in patients affected by abds . we have recently documented autoimmune responses , as well as protease and proteinase inhibitors in areas where the s6-ps240 was positive in the current study . these areas include disease blisters , the epidermal corneal layer , upper dermal inflammatory infiltrates ( especially around neurovascular supply packages ) , piloerector muscles , sweat glands , and ducts and endothelial - mesenchymal cell junction - like areas . further , the aim of the current study was not to evaluate the presence of ribosomal s6-ps240 among all inflammatory skin diseases , but exclusively in abds . s6-ps240 reacts with human ribosomal protein s6 to phosphorylate at serine residue 240 ( ps240 ) . the phosphorylation of ribosomal protein s6 correlates with an increase in translation of mrnas that encode for proteins involved in cell cycle progression and thus controlling mammalian cell growth and proliferation ; thus , we speculate that this molecule could be activated for protein synthesis needed to repair lesional skin in these disorders . we note that s6-ps240 is expressed in lesional skin of patients with abds , and also in areas where an active metabolism is happening ( for unknown reasons ) ; however , because this was a pilot study , we do not know if this activation is specific for each abd . we further suggest that s6-ps240 intracellular signaling per se could be activated in abds and other inflammatory skin conditions , or could be related to a different , unspecified inflammatory signal present in these disorders .

background : the in situ signaling transduction within skin biopsies from patients affected by autoimmune skin blistering diseases is not well-characterized.aim:in autoimmune skin blistering diseases , autoantibodies seem to trigger several intracellular signaling pathways and we investigated the presence of the phosphorylated form of ribosomal protein s6-ps240 within autoimmune skin blistering diseases biopsies.materials and methods : we utilized immunohistochemistry to evaluate the presence of s6-ps240 in lesional skin biopsies of patients affected by autoimmune skin blistering diseases including patients with an endemic and nonendemic pemphigus foliaceus ( non epf ) , with bullous pemphigoid ( bp ) , pemphigus vulgaris ( pv ) , dermatitis herpetiformis ( dh ) , and the respective controls.results:most autoimmune bullous skin diseases biopsies stained positive for s6-ps240 around lesional blisters , including adjacent areas of the epidermis ; and within upper dermal inflammatory infiltrates , and/or mesenchymal - endothelial cell junctions within the dermis.conclusions:we document that s6-ps240 is expressed in lesional areas of skin biopsies from patients with autoimmune skin blistering diseases , as well as on eccrine glands and piloerector muscles . thus , the role of this molecule in autoimmune skin blistering diseases warrants further study .

a 15-year - old iranian girl was admitted to tehran pediatrics medical center , tehran ( iran ) in june 2006 . on admission also , she had submandibular soft - tissue asymmetry , night sweats , and proptosis ( figure 1 ) and round shape painless patches on the arm and leg extensor surfaces ( figure 2 ) . a 15-year - old woman with proptosis a ) painless patches on extensor surface of the arm . b ) painless patches on extensor surface of the leg she had previous medical history of frequent pharyngitis , hearing loss since age 3 , a left - sided orbital dermoid cyst at age 4 , and herpes - zoster infection at age 11 . physical examination revealed two large bilateral submandibular lymph nodes with diameters of 32 cm and 11.5 cm that were persistent despite antibiotic therapy . laboratory examination revealed mild leukopenia[3,700/cu mm ( normal range = 5000 - 10000/cu mm ) ] , iron deficiency anemia [ hb = 10 g / dl ( normal , 12 - 14 g / dl ) , red blood cell = 3,800/cu mm ( normal , 3.9 - 6.1/cu mm ) ] , platelet count of 421,000/mm ( normal , 150,000 - 400,000/mm ) , erythrocyte sedimentation rate of 98 mm/1 hour ( normal , < 20 mm/1 hour ) , and a 4.3 g / dl gamma globulin rate ( normal , 0.7 - 1.2 g / dl ) . tuberculin test and serological tests for viral infections including hbs ag , hbs ab , hbc ab , hcv ab , hav ab ( igm ) , hev ab ( igm ) , and vca ( igm ) , and also the test for toxoplasmosis were all negative . we performed biopsy of the neck lymph nodes for the second time as the result of the first one performed two years before admission has been reported as reactive adenitis . histological examination demonstrated numerous histiocytes invading the lymph sinuses . on immunohistochemical examination , these were positive for s-100 protein and negative for cd1a , a marker of langerhans histiocytosis ( figure 3 ) . her skin biopsy showed a dense inflammatory infiltrate into dermis , mainly histiocytes , containing vesicular nuclei , lymphocytes , neutrophils , and plasma cells ; i.e. , panniculitis . a ) lymph node architecture is rather preserved but sheets of large histiocytes with pale cytoplasm fill the sinusoids . b ) closer view : large histiocytes with abundant pale cytoplasm are seen , some ingesting blood elements ( emperipolesis ) . with the classical features of massive lymphadenopathy and evidence of sinus histiocytosis and the patient was treated with prednisone ( 40 mg / d ) for a period of one month , and thereafter the dose decreased and azathioprine 1 mg / kg was added . after one year , prednisone discontinued and all of the symptoms and signs progressively resolved , although no change occurred in her proptosis . rdd predominantly affects children and young adults with relatively male sex predominance.2 although some other reports are available from iran including rdd cases with intracranial1415 and kidney involvement16 , the disease is less common in asian populations.2 its etiology still remains obscure , but two hypotheses have been proposed : a disturbance in inguinal , and mediastinal lymph nodes are also commonly affected . antecedent non - specific fevers and pharyngitis may herald the onset of rdd , occasionally accompanied by pain , tenderness , malaise , night sweats , or weight loss . extranodal disease is documented in 43% of cell mediated immunity17 , and a focus of infection due to viruses such as human herpes viruses ( hhv-6 and hhv-8).18 painless lymphadenopathy is the most frequent presenting symptom and involves the cervical region in up to 90% of the cases . axillary , para - aortic , the cases , in some of them , without associated lymphadenopathy which may or may not develop later in the disease course.2 hepatosplenomegaly which was present in our case is relatively an uncommon finding in rdd as very few cases with splenomegaly and or hepatomegaly have been reported.1920 widespread concurrent nodal and extranodal involvements have also been reported by other authors . reported a case of rdd presented with inguinal lymphadenopathy in which lung , renal and bone were also extensively involved.21 in such patients , numerous extranodal involvements pose a diagnostic challenge , as was the problem in our case . involvement of the neck area , skin , soft tissue , liver , spleen , orbit , and bone elicited a wide differential diagnosis . rdd in lymph nodes may clinically mimic hodgkin and non - hodgkin lymphoma , infectious processes , granulomatous lymphadenitis , reactive lymphadenopathy or other histiocytoses including langerhans cell histiocytosis ( lch ) and metastatic carcinoma . histiocytic disorders , particularly langerhans cell histiocytosis must be distinguished from rdd affecting skin , soft tissue , and bone . another external manifestation is orbital soft - tissue mass with proptosis , which can present without any sign suggestive of lymphadenopathy.22 skin lesions of rdd may be solitary or multiple , macular or papulonodular , xanthomatous or erythematous , dermal or subcutaneous , and found in virtually any location including the face , ears , trunk , extremities , or genitalia.5 histological findings of skin lesion biopsy specimens are similar to those found in lymph nodes . however , the lesions of rdd can be localized in the soft tissue mimicking a subcutaneous mass or panniculitis cutaneous . also , it has been clinically mistaken for other dermatologic disorders including vasculitis , acne vulgaris , lupus vulgaris , sarcoidosis , hidradenitis suppurativa , granuloma annulare , malignant breast neoplasm , and other histiocytosis.23 the histological differential diagnosis includes lch , storage disorders such as gaucher disease , classical hodgkin lymphoma , metastatic melanoma and carcinoma , histiocytic sarcoma , and infections caused by histoplasma and mycobacterial organisms involving the lymph node . in the nasal cavity , perhaps the most frequently faced histological challenge is that of distinguishing shml from reactive sinus histiocytic proliferations which occur as nonspecific responses to a variety of instigating agents . although erythrophagocytosis is seen in reactive and neoplastic histiocytic proliferations including lch , emperipolesis in a setting outside of shml is extremely rare . the appearance of lymph node sinuses expanded by a histiocytic proliferation is a feature common to lch and shml2 , but in our case lch was unlikely because langerhans histiocytes with their familiar folded nuclei and eosinophil infiltrates were absent , as was immunoreactivity for cd1a , a reliable marker of lch.23 since rdd recognition , the constellation of clinical findings has formed an ever - expanding almanac as more and more cases of rdd are diagnosed so it should be included in the differential diagnoses for patients , whoever admitted to our medical center with any of the mentioned extranodal involvements . given the wide range of clinical presentations and the broad pathologic differential diagnosis , the clinical hallmark of massive lymphadenopathy is often crucial for diagnosis of rdd , however , several pitfalls may complicate pathologic diagnosis . mns and hossein saneian participated in diagnosis and treatment of the patient and fm participated in pathological study of the patient . all authors participated in writing the draft and editing the final version of the report .

rosai - dorfman disease ( rdd ) is a rare lymphoproliferative disorder with nodal and extranodal involvements . here we report a case of rdd in a 15-year - old female who presented with epigastric pain , fatigue , raynaud phenomenon in fingers , submandibular lymphadenopathy , proptosis , hepatosplenomegaly , and round shape painless patches on the extensor surfaces . histological examination of the submandibular lymph nodes and skin biopsy demonstrated evidences of rdd . patient was treated with prednisone and thereafter , with azathioprine . after one year , prednisone was discontinued and all of the symptoms and signs , except proptosis , were resolved . this report highlights the extranodal manifestations of rdd . the presentation , differential diagnosis , and treatment are discussed .

massage is a time - honored method by which women have received comfort throughout the millennia , yet it has not been rigorously evaluated in the modern day delivery suite . advocated by hippocrates and practiced by the romans , massage was reinvented in modern times in the late 1700s in sweden . swedish massage , now one of the most commonly taught techniques , consists of five basic strokes based on kneading , rolling , vibration , percussive , and tapping movement , with the application of oil to reduce friction on the skin . massage therapy has been theorized to create a stimulus that interferes with the transmission of pain to the brain , effectively closing the gate to the reception of pain . it has also been suggested that massage stimulates the release of endorphins and increases serotonin levels to inhibit the transmission of noxious nerve signals to the brain . a taiwanese trial randomized 60 nulliparous women to receive a 30-minute massage , first administered by the primary researcher , then by the woman s partner during each phase of labor . a nurse - rated pain intensity scale consisting of five observed levels of pain ( normal respiration , increased frequency or amplitude of respiration , intermittent gasping , persistent gasping , and agitation ) was significantly lower in the massage group compared to the control group in all phases of labor . a randomized controlled trial from turkey of 49 nulliparous and multiparous women reported that prenatal education followed by nurse - administered massage during labor reduced womens perception of pain . a pilot controlled trial from the uk randomized 35 nulliparous and multiparous women to three arms : massage administered by a partner , a placebo consisting of music with relaxation techniques , and a usual care group . the trial demonstrated a nonstatistically significant reduction in pain perception among women receiving massage therapy . in the us , 28 nulliparous women randomized to receive massage administered by a partner vs. coaching without massage reported lower levels of stress and pain during labor . in iran , a randomized controlled trial among 60 laboring nulliparous women reported a decrease in pain severity during the first stage of labor among women receiving massage therapy by a midwife compared to usual care . no study to our knowledge has evaluated the effect of massage therapy by a regulated massage therapist on labor pain and outcomes . in british columbia , registered massage therapists have completed a two - year training program and are regulated by the college of massage therapists . their services are remunerated by third - party insurance companies for individuals who ( or whose employers ) have purchased extended medical health care benefits and have a referral from a physician . we undertook a randomized controlled pilot trial to evaluate the potential effectiveness of massage therapy provided by registered massage therapists in managing labor pain . the study took place at bc women s hospital in vancouver , british columbia , canada . it provides primary care to women who are residents of the city of vancouver , regional referral care to residents of the lower mainland , and tertiary referral care for the entire province . our eligibility criteria included : nulliparity , singleton gestation , cephalic presentation , term gestation ( 3741 completed weeks of pregnancy ) , maternal age between 18 and 35 years , spontaneous labor ( defined for our purposes as painful contractions which have resulted in cervical change ( cervix is 1 cm dilated or more with effacement ( thinning ) at 25% [ 0.5 cm ] or more on admission to the labor unit ) , and ability to speak and read english . we excluded women with pre - existing medical conditions including : insulin dependent diabetes , renal , cardiac , or thyroid disease , hypertension , epilepsy , psychosis , use of illicit street drugs , or any other conditions arising during pregnancy which required nonroutine surveillance and/or intervention including gestational diabetes , gestational hypertension , 2nd or 3rd trimester hemorrhage , intrauterine growth restriction , presence of a fetal anomaly , or history of preterm prelabor rupture of membranes . a statement by women on admission that they had been in labor for more than 24 hours or those who presented with cervical dilation of 10 cm ( full dilation ) on admission were also exclusion factors . to ensure that women had the opportunity to learn about the study prior to labor , information pamphlets were available in hospital prenatal education classes and at the desk where women obtained hospital pre - registration packages . on admission to the triage area of the delivery suite , nurses informed eligible women about the study then asked if they would like to speak to the massage therapist to learn more about the study . the massage therapist opened a sequentially numbered envelope labeled with the treatment allocation : either massage during labor or massage during the first 24 hours postpartum . allocation was assigned to sequential numbers using a random seed generated by pasw , version 18 . the massage technique used was swedish massage , but the exact location and nature of the massage was negotiated between the woman and the therapist . women in either group continued to use other non - invasive pain management modalities as they wished ( for example : walking , showering , listening to music , visualization exercises , and use of a birthing ball ) . women s labor support persons were not restricted in any way from offering comfort and support . this was a pragmatic trial in that massage therapy was intended as one choice for pain management in addition to routinely available choices . the protocol provided massage therapy for up to five hours per participant , but women were permitted to choose to have the massage intermittently during this time or to receive it for only part of the time . this outcome was chosen because of the association of epidural use with intrapartum interventions , including need for augmentation of labor , prolonged first and second stage , need for assisted delivery , persistent occiput posterior position , postpartum hemorrhage , and delayed breastfeeding . the role of epidural analgesia with respect to caesarean section remains controversial , in large part due to the inability thus far to offer an alternative analgesic in randomized controlled trials that is sufficiently effective to prevent crossover to the epidural arm . crossover rates among studies reported in meta - analyses have ranged from 14% to as high as 51%62.1% in the opioid group . recent studies claiming that timing of epidural does not impact rates of caesarean section have reported on protocols that are not representative of north american practice , in that epidural analgesia was implemented on average at 1.6 cm of cervical dilation . as well , as many as 80% of participants in the delayed group also received a narcotic which , in itself , may slow labor and increase the rate of caesarean section . in addition to timing of epidural administration in labor , we compared the following factors among the healthy , nulliparous women admitted to hospital in spontaneous labor who were offered massage therapy vs. usual care : the severity of pain from contractions ; length of first and second stage of labor ; need for use of entonox , intravenous or intramuscular narcotics , and epidural analgesia ; cervical dilation at the time of epidural insertion among those women who receive epidural analgesia ; and mode of delivery : spontaneous vaginal , assisted ( vacuum / forceps ) , or caesarean section . intensity of pain was also measured by the short form mcgill pain questionnaire which utilizes 16 descriptors : throbbing , shooting , stabbing , sharp , cramping , gnawing , burning , aching , heavy , tender , splitting , sore , exhausting , sickening , fearful , punishing . the pain descriptors were read aloud and participants were asked whether or not the word described their pain and , if it did , to rank it on an intensity scale of 0 = none , 1 = mild , 2 = moderate , and 3 = severe . summary measures were calculated by simply summing the numerical values assigned to all of the selected words for each participant . the mcgill pain questionnaire has been used in a number of studies to measure the pain of labor . the sensory and affective measure of pain as measured by the mcgill form have been shown to have good internal validity ( cronbach s alpha = 0.83 ) and adequate convergent validity ( r = 0.48 , p < .001 ) with the ppi and ( r = 0.47 , p < .001 ) with a visual analogue scale . we undertook these measures on admission and at three time periods during labor : cervical dilation at 34 cm , 56 cm , and 78 cm . baseline measures not balanced by randomization were tested for their role as confounders in an analysis of covariance . among 131 women who were offered participation in the study , 77 ( 58.7% ) agreed to participate . our study protocol was approved by the university of british columbia clinical ethics research board and the bc women s hospital research review committee . among participants , 37 were randomly allocated to receive massage during labor and 40 were allocated to receive massage postpartum ( figure 1 ) . women in the massage group were younger , less likely to have a university education , or be employed ( table 1 ) . those in the standard care group in labor were more likely to speak english at home . with respect to pregnancy - related characteristics on admission to the study , women in the massage group were more likely to have had a doula in labor and less likely to have attended prenatal classes . none of the doulas - attending study participants were qualified as massage therapists ( table 2 ) . they arrived at an earlier stage of labor , as evidenced by fewer centimeters of cervical dilation and higher station of the vertex ( presenting part ) . sociodemographic characteristics of participants pregnancy characteristics of participants women in the massage therapy group , although they were admitted on average at a less advanced stage of labor , received epidural analgesia at higher cervical dilation compared to the standard care group ( 5.7 vs. 5.3 cm ) ( table 3 ) . the estimated marginal mean for cervical dilation at the time of epidural insertion after adjustment for station of the presenting part , cervical dilation , and status of membranes ( ruptured or not ) on admission , was 5.9 cm ( 95% ci 5.26.7 ) compared to 4.9 in the control group ( 95% ci 4.25.8 ) . obstetrical interventions and labour outcomes there were no statistically significant differences in length of labor , type of analgesia used , or mode of delivery . total scores on the short form mcgill pain questionnaire were consistently lower in the massage group at all stages of labor , but these differences were not statistically significant ( 13.3 vs. 16.9 at 3 4 cm , 13.3 vs. 15.8 at 56 cm , 19.4 vs. 28.3 at 78 cm ) . we report a delay in epidural insertion of one centimeter associated with massage therapy by a registered massage therapist , and a reduction in pain perception of up to 20 points on the mcgill pain questionnaire ( short form ) out of a total possible difference of 64 . these results in our study were not statistically significant . however , 1 cm dilation can take up to 2 hours to achieve in a nulliparous woman . delayed epidural may be associated with a reduction in assisted vaginal delivery and a decreased length of first stage and second . prior studies of massage therapy in labor have been extremely small , with the largest having 60 participants . the massage administered in these studies was intermittent for 2030 minute sessions or the duration was unspecified . our study has similarly demonstrated a reduction of pain using a complex measure of pain assessment , and is the first to report a trend towards delay in epidural use associated with massage therapy . our pilot study demonstrated that massage therapy is well accepted by women as evidenced by willingness of women to enroll in the trial ( approximately 60% of eligible women ) . in no case was the massage therapist asked to discontinue treatment by either the woman or her support person(s ) or the nursing or medical staff . we also demonstrated a delay in use of epidural that , if confirmed in larger studies , may impact labor outcomes . our inability to demonstrate statistically significant results may have been a consequence of our need to limit the time period for massage to five hours due to fatigue on the part of the therapists . future larger studies should be resourced to evaluate the ability of massage therapy to manage pain and minimize or delay use of epidural analgesia using shifts of therapists , as needed , to maintain the intervention as long as it is desired by the recipient .

introductionmassage is a time - honored method by which women have received comfort throughout the millennia , yet it has not been rigorously evaluated in the modern day delivery suite . no study to date that we are aware of has evaluated the effect of massage therapy by a regulated massage therapist on labor pain.the purpose of this study was to evaluate the effectiveness of massage therapy provided by registered massage therapists in managing pain among women in active labor.methodsbc women s hospital , vancouver , bc . research design : a randomized controlled trial . participants : 77 healthy nulliparous women presenting in spontaneous labor . intervention : swedish massage administered for up to five hours by a registered massage therapist during labor vs. standard care . main outcome measures include : cervical dilation at the time of administration of epidural , compared using estimated marginal means in an analysis of covariance . we also compared perception of pain at three time periods during labor according to cervical dilation at 34 cm , 57 cm , and 810 cm using the mcgill present pain intensity scale.resultsthe mean cervical dilation at the time of epidural insertion after adjustment for station of the presenting part , cervical dilation , and status of membranes on admission to hospital was 5.9 cm ( 95% ci 5.26.7 ) compared to 4.9 in the control group ( 95% ci 4.25.8 ) . scores on the mcgill pain scale were consistently lower in the massage therapy group ( 13.3 vs. 16.9 at 34 cm , 13.3 vs. 15.8 at 56 cm , and 19.4 vs. 28.3 at 78 cm ) , although these differences were not statistically significant.conclusionsour findings from this pilot study suggest that massage therapy by a registered massage therapist has the potential to be an effective means of pain management that may be associated with delayed use of epidural analgesia . it may therefore have the potential to reduce exposure to epidural analgesia during labor and decrease rates of associated sequelae .

the necessity for education of life skills is well revealed when we know these abilities can help individuals to manage conflicts and difficult life situations . generally , many of socio - psychological problems such as depression , alcoholism , delinquencies , interpersonal problems , loneliness , schizophrenia , etc . , are associated with the weaknesses in life skills and making social communications . although an increase in number of the students referring to counseling centers reflects their socio - cultural growth as asking help from others is believed to be a sign of mental maturation , it can also show the sophisticated problems they face , leading them to educational decline . the importance of the above issues led the researchers to investigate the efficacy of life skills training on general health in students to reduce their physical and psychological problems and to promote their general health through education of life skills in a new environment ( university ) . this is a quasi - experimental , one - group , pre - test , post - test study with no control group . inclusion criteria were studying in semester one in 2011 - 2012 , having a bachelor s degree , taking no tranquilizers , and not having attended any life skills education prior to research . the data were collected through a two - section questionnaire including personal characteristics and questionnaire of general health ( ghq ) which contained 28 questions on general health with four sub - scales of physical symptoms , anxiety , disorder in social function , and depression . general score of individuals health was calculated by summing up the scores of these sub - scales . chavoshi obtained validity of 88% for this test , and sadeghi movahed reported its reliability as 89% through cronbach s alpha . the questionnaire was initially filled by the students , and then educational program was held within 2 months in the form of eight 90-min sessions in islamic azad university , maragheh branch , iran , in sept - oct 2011 . the education was held through lectures and questions and answers sessions by a video projector . the life skills , taught in educational sessions , included 1 ) emotion management , 2 ) problem solving skill , 3 ) decisiveness , 4 ) self - awareness skill , 5 ) resiliency , 6 ) anger management , 7 ) skill of critical thinking , 8) skill of decision making , 9 ) skill of effective communication , and 10 ) skill of stress management . finally , 3 weeks after education , the subjects were assessed by the initial questionnaire . the findings showed that mean and sd of general health scores were 40.32 ( 10.59 ) and 18.15 ( 6.50 ) before and after education , respectively . paired t - test showed that score of general health decreased by 22 scores after education compared to before education , with a significant difference ( p < 0.001 , t = 11.2 ) . mean scores and sd of physical symptoms were 9.97 ( 4.24 ) and 5.3 ( 2.04 ) before and after education of life skills , respectively . paired t - test showed that the score of physical symptoms decreased by 4.9 scores after education compared to before education ( p < 0.01 , t = 6.7 ) . mean scores and sd of anxiety were 10.4 ( 3.28 ) and 4.2 ( 2.62 ) before and after education of life skills , respectively . paired t - test showed that score of anxiety decreased by 6.17 scores compared to before education and had a significant association ( p < 0.01 , t = 8.94 ) . mean scores and sd of social function were 9.52 ( 3.69 ) and 5.5 ( 1.81 ) before and after education of life skills , respectively . paired t - test showed that score of social function decreased by four scores after education compared to before education and had a positive significant association ( p < 0.01 , t = 6.35 ) . mean scores and sd of depression were 10.4 ( 5.24 ) and 3 ( 3.63 ) before and after education of life skills , respectively . paired t - test showed that score of depression decreased by 7.3 scores after education compared to before education ( p < 0.01 , t = 6.6 ) the results through paired t - test showed a significant difference in general health before and after education , which is consistent with the report of haghighi et al . with regard to sub - scale of physical symptoms , the findings of the present study agree with those of mousavi . with regard to sub - scale of anxiety , the results are consistent with those of haj amini et al . in relation with sub - scale of social function , the obtained findings agree with those of forneris and turner who showed that education of life skills promotes individuals ability to solve the problem and to make the best of social supports . with regard to sub - scale of depression , paired t - test showed that there is a significant difference in depression before and after education , which is in agreement with the study findings of amiri barmkouhi , butvin kantor , and popenhagen and qualley . nurses special hospital situations such as patients sigh and their critical condition and death , nurses insomnia , lack of assurance , and disturbances in their interpersonal communications in all levels enhance nurses and midwives stress , and worsen the vicious cycle of anxiety , which leads to their physical problems ultimately influencing the output of health system and the manner and quality of their care . with regard to the results of this study , level of communication skills , self - awareness , and stress management among nurses and midwives can be promoted through education of life skills to prevent the problems and/or lower the level of problems . based on the findings of the present study , it is suggested to consider life skill education along with other educational programs in the curriculum in order to promote the level of individuals general health , lower the incidence of depression , anxiety , physical problems , and to amend low social function to prevent physical and mental disorders . with regard to growing sophistication and changes in the society as well as development of social communication , preparation of individuals , especially the youngsters , to manage difficult situations

background : with regard to the importance of life skills , the present study deals with the effect of life skills training on general health of the students.materials and methods : this was a one - group , pre - test , post - test , quasi - experimental research . forty students were selected through purposive sampling method . the data collection tool was goldberg general health questionnaireresults : paired t - test showed a 22 score significant decrease in general health after education compared to before education ( p < 0.01).conclusion : this study showed that life skills education increases general health level of the students .

( eleusine coracana ) , foxtail millet ( setaria italica ) , prosomillet ( panicum miliaceum ) and khodomillet ( paspalum scrobiculatum ) were analyzed in the present study . each sample ( 50 g of seeds ) was homogenized in 100 ml of methanol using a waring blender at high speed for 1 min at 4c . the extract was stirred for 10 min at 4c and filtered through four layer of cheesecloth and the residue was re - extracted under the same condition with 100 ml of methanol . the combined filtrate was concentrated under vacuum at 65c to dryness and the dry residue was dissolved in 10 ml of methanol . these methanolic extracts were used for the determination of total phenolics , reducing capacity ( rp ) . for the estimation of water soluble proteins and reducing sugars , water extracts of the sample was used . all the methanolic extracts were tested for the presence of phenols , flavonoids , alkaloids and saponins by following standard methods . total phenolics of each extract were quantified colorimetrically using folin - ciocalteu reagent and chlorogenic acid as standard . five milliliters of folin - ciocalteu ( diluted ten - fold in distilled water ) , 2 ml of sodium bicarbonate ( 200 g.l ) and 2 ml of distilled water were added to 1 ml of extract . after 15 min incubation at room temperature , the absorbance was read at 730 nm using an uvmini-1240 recording spectrophotometer ( shimadzu , kyoto , japan ) . two milliliters of extracts were added to potassium ferricyanide ( 2.5 ml , 10 g.l ) and the mixture incubated at 50c for 20 min . trichloroacetic acid ( 2.5 ml , 100 g.l ) was added to the mixture , which was then centrifuged at 650g for 10 min . the supernatant ( 2.5 ml ) was mixed with distilled water ( 2.5 ml ) and ferric chloride ( 0.5 ml , 1 g.l ) . the water - soluble protein content of each sample was determined as per lowry 's method . each sample ( 50 g of seeds ) was homogenized in 100 ml of methanol using a waring blender at high speed for 1 min at 4c . the extract was stirred for 10 min at 4c and filtered through four layer of cheesecloth and the residue was re - extracted under the same condition with 100 ml of methanol . the combined filtrate was concentrated under vacuum at 65c to dryness and the dry residue was dissolved in 10 ml of methanol . these methanolic extracts were used for the determination of total phenolics , reducing capacity ( rp ) . for the estimation of water soluble proteins and reducing sugars , water extracts of the sample was used . all the methanolic extracts were tested for the presence of phenols , flavonoids , alkaloids and saponins by following standard methods . total phenolics of each extract were quantified colorimetrically using folin - ciocalteu reagent and chlorogenic acid as standard . five milliliters of folin - ciocalteu ( diluted ten - fold in distilled water ) , 2 ml of sodium bicarbonate ( 200 g.l ) and 2 ml of distilled water were added to 1 ml of extract . after 15 min incubation at room temperature , the absorbance was read at 730 nm using an uvmini-1240 recording spectrophotometer ( shimadzu , kyoto , japan ) . two milliliters of extracts were added to potassium ferricyanide ( 2.5 ml , 10 g.l ) and the mixture incubated at 50c for 20 min . trichloroacetic acid ( 2.5 ml , 100 g.l ) was added to the mixture , which was then centrifuged at 650g for 10 min . the supernatant ( 2.5 ml ) was mixed with distilled water ( 2.5 ml ) and ferric chloride ( 0.5 ml , 1 g.l ) . the water - soluble protein content of each sample was determined as per lowry 's method . the qualitative analysis for different bioactive phytochemical compounds reveals that , all the small millets tested were found to contain phenol , tannins , alkaloids , flavonoids and saponins [ table 1 ] . alkaloids affect a lot of metabolic activities in the body and most of them possess dramatic physiological activities hence they are widely used in medicine . flavonoids have been reported to possess certain biological properties such as antibacterial , antitoxic and anti - inflammatory activities and often function as strong antioxidants , free radical scavengers and metal chelators . in addition , the possible anti tumor action of certain flavonoids has also generated interest .saponins have been reported to possess anti - carcinogenic properties , immune modulation activities and regulation of cell proliferation as well as health benefits such as inhibition of the growth of cancer cells and cholesterol lowering activity . in the light of these observations the presence of phenols , tannins , alkaloids , flavonoids and saponins in the millets samples indicates that they have medicinal properties . qualitative test results for the presence of some important chemicals in selected small millet seeds the khodomillet showed maximum phenolic content ( 10.3% ) followed by finger millet ( 7.2% ) . the foxtail millet showed minimum phenolics ( 2.5%).as for as rp is concerned finger millet was having the highest ( 5.7% ) followed by foxtail millet ( 4.8% ) . davies reported that the oxidative damage is very important effect of cellular - free radicals which can leads to damage of cellular constituents . the antioxidant can donate either an electron or hydrogen to cellular molecules oxidized by free radicals .they can thus prevent damage of cellular constituents , including dna , proteins and lipids membranes from free radicals . in the light of above observation an important point rp found in all the millets can help in reducing the oxidative damage caused by free radicals . total phenolics and reducing capacity found in selected small millet seeds among four millets tested , the finger millet showed maximum reducing sugar content ( 391.3 mg / g ) and the khodomillet showed minimum reducing sugar ( 130.43 mg / g).overall , the reducing sugar content of these small millets ranges between 130.43 and 391.30 mg / g [ table 3 ] . the water - soluble protein content was maximum in foxtail millet ( 305.76 mg / g ) and minimum in prosomillet ( 144.23 mg / g ) . reducing sugar and soluble proteins in selected small millet seeds table 4 represents the crude fiber content of the four small millets tested . from this table it is very clear that all the selected millet grains tested found to contain crude fiber content ranging from 13.3 to 14.3% . this information supports that the selected small millets are healthy sources of carbohydrates for persons with insulin sensitivity or diabetes . the high - crude fiber in the millets may enhance their digestibility and also aid the peristaltic movement of the intestinal tract . millets occupy an important place in the world food and economy .they can adapt themselves to marginal soils and varied environmental conditions . millets are staple diet for nearly 1/3 of the world 's population . by considering these points all the four millets tested contain large quantities of phenolics and other compounds which prevent deterioration of human health .

objective : the aim of this study was to evaluate the nutraceutical properties and nutritional value of grains of four selected small millets viz . finger millet , foxtail millet , prosomillet and khodomillet.materials and methods : the qualitative analysis of phytochemicals viz . phenolics , flavonoids , alkaloids and saponins present in the four small millets was done . the water - soluble proteins , crude fiber content and the reducing power of the grains of these four millets were analyzed.results and conclusions : the khodomillet showed maximum phenolic content ( 10.3% ) and foxtail millet showed minimum phenolics ( 2.5% ) . as far as reducing capacity was concerned , finger millet was highest ( 5.7% ) . the prosomillet showed least reducing property ( 2.6% ) . the finger millet ( 391.3 mg / g each ) showed maximum reducing sugar content . the prosomillet showed minimum reducing sugar ( 195 mg / g ) . the foxtail millet showed maximum protein content ( 305.76 mg / g ) and prosomillet showed minimum protein content ( 144.23 mg / g ) . the khodomillet showed maximum crude fiber content ( 14.3%).the finger millet showed maximum reducing sugar content ( 391.3 mg / g ) whereas , the khodomillet showed minimum reducing sugar ( 130.43 mg / g ) .

a loss of bone results in fragility and increased risk of fracture . in oa , there is a proliferation of poorly mineralised bone . in parallel with these changes in the bone , patients with op generally have a below average body mass index whereas in primary generalised oa there is a recognised link with obesity and a suggested systemic aetiology independent of weight - bearing . defective co - regulation and lipid metabolism suggests possible mechanisms for the bone pathologies observed in these diseases . osteoblasts can be stimulated in vitro towards an adipocytic phenotype by increasing various fatty acids in the culture environment . in op there are fewer osteogenic cells and a greater number of adipocytes in the marrow . structurally , op bone has few and narrow trabeculae with large spaces between them . in oa the greater porosity in op combined with a change in tissue types suggests that one might expect to find a higher fat content in op cancellous bone . however , anecdotal evidence suggests an increased amount of fat in oa bone : in the laboratory fat globules are often found floating in the cell culture medium , and during surgery fat is commonly expressed from the bone during resection of the tissue . to try to resolve this we have measured the fat content of the bone from the femoral heads of patients with either op or oa . tissue was obtained from 5 femoral heads from patients undergoing total hip replacement for oa and 5 having a hemiarthroplasty for osteoporotic fracture of the femoral neck . a 9 mm diameter core of bone containing marrow was removed from the superior aspect of each femoral head as described previously . cores were broken up into fragments , frozen in liquid nitrogen and ground in a freezer mill ( model 6750 , glen creston ltd , middlesex , england ) . lipids were extracted from a known mass of tissue using chloroform - methanol extraction and weighed . the fatty acid composition of the extracted lipid was determined . first , the fatty acids were converted to their methyl esters ( fame ) by transmethylation using 0.5 m sodium methoxide as described by christie with one modification ; the sample lipid was dissolved in toluene instead of tetrahydrofuran . samples and standards were analyzed by running for 40 minutes on a varian 3800 gas chromatograph fitted with a j & w scientific column , db-225 . the mass of lipid per unit mass of tissue , was found to be 0.24 0.04 g / g ( mean sd , n = 5 ) in the oa group and 0.21 0.05 g / g in the op group . bone mass was taken to be tissue mass minus lipid mass , and lipid / bone became 0.31 0.07 g / g ( oa ) and 0.27 0.07 g / g ( op ) . however , the proliferation of bone in oa and the loss in op means that the apparent density of oa bone is considerably greater ( 0.71 g cm ) than op bone ( 0.38 g cm ) so the fractional volume available for the fat is considerably smaller ; porosity 59% in oa , 80% in op . assuming that the bone defines the total tissue volume , this volume was found by dividing the mass of the bone by the apparent density . the amount of lipid per unit volume of tissue then became 0.22 0.05 g cmin oa and 0.10 0.02 g cmin op ( p = 0.002 , t - test ) . there were a number of differences in the fatty acid composition of the extracted lipids between oa and op . those that were significant ( student 's t - test ) are shown in table 1 . the saturated stearic acid ( c18:0 ) was lower in oa than op bone , but the omega-6 ( n-6 ) fatty acids were higher by between 5090% . fatty acid composition of lipids extracted from bone and marrow which differed between osteoarthritic and osteoporotic patients , expressed as a percentage of total fatty acid mass ( mean sd ) . despite the greater marrow space available in op bone , this study shows that the amount of fat in a given volume of oa cancellous bone tissue is approximately twice that found in the same volume of op bone . there are also significant differences in the fat composition in terms of fractional amounts of specific fatty acids between the two diseases . it is notable that all the fatty acids significantly increased in oa are of the omega-6 ( n-6 ) variety , which are the precursors to the most strongly pro - inflammatory eicosanoids . arachidonic acid is reported to be increased in cartilage , serum and synovial fluid of oa patients and our study shows it to be almost double in oa bone compared with op bone . we have hypothesised that primary generalized osteoarthritis ( oa ) may be a systemic disorder affecting the whole musculoskeletal system and involving altered lipid metabolism . the proliferation of bone and fat in oa points towards lipids playing a significant role in the pathogenesis of oa and the increased levels of ( n-6 ) fatty acids suggest there may be an inflammatory component , albeit perhaps , requiring a broader interpretation of inflammation . it may also provide part of the key to understanding why oa and op appear to lie at opposite ends of the spectrum of bone masses , though the mechanisms mediating this are still unclear . msp participated in the ' high fat content of bone in osteoarthritis ' and undertook all the laboratory work and performed statistical analysis . we thank the orthopaedic surgeons of grampian universities hospital trust for kindly letting us use tissue donated by their patients , and dr j.r .

backgroundosteoarthritis ( oa ) is strongly linked with obesity and patients with osteoporosis ( op ) have a low body mass index . anecdotal evidence , clinical and laboratory , suggests that oa bone contains more fat . however , conversion of osteoblasts to adipocytes is reported in op and this would suggest that the more porous op cancellous bone would have a high fat content.objectivesto test the hypothesis that oa bone contains more fat than op bone.methodscores of cancellous bone were obtained from femoral heads of patients undergoing surgery for either oa or op . lipids were extracted using chloroform - methanol , weighed and expressed as a fraction of core mass and volume . a fatty acid analysis was performed using gas chromatography.resultsoa bone contained twice as much fat per unit volume of tissue as op . levels of n-6 fatty acids were elevated in oa , especially arachidonic acid ( c20:4 n-6 ) which was almost double that found in op.conclusionsthese data support the hypothesis that lipids may play a significant role in the pathogenesis of oa and may provide part of the key to understanding why oa and op lie at opposite ends of the spectrum of bone masses .

coronary artery aneurysms ( caa ) represent anomalies identified in 0.15%4.9% of patients undergoing coronary angiography . at present the term aneurysm refers to both diffuse , i.e. , over 150% dilation of the largest diameter of a coronary artery and limited spherical or saccular dilation . they are most commonly found in the right coronary artery ( rca ) and , to lesser extent , in the proximal portion of the left anterior descending ( lad ) , or left circumflex artery . aneurysms of the left main coronary artery ( lmca ) are extremely uncommon , with an incidence of 0.1% . it has been demonstrated that atherosclerosis is the main cause of these anomalies in adults and kawasaki disease in children and adolescents . other causes include trauma , polyarteritis nodosa , systemic lupus erythrematosus , syphilis , and idiopathic . many complications are related with caa includeing rupture , thrombosis , embolization , dissection , mechanical obstruction , and erosion into surrounding structures with or without fistula formation . eventually , they are a potential cause of myocardial ischemia and infarction . the management of coronary artery aneurysm is not yet well established , owing to its rarity and unpredictable natural history . treatment options include anticoagulation , custom - made covered stents , reconstruction , resection , and exclusion with bypass . , our report on an old case illustrates the potential complication of lmca aneurysm and presents its management . echocardiography revealed a hypokinetic interventricular septum and left ventricular anterior wall and demonstrated a giant coronary artery aneurysm involving the left main coronary artery at the parasternal short axis view . the myocardial perfusion scan showed inducible ischemia in the basal anterior wall of the left ventricle . left coronary angiography revealed a 3.0 2.0 cm saccular caa originating from a distal bifurcation of the lmca ( figure 1 ) . because of the inability to visualize the distal segment of the lad due to entrapment of contrast media in the caa , a 64-slice multidetector computed tomography coronary angiography was performed . it showed a saccular caa at the bifurcation of lad and circumflex artery ( figure 2 ) . due to ischemic symptoms and its risk of rupture , surgical resection of caa her current medications included nitrate , beta blocker , aspirin , ace inhibitor and statin . lmca : left main coronary artery ; lad : left anterior descending ; lcx : left circumflex coronary artery ; rca : right coronary artery . lmca aneurysms are exceedingly rare clinical entities , encountered incidentally in approximately 0.1% of patients who undergo routine angiography . isolated caa are very infrequent , and usually present as incidental findings at routine coronary angiography . most caas occur as a consequence of atherosclerosis , but other causes include congenital malformation , kawasaki disease , traumatic injury , polyarteritis nodosa , systemic lupus erythematosus , ehlers danlos syndrome , scleroderma , marfan syndrome , and takayasu 's arteritis . percutaneous coronary intervention or bypass surgery is the first treatment choice for a caa in settings of acute coronary syndromes . , the rarity of giant coronary aneurysms makes it difficult to standardize treatment or firmly establish guidelines supporting medical versus surgical management in elective settings . consequently , there are no guidelines or consensus as to the ideal approach in patients with coronary artery aneurysms . management options of caa include three options : surgical ligation of the caa accompanied by distal bypass surgery ; percutaneous stenting with covered stents ; and conservative medical management with continued antiplatelet therapy . a variety of surgical management options of caa , including thrombectomy , coronary artery reconstruction , and coronary artery bypass grafting , with or without aneurysm ligation , are described . nevertheless , the current case demonstrated that caa might have potential for thromboembolism and risk of acute myocardial infarction . many investigators have hypothesized that abnormal flow within an aneurysm predisposes patients to thrombus formation and distal embolization , even in the absence of obstructive coronary disease .

coronary aneurysms represent anomalies identified in 0.15%4.9% of patients undergoing coronary angiography . at present , there is no uniform definition of this pathology . aneurysms of the left main coronary artery ( lmca ) are extremely uncommon , with an incidence of 0.1% . it has been demonstrated that atherosclerosis is the main cause of these anomalies in adults , and kawasaki disease in children and adolescents . other causes include connective tissue disorders , trauma , vasculitis , congenital , mycotic , and idiopathic . these dilated sections of the coronary artery are not benign pathology because they are subject to spasm , thrombosis , and subsequent distal embolism , spontaneous dissection and rupture . treatment options include anticoagulation , custom - made covered stents , reconstruction , resection , and exclusion with bypass . our report on an old case illustrates the giant saccular lmca aneurysm leading to myocardial ischemia due to coronary steal phenomenon .

a 53-year - old male presented with an enlarging mass of the left upper eyelid since one year . on examination , a protuberant , nodular , ulcerated brown to black mass measuring 5 4.5 4 cm was seen arising from the skin of the upper eyelid and hanging downwards over the cheek [ fig . 1 ] . the lid margin was not involved . the best corrected visual acuity was 20/30 n6 and 20/40 n8 in the right and left eyes respectively . vision did not improve beyond that due to nuclear sclerosis and posterior subcapsular cataract . excision of the mass was done maintaining a margin of 8 mm around the tumor base to ensure adequate excision . hence , for reconstruction a free tarsal graft was sourced from the right upper eyelid and sutured in position to the remnant of the tarsus on the excised eyelid of the left eye . the skin and orbicularis oculi muscle were undermined from the area above the eyelid and then advanced inferiorly to cover the tarsal graft . postoperative appearance was cosmetically acceptable and there was neither lagophthalmos nor corneal exposure on closure of the eye . histopathologically , features were of malignant melanoma ( clarks level v , breslow thickness 45 mm ) . epithelioid and spindle tumor cells containing melanin pigment were seen with brisk mitoses ( 3 to 5 mitoses / high - power field ) and junctional activity [ fig . 2 ] . the patient was briefed about additional investigations for staging , further surgery and radiotherapy / chemotherapy as advised by the oncologist . he was not willing to undergo further treatment . keeping in mind the poor prognosis for survival in melanoma with metastasis melanoma of the eyelid accounts for less than 7% of head and neck region cutaneous melanomas.1 the majority are seen in the sixth to seventh decade of life . either the upper or lower eyelid may be involved and predominantly it is of nodular type.1,3 to the best of our knowledge in the available literature , among the nodular melanomas the present case is the largest.1 - 3 - 6 the maximum size recorded is 40 42 mm but the type of melanoma is not mentioned.6 among the different types of melanomas , lentigo maligna melanoma was among the largest tumors at presentation ( 750 mm ) , which despite being thinner , was considered to be a greater surgical challenge.7 melanoma of the eyelid skin has slightly better prognosis than its counterpart elsewhere . though melanomas developing at the mucocutaneous lid margins were described to be at a greater risk of metastasis in one series,1 the same was not confirmed by the other.3 simple thickness measurement is preferred to stage melanoma of the eyelid skin since the total dermis is exceptionally thin in this region and a stage v melanoma on clarks scale would often be a much smaller lesion than such a lesion at other sites.7 the recommended treatment is complete surgical excision with a margin of normal skin to surround the tumor . a narrow excision margin of 5 mm or less is associated with a greater frequency of recurrence.7 regional lymph node dissection in cases of completely excised cutaneous melanoma of head and neck did not result in increased survival , regardless of depth of tumor invasion.8 about 15 months later the patient presented with marked enlargement of the left preauricular metastatic lymph node .

cutaneous melanoma of the eyelid is a rare entity . we present a 53-year - old male who had a nevus on the left upper eyelid skin since childhood , which transformed into a huge ulcerated hanging mass in the same region . excision of the mass was done and histopathology confirmed the diagnosis of nodular malignant melanoma . a small preauricular lymph node showed metastatic melanoma on fine needle aspiration cytology .

cardiovascular prevention and rehabilitation improves functional and clinical status , health - related quality of life , and prognosis in patients with coronary heart disease ( chd ) recovering from acute events and invasive interventions.1 for more than a decade , cardiac rehabilitation ( cr ) has been recommended for chd as part of integrated cardiac care.2,3 despite this , studies from the us and europe , including denmark , have documented that less than half of eligible patients participate in cr.4 systematic monitoring of delivery and outcomes of cr is recommended to meet this challenge.5,6 thus , the national working group on preventive cardiology and rehabilitation , under the danish society of cardiology , initiated a national clinical quality registry on cr approved by the danish health and medicines authority , in 2011 . although danish cardiac rehabilitation database ( dhrd ) was initially implemented on september 1 , 2013 , as a result of a breakdown of the database system , data collection ceased until august 14 , 2015 , at which point the database was implemented once again . the overall aim of the dhrd is to monitor and improve the quality of phase ii cr throughout denmark , in order to improve the outcome for patients recovering from cardiac events . phase ii cr in denmark refers to the initial 812 weeks of outpatient cr performed at hospitals and municipalities . data are collected at a patient level as well as program level ( figure 1 ) , as recommended by scientific associations in europe and the us.5,6 furthermore , the database aims to support research within the field of cr . it is mandatory for all hospitals delivering phase ii cr to register all patients onto the dhrd , who are discharged alive and receiving cr following hospitalization for chd ( ie , acute coronary syndrome , or stable angina pectoris with proven stenosis on coronary angiography treated with percutaneous coronary intervention , coronary artery bypass grafting , or medication alone ) . all patients discharged alive from hospitals are identified from the national patient register7 using the who s international classification of diseases , 10th edition ( icd-10 ) coding system : acute coronary syndrome ( st - elevation myocardial infarction , non st - elevation myocardial infarction , and unstable angina ) as primary diagnosis , or secondary diagnoses ( di210di219 , di248 , di240 , di249 ) and stable angina pectoris as primary diagnoses ( di209 , di251 , di251b , di251c ) . furthermore , the nordic classification of surgical procedures is used to identify coronary angiograms and invasive procedures ( coronary angiograms : uxac40 , uxac85 , uxac90 , uxuc85 , uxuc86 , uxuc87 , ufya20 ; percutaneous coronary intervention : kfng00 , kfng02 , kfng02a , kfng05 , kfng05a , kfng10 , kfng12 , kfng20 , kfng22 , kfng30 , kfng40 , kfng96 , kzfx01 ; and coronary artery bypass grafting : kfna , kfnb , kfnc , kfnd , kfne , kfnf , kfnh , kfnj , kfnk , kfnw ) . the database will include information on approximately 14,000 patients annually . based on administrative data on ambulatory visits ( ie , data from the danish national patient register7 cross - checked with procedure codes referring to cr services ) , 75% of eligible patients are receiving one or more outpatient rehabilitation services from all 35 hospitals in the five regions of denmark that were delivering cr in denmark by 2013.8 the database is also capable of including other patient groups receiving cr . patient - level data are collected by the clinical team and registered directly onto an online system at the time of entry into phase ii cr . the team comprises multidisciplinary professionals involved in the rehabilitation intervention ( ie , nurses , medical doctors , physiotherapists , and dieticians ) . to minimize the registration workload and double registration , simultaneous linkage to national administrative patient registers has been established ( the danish civil registration system,9 the danish national patient register,7 and the danish national database of reimbursed prescriptions).10 linkage to the clinical laboratory information system11 is also planned . at baseline , data are captured from the aforementioned registers and then validated and approved by the clinical staff , by reading and validating the captured information . registration of data into the dhrd began on august 14 , 2015 , which led to the collection of data on 3,846 patients by march 2016 . the quality of data is assessed as part of an annual data audit with feedback to clinicians . patient - level data are collected by the clinical team and registered directly onto an online system at the time of entry into phase ii cr . the team comprises multidisciplinary professionals involved in the rehabilitation intervention ( ie , nurses , medical doctors , physiotherapists , and dieticians ) . to minimize the registration workload and double registration , simultaneous linkage to national administrative patient registers has been established ( the danish civil registration system,9 the danish national patient register,7 and the danish national database of reimbursed prescriptions).10 linkage to the clinical laboratory information system11 is also planned . at baseline , data are captured from the aforementioned registers and then validated and approved by the clinical staff , by reading and validating the captured information . registration of data into the dhrd began on august 14 , 2015 , which led to the collection of data on 3,846 patients by march 2016 . the quality of data is assessed as part of an annual data audit with feedback to clinicians . the variables recorded in the dhrd are related to patient characteristics at baseline , for example , smoking status , exercise capacity , height , weight , blood pressure , and pharmacological therapy . also , data on performed diagnostic tests ( eg , diabetes and depression ) are recorded in the database , along with the individual plan for rehabilitation ( eg , training sessions , dietary treatment , and/or smoking cessation ) . data on physical capacity , lifestyle , and patient - reported outcome measures are reentered at follow - up , in order to monitor progression and outcome of cr . the data collected are aligned with the european core cr dataset ( mcgee , unpublished data , 2004 ) and the variables of european cardiac rehabilitation database project , in order to make sure that data from denmark can be compared to data from other european countries . data at a program level are collected every third year through surveys targeted at cr staff . these surveys gather information about the structure and provision of cr , and provide program - level information that can be compared with patient outcome over time . a set of outcome variables has been defined and approved nationally , in order to provide a set of benchmark quality indicators . the performance on the quality indicators is published in annual feedback reports at a national , regional , and hospital level as part of the annual audit of cr . the indicator list and benchmarks are subject to regular adjustments , in order to keep the database in line with current evidence . the database has been implemented since the summer of 2015 ; consequently , the first patient - level data will be available by autumn 2016 . applications for access to use data are reviewed by the chair and executive committee upon application to the danish clinical registries . in the short term , program - level data and administrative data have been presented as part of an annual report from dhrd8 and will be analyzed as part of an implementation research program investigating the gap between guidelines , clinical practice , and use of a clinical registry.12 data are collected and maintained according to danish data protection laws and regulations , without the need to obtain patient consent . the dhrd was initiated by the national working group on preventive cardiology and rehabilitation , under the danish society of cardiology , and was approved as a national clinical quality registry on cr by the danish health and medicines authority in 2011 . the dhrd is supported by the cross - disciplinary professional associations : the danish society of cardiology , the danish nurses organisation , the association of danish physiotherapists , and the danish association of clinical dieticians . the database is available at www.danheart.dk ; however , this web site can only be accessed through the danish hospital internet networks . the danish clinical registries , which constitutes the infrastructure of the danish national clinical quality registries , has responsibility for the maintenance of majority of the data and data protection , as well as seeking funding . the database is headed by a steering committee with an elected chair , an executive committee , and an academic secretariat . data are collected and maintained according to danish data protection laws and regulations , without the need to obtain patient consent . the dhrd was initiated by the national working group on preventive cardiology and rehabilitation , under the danish society of cardiology , and was approved as a national clinical quality registry on cr by the danish health and medicines authority in 2011 . the dhrd is supported by the cross - disciplinary professional associations : the danish society of cardiology , the danish nurses organisation , the association of danish physiotherapists , and the danish association of clinical dieticians . the database is available at www.danheart.dk ; however , this web site can only be accessed through the danish hospital internet networks . the danish clinical registries , which constitutes the infrastructure of the danish national clinical quality registries , has responsibility for the maintenance of majority of the data and data protection , as well as seeking funding . the database is headed by a steering committee with an elected chair , an executive committee , and an academic secretariat . the national dhrd , aimed at monitoring and improving the quality of cr programs , has recently been established in denmark . the dhrd is unique due to the direct and simultaneous linkages to the administrative hospital registers . this resource makes follow - up on clinically important outcomes , such as the number of hospitalizations and mortality rate , directly accessible . accreditation by use of clinical quality registries has been pointed out as an important tool to improve clinical practice within cr and clinical follow - up care13 ( figure 2 ) , and referral to cr has been added as a performance measure following acute coronary syndrome by the european society of cardiology and the american heart association.14,15 the growing literature indicates that clinical quality registries can provide vital information that can be used to facilitate improvements in practice16 with positive effects primarily on the processes of care , whereas measures on outcome of care are less often positively affected.16 findings , however , are heterogeneous , indicating that neither a registry itself nor the reporting of data initiates change as quality improvement requires comprehensive approaches,17 including successful implementation of the registry and continuous data quality assurance , as well as transparency and timely feedback.18 based on experiences from the field of stroke care , embracing a comprehensive quality assurance approach , including a culture with focus on quality , thorough data entry , and availability of feedback as well as willingness to act on feedback , is critical in order to achieve improved quality of care.18 this can not be achieved by dhrd alone , but is a shared responsibility of the cr team and the health care sector . the dhrd includes all hospitals offering cr and will , therefore , reflect all hospital - based cr services at a national level . since 2007 , the municipalities in denmark have had the overall responsibility for prevention and rehabilitation following discharge . cr services were , hence , transferred from hospitals to the municipalities ( either partly or fully ) in 2007 . quality assurance and accreditation of municipality - based cr will , therefore , become an important focus for dhrd in the future . a high reporting and coverage rate of patients with chd is , therefore , essential . coverage of the database will be closely monitored and routinely evaluated by matching data to the administrative data in the danish national patient register.7 the aim is to achieve > 90% coverage of cr activities in all cr programs . dhrd is an online , clinical quality database that aims toward providing higher quality cr for patients with chd in denmark . data can be assessed as a part of research related to both the outcome and organization of cr .

aim of databasethe danish cardiac rehabilitation database ( dhrd ) aims to improve the quality of cardiac rehabilitation ( cr ) to the benefit of patients with coronary heart disease ( chd).study populationhospitalized patients with chd with stenosis on coronary angiography treated with percutaneous coronary intervention , coronary artery bypass grafting , or medication alone . reporting is mandatory for all hospitals in denmark delivering cr . the database was initially implemented in 2013 and was fully running from august 14 , 2015 , thus comprising data at a patient level from the latter date onward.main variablespatient - level data are registered by clinicians at the time of entry to cr directly into an online system with simultaneous linkage to other central patient registers . follow - up data are entered after 6 months . the main variables collected are related to key outcome and performance indicators of cr : referral and adherence , lifestyle , patient - related outcome measures , risk factor control , and medication . program - level online data are collected every third year.descriptive databased on administrative data , approximately 14,000 patients with chd are hospitalized at 35 hospitals annually , with 75% receiving one or more outpatient rehabilitation services by 2015 . the database has not yet been running for a full year , which explains the use of approximations.conclusionthe dhrd is an online , national quality improvement database on cr , aimed at patients with chd . mandatory registration of data at both patient level as well as program level is done on the database . dhrd aims to systematically monitor the quality of cr over time , in order to improve the quality of cr throughout denmark to benefit patients .

transdural nerve root entrapment in the intervertebral disc space after incidental durotomy during lumbar disc surgery very rarely causes severe recurring radiating pain . there are several methods for the repair of dural tear including primary repair , tissue sealant , blood patch , and tissue grafting10 ) . we have reported 4 cases of lumbar rootlet entrapment in the intervertebral space after lumbar disc surgery , discuss the postulated mechanism , and provide a literature review . a 52-year - old female presented with a 2-month history of low back pain and right leg pain . preoperative magnetic resonance imaging ( mri ) showed disc herniation at l4 - 5 on the right side ( fig . 1 ) . the patient underwent hemilaminectomy and discectomy ( hld ) at l4 - 5 on the right side . during the operation , we noted that the ventral dura was severely adhered to the surrounding tissue . during dissection however , after postoperative day 15 , she developed extremely severe recurring radiating pain in the right leg . repeat mri showed that a rootlet was entrapped into the l4 - 5 disc space ( fig . the patient 's symptoms improved postoperatively and finally disappeared after 6 months . a 66-year - old male presented with a 1-month history of back pain and left leg pain . initial mri showed disc bulging at l2 - 3 and l3 - 4 and foraminal stenosis at l4 - 5 bilaterally ( fig . he underwent bilateral hld at l2 - 3 and l3 - 4 , together with the insertion of a diam ( medtronic , inc . , tn , usa ) . after brief improvement , he experienced a severe recurrence of symptoms . over a 5-month period , he underwent hld , percutaneous endoscopic lumbar discectomy ( peld ) , and unilateral transforaminal lumbar interbody fusion ( tlif ) at l4 - 5 on the left side . 2 ) . magnetic resonance myelography showed continuity of the csf within the disc space ( fig . we suspected that the severe recurring leg pain was caused by rootlet entrapment that had developed after the first operation . there was a ventral dural defect , which was not observed during the first operation , and rootlet entrapment in the intervertebral disc space . a 49-year - old female had back pain and left leg pain for 6 months . initial mri showed extraforaminal disc herniation at l4 - 5 on the left side ( fig . repeat mri showed recurrence of extraforaminal and paramedian disc herniation at the l4 - 5 level on the left side ( fig . 3 ) . she underwent hld on the left side with interspinous soft stabilization at the l4 - 5 level . during the operation , a severe ventral dural adhesion was observed that was attributed to prior endoscopic surgery . repeat mri showed rootlet entrapment through a dural defect at the l4 - 5 level on the left side ( fig . her symptoms improved and finally disappeared after 6 months . a 59-year - old female presented with a 1-month history of back pain and bilateral leg pain , more severe on the left . preoperative mri showed disc herniation at l1 - 2 , ossification of the posterior longitudinal ligament ( opll ) , central spinal stenosis at l1 - 2 , and fusion of l2 - 3 - 4 - 5 with pedicle screws ( fig . we performed anterior lumbar interbody fusion ( alif ) , lateral screw insertion , and opll removal at l1 - 2 . during alif , the ventral dura was torn and this dural defect was compactly sealed with tachocomb and fibrin glue . however , after 2 months , she complained of severe recurring pain in both legs . repeat mri showed rootlet entrapment through the ventral dural defect site at l1 - 2 ( fig . a 52-year - old female presented with a 2-month history of low back pain and right leg pain . preoperative magnetic resonance imaging ( mri ) showed disc herniation at l4 - 5 on the right side ( fig . 1 ) . the patient underwent hemilaminectomy and discectomy ( hld ) at l4 - 5 on the right side . during the operation , we noted that the ventral dura was severely adhered to the surrounding tissue . during dissection however , after postoperative day 15 , she developed extremely severe recurring radiating pain in the right leg . repeat mri showed that a rootlet was entrapped into the l4 - 5 disc space ( fig . a 66-year - old male presented with a 1-month history of back pain and left leg pain . initial mri showed disc bulging at l2 - 3 and l3 - 4 and foraminal stenosis at l4 - 5 bilaterally ( fig . he underwent bilateral hld at l2 - 3 and l3 - 4 , together with the insertion of a diam ( medtronic , inc . , tn , usa ) . after brief improvement , he experienced a severe recurrence of symptoms . over a 5-month period , he underwent hld , percutaneous endoscopic lumbar discectomy ( peld ) , and unilateral transforaminal lumbar interbody fusion ( tlif ) at l4 - 5 on the left side . 2 ) . magnetic resonance myelography showed continuity of the csf within the disc space ( fig . we suspected that the severe recurring leg pain was caused by rootlet entrapment that had developed after the first operation . there was a ventral dural defect , which was not observed during the first operation , and rootlet entrapment in the intervertebral disc space . a 49-year - old female had back pain and left leg pain for 6 months . initial mri showed extraforaminal disc herniation at l4 - 5 on the left side ( fig . repeat mri showed recurrence of extraforaminal and paramedian disc herniation at the l4 - 5 level on the left side ( fig . 3 ) . she underwent hld on the left side with interspinous soft stabilization at the l4 - 5 level . during the operation , a severe ventral dural adhesion was observed that was attributed to prior endoscopic surgery . repeat mri showed rootlet entrapment through a dural defect at the l4 - 5 level on the left side ( fig . a 59-year - old female presented with a 1-month history of back pain and bilateral leg pain , more severe on the left . preoperative mri showed disc herniation at l1 - 2 , ossification of the posterior longitudinal ligament ( opll ) , central spinal stenosis at l1 - 2 , and fusion of l2 - 3 - 4 - 5 with pedicle screws ( fig . we performed anterior lumbar interbody fusion ( alif ) , lateral screw insertion , and opll removal at l1 - 2 . during alif , the ventral dura was torn and this dural defect was compactly sealed with tachocomb and fibrin glue . however , after 2 months , she complained of severe recurring pain in both legs . repeat mri showed rootlet entrapment through the ventral dural defect site at l1 - 2 ( fig . recurrent disc herniation , remnant herniated disc material , postoperative epidural hematoma , and nerve root inflammation can all cause recurrence of this radiating pain . a few studies have reported rare causes of postoperative recurrence of radiating pain , such as the presence of a pseudomeningocele and posttraumatic spinal cord or nerve root herniation through a dural defect site2,3,9,11 - 13,15,17 ) . however , only a few cases of nerve root entrapment in the intervertebral space after lumbar disc surgery have been reported17 ) . in most cases , the occurrence of a pseudomeningocele and posttraumatic spinal cord or nerve root herniation after spinal surgery is due to the presence of a dural tear that arises from the dorsal aspect . however , in the case of nerve root entrapment in the intervertebral space , the iatrogenic dural tear is located on the ventral side . the incidence of unintended intraoperative durotomy is between 0.3% and 17.4% and varies depending on the type of surgical procedure1,4,5,8,10,12 - 14,16 ) . because many patients do not show symptoms , the exact incidence of postoperative pseudomeningocele is not known , but the overall incidence is reported to be less than 2%1,5,9,11,15 ) . however , iatrogenic entrapment of the nerve root in the intervertebral space through a ventral dural defect is extremely rare . one article reported 2 cases of nerve root entrapment in the intervertebral space after lumbar disc surgery17 ) . the author noted that a small dural defect , particularly one that was located at the level of the intervertebral space , could lead to transdural root herniation and root entrapment in the intervertebral space . this is the only article reporting nerve root entrapment in the intervertebral space after lumbar disc surgery . the mechanism postulated for nerve root entrapment in the intervertebral space is a water - hammer effect resulting from the difference between the intradural pressure and the intervertebral space pressure7,12 ) . this increased intradural pressure may cause compression of the spinal cord leading to widening of small unrepaired dural defects . the nerve rootlet can become entrapped in the intervertebral space through the dural defect , causing rootlet irritation , leading to severe radiating pain . the typical appearance of rootlet entrapment is a beak - like appearance of the ventral dura and rootlet in the sagittal view . in the axial view however , the diagnostic value of myelography is limited if the subarachnoid space does not extend outside the dural space . before exploration , it is important to obtain a radiographic image to confirm the location of the dural defect . in addition , a pseudomeningocele may entrap nerve roots or the spinal cord and cause radicular symptoms1,9,13,15,16 ) . one study reported that of 6 patients with a dural defect that was not repaired during the first operation , 5 developed psuedomeningocele , and all 6 patients eventually underwent dural repair because of failure of conservative therapy4 ) . another study reported a case of cauda equina syndrome resulting from a pseudomeningocele ; the cauda equina syndrome was caused by herniation of the cauda equina roots through the dural defect1 ) . another study reported that patients with incidental durotomy had poorer outcomes after surgery ; in this 10-year follow - up study , a significant number of patients with incidental durotomy complained of headaches after surgery16 ) . in addition , patients with incidental durotomy tended to undergo repeat operations and were unable to work for a longer duration . csf leakage does not usually occur in these cases , particularly in the cases of small dural tears on the ventral side . although conservative treatments such as bed rest and closed subarachnoid drainage have been attempted , midline durotomy and meticulous surgical dural repair remain the definitive treatment . one study reported that bed rest is not a definitive treatment ; in this study , the patients who did not undergo dural repair developed complications6 ) . another study reported that the valsalva maneuver may help identify the dural tear in suspected cases10 ) . the authors also reported that prompt identification and careful closure of the dural tear during the first surgery leads to a successful outcome . in our four cases , prompt diagnosis and operation were performed in all cases except case number 2 . in case 2 , correct diagnosis was delayed and the patient suffered from radiating pain for several months . however , postoperatively , there was no neurologic deficit , and there was good improvement in all cases . if a patient presented with recurrent pain after brief improvement , the surgeon must cautiously watch the operated level first . iatrogenic thinning and tearing of the dura can cause rootlet entrapment even if the dura is minimally torn . the results obtained for our cases indicate that complete surgical repair of the ventral dura defect is required to prevent nerve rootlet entrapment and other complications , even if the dural defect is minimal . if a dural tear is suspected , a valsalva maneuver should be performed before wound closure even if there is no csf leakage .

four patients underwent lumbar surgery . in all four patients , the dura was minimally torn during the operation . however , none exhibited signs of postoperative cerebrospinal fluid leakage . in each case , a few days after the operation , the patient suddenly experienced severe recurring pain in the leg . repeat magnetic resonance imaging showed transdural nerve rootlets entrapped in the intervertebral disc space . on exploration , ventral dural tears and transdural nerve rootlet entrapment were confirmed . midline durotomy , herniated rootlet repositioning , and ventral dural tear repair were performed , and patients ' symptoms improved after rootlet repositioning . even with minimal dural tearing , nerve rootlets may become entrapped , resulting in severe recurring symptoms . therefore , the dural tear must be identified and repaired during the first operation .

severe hypertriglyceridemia ( shtg ) with acute pancreatitis ( ap ) is a medical emergency . the main pharmacotherapy for high levels of triglycerides ( tg ) consists of insulin , heparin , omega-3 fatty acids , fibrates , statins , or niacin ( nicotinic acid ) ; however , slow mode of action of these agents is a concern in potentially life threatening situation . plasmapheresis is a therapeutic option in such an emergency in rapidly lowering tg and has been used in studies with varied results . we used early plasmapheresis in 2 cases of shtg induced severe ap ( sap ) and found significant rapid reduction of tg and improvement in organ failure . a 34-year - old female uncontrolled type ii diabetes mellitus , obese ( body mass index [ bmi ] 39/kg / m ) admitted with pain in epigastric region and vomiting since 3 days . on examination patient had pulse 135/min , respiratory rate ( rr ) 32/min , blood pressure ( bp ) 88/46 mm of hg , with normal respiratory and cardiovascular examination on auscultation , abdominal distention , epigastric tenderness and guarding . she was admitted in intensive care unit ( icu ) , with apache ii score 14 , started on fluid resuscitation and other supportive management . the blood was highly lipemic and on ultracentrifuge showed tg 9230 mg / dl [ table 1 ] . she had no history of alcohol use , drug intake , gallstones , and pancreatitis . the patient was managed as shtg induced sap and diabetic ketoacidosis with enteral fenofibrate other supportive management . her condition further deteriorated next day with increasing respiratory distress requirement of vasopressors to maintain bp and she was started on plasmapheresis . her tg after plasmapheresis decreased to 1620 mg / dl and 435 mg / dl after 1 and 2 session respectively [ figure 1 ] . her contrast enhanced computerized topography ( cect ) abdomen revealed severe pancreatitis with balthazar score 7 . she was shifted from icu on day 7 and discharged on day 14 with oral atorvastatin , fenofibrate and insulin . on her follow - up after 1-month a 35-year - old male admitted with pain abdomen since 5 days and vomiting since 2 days . on examination his temperature 38.3c , pulse 124/min , bp 118/46 mm hg , rr 27/min , bmi 35.7 kg / m and decrease air entry in bases of both lungs with normal cardiovascular examination . he was started on fluid resuscitation and shifted to icu with apache ii score 11 . his abg showed metabolic acidosis and on ultrasound abdomen was unremarkable with obscured pancreas due to bowel gas . he had a history of poorly controlled type ii diabetes mellitus with hypertriglyceridemia , but he stopped fenofibrate since 6 months . his blood was lipemic and after ultracentrifuge showed tg 6241 mg / dl [ table 1 ] . he was taken for urgent plasmapheresis on day 2 in view of deteriorating clinical condition with replacement by thawed fresh frozen plasma [ figure 2 ] . postplasmapheresis , his tg decreased to 445 mg / dl and patient showed significant clinical improvement with resolution acidosis and respiratory distress . he was started on oral fat - free diet and fenofibrate on day 4 and discharged on day 10 . on follow - up after 2 month his tg were 109 mg / dl . severe hypertriglyceridemia with serum triglyceride concentrations > 1000 mg / dl is a risk factor for ap . shtg can also interfere with clinical laboratory tests , making patient diagnosis and management more difficult . in both of our patients due to very high levels of tg , the serum sample so lipemic that no sample testing could be performed initially . a proposed mechanism is hydrolysis of tg by pancreatic lipase , leading to accumulation of high concentrations free fatty acids and chylomicrons which can produce acinar cell injury and capillary plugging causing ischemia and acidosis activating trypsinogen and ap . conventional management of hypertriglyceridemia dietary fat restriction and pharmacotherapy is time consuming . also in the patients with sap urgent lowering of tg is necessary to prevent disease complications and oral pharmacological therapy may not always be feasible . the indications of plasmapheresis or lipid apheresis in such cases are ( a ) patient refractory to nutritional and pharmacological approaches , ( b ) serum tg exceed 1000 mg / dl , ( c ) serum lipase 3 times the upper limit of normal , ( d ) severe hypocalcemia , ( e ) lactic acidosis , and ( f ) worsening inflammation and organ dysfunction . our patients in case 1 had 5 and case 2 had 4 out of 6 criteria respectively . the beneficial effect of plasmapheresis is believed to be because of rapid decrease in tg levels , however , removal of excessive proteases from the plasma which are key enzymes in inflammation and replacement of consumed protease inhibitors might be an additionally benefit . in a recent review on plasmapheresis in hypertriglyceridemia - induced ap , though the triglyceride levels reduced by 4680% , there was still no benefit in outcome because of insufficient studies . in another observation study , the plasmapheresis effectively reduced tg faster than could be expected with conservative treatment and improve outcome . there are few reports showing that reduction in morbidity and mortality with plasmapheresis can be achieved when apheresis is used early . we used plasmapheresis in both of our cases within 48 h of diagnosing ap with hypertriglyceridemia . both the patients not only showed rapid reduction of tg but also improvement in organ failure . plasmapheresis is an effective therapeutic option for shtg induced sap with rapid reduction of serum tg and can be considered early in the management .

hypertriglyceridemia can cause severe diseases such as acute pancreatitis ( ap ) and coronary artery disease . the routine management of hypertriglyceridemia is dietary restriction of fat and lipid - lowering medications to manage the secondary or precipitating causes of hypertriglyceridemia . however , in cases of ap with severe hypertriglyceridemia ( shtg ) ( triglycerides [ tg ] > 1000 mg / dl ) rapid reduction of tg levels to well below 1000 mg / dl can improve outcome and prevent further episodes of pancreatitis . plasmapheresis is a therapeutic option in such medical emergencies . we discussed 2 cases of severe ap with shtg where we used early plsmapheresis along with other supportive management .

a 58-year - old man was admitted in august 2011 with a 2-month history of progressive pain of the right lower limb . one year prior , he was diagnosed with stage t3n1m0 nasopharyngeal carcinoma ( npc ) according to the union for international cancer control ( uicc , 2009 ) classification and treated with radical radiotherapy ( 70 gy in 35 fractions , 5 fractions per week ) combined with 3 courses of concurrent cisplatin chemotherapy . during physical examination , a tender , unfixed lymph node measuring 1.0 cm 1.0 cm 0.9 cm could be palpated in level iii of the right cervicum , and this finding was confirmed by ultrasonography ( figure 1 ) . the skin of the cervical region was normal in appearance , and no lesions were found in the oral cavity . no facial nerve palsy was present . during the course of the disease , there were no reports of headache , diplopia , abnormal deglutition , nasal occlusion , or blood - stained nasal discharge . emission computed tomography ( ect ) and magnetic resonance imaging ( mri ) scans revealed metastasis from npc to the lumbar vertebra 2/3 and a single lymph node in level iii of the right cervical region . laboratory studies , which included full blood cell count , electrolytes , urinalysis , and liver function tests , showed results within normal limits . according to the presentation , physical examination , and laboratory examination , this patient was diagnosed , after radio - therapy , with npc with metastasis to the lumbar vertebra and a single lymph node in level iii of the right cervical region . the patient was unwilling to undergo radiotherapy again and instead was treated with palliative radiotherapy for metastasis in the lumbar vertebra and radiofrequency ablation for lymph node metastasis in the right cervical region . this patient did not undergo radiotherapy for the right cervical lymph node because of local radiation - induced injury from the treatment of primary npc . thus , this patient underwent a radiofrequency ablation treatment to destruct the right cervical lymph node . the follow - up protocol included clinical and laboratory examinations every 3 months in the first year after therapy and every 6 months thereafter . the patient was in good condition at the last follow - up in february 2012 and was living a normal life . a 57-year - old woman presented with metastasis of esophageal carcinoma after chemoradiotherapy . she was previously diagnosed with stage t3n1m0 esophageal carcinoma ( uicc 2009 ) in 2010 and underwent radical radiotherapy ( 60 gy in 30 fractions , 5 fractions per week ) with 4 courses of synchronous chemotherapy ( 5-fluorouracil plus cisplatin ) . positron emission tomography / computed tomography ( pet / ct ) scan showed signs of primary local advance and solitary metastasis in the right supraclavicular lymph node in april 2011 . ultrasound revealed the lymph node was 2.6 cm 1.4 cm 1.2 cm ( figure 2 ) . the patient refused to undergo radiotherapy for the right supraclavicular lymph node because of the severe adverse effects of previous radiotherapy . subsequently , the patient underwent systemic chemotherapy ( 5-fluorouracil plus cisplatin ) for local esophageal carcinoma and radiofrequency ablation for the right supraclavicular lymph node . after 1 month of radiofrequency , the right supraclavicular lymph node was not enhanced on contrast - enhanced ct scans , but the local lesion had advanced . hence , gemcitabine was added to control the local progressive primary disease . at the last follow - up in february 2012 , the patient was in good condition , and there was no evidence that distant lymph node metastasis had recurred . a , ultrasound image shows lymph node metastasis . the internal jugular vein ( red ) is located on the inner side of the lymph node and is oppressed by the lymph node and the common carotid artery ( blue ) . b , a radiofrequency needle was punctured into the lymph node ( red arrow ) , and a 22-gauge percutaneous transhepatic cholangiography needle ( green arrow ) was punctured between the lymph node and surrounding tissues to inject deionized water . c , 1 month after the ablation , the target lymph node was not enhanced on contrast - enhanced ultrasound image ( green circle ) . d , the general ultrasound image of image c. a , ultrasound image shows lymph node metastasis ( inside the green circle ) . b , the internal jugular vein ( mixture of yellow and blue ) and the common carotid artery ( blue ) are located on the inner side of the lymph node . c , a radiofrequency needle ( green arrow ) was punctured into the lymph node . d , the treated lymph node was not enhanced on ct scan ( red circle ) . a 58-year - old man was admitted in august 2011 with a 2-month history of progressive pain of the right lower limb . one year prior , he was diagnosed with stage t3n1m0 nasopharyngeal carcinoma ( npc ) according to the union for international cancer control ( uicc , 2009 ) classification and treated with radical radiotherapy ( 70 gy in 35 fractions , 5 fractions per week ) combined with 3 courses of concurrent cisplatin chemotherapy . during physical examination , a tender , unfixed lymph node measuring 1.0 cm 1.0 cm 0.9 cm could be palpated in level iii of the right cervicum , and this finding was confirmed by ultrasonography ( figure 1 ) . the skin of the cervical region was normal in appearance , and no lesions were found in the oral cavity . no facial nerve palsy was present . during the course of the disease , there were no reports of headache , diplopia , abnormal deglutition , nasal occlusion , or blood - stained nasal discharge . emission computed tomography ( ect ) and magnetic resonance imaging ( mri ) scans revealed metastasis from npc to the lumbar vertebra 2/3 and a single lymph node in level iii of the right cervical region . laboratory studies , which included full blood cell count , electrolytes , urinalysis , and liver function tests , showed results within normal limits . according to the presentation , physical examination , and laboratory examination , this patient was diagnosed , after radio - therapy , with npc with metastasis to the lumbar vertebra and a single lymph node in level iii of the right cervical region . the patient was unwilling to undergo radiotherapy again and instead was treated with palliative radiotherapy for metastasis in the lumbar vertebra and radiofrequency ablation for lymph node metastasis in the right cervical region . this patient did not undergo radiotherapy for the right cervical lymph node because of local radiation - induced injury from the treatment of primary npc . thus , this patient underwent a radiofrequency ablation treatment to destruct the right cervical lymph node . the follow - up protocol included clinical and laboratory examinations every 3 months in the first year after therapy and every 6 months thereafter . the patient was in good condition at the last follow - up in february 2012 and was living a normal life . she was previously diagnosed with stage t3n1m0 esophageal carcinoma ( uicc 2009 ) in 2010 and underwent radical radiotherapy ( 60 gy in 30 fractions , 5 fractions per week ) with 4 courses of synchronous chemotherapy ( 5-fluorouracil plus cisplatin ) . positron emission tomography / computed tomography ( pet / ct ) scan showed signs of primary local advance and solitary metastasis in the right supraclavicular lymph node in april 2011 . ultrasound revealed the lymph node was 2.6 cm 1.4 cm 1.2 cm ( figure 2 ) . the patient refused to undergo radiotherapy for the right supraclavicular lymph node because of the severe adverse effects of previous radiotherapy . subsequently , the patient underwent systemic chemotherapy ( 5-fluorouracil plus cisplatin ) for local esophageal carcinoma and radiofrequency ablation for the right supraclavicular lymph node . after 1 month of radiofrequency , the right supraclavicular lymph node was not enhanced on contrast - enhanced ct scans , but the local lesion had advanced . hence , gemcitabine was added to control the local progressive primary disease . at the last follow - up in february 2012 , the patient was in good condition , and there was no evidence that distant lymph node metastasis had recurred . the yellow arrow indicates the enlarged lymph node . the internal jugular vein ( red ) is located on the inner side of the lymph node and is oppressed by the lymph node and the common carotid artery ( blue ) . b , a radiofrequency needle was punctured into the lymph node ( red arrow ) , and a 22-gauge percutaneous transhepatic cholangiography needle ( green arrow ) was punctured between the lymph node and surrounding tissues to inject deionized water . c , 1 month after the ablation , the target lymph node was not enhanced on contrast - enhanced ultrasound image ( green circle ) . d , the general ultrasound image of image c. a , ultrasound image shows lymph node metastasis ( inside the green circle ) . b , the internal jugular vein ( mixture of yellow and blue ) and the common carotid artery ( blue ) are located on the inner side of the lymph node . c , a radiofrequency needle ( green arrow ) was punctured into the lymph node . d , the treated lymph node was not enhanced on ct scan ( red circle ) . patients with advanced cancer have the risk of local recurrence and distant metastasis . for treating distant lymph node metastasis , radiotherapy and chemotherapy are usually the first choices ; experience with other therapies our results suggest that radiofrequency ablation may play an essential role in treating distant lymph node metastasis . to the best of our knowledge , only two papers have been published regarding radiofrequency ablation for distant lymph node metastasis , and both focus on deep metastatic lymph nodes but not superficial distant lymph node metastasis , . there are several possible reasons for limited studies of radiofrequency ablation in patients with superficial distant lymph node metastasis . first , radiofrequency guided by ultrasound is difficult to master ; this technique requires skill and expertise , especially for treatment of small lymph nodes . second , radiofrequency ablation may cause collateral damage to adjacent structures and pain . for these reasons , the outcome of radiofrequency ablation for patients with superficial distant lymph node metastasis is usually unsatisfactory . thus , we modified the radiofrequency protocol and injected deionized water to separate the ablation target and surrounding tissues , which , we hypothesized , would prevent additional injury . until recently , there were no guidelines for minimally invasive treatment for late - stage cancer patients in poor condition who could not stand additional chemotherapy or radiotherapy . in these two patients , a 22-guage fine needle was used to puncture the surrounding tissues of the metastatic lymph node . deionized water was injected to separate the ablation target and surrounding tissues until the space between them was more than 3 mm . after injection was completed , the lymph node was surrounded by several small water pools . indeed , both lesions were completely controlled locally and disappeared in the follow - up without any complications . several researchers have proclaimed that cancer is a systemic disease , and lymph node metastasis is a small part of disease spread . hence , regional treatment only debunks the tumor burden but does not prevent more distant spread . to date , whether lymph nodes constrain or suppress cancer cell metastasis is not clear . however , an increasing number of investigators have shown that cancer cells develop metastatic potential as tumors grow and their properties evolve , . thus , distant lymph node metastasis is not only an indication of changes in malignant tumor biology but also a source of local recurrence or progression . the effective of regional treatment for isolated lymph node metastasis is confuse : local control or progression ? chemotherapy suppresses tumor progress , but accompaning with many adverse effects , whereas radiotherapy is limited by its dose constraints . in the cases presented here , we focused on late - stage patients with distant lymph node metastasis who could not stand additional chemotherapy or radiotherapy but needed minimally invasive , yet radical treatment . therefore , we selected ultrasound - guided radiofrequency ablation to treat these patients . compared with conventional curative treatment , including chemotherapy and radiotherapy , radiofrequency ablation has the following advantages as a treatment for distant lymph node metastasis : ( 1 ) it is less invasive , which is particularly important for patients unable to bear the trauma of surgery and additional radiotherapy ; ( 2 ) it is cheaper and requires shorter hospitalization ; ( 3 ) it can be repeated several times ; and ( 4 ) it has fewer compli - cations . another ultrasound - guided approach for local treatment is percutaneous ethanol injection , which has a comparative effect to radiofrequency ablation . compared with ethanol injection , radiofrequency ablation is more effective in neoplasm destruction , which does not permit adequate diffusion of ethanol , but it has a higher risk of collateral damage to adjacent structures , . thus , our approach was to inject deionized water to separate the ablation target and surrounding tissues . furthermore , radiofrequency ablation induces thermal destruction of tissues by heating cells to a temperature higher than 60c , causing irreversible cellular modification called coagulative necrosis , . when the temperature of the tip of the needle reaches a preset point ( 95c in this study ) , the instrument begins active treatment time and maintains the temperature , causing cellular coagulative necrosis . our results preliminarily suggest that radiofrequency ablation is an effective and safe locoregional treatment for superficial distant lymph node metastasis .

patients with late - stage cancer commonly have distant lymph node metastasis ; however , poor health often contraindicates surgical treatment . although the quality of life and overall survival for these patients are low , there is neither a consensus nor a guide for treatment . ablation technique and surrounding tissue damage are two possible reasons for limited study of radiofrequency ablation in patients with superficial distant lymph node metastasis . here , we report two patients treated successfully with ultrasound - guided radiofrequency ablation for superficial distant lymph node metastasis . in these patients , deionized water was injected to the surrounding tissues of the lymph node to decrease heat injury . results from these patients suggest that radiofrequency ablation may play an important role in the treatment of patients with distant lymph node metastasis .

the vertical rectus abdominis musculocutaneous flap ( vram ) is a reliable method for primary closure of perineal skin defects up to medium size , which otherwise might have been left for healing by secondary intention [ 118 ] . the vram - flap is indicated not only for closure of perineal skin defects , following ( e.g. abdominoperineal resection of the rectum ) , but also for reconstruction of the posterior vaginal wall and not the least obliteration of dead - space in the pelvis following resection of the levator ani muscles . the flap provides well - vascularized tissue in an area , which frequently has been subjected to preoperative radiation therapy , and may contribute to wound healing [ 11,1620 ] . the flap can further prevent herniation of the bowel to a subcutaneous location in the perineum if the muscular portion of the flap is sutured to the remnants of the levator ani muscles . lateral undermining above the abdominal fascia can , if necessary , be performed to facilitate skin closure if a wide skin paddle has been used . the hernia is the most common donor site complication with a reported incidence of 19% , followed by skin infections reported in 1521% [ 2224 ] . wound infection is the most common perineal complication , reported in 1012% of patients in retrospective as well as prospective studies . wound dehiscence has been reported in 711% of the patients and wound abscess in 34% . less common complications in the perineum are partial or total flap and/or fat necrosis in the case of pedicle kinking or twisting . our report concerns a 52-year - old male patient presenting with an adenocarcinoma of the rectum t4b , n1b , m0 with metastatic spread to mesorectal lymph nodes and engagement of the right levator muscle . preoperatively , the patient received 50.4 gy radiation therapy and concomitant chemotherapy with capecitabine ( xeloda ) . the tumor downsized whereupon the patient was operated with an abdominoperineal resection of the rectum . due to engagement of the levator muscles and need of a wide skin excision , a reconstruction of the perineum with a musculocutaneous vram - flap was planned . in the supine position , a vram flap was then elevated with a skin island positioned vertically over the right rectus muscle , from slightly below the level of the umbilicus to the xiphoid . the entire posterior rectus sheath , as well as the anterior rectus sheath below the umbilicus , were left intact , and the rectus muscle was divided at the costal margin . the cranial tip of the elevated vram flap skin island was sutured to the rectal specimen , carefully securing a correct orientation of the flap when transferring it into the pelvic cavity to prevent twisting of the pedicle . a colostomy was constructed through the left rectus abdominis muscle before turning the patient to a prone position . after completion of the posterior dissection and removal of the rectum , the vram flap was pulled out through the perineal defect . the lateral and medial edges of the rectus muscle and the anterior rectus sheath were sutured to the remnants of the levator muscles . after de - epithelization of the distal portion of the skin island , a ct - scan showed small intestinal herniation at the level of the umbilicus ( figures 1 and 2 ) . the patient was readmitted to or and a herniation of the small bowel between the anterior rectus sheath of the lower abdomen and arcuate line / posterior rectus sheath was found . the bowel was considered viable and was repositioned into the abdomen followed by renewed and reinforced suturing of the upper posterior to the lower anterior rectus sheath . healing was thereafter without complications , and the patient could quickly be mobilized and subsequently discharged . at follow - up three weeks after discharge , the perineal and the donor areas had healed , and no signs of an incisional hernia or abdominal bulging were evident . posterior rectus sheath ( top arrow ) . herniated small bowel beneath the staple - lines ( middle arrow ) . intra - abdominally dilated and fluid - filled proximal loops of small bowel are visualized . posterior rectus sheath ( top arrow ) . herniated small bowel beneath the staple - lines ( middle arrow ) . intra - abdominally dilated and fluid - filled proximal loops of small bowel are visualized . left rectus abdominis muscle ( black arrow ) . at 1 year follow - up , the flap was viable and the perineum well healed . unfortunately , a routine ct - scan showed signs of tumor recurrence with peritoneal carcinomatosis . there are several options for perineal flap reconstruction , such as the gracilis flap , the inferior gluteal artery flap and the omental flap [ 24,2628 ] . an elegant , but technically more challenging , solution for perineal reconstruction is the rectus muscle sparing perforator flap based on the deep inferior epigastric vessels . in our experience , however , the vram - flap is robust , quick and useful for closure of perineal skin defects alone or with defects in the posterior vaginal wall . the flap further eliminates pelvic dead space if a wide resection of the levator ani muscles has been necessary . commonly , the right rectus abdominis muscle is used as the donor site , as the left usually is used for construction of a colostomy . our case illustrates that the semilunar or arcuate line , i.e. where the posterior rectus sheath connects to the peritoneum , can be a locus minoris resistentiae with respect to herniation of bowel when raising a vra flap . the semilunar line is sometimes rather a gradual distal thinning , than a distinct structure ( figure 3 ) , of the posterior rectus fascia below the level of the umbilicus . we have not routinely used alloplastic mesh for donor site reinforcement , but it must be considered if any risk factor of an incisional hernia is present . we suggest that the skin and fascial incision of the vram flap below the level of the umbilicus is limited , if possible , in order to enable a strong suture of the anterior rectus fascia to the distal part of the posterior rectus sheath . particular attention is to be taken in suturing the linea semilunaris / posterior rectus sheath of the upper abdomen to the anterior rectus sheath of the lower abdomen if the linea semilunaris is indistinct . the authors report no conflicts of interest . the authors alone are responsible for the content and writing of this article .

a patient with locally advanced adenocarcinoma of the rectum was operated with abdominoperineal resection and perineal reconstruction with a vertical rectus abdominis musculocutaneous flap . six days postoperatively , there was herniation of the small bowel , between the anterior and posterior rectus sheaths , to a subcutaneous location .

recent studies demonstrate roles for regulatory noncoding rna molecules ( ncrnas ) in normal cns development and function and in the onset and progression of various neurodegenerative diseases . ncrnas are functional rna molecules expressed specifically in the central nervous system that do not encode proteins . they are classified as small ncrnas comprising fewer than 400 nucleotides and long ncrnas comprising more than 400 nucleotides . small ncrnas include ribosomal rnas ( rrnas ) , transfer rnas ( trnas ) , small nucleolar rnas ( snrnas ) , micrornas ( mirnas ) , short small interference rnas ( sirnas ) , and piwi - interacting rnas . long noncoding rnas ( lncrnas ) include heterogeneous regulatory molecules such as long intergenic noncoding rnas ( linc rnas ) and natural antisense transcripts ( nats ) [ 13 ] . ncrnas play critical roles in neuronal processes such as transcription of neuronal genes , brain morphogenesis , neuronal cell specification , and formation of memory . micrornas ( mirnas ) are small rna molecules ( 2123 nucleotides ) involved in the regulation of gene expression that bind posttranscriptionally to the 3-untranslated region of target mrnas and either inhibit translation or degrade the target mrna . a single - stranded rna , mirna , is derived from a 70100-nucleotide hairpin precursor called pre - mirna that plays a key role in posttranscriptional regulation of target gene expression . due to their small size , mirnas are potentially a valuable tool for therapy of cancer , neurodegenerative , and cardiovascular diseases [ 5 , 6 ] . the mirnas are transcribed by either rna polymerase ii or iii in the nucleus to yield primary transcripts ( pri - mirnas ) of different lengths that are processed by the drosha / dgcr8 enzyme complex into a ~70 base pair precursor mirna . the precursor mirnas are transported into the cytoplasm where cytoplasmic rnase iii enzymes , dicer and loquacious , process them into ~22-nucleotide mirna duplexes with guide and passenger strands . the guide strand functions as a mature mirna and is incorporated into an rna - induced silencing complex ( risc ) . this complex contains an argonaute ( ago ) protein as a primary component that binds to the target mrna and degrades the passenger strand . mature mirna guides risc to recognize target sequences located in the 3utr of mrnas , which leads to the inhibition of translation or degradation of mrna [ 6 , 7 ] . neurodegeneration refers to the death of neurons during the normal course of brain development , and many studies demonstrate the involvement of mirnas . the mirnas are key regulators of cns development involving brain plasticity , neuronal cell maturation , neuronal cell differentiation , and synaptogenesis [ 8 , 9 ] . dysregulation of mirnas leads to the development of neurodegenerative diseases such as alzheimer 's disease , parkinson 's disease , and huntington 's disease . alzheimer 's disease ( ad ) is the most common form of dementia , among elderly adults , and causes memory impairment as well as problems with thinking , decision - making , and behavior . ad is characterized by dysregulated processing of amyloid precursor protein ( app ) and the accumulation of amyloid beta ( a ) peptide in brain hippocampus . -secretase , also known as -site app - cleaving enzyme 1 ( bace 1 ) , cleaves app to generate a peptides . several studies show that increased expression of app , an integral membrane protein , is associated with ad . . showed that mir-101 negatively regulates the expression of app and a accumulation in cultured hippocampal neurons , thus suggesting an essential role for mirna in the development and progression of ad . postmortem studies of human brain hippocampus showed increased levels of bace1 , upregulation of mir-9 , mir-125b , and mir-125b , mir-146a , and downregulation of mir-15a , mir-107 , and mir-29a / b-1 , which suggests a link between mirnas and protease in the progression of the disease [ 3 , 9 ] . decrease in the expression of mir-107 was observed in patients who exhibit early stages of ad . affymetrix exon array microarrays demonstrated a sharp increase in bace1 mrna expression and a decrease in mir-107 expression . in addition , the mir-29a / b-1 cluster is down - regulated in ad patient 's brain while upregulation of bace1 is observed , which suggests a role for the mir-29a / b-1 cluster in negative regulation of bace1 expression that leads to the accumulation of a peptide . certain patterns of mirna expression in the grey matter of cortex also lead to ad pathogenesis . mir-211 is downregulated in alzheimer 's disease brain , whereas there is an upregulation of mir-424 . a murine model of ad showed that there was no correlation between bace1 mrna and levels of proteins in the hippocampus of appswe / ps1 mice . . supports the concept that there is an association between dysfunctional mirna regulation of bace1 expression and ad by further analysis of mir-298 and mir-328 in the hippocampus of appswe / ps1 mice . in addition , a novel noncoding rna 17a expressed in human brain is upregulated in cerebral tissues of ad patients and leads to increased secretion of a peptides , gpr51 alternative splicing , and ultimately , impaired gaba b function . a similar study showed that neuroblastoma differentiation marker 29 ( ndm29 ) , a rna polymerase iii - dependent noncoding rna , enhances the synthesis of amyloid precursor protein , eventually resulting in an increase of a secretion that promotes the formation of a peptides as they may occur in alzheimer 's disease . nf-b signaling regulates mir-146a , which is upregulated in ad brains , and downregulation of cfh protein is observed in ad brains , which suggests that mir-146a targets cfh protein , a brain inflammatory response repressor . the death of dopamine generating cells in the brain substantia nigra and accumulation of alpha - synuclein leads to the development of parkinson 's disease , which is characterized by motor abnormalities and sensory , mood , and cognitive changes . a study suggests that -synuclein is regulated posttranscriptionally by mir-7 and mir-153 , which bind directly to the 3-untranslated region of synuclein and suppress its expression . in addition , downregulation of synuclein due to mir-7 and mir-153 protects cells from oxidative stress . in primary neurons , increased translation of a luciferase construct that bears synuclein 3-untranslated region was reportedly caused by inhibition of micro - rnas mir-7 and mir-153 . elevated levels of fibroblast growth factor 20 ( fgf20 ) genes also lead to overexpression of synuclein and eventually to the death of dopaminergic neurons . furthermore , this demonstrates that binding of mir-433 to a single nucleotide polymorphism in the promoter region of fgf20 disrupts the target site for mir-433 , which eventually results in overexpression of synuclein . downregulation of mir-7 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(mptp- ) induced neurotoxin pd mouse model suggests that it may protect cells against oxidative stress . the most vital gene in parkinson 's disease , lrrk2 that functions in the dopamine generating cells negatively regulates let-7 and mir-184 , which causes overexpression of their targets e2f1 and dp eventually , leads to defects in cell division and cell death . expression of mir-133b is detected in the midbrain dopaminergic neurons but not detected in parkinson 's disease midbrain tissue . a negative feedback loop with the transcription factor pitx3 , found in midbrain dopamine generating neurons , is formed by the downregulation of mir-133b , which is a dopaminergic neuron - specific mirna . furthermore , a recent study suggests that overexpression of synuclein by mir-433 leads to increased risk of ad . also , activation of two neuroprotective genes pten - induced putative kinase ( pink1 ) and parkinson disease 7 ( park7 ) normally involved in protecting cells from oxidative stress leads to development of parkinson 's disease through pten signaling . huntington 's disease is an autosomal dominant neurodegenerative disease characterized by cognitive decline and impaired movement . it is caused by trinucleotide expansion in the gene that encodes a polyglutamine stretch near the n - terminus of huntingtin . multiple studies of mirnas in mouse and human brain have shown mir-22 , mir-29c , and mir-128 are down - regulated in mice and mir-9/9 * , mir-29b , and mir-124a are down - regulated in humans [ 25 , 26 ] . showed that mir-221 and mir-222 are both down - regulated in hd . also , downregulation of mirnas let-7a , let-7c , let-7d , and let 7e was observed in hd - fc ( frontal cortex ) and hd - st ( striatum ) whereas there was upregulation of mir-30b , mir-30c , and mir-30e in hd - fc and hd - st . the mir-30a , that is , upregulated in hd - fc and hd - st has been shown to target bdnf , which is a rest - modulated neuronal gene . loss of bdnf leads to loss of medium spiny neurons [ 28 , 29 ] rest / corest regulates many mirnas . rest repressor complex regulates mir-9 and mir-9 * that target rest / corest expression and are considered to be a part of a double - negative feedback loop . expression of mir-9/9 * , mir-124a , and mir-132 is regulated by the rest repressor complex including msin3 , rest corepressor 1 ( corest ) , and mecp2 . rest silencing complex and mir-9/9 * give rise to a negative feedback loop during the development of huntington 's disease due to the effects of mir-9 and mir-9 * on rest and corest . several mirnas such as mir-9/9 * , mir-129a , mir-132 , mir-29b , mir-29a , mir-330 , mir-17 , mir-196 , mir-222 , mir-485 , and mir-486 are affected in hd due to the disrupted mirna transcriptome [ 27 , 30 ] . moreover , reports suggest that mir-34b is elevated in plasma of huntington 's disease patients even before the onset of symptoms , which implies that mir-34b may be useful as a potential diagnostic biomarker for hd [ 32 , 33 ] . clearly , there is evidence for mirnas as potential biomarkers to aid in the diagnosis of neurodegenerative diseases . for instance , rna interference ( rnai ) knocks down the translation of certain disease - associated molecules due to the presence of short hairpin rnas , synthetic double - stranded rnas , and the precursors of artificial mirnas that are expressed by viral vectors . these drugs are synthetic rna molecules that mimic a mechanism of action similar to that of endogenous ncrnas sirnas or mirnas . thus , rna interference technology has emerged as a potential therapeutic tool for several neurodegenerative diseases . wang et al . suggest the following two different potential roles of mir-146 : ( 1 ) as a useful biomarker in the early diagnosis of ad since it can be detected in human blood monocytes , which aids in easy collection , and ( 2 ) as a therapeutic tool . they also suggest that anti - mir-146a can be used with therapeutic potential to suppress the up - regulatory effects of mir-146 . another study conducted to examine the pattern of a driven neurogenesis in a transgenic mouse model of ad - tg-19959 showed that the use of lna - modified sirnas led to a marked decrease in the levels of insoluble a peptides and altered the pattern of aggregation of soluble a in the tg-19959 mouse brain by targeting bace1 and bace - as . identified two diagnostic biomarkers : dysregulation of mirna in ad patients ' brains and changes in mirna specific to ad in cerebrospinal fluid . several mirnas such as mir-133b , mir-7 , mir-153 , let-7 , mir184 , and mir-433 may be involved in the pathophysiology of pd and offer a novel approach for therapeutic targets . in addition , the mirna pathway is known to play a crucial role in translational regulation in the pathophysiology of pd and hence is considered one of the most important translation regulation pathways . ( 2005 ) showed notable signs of improvement in the behavioral abnormalities and neuropathology among hd patients with the use of an adenoassociated virus serotype 1 ( aav1 ) vector that targets the mutant human htt in the brain of mouse giving rise to u6 promoter - driven shrna effector system . in addition , noncoding small rna - based technology plays a pivotal role in the treatment of huntington 's disease . antisense oligonucleotides ( aos ) help to prevent mrnas bearing mutations by redirecting pre - mrna splicing . overall , data suggest that various noncoding rnas could serve as useful diagnostic biomarkers and therapeutic targets for neurodegenerative diseases . ncrnas , especially mirnas , are known for their roles in normal development and function of the central nervous system . they are involved in targeted gene expression and act as key regulators in several neuroprotective mechanisms . it is a well - established fact that dysregulation of mirnas eventually leads to the development of various neurodegenerative diseases . alterations in the patterns of mirna expression will probably serve as diagnostic biomarkers of brain function , and the initiation and progression of neurological disorders and neurodegenerative diseases . further research in mirna expression patterns and profiling will result in the discovery of many more novel biomarkers . in - depth study to determine the functions of long noncoding rnas in rna - mediated gene regulation is likely to remain an area of intense research interest .

noncoding rnas are widely known for their various essential roles in the development of central nervous system . it involves neurogenesis , neural stem cells generation , maintenance and maturation , neurotransmission , neural network plasticity , formation of synapses , and even brain aging and dna damage responses . in this review , we will discuss the biogenesis of microrna , various functions of noncoding rna 's specifically micrornas ( mirnas ) that act as the chief regulators of gene expression , and focus in particular on misregulation of mirnas which leads to several neurodegenerative diseases as well as its therapeutic outcome . recent evidences has shown that mirnas expression levels are changed in patients with neurodegenerative diseases ; hence , mirna can be used as a potential diagnostic biomarker and serve as an effective therapeutic tool in overcoming various neurodegenerative disease processes .

the infection is endemic in rural areas of the developing countries of asia , africa , latin america , and central europe . prevalence has been found to be mainly related to socioeconomic factors and feeding habits , especially in asia and africa . the illness is especially common in areas where pork is consumed such as sub - saharan africa , india , and in most countries of southeast asia . ncc is characterized by the deposition of cysticerci in the brain as a result of eating of undercooked pork . it is the most common parasitic disease of the central nervous system ( cns ) . ncc is reported to be responsible for nearly half of the late onset cases of epilepsy in the endemic areas , and is also associated with psychiatric manifestations . in an earlier study from venezuela , nearly 18% of patients admitted to a psychiatric hospital tested positive for cysticercosis on western blot test . most of the positive cases suffered from schizophrenia , organic mental illness , mental retardation , or epilepsy . clinical presentation of ncc is diverse and perplexing , varying from an asymptomatic form to a the polymorphous symptomatology seen in ncc is mimicked only by neuro - tuberculosis and neurosyphilis in india and other developing countries , and multiple sclerosis in the western countries . psychiatric symptoms are commonly a part of the clinical presentation of an infectious process . though psychiatric aspects of classic infectious diseases , such as neurosyphilis and newer infectious diseases such as human immunodeficiency virus ( hiv ) have been well described in literature and are well researched , psychiatric manifestations of ncc have not been investigated to that extent . usual presentation of ncc is with focal seizures or raised intracranial pressure due to internal hydrocephalus . though the disease is endemic in india , there are only a few reports on neuropsychiatric manifestations of the illness from india , with most publications limited to one or two cases . there are reports with ncc presenting as organic psychotic condition , mania , schizophrenia like symptoms or catatonic symptoms . sporadic cases of ncc have been described on investigations in patients with first episode schizophrenia in the western world . a study from brazil found signs of psychiatric morbidity in 66% of the patients with ncc . eighty eight percent of the patients showed some signs of cognitive decline . in a recent study from brazil , there a dearth of systematic studies on psychiatric manifestations is in ncc from india , though the illness is endemic . the present study was conducted to study the prevalence of psychiatric morbidity and its clinical correlates in patients with ncc . the study was conducted at the institute of human behaviour and allied sciences , delhi . patients presenting with epilepsy in the outpatient clinic or admitted to the inpatient facility of the neurology services were screened for the study . inclusion criteria for the case group included age 15 - 50 years and diagnosis of ncc , based on neuroimaging ( computed tomography ( ct ) scan / magnetic resonance imaging ( mri ) , wherever feasible ) findings , clinical features and immunodiagnostics . controls were patients with idiopathic epilepsy in the age group 15 - 50 with no evidence of ncc , based on neuroimaging , clinical features and immunodiagnostics , and no significant abnormality on imaging . patients with other primary neurological or medical conditions that could present psychiatric symptoms , current alcohol and substance abuse ( other than nicotine use ) and those refusing consent were excluded from the study . socio - demographic and clinical information was collected on a semistructured proforma designed for the study . detailed psychiatric history was taken and clinical diagnosis was made in discussion with a consultant psychiatrist . diagnosis was made according to international classification of diseases , 10 edition ( icd-10 ) criteria . the study was conducted at the institute of human behaviour and allied sciences , delhi . patients presenting with epilepsy in the outpatient clinic or admitted to the inpatient facility of the neurology services were screened for the study . inclusion criteria for the case group included age 15 - 50 years and diagnosis of ncc , based on neuroimaging ( computed tomography ( ct ) scan / magnetic resonance imaging ( mri ) , wherever feasible ) findings , clinical features and immunodiagnostics . controls were patients with idiopathic epilepsy in the age group 15 - 50 with no evidence of ncc , based on neuroimaging , clinical features and immunodiagnostics , and no significant abnormality on imaging . patients with other primary neurological or medical conditions that could present psychiatric symptoms , current alcohol and substance abuse ( other than nicotine use ) and those refusing consent were excluded from the study . socio - demographic and clinical information was collected on a semistructured proforma designed for the study . detailed psychiatric history was taken and clinical diagnosis was made in discussion with a consultant psychiatrist . diagnosis was made according to international classification of diseases , 10 edition ( icd-10 ) criteria . thirty one ( 62% ) subjects in the case group belonged to the age range 15 - 25 and 13 ( 26% ) to the age range 26 - 35 . the corresponding figures for the controls were 43 ( 86% ) and three ( 6% ) , respectively . twenty six ( 52% ) subjects in the case group and 39 ( 78% ) in the control group were never married . forty six ( 92% ) cases and 39 ( 78% ) controls were hindus and the rest were muslims . sample was predominantly urban with 78% of the cases and 86% of the controls belonging to the urban background . about half of the subjects in both the groups had studied for less than 10 years . there were no significant differences between the case and control group on various socio - demographic characteristics . thirty four ( 68% ) patients from the case group received a psychiatric diagnosis , compared to 22 ( 44% ) from the control group ( p=0.02 ) . major depression was the most frequent diagnosis in both cases ( 36% ) as well as controls ( 30% ) , followed by mixed anxiety depression diagnosed in 18% and 10% of the cases and controls , respectively . a few patients in the case group received other diagnoses like agoraphobia , panic disorder , generalized anxiety disorder , and others . psychiatric diagnosis in cases and controls lesions of ncc were present in 39 cases out of 50 , out of whom 25 patients had a psychiatric diagnosis . parietal area was the most commonly affected area ( 34% ) , followed by frontal ( 24% ) area . in 22% cases , fronto - parietal or temporo - parietal areas were affected . in patients with a psychiatric diagnosis , 17 had a left sided lesion , seven had a right sided lesion and one had disseminated lesions . patients having a lesion on the dominant side were more likely to suffer from a psychiatric disorder ( p=0.05 ) . patients in the case group scored higher on cprs items like apparent sadness ( p=0.03 ) , inner tension ( p=0.012 ) , hypochondriasis ( p=0.03 ) , phobia ( p=0.009 ) , falling memory ( p=0.002 ) , increased sleep ( p=0.004 ) , slowness of movements ( p=0.04 ) muscular tension ( p=0.000 ) , autonomic disturbances ( p=0.000 ) , aches and pains ( p=0.04 ) , and slowness of movements ( p=0.04 ) . scores on mmse ranged from 15 to 30 in cases ( mean 25.223.91 ) as well as in controls ( mean 25.183.43 ) . no significant difference was also observed on mmse scores between the cases with and without psychiatric disorder . subjects in the case group showed a higher frequency of partial seizures with or without generalization ( 24 , 48% ) , compared to the control group ( 12 , 24% ) ( p=0.05 ) . primary generalized seizures were more common in controls having idiopathic epilepsy ( 36 , 72% ) controls , as compared to the case group ( 24 , 48% ) . it is known to be a leading cause of epilepsy in endemic areas like india . the disease can also present as unfamiliar manifestations like disordered behavior , transient paresis , intermittent obstructive hydrocephalus , disequilibrium , meningoencephalitis , involuntary movements , failing vision , and mental disturbances . focus in the present study was on psychiatric morbidity in patients of epilepsy with ncc . we found psychiatric morbidity in 68% of the patients of epilepsy with ncc , which was significantly higher than the control group of patients of epilepsy without ncc . there was no difference in cognitive functions between the cases and controls , though both showed some cognitive decline in form of mmse score of about 25 . in an earlier study on psychiatric morbidity in ncc from brazil , psychiatric symptoms and cognitive decline depression was the most frequent psychiatric diagnosis , seen in 52.6% of cases and psychotic disorders were diagnosed in 14.2% . our sample was relatively younger with 88% of the patients in the age group of 15 - 34 , as compared to the brazilian sample which had a mean age of 36.7 years with a range of 18 - 60 . mean mmse score of our cases ( 25.22 , range 15 - 30 ) was comparable to the brazilian sample ( 26.9 , range 12 - 30 ) . prevalence of overall psychiatric morbidity was higher in the patients with ncc than those without ncc , though we could not get significant differences in the individual diagnostic categories due to small numbers in the individual categories . major depression and mixed anxiety depression were the two most common diagnoses , constituting 36% and 18% of the sample , respectively , which was slightly higher than 30% and 5.5% in the control group . the presence of high prevalence of depression among controls can be explained by the fact that depression can be a consequence of epilepsy . one recent study from brazil also found a high prevalence of depressive symptoms in epilepsy patients , in fact higher than those having epilepsy with ncc . depressive symptoms were also common in the controls to the extent of 100% in headache cases , 92% in epilepsy patients , but lower ( 83 - 88% ) in the ncc group . the study had an important limitation of assessing depression only using the hamilton rating scale of depression and not carrying out a clinical evaluation . our patients with ncc scored higher on cprs items like inner tension , hypochondriasis , phobia , lassitude , failing memory , increased sleep , reduced sexual interest , autonomic disturbances , aches and pains , and loss of sensation or movement as compared to controls . , in which 75% of cases had present state examination ( pse ) sub - scores suggesting non - specific neurotic syndromes . none of our patients reported psychotic symptoms or received a psychotic diagnosis , though forlenza et al . parietal lobe was the most affected area in our cases , followed by frontal lobe and disseminated lesions . left sided lesions were associated with more psychiatric morbidity , explained by the fact that a lesion of ncc on the dominant side accounted for the morbidity . the patients with ncc had more focal seizures due to the presence of a focus , whereas patients with idiopathic epilepsy had primary generalized seizures . psychiatric manifestations are more common in patients of epilepsy with ncc than those without ncc . ncc can lead to a range of psychiatric symptoms , mostly in the non psychotic spectrum . it is important to consider ncc in differential diagnosis of patients in endemic areas presenting with psychiatric symptoms , especially those showing poor response to the standard treatment and in those with history of seizures .

background : neurocysticercosis ( ncc ) is an endemic parasitic infection of asia , africa , latin america , and central europe . neuropsychiatric manifestations of the illness include epilepsy and behavioral disturbances . there is a dearth of systematic studies on psychiatric manifestations of ncc from various asian counties . the present study assessed the prevalence of various psychiatric disorders in a cohort of patients with ncc attending a neurological service.materials and methods : detailed psychiatric assessment was carried out on 50 patients of ncc with epilepsy and 50 patients of epilepsy without any evidence of ncc . comprehensive psychopathological rating scale was used to elicit the symptoms . cognitive functions were assessed using mini mental status examination . psychiatric diagnoses were made as per international classification of diseases , 10th edition ( icd-10).results : sixty eight percent of the patients with ncc suffered from a psychiatric disorder , as compared to 44% of those without ncc ( p=0.02 ) . major depression and mixed anxiety depression were the two most common diagnoses . none of the patients was to found to suffer from a psychotic disorder . the most frequent site of brain lesion of ncc was the parietal lobe , followed by frontal lobes and disseminated lesions . left sided lesions were associated with greater psychiatric morbidity . focal seizures with or without secondary generalizations were present more frequently in patients with ncc whereas primary generalized seizures were more common in patients with idiopathic epilepsy ( p=0.05).conclusion : psychiatric manifestations are more common in patients of epilepsy with ncc than those without ncc . the treating clinician need to be vigilant about the phenomenon .

the sequential deletion method and other biological and biochemical experiments are generally used to locate the functional domain of a protein . for example , a previous study ( 1 ) used the sequential deletion method accompanied by manual pcr primers design to generate the n - terminal truncated mutants of different lengths ( figure 1 ) , which in turn were used in further biological experiments to decipher the functional domain of the 5s rna - protein complex ( 5s rrnp ) . the 5s rrnp is believed to be formed by a co - translation event leading to the binding of the 5s rrna to the nascent ribosomal protein l5 . lin et al . ( 1 ) used an in vitro translation system to investigate how and when 5s rrna triggers the formation of the eukaryotic 5s rrnp . the l5 and truncated l5 mutant mrnas were prepared on a large scale for their investigation and a great amount of time was needed to manually modify the in - frame pattern of atg start codon for conventional pcr and truncated mutant translation experiments . the illustration of the produced n - terminal truncated mutants . in order to save time and money needed in the traditional sequential deletion method , this web - based application system ntmg is proposed to automatically do the multiplex pcr assays design in order to generate the various n - terminal truncated mutants . given a protein cdna sequence , the ntmg will first find those atg - like codons that are suitable to act as the starting positions of truncated mutants . then , the ntmg will design the forward primers for all possible truncated mutants . finally , with all these primers , the ntmg will choose those primers that can be divided into the least number of groups such that each group constitutes a multiplex pcr assay . in this section , we describe the input to the ntmg , the methodology of the ntmg and the output of the ntmg . since the primer design and the multiplex pcr primer design are two important parts of the ntmg , some factors concerning the primer design such as the primer length and the melting temperature are input as parameters . there are also some factors that may affect the multiplex pcr amplification with multiple primers in the same tube ( 2,3 ) . these factors include the cross - dimerization , the melting temperature , the products co - existence and others . figure 2 gives the input screen of the ntmg . on the top of the screen , the cdna sequence , the start codon address and the stop codon address are input . then comes four classes of parameters : primer criteria ( 47)these include the forward primer length ( default 2030 bp ) , the reverse primer length ( default 1428 bp ) and the gc content ( default 40 - 60%).temperature criteria ( 5,810)these include melting temperature ( default 5160c ) , the melting temperature range for each group ( default 5c ) , the molar concentration of monovalent cation ( default 50 mmol / l ) , the molar concentration of mg ( default 1.25 mmol / l ) and the dntps concentration ( default 0.02 mmol / l).complementary criteria ( 4,8,1012)these include the terminal repeated sequence ( default 3 bp ) , the intra self - complementary sequence ( default 3 bp ) , the specificity ( default 65% ) , the cross - dimer distance ( default 10 bp ) , the cross - dimer total similarity ( default 50% ) and the cross - dimer terminal similarity ( default 3 bp).grouping criteriathese include the product length difference ( default 80 bp ) and the maximum number of primers in each group ( default 16 ) . figure 2.the input screen of the ntmg . primer criteria ( 47 ) these include the forward primer length ( default 2030 bp ) , the reverse primer length ( default 1428 bp ) and the gc content ( default 40 - 60% ) . temperature criteria ( 5,810 ) these include melting temperature ( default 5160c ) , the melting temperature range for each group ( default 5c ) , the molar concentration of monovalent cation ( default 50 mmol / l ) , the molar concentration of mg ( default 1.25 mmol / l ) and the dntps concentration ( default 0.02 mmol / l ) . complementary criteria ( 4,8,1012 ) these include the terminal repeated sequence ( default 3 bp ) , the intra self - complementary sequence ( default 3 bp ) , the specificity ( default 65% ) , the cross - dimer distance ( default 10 bp ) , the cross - dimer total similarity ( default 50% ) and the cross - dimer terminal similarity ( default 3 bp ) . these include the product length difference ( default 80 bp ) and the maximum number of primers in each group ( default 16 ) . first , a cdna sequence is input , then the ntmg searches the sequence with in - frame criterion in order to find all the atg - like codons . an atg - like codon is a xtg , an axg or an atx with x representing a , t , c or g. for each atg - like codon , the ntmg generates candidate primers using the sliding window . the ntmg also modifies the atg - like codon into the atg codon in each candidate primer . hence , each candidate primer contains the atg start codon with in - frame criterion that can translate correctly to truncated mutants . after that , the ntmg applies the primary criteria and the secondary criteria to check if the candidate primers satisfy all the criteria . those candidate primers that pass the criteria checking are then divided into classes according to the melting temperature . each class contains primers whose melting temperatures are within the same range ( default 5c ) . so the primers chosen from the same class may be used in the same pcr experiment . for candidate primers in the same class , the ntmg does the cross - dimer check and the co - existence check and builds the cross - dimer matrix and the co - existence matrix . these two matrices are then anded to produce a new matrix which acts as an adjacency matrix of a graph . previous studies ( 13,14 ) proposed the transformation of minimizing the number of primers into the finding of the maximum clique in a graph . next , each class is further divided into subclasses according to the positions of the atg - like codons . the proposed genetic algorithm is then applied for each class in order to choose a set of primers , one from each subclass and the objective is to divide these primers into as few groups as possible such that each group of primers can be put in a tube in the pcr experiment . that is , the genetic algorithm tries to find a good multiplex pcr assay design . a heuristic maximum clique algorithm is proposed to calculate the fitness of a chromosome in the genetic algorithm . this heuristic algorithm tries to find the maximum clique in the graph previously mentioned and the maximum clique corresponds to the minimum number of grouping . the ntmg is written in java using java 2 platform standard edition 5.0 development kit ( j2sdk ) and employs the java server page ( jsp ) on the apache tomcat server ( http://tomcat.apache.org/ ) . the ntmg outputs the number of primer groups , the number of forward primers , the number of reverse primers and the primers in each group ( figure 4 shows a solution report ) . figure 2 gives the input screen of the ntmg . on the top of the screen , the cdna sequence , the start codon address and the stop codon address are input . then comes four classes of parameters : primer criteria ( 47)these include the forward primer length ( default 2030 bp ) , the reverse primer length ( default 1428 bp ) and the gc content ( default 40 - 60%).temperature criteria ( 5,810)these include melting temperature ( default 5160c ) , the melting temperature range for each group ( default 5c ) , the molar concentration of monovalent cation ( default 50 mmol / l ) , the molar concentration of mg ( default 1.25 mmol / l ) and the dntps concentration ( default 0.02 mmol / l).complementary criteria ( 4,8,1012)these include the terminal repeated sequence ( default 3 bp ) , the intra self - complementary sequence ( default 3 bp ) , the specificity ( default 65% ) , the cross - dimer distance ( default 10 bp ) , the cross - dimer total similarity ( default 50% ) and the cross - dimer terminal similarity ( default 3 bp).grouping criteriathese include the product length difference ( default 80 bp ) and the maximum number of primers in each group ( default 16 ) . figure 2.the input screen of the ntmg . primer criteria ( 47 ) these include the forward primer length ( default 2030 bp ) , the reverse primer length ( default 1428 bp ) and the gc content ( default 40 - 60% ) . temperature criteria ( 5,810 ) these include melting temperature ( default 5160c ) , the melting temperature range for each group ( default 5c ) , the molar concentration of monovalent cation ( default 50 mmol / l ) , the molar concentration of mg ( default 1.25 mmol / l ) and the dntps concentration ( default 0.02 mmol / l ) . complementary criteria ( 4,8,1012 ) these include the terminal repeated sequence ( default 3 bp ) , the intra self - complementary sequence ( default 3 bp ) , the specificity ( default 65% ) , the cross - dimer distance ( default 10 bp ) , the cross - dimer total similarity ( default 50% ) and the cross - dimer terminal similarity ( default 3 bp ) . these include the product length difference ( default 80 bp ) and the maximum number of primers in each group ( default 16 ) . the input screen of the ntmg . first , a cdna sequence is input , then the ntmg searches the sequence with in - frame criterion in order to find all the atg - like codons . an atg - like codon is a xtg , an axg or an atx with x representing a , t , c or g. for each atg - like codon , the ntmg generates candidate primers using the sliding window . the ntmg also modifies the atg - like codon into the atg codon in each candidate primer . hence , each candidate primer contains the atg start codon with in - frame criterion that can translate correctly to truncated mutants . after that , the ntmg applies the primary criteria and the secondary criteria to check if the candidate primers satisfy all the criteria . those candidate primers that pass the criteria checking are then divided into classes according to the melting temperature . each class contains primers whose melting temperatures are within the same range ( default 5c ) . so the primers chosen from the same class may be used in the same pcr experiment . for candidate primers in the same class , the ntmg does the cross - dimer check and the co - existence check and builds the cross - dimer matrix and the co - existence matrix . these two matrices are then anded to produce a new matrix which acts as an adjacency matrix of a graph . previous studies ( 13,14 ) proposed the transformation of minimizing the number of primers into the finding of the maximum clique in a graph . next , each class is further divided into subclasses according to the positions of the atg - like codons . the proposed genetic algorithm is then applied for each class in order to choose a set of primers , one from each subclass and the objective is to divide these primers into as few groups as possible such that each group of primers can be put in a tube in the pcr experiment . that is , the genetic algorithm tries to find a good multiplex pcr assay design . a heuristic maximum clique algorithm is proposed to calculate the fitness of a chromosome in the genetic algorithm . this heuristic algorithm tries to find the maximum clique in the graph previously mentioned and the maximum clique corresponds to the minimum number of grouping . the ntmg is written in java using java 2 platform standard edition 5.0 development kit ( j2sdk ) and employs the java server page ( jsp ) on the apache tomcat server ( http://tomcat.apache.org/ ) . the ntmg outputs the number of primer groups , the number of forward primers , the number of reverse primers and the primers in each group ( figure 4 shows a solution report ) . a web - based application system called the ntmg is provided for researches who need to apply the sequential deletion method to locate the functional domain of a protein . each group of primers can be put in a tube and all tubes can be accommodated in a single batch of the multiplex pcr amplification under the same condition . we conducted a wet laboratory experiment on the multiplex pcr assay design proposed by the ntmg on input hl5 cdna . the ntmg found 48 forward primers and one reverse primer and it divided them into 8 groups . in the wet pcr experiment , 44 pcr products had been found and the success rate is 91.7% ( see supplementary data ) . hence , the ntmg is of practical use to researchers who need to apply the sequential deletion method . as a future work , we plan to develop the more general multiplex pcr assay design . given a set of pcr experiment requirements , we plan to develop a system that can automatically find the primers and try to divide the primers into as few groups as possible such that the primers in each group can be put in a tube and all tubes can be accommodated in a single batch of the multiplex pcr experiment .

the sequential deletion method is generally used to locate the functional domain of a protein . with this method , in order to find the various n - terminal truncated mutants , researchers have to investigate the atg - like codons , to design various multiplex polymerase chain reaction ( pcr ) forward primers and to do several pcr experiments . this web server ( n - terminal truncated mutants generator for cdna ) will automatically generate groups of forward pcr primers and the corresponding reverse pcr primers that can be used in a single batch of a multiplex pcr experiment to extract the various n - terminal truncated mutants . this saves much time and money for those who use the sequential deletion method in their research . this server is available at http://oblab.cs.nchu.edu.tw:8080/websdl/.

the clinical aspects of asthma are paroxysmal respiratory distress , recurrent cough , wheezing , and chest tightness . park reported that acute asthma reversibly increases lung compliance and total lung capacity ( tlc ) . the authors confirm anecdotal evidence of a smaller horizontal curve of the ribs as a characteristic finding on chest radiographs of asthma patients . since the first rib is relatively short and the 12 rib is easily bothered by shadow of the diaphragm and abdominal soft - tissue ; the author chose the sixth rib for calculation of arc . because the number of ribs is 12 in each one side of chest , we choose the six ribs and using a chest radiograph of an asthma patient [ figure 1 ] , we drew a line ( ab ) horizontally through the middle point of the six ribs , and point c was defined as the crossing point where the six ribs reaches the thoracic cage . this was repeated for a non - asthma patient [ figure 2 ] , and we found the arc to be larger than that of the asthma patient . we then collected the same number of cases of asthma and non - asthma patients from a medical center in northern taiwan , and measured the arc for statistical analysis . ab was drawn horizontally through the middle point of the sixth rib ; point c is where the sixth rib reaches the thoracic cage . the angle between the lines ab and ac was defined as the angle of rib curve a chest radiograph of a non - asthma patient . we performed a retrospective review of 57 cases of asthma who were admitted between january 2011 and february 2011 , and 57 non - asthma patients who visited our emergency department without chest complaints for analyses . asthma in the study subjects was defined as discharged with a diagnosis of asthma from chest ward and labeled by a pulmonologist . non - asthmatic patients were randomized selected from emergency department in northern taiwan medical center without chest complaints and shortness of breath . exclusion criteria in non - asthmatic patients included presentation as dyspnea or any other chest complaint in the emergency department . the diagnosis of the 57 non - asthma patients admitted to the emergency department in northern taiwan medical center from march 1 , 2011 to march 10 , 2011 included gastroenteritis ( n=11 ) , trauma ( n=9 ) , urinary tract infection ( n=4 ) , depression ( n=4 ) , drug overdose ( n=3 ) , rhinitis / pharyngitis / tonsillitis ( n=3 ) , intracranial hemorrhage ( n=3 ) , headache / dizziness ( n=3 ) , abdominal pain ( n=2 ) , maylagia / neuralgia ( n=2 ) , upper gastrointestinal bleeding ( n=2 ) and infectious diarrhea , pneumonia , constipation , pelvic inflammatory disease , stroke , appendicitis , hyponatremia , convulsions , pancreatitis , hypertension and urolithiasis in one case each . we measured the arc of each case and analyzed the data using the spss statistical software ( spss for windows , version 11.0 , spss inc . , and chicago , il ) . the document number for pulling and reading medical records of the asthma patients is 2511243 . the student 's t - test was used for statistical analyses , and significance was set at a p value of less than 0.05 . the asthma group consisted of 15 males and 42 females with a mean age of 48.1 years ( sd 11.8 , range : 31 - 64 years ) . the non - asthma group consisted of 30 males and 27 females with a mean age of 35.2 years ( sd 12.2 , range : 20 - 61 years ) . the arc was smaller in asthma patients than in non - asthma patients ( 10.7 4.7 vs. 14.3 4.7 , p < 0.0001 ) . in the asthma group , the mean male arc was smaller than the mean female arc ( 8.4 4.1 vs. 11.5 4.7 , p = 0.026 ) ; however , there was no statistical difference in gender in the non - asthma group ( p = 0.405 ) [ table 1 ] [ figure 3 ] . in asthma and non - asthmatics patients , age is not significantly related to arc ( p = 0.714 , and p = 0.107 ) [ figure 4 ] . basic data and comparisons of age and angle of rib curves of the asthma and non - asthma groups ( ) = n , = significant statistical difference comparisons of angle of rib curves ( arcs ) in different groups by asthma , non - asthma , and gender . asthma male have the smallest arc than other group ( ) = n in asthma ( blue spots ) and non - asthmatics patients ( red spots ) , age is not significantly related to angle of rib curve ( p=0.714 , and p=0.107 ) asthma is commonly seen in daily clinical practice . it is a systemic disease that involves inflammation of the pulmonary airways and bronchial hyperresponsiveness leading to the usually reversible clinical symptom of a lower airway obstruction . in acute episodes of asthma , hyperacute asthma was so - called acute respiratory failure within 3 h after acute exacerbation of asthma . physiologically , bronchial hyperresponsiveness is documented by decreased bronchial airflow after bronchoprovocation with allergens such as cold air , respiratory tract infection , and cigarette smoke . the gross pathology of asthmatic airways displays lung hyperinflation , smooth muscle hypertrophy , mucosal edema , and mucus gland hypersecretion . acute reversible increases in tlc do occur during exacerbations of asthma was described in the year of 1990 . there was a significantly smaller arc in the asthma group than the non - asthma group , and a smaller arc in the males in the asthma group compared to females . the lesser curving of the ribs in asthma may results from the hyperinflation in asthma patients . in asthmatic patients , inspiratory with continuous outward motion of the upper anterior rib cage produced a horizontal aligned ribs in chest radiography . in non - asthmatics expiration , the respiratory muscles are completely relaxed , but this is not the case in patients with asthma . therefore , a smaller arc may be the anatomic consequence of asthma rather than the cause . female asthmatic patients have significantly lower strength of inspiratory and expiratory muscle than male , this related to this study 's finding of smaller arc in male asthmatic patients than female 's . lesser the hyperinflation associated with bronchoconstriction , lesser is the end - expiratory volume in the rib cage leading to larger arc . we all know that diagnoses of asthma including evaluation for reversibility of airflow obstruction and bronchial hyperresponsiveness , not depending on radiographic trait of chest radiographs . however , this study applied an interesting method and glance in raising suspicion of asthma patients . this is the first study to report that the ribs of asthma patients are less sloped than in patients without asthma . in the opinion of the author , this trait of the chest radiograph can help a physician arouse a suspicion of bronchial asthma in day to day clinical practice .

objectives : a novel and interesting observation is that ribs go less sloped in asthma patients radiograph than non - asthmatics people . the aim of this study was to investigate whether a smaller horizontal curve of the ribs is a special trait on chest radiograph of asthma patients.materials and methods : a retrospective review of the chest radiographs of 57 cases of asthma who were admitted between january 2011 and february 2011 , and 57 non - asthma patients was performed . chest radiographs were examined and lines drawn horizontally through the middle point of the sixth rib , and to where the sixth rib reaches the thoracic cage . the angle between these two lines was defined as the angle of rib curve ( arc ) . the arcs were then compared between groups using the student 's t-test.results:the mean arc was smaller in asthma patients than in non - asthma patients ( 10.7 4.7 vs. 14.3 4.7 , p < 0.0001 ) . in the asthma group , the mean male arc was smaller than the mean female arc ( 8.4 4.1 vs. 11.5 4.7 , p = 0.026 ) ; however , there was no statistical difference in gender in the non - asthma group ( p = 0.405).conclusions : this is the first study to report that the ribs of asthma patients are less sloped than in patients without asthma . this photographic trait may be helpful in daily practice for suspecting a diagnosis of bronchial asthma .

this study was performed at the olympic village polyclinic during the 2002 winter olympiad in salt lake city , utah , usa , during february and march 2002 . athletes and nonathletes with upper / lower respiratory symptoms ( with or without febrile / systemic illness ) were screened for influenza by various modalities . viral test results from the polyclinic and public health reports of influenza in the local community were reviewed daily . patients with ili or confirmed influenza were offered treatment with oseltamivir ; close contacts were offered prophylaxis ( detailed methods available from corresponding author by email ) . a total of 2,635 medical visits were recorded during the games ; patients with any respiratory symptom represented 12% . of these , 188 satisfied the symptom criteria for the study ( available from corresponding author ) and were screened for influenza ( table 1 ) . influenza a was detected in 28 ( 15% ) and influenza b in 8 ( 4% ) patients ( table 2 ) . athletes a isolates , 8 were further analyzed and found to be consistent with the a / sydney/97(h3n2 ) strain ( represented in the 20012002 vaccine ) . * all patient specimens were screened for influenza by direct fluorescent antibody ( dfa ) and viral culture . selected samples that were negative by dfa and viral culture were screened by reverse transcription polymerase chain reaction for influenza . rapid tests for influenza and streptococcal antigen were conducted on selected patients based on their symptoms and the clinician 's discretion . athletes are a significant group when influenza a cases alone are considered , odds ratio 3 , 95% ci ( 1.17.5 ) p = 0.03 . symptom duration was grouped as < 48 h or > 48 h. patients with confirmed influenza ( table 2 ) were more likely to be male , have a temperature > 37.8c , and have a history of cough or chills . no significant differences were found in symptom duration or influenza vaccination status among those with and without influenza . athletes were more likely to have a diagnosis of influenza a than other pooled groups of nonathletes ( odds ratio [ or ] 3 , 95% confidence interval [ ci ] 1.17.5 , p = 0.03 ) . twenty - five of 188 patients who were screened by direct fluorescent - antibody assay ( dfa ) for influenza were positive . when the results were compared to viral culture alone , sensitivity was 70% , specificity was 99% , positive likelihood ratio was 54 , and negative likelihood ratio was 0.3 . ten ( 6% ) of the 160 who received a rapid influenza test had positive results . the sensitivity of the rapid test for diagnosing influenza ( when compared to a confirmed diagnosis by viral culture , polymerase chain reaction , or dfa ) was 17% , while the specificity was 97% . the conventional syndromic definition of ili ( fever and either cough or sore throat ) ( 7 ) had a low positive likelihood ratio of 2.7 , negative likelihood ratio of 0.5 , sensitivity of 67% , and specificity of 78% in predicting influenza . of those with confirmed influenza , vaccinees were likely to have lower fevers , although the results were not significant . physicians prescribed oseltamivir for 60 ( 32% ) of 188 patients screened for influenza . of the medicated patients , 40 ( 67% ) were treated for ili within 48 hours of symptom onset ; influenza was confirmed in 21 . oseltamivir prophylaxis ( for 5 days ) was prescribed in 20 ( 33% ) patients who had a history of contact with influenza patients ; 1 case of influenza was confirmed in this group . cluster i consisted of 13 law enforcement personnel who worked and lived in close proximity . in early february , 3 members came to the clinic 4 days apart with ili , and influenza a was diagnosed ( 2 cases by dfa , 1 by viral culture ) . oseltamivir prophylaxis was promptly initiated in the remaining 10 asymptomatic members ; the oseltamivir was well tolerated . cluster ii consisted of 12 members of a national team who had trained together at a common location 3 days before their arrival at the olympic village . two days after they arrived , the index patient ( unvaccinated for influenza ) came to the clinic with ili of 24 hours ' duration and was given oseltamivir . upon confirmation of influenza a by dfa , unvaccinated asymptomatic close contacts of the patients were offered oseltamivir prophylaxis ; 8 of 11 accepted . in the next 4 days , 3 vaccinated teammates who had not received prophylaxis came to the clinic with ili of 24 hours ' duration . cluster iii consisted of 8 participants of 1 sport ( which had 80 participants with common training venues ) sought treatment at the polyclinic within 9 days with respiratory symptoms ( 5 had ili , 3 were afebrile ) . of the 3 afebrile participants , 2 were provided prophylaxis based on their contact history and symptoms . no reports of ili or confirmed influenza occurred among participants from this group after treatment / prophylaxis was initiated . this is the first systematic influenza study at any large international sports gathering and demonstrates the feasibility of managing influenza at such events . the intervention strategy integrated a policy of empiric treatment based on clinical data and viral testing with a public health surveillance approach , including daily review of all viral test results from the polyclinic and reports of influenza in the community . potential clusters of influenza were promptly identified , index patients were treated with oseltamivir , and contacts were given oseltamivir prophylaxis . we examined several methods of detecting influenza from respiratory samples and found dfa testing to be the most useful surveillance tool in this setting . this observation is consistent with the variability typically associated with rapid testing regarding patient age , duration of symptoms , type of kit , and timing of specimen acquisition ( 79 ) . the world health organization and others have suggested that vaccination is beneficial for athletes ( 2,4,1012 ) . although this study was not designed to address the effectiveness of influenza vaccination , we support issuing a public health alert that encourages administering influenza vaccine to all athletes and staff before a large international event is staged . team physicians may not have reported all episodes of ili to the polyclinic , though this scenario is unlikely , given their frequent direct communication . alternative strategies for influenza control , such as mass vaccination ( 13 ) , were not examined in this study . followup was not attempted since patients often dispersed to various international destinations after their events . in summary , the surveillance and intervention strategy used in this study may serve as a model for mobilizing teams to provide health care to a large assembly of participants . initiating empiric treatment for influenza based on clinical and epidemiologic data , combined with testing by dfa ( with subsequent confirmation by viral culture ) , may be a prudent approach to influenza control in large gatherings . similar approaches may enhance preparedness for public health threats and emerging respiratory pathogens such as avian influenza and agents of bioterrorism .

prospective surveillance for influenza was performed during the 2002 salt lake city winter olympics . oseltamivir was administered to patients with influenzalike illness and confirmed influenza , while their close contacts were given oseltamivir prophylactically . influenza a / b was diagnosed in 36 of 188 patients , including 13 athletes . prompt management limited the spread of this outbreak .

the humanized monoclonal antibody bevacizumab ( avastin genentech / roche ) is increasingly used to treat malignant solid tumors . this antibody recognizes and blocks vascular endothelial growth factor ( vegf)-a . the latter is a chemical signal that stimulates the growth of new blood vessels ( angiogenesis ) . in the kidney , podocyte - speci?c deletion of a single vegf allele causes proteinuria and capillary endotheliosis in rodents , and disrupted glomerular vegf signaling is strongly implicated in the pathogenesis of human preeclampsia , a syndrome characterized by proteinuria and hypertension [ 2 , 3 , 4 ] . in the institutional review case series described here , six patients developed a syndrome characterized by proteinuria and hypertension after starting therapy with bevacizumab . history of patients before commencing treatment , was unremarkable for hypertension and kidney disease , while urinalysis was normal . patients were identified clinically after developing edema , hypertension , proteinuria , and/or hypoalbuminemia ( table 1 ) . all six patients developed proteinuria grade 2 ( 23 + protein in dipstick urinalysis or 1.03.5 g in 24-hour urine for protein ) or higher , and new or exacerbated hypertension required on average two antihypertensive medications . glomerulonephritis and microangiopathic hemolytic anemia were excluded based on the results of blood and urine sediment tests . in most patients , subsequently , in patients with follow - up information , there was a dramatic improvement ( patients 1 , 2 , 3 , 5 ) of proteinuria . since 2003 , at least 481 patients have been treated with bevacizumab at our institution ; thus , the cumulative crude incidence of renal adverse events is 1.2% . however , the true prevalence of bevacizumab - associated renal toxicity is likely higher because patients were not routinely screened in a systematic , prospective , and long - term manner for the development of new proteinuria . interestingly , all patients experienced prolonged progression - free survival , defined as the time interval from treatment initiation to documented progression or death . with the exception of one of the patients , who received paclitaxel and bevacizumab as first - line treatment for metastatic breast cancer , all other patients received the antibody in combination with various agents as fourth- or fifth - line treatment . progression - free survival of more than 16 months for taxane / anthracycline refractory metastatic breast cancer , or of more than 6 months for a heavily pre - treated patient with metastatic non - small cell lung cancer , compared favorably to reported trials of such patient populations [ 5 , 6 ] . even the patient with small cell lung cancer died as a result of septic shock secondary to infection , without evidence of disease progression . nephrotic - range proteinuria , which denotes structural damage to the glomerular filtration barrier , occurs in 12% of bevacizumab - treated patients . although several potential causes of this type of proteinuria have been suggested [ 8 , 9 ] , it is difficult to distinguish the general effects of therapy , such as an immunologic response to the monoclonal antibody , from the direct effects due to inhibition of endogenous vegf signaling in non - cancerous tissues . recently , it was shown that local reduction of vegf within the kidney was sufficient to trigger the pathogenesis of thrombotic microangiopathy by the use of a conditional gene targeting to delete vegf from renal podocytes in adult mice . this resulted in a profound thrombotic glomerular injury , providing evidence that the glomerular injury of patients treated with bevacizumab is probably due to a direct targeting of vegf by the antiangiogenic therapy . given that the altered glomerular permeability appears to be a direct consequence of vegf inhibition , proteinuria may indeed correlate with drug efficacy . interestingly , hypertension , which represents another vascular toxicity of bevacizumab , has already been proposed as a predictive marker for antiangiogenic treatment efficacy . whether the development of proteinuria might also serve as a surrogate marker of antitumor efficacy is unknown . this could be proven only in the context of a clinical trial designed specifically to address this question . however , a large number of patients should be enrolled in such a study due to the relative low incidence of grade 2 or higher proteinuria . in addition , the recent fda oncologic drugs advisory committee 's vote in favor of removing the metastatic breast cancer indication from the drug labeling makes the design of such a trial highly unlikely . on the other hand , treatment options for these life - threatening advanced cancers are limited , and optimizing safe and effective drug dosing may be critical to achieve the best therapeutic impact . clinicians should be aware of the hypothesis that individuals experiencing bevacizumab - induced proteinuria potentially represent a group of patients who derive a great benefit from anti - angiogenic treatment and consider the pros and cons before withholding this effective anticancer therapy .

nephrotic - range proteinuria , which denotes structural damage to the glomerular filtration barrier , occurs in 12% of bevacizumab - treated patients . the glomerular injury and subsequent proteinuria is probably due to a direct targeting of vascular endothelial growth factor ( vegf ) . we report a case series of six patients who developed a syndrome characterized by proteinuria and hypertension after starting therapy with bevacizumab and who experienced prolonged progression - free survival . given that altered glomerular permeability appears to be a direct consequence of vegf inhibition , we hypothesize that proteinuria may indeed correlate with drug efficacy . optimizing safe and effective drug dosing is critical to achieve the best therapeutic impact due to limited treatment options for many life - threatening advanced cancers . clinicians should be aware that the development of proteinuria might serve as a surrogate marker of bevacizumab antitumor efficacy and determine the appropriate criteria for withholding this effective anticancer therapy .

tight regulation of gene activity at the transcriptional level plays a crucial role in orchestrating developmental processes , but control of gene expression is also important for the maintenance of the homeostatic situation or for the induction of the adaptive processes that are needed to anticipate on environmental changes . although changes in gene expression levels can now routinely be monitored on a genome - wide scale using microarray analysis , the molecular mechanisms and the specific transcription factors ( tfs ) that drive specific changes remain largely unknown . according to gene ontology annotations , the human genome contains more than 800 tfs , which have been characterized to varying degrees . for many of them , information on dna - binding sites is available and although most of this information is obtained using in vitro assays and only verified in independent assays in a limited number of cases , the major bottleneck for the use of transcription factor binding site ( tfbs ) profiles is that they are very short , often between 6 and 10 nt , and allow relatively high degrees of degeneracy in the sequence . as a result , most tfbss can be found in every randomly picked genomic segment of several thousands of bases , making predictions on the tfs , which can bind specific promoter regions and might regulate the expression of a gene , very difficult . the use of orthologous sequences may help in the recognition of conserved and , therefore , potentially functional sequences . although gene - coding sequences are readily identified by their overall high degree of conservation , the identification of short regulatory elements usually requires a special approach , especially at the level of the initial alignment of orthologous sequences . there is an important drawback to the use of the traditional local alignment programs , such as blast and fasta , as these programs can not deal very well with relatively long sequences with a high degree of divergence . to this end , several global alignment algorithms , such as lagan and avid ( 13 ) , and modified local aligners , such as blastz ( 4 ) , have been developed that aim for the best pairwise alignment of long sequences up to complete genomes . when applied to promoter regions , highly conserved elements can be revealed that can be queried for the presence of potential tfbss . however , correct alignment of binding sites with degenerated sequence of only 610 nt is still challenging for global alignment algorithms and may be easily missed , especially when using orthologous sequences from more diverged species . we have developed an alternative algorithm , conreal ( conserved regulatory elements anchored alignment ) that does not depend on prior alignment of orthologous promoter sequences ( 5 ) . first , all potential tfbss are determined independently for each orthologous promoter using tfbs matrices ( 6 ) . next , binding sites for the same tfs are anchored between the orthologous promoters , starting with the binding sites with the highest score and assuming colinear conservation of binding sites . we show that this algorithm performs just as well as other approaches that depend on prior alignment , when applied to closely related species , such as human , mouse and rat , but is more useful for aligning promoter elements of more diverged species , such as human and fugu , since it identifies conserved tfbss that are not found by other methods ( 5 ) . although we observed a major overlap in the predictions by different algorithms , the algorithm - specific sets of predicted sites are still significant . however , it is extremely difficult to conclude which approach performs best , owing to the lack of sufficient validated experimental data , and therefore we feel that it is important to include and compare different approaches for tfbs prediction . although this may not be very practical when analysing genome - wide regulatory networks , the analysis of individual promoters of , for example , one 's specific gene of interest may benefit from such an approach . to this end , we have developed a user - friendly web - interface to our conreal algorithm , with the option to include the lagan- , blastz- and avid - based algorithms , to identify and visualize conserved tfbss in orthologous promoters of interest . conreal web server requires as input a pair of orthologous sequences that can be either provided by a user or generated by the server through a three - step process . in the latter case , a user starts by providing a keyword or gene name ( figure 1a ) . a list of genes from the ensembl genome database ( 7 ) matching the query for the selected species will be returned , including gene description annotation and links to the ensembl database for additional information ( figure 1b ) . when a gene from the first species is selected , a list of orthologous ensembl genes becomes available for selection of the sequence from the second species for pairwise analysis . at this point , graphical representation of a gene structure is provided in gene coordinates , and the region of interest can be selected by specifying the range of the coordinates ( figure 1c ) . after all the necessary information is gathered , sequences are retrieved from ensembl database and forwarded to the conreal submission page , where parameters for the analysis can be specified ( figure 1d ) . there are three parameters that can be set : ( i ) threshold for position - weight matrices ( pwms ) that reflects how similar a pwm and a site could be ; ( ii ) length of sequences flanking tfbs to include for the calculation of identity between a pair of sites ; and ( iii ) threshold for percentage of identity in a pair of sites to be included in a final report . in addition , it is possible to specify one or multiple alignment methods to be used ( conreal , lagan , blastz and mavid ) and a source of pwms . vertebrate matrices from jaspar database of curated profiles ( 8) and 546 matrices from transfac database ( 6 ) . computations are performed in parallel on a linux cluster , allowing analysis of long sequences ( up to 20 kb ) within a relatively short period of time ( 12 min ) . results are visualized graphically showing aligned positions in the orthologous sequences and the density of predicted tfbs ( figure 2a ) . in addition , a pairwise alignment of sequences provides single nucleotide resolution information ( data not shown ) , and a table with predicted conserved tfbs , sorted by position in the alignment and linked to jaspar and transfac databases , supplies more detailed information on the tfs ( figure 2b ) . furthermore , when multiple algorithms were selected for analysis , the overlap between predictions by different algorithms is shown for every tfbs ( figure 2b , last column ) . conreal web server allows prediction of conserved tfbss in orthologous sequences . although similar web services exist , e.g. consite ( 9 ) or rvista ( 10 ) , the unique feature of conreal web server is that predictions can be performed by three different methods and compared with each other . this approach allows better interrogation of the region of interest , particularly when highly diverged sequences are analysed . additionally , a convenient interface for the retrieval of orthologous sequences from ensembl database is provided , improving accessibility for general usage without the need to go through laborious sequence retrieval processes that may need relatively advanced skills . the graphical visualization of the resulting alignments facilitates recognition of incorrect gene annotations ( e.g. first exon missing in one of the species ) and may help in defining the correct regions for reanalysis . . however , distant regulatory elements may be as far away as 110 mb and will be missed using this approach , but there is currently no good alternative computational approach to reliably identify such sequences . taken together , the conreal web server is a versatile tool that assists in the analysis of transcriptional regulation on a gene - to - gene basis , which may be useful for many different applications and research areas .

the use of orthologous sequences and phylogenetic footprinting approaches have become popular for the recognition of conserved and potentially functional sequences . several algorithms have been developed for the identification of conserved transcription factor binding sites ( tfbss ) , which are characterized by their relatively short and degenerative recognition sequences . the conreal ( conserved regulatory elements anchored alignment ) web server provides a versatile interface to conreal- , lagan- , blastz- and avid - based predictions of conserved tfbss in orthologous promoters . comparative analysis using different algorithms can be started by keyword without any prior sequence retrieval . the interface is available at .

the recent withdrawal of cerivastatin ( baycol or lipobay ) from the world market generated substantial attention in the lay media . according to press reports , the use of cerivastatin was linked to rhabdomyolysis , which lead to kidney failure , and was responsible for 31 fatalities in the united states and a further 21 deaths worldwide . in addition , there were 385 nonfatal cases reported among the estimated 700,000 users in the united states , most of whom required hospitalization . in many of the fatal cases , patients had received the full dose of cerivastatin ( 0.8 mg / day ) or were using gemfibrozil ( lopid ) concomitantly . the media reports caused concern among the users of all statins and triggered a large number of calls to treating clinicians . the american heart association and the american college of cardiology took a stand , by issuing a statement aimed at reassuring statin users that the five remaining members of this drug grouping lovastatin , pravastatin , simvastatin , atorvastatin , and fluvastatin are safe , that only in extremely rare situations do they cause rhabdomyolysis , and that the health benefits clearly outweigh any risks . simultaneously , however , the german government accused bayer of withholding vital information from its regulatory agency . other regulatory agencies in the united states and europe , are reviewing the safety data or considering changes to the labeling for the other five statins , and united states law firms are putting advertisements in the press for victims of rhabdomyolysis . at the time of withdrawal , baycol had slightly less than 4% of the statin market in the united states . the statin manufacturers are obviously concerned , since worldwide sales in 2001 are projected to be us$16 billion . this commentary will address the important clinical and public health questions , raised by the withdrawal of cerivastatin . cerivastatin , as well as other lipid - lowering agents , received initial regulatory approval based on their effects on serum lipoproteins . following approval , the three fermentation - derived statins simvastatin , pravastatin , and lovastatin have been shown to reduce the risk of mortality and/or major coronary events . however , the available documentation for long - term efficacy and safety for the synthetic statins atorvastatin , fluvastatin , and cerivastatin is weak or nonexistent . the fibrates were also approved based on surrogate efficacy , primarily , an increase in high - density lipoprotein ( hdl)-cholesterol . subsequently , gemfibrozil was shown to reduce coronary events in the veterans affairs hdl - cholesterol intervention trial ( va - hit ) , despite only a very small , observed increase in hdl - cholesterol . in contrast , bezafibrate , in the bezafibrate infarction prevention ( bip ) study , caused a marked increase in hdl - cholesterol but had no effect on the risk of coronary events . second , a drug may have multiple mechanisms of action , and reliance on one action for regulatory approval ignores the potential consequences of its other actions . statins are pleiotropic and have known effects on nitrate oxide availability and vascular inflammation that could be of clinical relevance . additionally , the dose - responses for these pleiotropic effects appear to differ from the dose - response for the low - density lipoprotein ( ldl)-cholesterol lowering effect , at least in animal studies . this raises questions about its recommended or optimal dose . if , in humans , these pleiotropic effects do contribute to the mortality / morbidity benefit of statins , and if their dose - responses are different , then it follows that the optimal clinical dose can not be determined from the ldl - cholesterol reduction . large , long - term outcome trials would be required to determine recommended dose and clinical efficacy . third , small short - term trials , designed to determine drug actions on lipoproteins , provide insufficient data on drug safety . unfortunately , there are no surrogates for drug safety . the practice of medicine ought to rely on direct scientific evidence of both efficacy and safety , rather than on extrapolations based on surrogate efficacy cerivastatin is at least 10 times more likely than the other statins to cause fatal rhabdomyolysis . statins may be similar in terms of clinical efficacy , but the current documentation for atorvastatin and fluvastatin is weak . however , several ongoing trials will provide important efficacy and safety information on these two agents . in the marketing of atorvastatin and fluvastatin , it has been implied that these two synthetic statins convey the same clinical benefits as the fermentation - derived statins . accordingly , the united states food and drug administration ( fda ) issued letters of warning to the manufacturers of these products , regarding their false claims about existing health benefits . the best clinical trial documentation of long - term safety and efficacy comes from large - scale trials of simvastatin and pravastatin . a recent meta - analysis based on three placebo - controlled trials with approximately 20,000 patients followed for over 5 years did not reveal any serious or unexpected adverse events . the practice of medicine ought to be based on scientific evidence for each individual drug rather than presuming that all drugs of a similar grouping are interchangeable . this question can only be answered for the statins that have been properly examined in large , long - term trials . clinicians can be certain that the known benefits clearly outweigh the known risks for simvastatin and pravastatin . documentation for lovastatin is fairly convincing , but is still insufficient for atorvastatin and fluvastatin . we take the position that large , long - term trials are desirable to evaluate individual drugs that are prescribed for lifelong use . initial approval of the first member of a novel class of therapeutic agents that has potential important health care benefits , may in some cases be justified on the basis of surrogate efficacy . however , subsequent drugs with similar mechanisms of action should not be rushed through the approval process but receive careful consideration regarding their net risk - benefit ratio and optimal dose , prior to regulatory approval . the cerivastatin experience supports the position that unexpected serious adverse events may not be detected until a large number of patients have been exposed for an extended period of time . in relative terms , it is quite likely that the clinical benefit of cerivastatin , yet unproven , could outweigh the minimal risk of fatal rhabdomyolysis . our assumption is that the regulatory agencies worldwide might have left cerivastatin on the market if it had been the only marketed statin . in the presence of other statins , in particular , simvastatin and pravastatin cerivastatin was clearly inferior . it will be interesting to see if drug inferiority in the future will be an important factor in the regulatory decision - making process . the issues raised in this commentary have implications , not only for the drug approval process but perhaps more importantly , for the public 's faith in prescription drugs . withdrawal of approved and widely used drugs such as cerivastatin , because of serious life - threatening side effects , erodes public confidence in the medical care system . a lack of confidence may , in part , be responsible for the increasing reliance of the general public on alternative medical therapies . approval of any drug for lifelong use on the basis of just a few thousand patients is risky and may not serve the public , as illustrated by the experience with cerivastatin and several other recently withdrawn drugs . curt furberg , none declared ; bertram pitt has been involved in trials of pravastatin , atorvastatatin , cerivastatin , and simvastatin . bip = bezafibrate infarction prevention ; va - hit = veterans affairs hdl - cholesterol intervention trial . fda = ( united states ) food and drug administration ; hdl = high - density lipoprotein ; ldl = low - density lipoprotein .

cerivastatin was recently withdrawn from the market because of 52 deaths attributed to drug - related rhabdomyolysis that lead to kidney failure . the risk was found to be higher among patients who received the full dose ( 0.8 mg / day ) and those who received gemfibrozil concomitantly . rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins . we address three important questions raised by this withdrawal . should we continue to approve drugs on surrogate efficacy ? are all statins interchangeable ? do the benefits outweigh the risks of statins ? we conclude that decisions regarding the use of drugs should be based on direct evidence from long - term clinical outcome trials .

the gastric bypass in its various forms has been performed since 1967 . in 1991 , the national institutes of health issued a consensus statement advocating surgery as the most consistent and effective therapy for morbid obesity . since then , obesity has become an epidemic with obesity rates of more than 20% in many states . with the advent of the laparoscopic technique in 1994 , bariatric surgery has continued to expand dramatically from 6868 cases in 1996 , 45473 cases in 2001 , to 103 000 cases by 2003 improved results have been documented with increased hospital volume and surgeon experience . many methods for laparoscopic construction of both the gastrojejunal ( gj ) and jejunojejunal ( jj ) anastomoses have been described . this represents a follow - up to our prior report describing the triple stapling technique for the jejunojejunostomy in 256 patients without incidence of obstruction or leak . a retrospective analysis of patients from 10/01 to 12/04 who underwent laparoscopic roux - en - y gastric bypass ( lrygb ) utilizing the triple stapling technique was done . the lrybg was performed by or under the supervision of the principal author ctf at a university affiliated program that maintains a fellowship in minimally invasive surgery . briefly , a 25-mm circular eea anvil ( us surgical , norwalk , ct ) was introduced transorally and brought out through the gastric pouch staple line after creation of an approximately 15-cc to 30cc lesser curvature based gastric pouch . the triple stapling technique ( tst ) for the jejunojejunostomy ( jj ) was performed by utilizing 2 firings of a 45-mm to 2.5-mm stapler each 180 degrees apart followed by closure with a final 45-mm or 60-mm to 2.5-mm stapler ( us surgical , norwalk , ct ) or ( ethicon , cincinnati , oh ) . the gastrojejunostomy ( gj ) was created using an antecolic antegastric right oriented roux limb . patients were ambulated later on the day of surgery unless they were admitted to the intensive care unit ( icu ) . a water soluble upper gastrointestinal ( ugi ) radiological study was done on the morning of postoperative day 1 . demographic data , body mass index ( bmi ) , operative data , and postoperative course were documented . follow - up was carried out at 1 week , 1 month , 3 months , 6 months , 1 year , and yearly thereafter . patients mean age was 41.1 years ( range , 14 to 68 ) , mean bmi was 49.7 ( range , 35 to 91 ) and 82% were females . one conversion to open ( 0.23% ) was necessary secondary to severe adhesions in a patient with 3 prior abdominal operations . concomitant procedures performed included hiatal hernia repair in 16 patients ( 3.7% ) , cholecystectomy in 27 ( 6.2% ) , near total gastrectomy in 1 patient with a gastrointestinal stromal tumor , partial gastrectomy in 1 patient with an antral polyp , splenectomy for idiopathic thrombocytopenic purpura ( 1 ) , partial left hepatic lobectomy for a symptomatic hemangioma ( 1 ) , and partial small bowel resection ( 2 ) secondary to an unreducible intussusception ( 1 ) , and jejunal diverticulum ( 1 ) . postoperative day 1 ugi testing was negative in all cases . ultimately , however , 3 leaks occurred at the gj anastomosis ( 0.7% ) . all 3 patients underwent reoperation on postoperative day 9 . despite prolonged hospitalization , all 3 patients survived . one patient with a history of non - hodgkin 's lymphoma in remission ( 0.2% ) had emesis and underwent repeat ugi that exhibited lack of progression of contrast beyond the jj . he underwent further reoperation twice with fascial biopsies and washout ; however , he eventually died on postoperative day 10 . autopsy did not reveal an intra - abdominal or systemic source of infection or rhabdomyolysis . patients required transfusion of an average of 2.21.1 units ( range , 0 to 5 ) , but none required surgical or endoscopic intervention . the first was described above ; the other was a 68-year - old patient with renal failure on dialysis who underwent an uneventful surgery but died later the day of surgery from a cardiac arrhythmia . gj stenosis occurred in 4 patients ( 0.9% ) and responded to endoscopic dilatation . in no circumstance was reoperation necessary . the availability of laparoscopic bariatric surgery and its many benefits has been instrumental in the dramatic increase in the number of procedures . the learning curve has been stated as 100 cases while nguyen et al have shown improved results with higher volume hospitals ( > 100 cases per year ) with regard to length of hospital stay , morbidity rate , and mortality rate . most authors utilize a double stapling technique that places the roux limb at risk for stenosis and obstruction . alternatively , many authors utilize a single stapling technique and subsequently close the enterotomy with a running suture . we feel that the best method to minimize the risk of stenosis , obstruction , or leak is the above - described triple stapling technique . creation of a wide side - to - side jejunojejunostomy and closure of the enterotomy in the center of this anastomosis has minimized the risk of stenosis or obstruction . it must be emphasized that particular attention must be given to avoid including the posterior wall when closing the enterotomy with the last firing of the stapler . it remains unclear whether the cause of the afferent roux limb obstruction in this series was due to obstruction from a technical error or possibly secondary to an obstructing clot . this patient had an unusual course with very high fevers reaching 107f despite negative cultures , muscle , and fascial biopsies and a negative autopsy . the patient 's prior history of non- hodgkin 's lymphoma may be related to the patients deteriorating course and intense systemic inflammatory syndrome response . we have thereafter been cautious in performing lrygb in patients with a prior history of treated malignant blood diseases . internal herniation has been documented in up to 4.5% of cases after laparoscopic retrocolic roux - en - y gastrojejunostomy . champion and williams documented a markedly reduced incidence of small bowel obstruction after changing from retrocolic to antecolic roux - en - y construction . the orientation of roux limb in antecolic roux en - y gastric bypass has been shown to have significant impact . changing from left to right orientation has decreased the rate of internal herniation from 9% to 0.5% . the transection of the jejunal mesentery with only 1 staple firing also pulls the jj cephalad juxtaposed closely to the gj anastomosis anterior to the colon and may also further reduce the likelihood of internal herniation . the absence of internal herniation in this series is therefore likely due to all of the abovementioned factors . in addition , no leaks have occurred at the jj . because leaks and anastomotic dehiscence as far as 7 weeks postoperatively have been reported with the use of absorbable sutures , leaks may also occur if the staple lines are too close together or are placed parallel to each other , thus resulting in ischemia with subsequent necrosis . the triple stapling technique utilizes coaxial followed by a perpendicular staple line and is therefore consistent and reproducible in avoiding ischemia and may be quicker in completing the jj . the cause of the higher incidence of gi bleeding in this series is unclear because endoscopy is not used postoperatively secondary to concerns of disruption of the fresh anastomoses . we have altered our dvt prophylaxis regimen as enoxaparin is now given beginning 12 hours postoperatively . it is too early to know whether this will result in lower gi bleeding rates . nevertheless , the intraluminal bleeding resolved spontaneously in each case with or without transfusion . in no case was reoperation necessary . studies typically document a 1.6% to 20% stenosis rate . in a study by go et al , a stenosis rate of 6.8% occurred at an average of 7.7 weeks ( range , 3 to 24 ) postoperatively . endoscopic dilatation was utilized an average of 2.1 times to relieve the stenosis with an ultimate 95% success rate and 3% complication rate that included 1 perforation . utilizing a 25-mm circular eea anvil placed transorally and brought out through the gastric pouch staple line construction of the jejunojejunostomy utilizing the triple stapling technique is expeditious , safe , and associated with minimal complications .

objective : to evaluate the outcomes of a single surgeon 's experience with laparoscopic roux - en - y gastric bypass ( lrygb ) utilizing the triple stapling technique for creation of the jejunojejunostomy.methods:a retrospective review of patients who underwent lrygb utilizing the triple stapling technique for creation of the jejunojejunostomy ( jj ) between 10/01 and 12/04 was performed.results:lrygb was performed in 435 consecutive patients . the mean age was 41 years ( range , 14 to 68 ) , and 82% were female . mean initial body mass index was 50 ( range , 35 to 91 ) . one conversion to open ( 0.2% ) was necessary . mean operating time was 14426 minutes . mean length of stay was 2.31.5 days . there were 3 leaks at the gastrojejunostomy anastomosis ( 0.7% ) . no leaks occurred at the jj anastomosis . one patient underwent revision of the jj ( 0.2% ) secondary to obstruction of the jj on upper gastrointestinal study . intraluminal bleeding occurred in 21 patients ( 4.8% ) . patients required blood transfusion of 2.21.1 units ( range , 0 to 5 ) , but none required surgical or endoscopic intervention . mortality occurred in 2 patients ( 0.5% ) . mean excess body weight loss was 72% at 1 year.conclusion:construction of the jejunojejunostomy utilizing the triple stapling technique is expeditious , safe , and associated with minimal complication .

owing to the large variety of morphologies reported , the possibility of synthetically fine - tuning their structure and their documented application in chemical and electrical devices , nanowires have come to represent a major field of research interest in recent years . among the features that can be synthetically controlled , variation of the crystal structure is particularly important by virtue of its role in defining manifold electronic properties . compared to nano particulate systems , the length of as - grown nano wires may be large relative to the nanoscale . this implies anisotropies in terms of properties , whereby there may be only two quantum - confined and one non - quantum - confined dimension manifest in the system . it is in this context that metal oxide , and especially wide band - gap semiconductors like zinc oxide , have become popular for , amongst other reasons , their possible applications in optoelectronics . in spite of a profusion of early experiments with magnetron sputtering , hydrothermal and melt growth having been reported , vapour phase techniques have become increasingly widespread for the synthesis of zno nanostructures of defined shape and size . the structural sensitivity of the resulting nanostructures with regard to the specific conditions of the technique and the experimental parameters has led to the results reported in the literature so far revealing quite diverse architectures . metal organic cvd ( mocvd ) has , for instance , proved to be a successful route by which to grow high - quality and structurally reproducible nanowires through the deployment of zinc acetylacetonate as a precursor . accordingly , the ease of use of this substrate and the extensive previous investigations reported into the experimental parameters affecting the growth behaviour induced by it by dalal et al . , have led to a vapour deposition method using a zno / graphite powder substrate being utilized for the present study . using this method , both monometallic and a variety of bimetallic nanoparticles have already been studied for their catalytic properties in nanowire growth . in previous experiments , however , the method of catalyst deposition , mostly itself performed by evaporation or sputtering of a very thin layer under high vacuum , has required expensive and demanding equipment . furthermore , due to there having been a lack of capping agents present , sputtered metal particles have tended to agglomerate in order to reduce their overall surface energies . , it is clear that particles synthesized by wet chemical routes may offer significant advantages , as their characteristics are not limited to the restrictions inherent in the pvd process . this has led us to extend our previous research on the versatile catalytic properties of pdzn nanoparticulates . both titanium and stainless steel tem sample grids were first tio2 coated by either dip or droplet coating with a ti(opr)4 solution and subsequently calcined under air at 500c ( see below ) . the prepared grids were dip coated with a methanol suspension of pdzn colloid ( molar metal ratio 50:50 ) with a total metal concentration of 0.490 mg / ml . as a control sample , a silicon wafer was coated with particles under the same conditions , but without having been previously tio2-coated , since highly polished si supports are known to be inactive in the cvd growth of zno nanostructures . cvd was then carried out in a quartz tube inside a carbolite furnace for 30 min at temperatures ranging from 560 to 820c . subsequent analyses were carried out by both hrsem and hrtem along with eds and saed . an overview of the parameter combinations investigated is shown in table 1 . selected images for titanium grids at 680 and 820c and for stainless steel grids at 640 and 760c initial colloid metal concentrations of 0.490 mg / ml were chosen for the catalyst coating . sample preparation and cvd conditions colloid metal concentration used for support coating : 0.490 mg / ml representative sem ( left ) and tem ( right ) images of samples a 2 ( stainless steel grid , dip coated , deposition temp . 640c ) , b 9 ( stainless steel grid , droplet coated , deposition temp . c(cat ) = 0.490 mg / ml ( see electronic supplementary information ) as fig . 1 shows , the chosen nanocolloid concentration of 0.490 mg / ml turned out to be highly active in promoting the catalytic growth of zno nanostructures . sem and tem analyses revealed a wide structural diversity in the resulting materials for the selected temperature and pressure parameters . in agreement with findings previously reported by the authors , a variety of morphologies formed in parallel with nanowires of homogeneous morphology . examples include three - dimensional nanoscale structures that constitute a near - continuous layer ( fig . 2 demonstrates the nanowires produced in this work have grown in the hexagonal wurtzite form of zinc oxide in all investigated cases . interestingly , for both grid materials tested , experiments conducted at deposition temperatures of below 700c yielded nanowires whose tips were capped by droplet structures ( e.g. fig . we take this to be indicative of a vapour - liquid solid ( vls ) growth mechanism . such an observation is interesting insofar as this mechanism , although common when different growth techniques are employed , has not previously been observed for the experimental conditions deployed here . repeated attempts have been made to investigate the nature and composition of the wire tip areas in order to establish the presence of palladium . ongoing work is seeking to overcome this limitation by deploying a higher resolution eds system . representative wire ( a ) and the corresponding saed pattern ( b ) of sample 8 ( stainless steel grid , droplet coated , deposition temperature of 680c ) the observation of zno nanomaterials that exhibit a partly randomized morphology in conjunction with high structure densities when compared to the results of experiments conducted using different catalysts , such as au , supports the conclusion that the presently employed pdzn systems represent highly active growth catalysts . furthermore , our results confirm previous investigations by dalal et al . , who pointed out the importance of parameters such as the oxygen partial pressure , the system pressure , the deposition temperature and the catalyst layer thickness in playing a crucial role in defining the specifications of the resulting nanowires in terms of their diameters and areal densities . the best results reported here were achieved using a droplet - coated ti grid and subsequent deposition at 820c to produce one - dimensional nanowire structures , which are morphologically homogeneous compared to different growth conditions ( sample 12 , fig . in comparison , the corresponding stainless steel grid produced predominantly two - dimensional nanobelt structures under otherwise identical conditions ( electronic supplementary information ) . using the same coating method , a stainless steel grid gave comparable wire structures at 760c ( sample 9 , fig . 1b ) , showing that the support metal must have an as yet unknown electronic influence on the particles , the nature of which is the subject of ongoing study . in this regard , our results seem to confirm the general trend , whereby higher temperatures allow greater morphological control over the formation of homogeneous wire structures as reported by choy et al . . using atomic layer deposition ( ald ) , the authors reported preferential growth of wires along the wurtzite c - axis at temperatures of 280c , with polycrystalline products being preferred at lower temperatures . in conclusion , we have demonstrated the high activity of pdzn nanoparticles in the cvd growth of zinc oxide nanowires . we have also shown that , using otherwise identical experimental conditions , the choice of both support metal and deposition temperature is of crucial importance for the resulting nanostructure morphology . on either grid material , and irrespective of coating method , increased temperatures tended to yield more one - dimensional and morphologically homogeneous structure types . thus , zno growth on titanium supports at 820c gave only homogeneous one - dimensional nanowires ( sample 12 , fig . ongoing work seeks to develop control over all parameters that influence nanowire morphology , including catalyst dimensions and composition . the present research demonstrates that an efficient zno nanowire growth catalyst can be generated without the need for high vacuum equipment . the refinement of precise control over nanocatalyst dimensions , defect density , structure and composition promises applications in the commercial manufacture of catalysts for the development of new zno nanowire devices . the online version of this article ( doi:10.1007/s11671 - 010 - 9567 - 4 ) contains supplementary material , which is available to authorized users . the authors would like to acknowledge the european commission ( noe excell nmp3-ct-2005 - 515703 , volker engels ) and the nokia research centre cambridge , uk , through the nrc / cambridge university framework research agreement project on large area sensing surfaces ( aron rachamim , sieglinde pfaendler and sharvari dalal ) . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and source are credited . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and source are credited .

zno nanowires have been grown by chemical vapour deposition ( cvd ) using pdzn bimetallic nanoparticles to catalyse the process . nanocatalyst particles with mean particle diameters of 2.6 0.3 nm were shown to catalyse the growth process , displaying activities that compare well with those reported for sputtered systems . since nanowire diameters are linked to catalyst morphology , the size - control we are able to exhibit during particle preparation represents an advantage over existing approaches in terms of controlling nanowire dimensions , which is necessary in order to utilize the nanowires for catalytic or electrical applications.(see supplementary material 1 )

newcastle disease ( nd ) is a highly contagious viral infection of avian species especially poultry caused by newcastle disease virus ( ndv ) , a paramyxovirus called avian paramyxovirus type 1 ( apmv-1 ) . although other host species are usually susceptible , the disease has a significant economic impact on poultry production . there are about nine strains of ndv which are distinguished on the basis of pathogenicity test . nd is mostly caused by velogenic strains of ndv rather than mesogenic or lentogenic strains which about 80100% and 25% mortality , respectively , from disease [ 35 ] . overall , seropositive rate of 32.5% was reported by for sokoto state , nigeria . reference reported a prevalence of 3.2% for ndv in clinically healthy chickens in nsukka area , nigeria . reference reported a higher incidence rate ( 68.4% ) of nd during the dry season against 34.6% in the rainy season and higher rate in the young ( 20.7% ) against 12.1% in the adult . newcastle disease can cause great mortality in birds without any clinical signs , sometimes reaching 100 percent in unvaccinated poultry flocks and even in vaccinated poultry . this disease is endemic , causing huge economic loses to farmers and hampering growth of poultry industries in nigeria , which has an estimated poultry population of 137.6 million , with backyard poultry population constituting 84% ( 115.8 million ) and 16% ( 21.7 million ) of exotic poultry . there is no means of treatment for this disease except vaccination which is not effective as outbreaks are reported yearly in vaccinated chickens . lack of data regarding the prevalence of this disease in most parts of nigeria has made policy formulation on controls and prevention difficult . therefore , this research was carried out to determine the prevalence of ndv in local chicken in the federal capital territory abuja , nigeria . this study was carried out in local chicken of different sexes in kubwa and lugbe , abuja - fct , nigeria . abuja is located on longitude 7 , 29 east and latitude 9 , 4 north . about five milliliter ( 5 ml ) of blood was collected into a sample bottle containing acd from each of two hundred ( 200 ) local adult chickens by exsanguination in kubwa and lugbe markets in abuja , federal capital territory , nigeria . sera were obtained by centrifugation and transported to the avian viral research unit , national veterinary research institute ( nvri ) , vom , plateau state , for laboratory analysis . antibody titer for ndv was determined from each serum sample using the oie hi test protocol . briefly , 0.025 ml of pbs was dispensed into all wells of a plastic 96-well microtiter plate ( v - bottomed wells ) and 0.025 ml of serum was placed in the first well . 0.025 ml of the positive control serum ( with known hi titer ) and negative control sera were added to two respective wells of the microtiter plates . with the aid of a multichannel micro pipette , the last 0.025 ml was discarded and 0.025 ml of antigen containing 4 hau was added to all the wells except row h which serves as back titration . back titration was carried out ; thus , 0.025 ml of antigen suspension containing 4 hau was added into each of the first two wells of row h ( 4 hau control from h1h6 ) , and twofold dilution was made from h2 to the h6 and the last 0.025 ml was discarded in order to obtain 4 , 2 , 1 , 0.5 , 0.25 , and 0.25 hau . 0.025 ml of pbs and albumin was added in all wells of row h and mixed by tapping gently and plates were placed at 20c for 30 minutes . mixing was done gently by tapping and the plates were placed on the bench at 20c for 30 minutes and observed for hi . geometric mean of hi antibody titer ( gmt ) and percentages of detectable ndv hi antibody titer were calculated . the statistical package for social sciences ( spss ) programme ( version 13 ) was used to compare if there was any significant difference between the geometric means of the hi antibody titer . result showed that the seroprevalence rate of ndv antibodies for kubwa village market was 15 positive samples ( 30.0% ) , kubwa monday market had 7 positive samples ( 14.0% ) , gaso lugbe market had 6 positive samples ( 12.0% ) , and sabo lugbe market had 6 positive samples ( 12.0% ) . the mean hi titer for the respective markets includes 5.1 , 4.9 , 5.0 , and 5.5 ( table 1 ) . the present study revealed the prevalence of haemagglutination antibodies in samples from the four markets in kubwa and lugbe and this indicates that newcastle disease virus infection is endemic in the area , and the markets are serving as mixing point of infected birds with susceptible ones . the sellers and buyers as well as there is therefore a great threat to commercial poultry production in the federal capital territory . the implication of the spread and the carrier status of the rural household chickens could be of importance considering the fact that rural chickens were reported to constitute over 90% of chicken population in nigeria and are capable of scavenging around the environment spreading of the ndv to vaccinated and unvaccinated healthy exotic birds . haemagglutination inhibition ( hi ) antibody titer between 0log2 and 3log2 is considered negative because they produce no antibody against the virus while hi antibody titer between 4log2 and 8log2 is considered positive for antibodies production against the virus based on oie recommendation of 2000 [ 8 , 9 ] . in all the four ( 4 ) markets studied an hi antibody titer of 4log2 and the above ones were observed and this is indicative of exposure to the virus at one time or the other and eventual production of neutralizing antibodies to protect the chicken up to the point of sale . the high hi antibody titer may be due to infection by a virulent strain of the virus such as mesogenic strains which are viruses causing clinical signs consisting of respiratory and neurological signs with low mortality and lentogenic strains which are viruses causing mild infection of the respiratory tract without visible morbidity and mortality . in the us , however , the virus has been eradicated due to stringent adherence to poultry management rules and any virulent strains are of foreign origin from places where strict compliance to management regulations and good sanitary practices is lacking . from the table , the overall ndv seroprevalence of 17.0% obtained was lower than the result obtained by ibitoye et al . in a retrospective study where they reported an ndv seroprevalence of 80.9% for chicken in sokoto state . this may be due to the seasonality of ndv having high occurrence in the months of march and october which coincide with onset of the rainy season and dry season , respectively . the high wind movement transfers infection from one poultry house or flock to the other [ 7 , 9 ] . fct is neighbour to plateau state where the national veterinary research institute is situated and thus could be benefiting from the surveillance services of the institute , thus stemming the tide of the disease . the seroprevalence of ndv antibody was higher in kubwa village market ( 30.0% ) than in kubwa monday market ( 14.0% ) and other markets studied . the high rate may be due to the higher concentration of commercial poultry in kubwa village market than the other markets studied . higher seroprevalence rate of newcastle disease virus antibodies was detected in both household ( 26.8% ) and live bird markets ( 35.8% ) and an overall seropositive rate is 32.5% by jibril et al . . village chickens are naturally resistant and can withstand the infection without showing any clinical symptoms , thus acting as potential source of infection for commercial chicken . this means that village chickens act as host / carrier of ndv ; thus , chickens raised in the backyard of farm workers could increase the threat of nd outbreaks [ 9 , 12 ] . management practices such as disease monitoring programme , appropriate prevention , and control measures should be put in place in order to prevent loss of poultry and income due to outbreaks of the disease . new birds should be quarantined and local poultry farmers should ensure that they vaccinate their flocks . most importantly , awareness programme among the farmers about the disease and routine survey to assess the degree of newcastle disease distribution will help in planning appropriate intervention strategy . newcastle disease virus is prevalent in local chickens sold in the four markets studied in fct which are likely to serve as host / carrier of ndv to commercial flocks . further studies are required to determine the strains circulating in order to control them appropriately .

newcastle disease is a contagious disease of birds and is the greatest constraint to the development of rural poultry production in nigeria and most developing countries . the only effective means of control is vaccination which is not properly carried out in nigeria . therefore , this project determined the prevalence rate of newcastle disease virus ( ndv ) in local chicken in the federal capital territory , abuja , nigeria . about 5 ml of blood was collected from each of 200 chickens at the point of sale by exsanguination and sera obtained were analyzed using haemagglutination inhibition ( hi ) test to determine the prevalence of ndv . of the 200 samples screened 34 were positive for hi antibody to ndv giving a prevalence rate of 17% . the prevalence rate obtained in this study is significant ( p < 0.05 ) and indicates endemicity of the disease . there was no statistically significant ( p > 0.05 ) difference in the seroprevalence of ndv antibodies among the four markets studied . further studies are required to determine the strains circulating for appropriate preventive and control measures .

autophagy , responsible for a variety of cellular homeostasis functions , is necessary for the degradation of long - lasting proteins and nonfunctional organelles . when over - activated , however , the process of autophagy may deplete essential molecules and organelles responsible for cellular survival . it has been shown that lifelong calorie restriction by 40% increases the expression of autophagic markers in the heart . this finding implies that up - regulation of autophagy by calorie restriction may have a protective role on the cardiomyocytes by reducing levels of oxidative damage due to aging and cardiovascular diseases . one study has shown that a lack of atg5 , a cardiac - specific protein that is required for the activation of autophagy , leads to cardiac hypertrophy , left ventricular dilatation , and contractile dysfunction , along with increased levels of ubiquitination . this study also demonstrated that a reduced expression level of atg7 , a protein necessary for the formation of autophagosome , is responsible for reduced cellular viability and remarkable features of cardiomyocyte hypertrophy . in addition , lysosomal - associated membrane protein 2 is thought to be involved in the pathogenesis of cardiomyopathy , as its deficiency has been shown to accumulate autophagic vacuoles and impair the autophagic degradation of dysfunctional proteins . overall , these findings unanimously support that cardiomyocyte autophagy is essential for controlling protein quality , and maintaining cellular function and survival . however , it should be noted that increased or excessive autophagy may be detrimental under some circumstances , including pressure overload - induced heart failure . glucose deprivation , a condition similar to myocardial ischemia , induces autophagy , while pharmacological inhibition of autophagy has been shown to reduce cellular survival in cultured cardiomyocytes . it may serve to maintain energy production in response to energy deprivation , including acute ischemia , and also may be responsible for the clearance of long - lived proteins and dysfunctional organelles during chronic ischemia or reperfusion . macroautophagy degrades proteins and organelles , thereby generating fatty acids and amino acids that are all used for mitochondrial adenosine triphosphate ( atp ) production , which promotes cardiomyocyte survival . adenosine monophosphate ( amp)-activated protein kinase ( ampk ) is an energy sensing kinase , taking action when the cellular amp - to - atp ratio increases . ampk activates autophagy by activating ulk1 , a serine / threonine - protein kinase , and by relieving the mammalian target of rapamycin ( mtor)-mediated inhibition of macroautophagy . mtor tightly regulates autophagy by inhibiting the ulk1 kinase complex and accordingly prevents autophagy activation , along with phosphorylation of the tuberous sclerosis complex ( tsc ) . this signaling pathway is accordingly called ampk - mtor , and is considered critical in regulating the activation of autophagy under circumstances such as energy stress and glucose starvation ( fig . 1 ) . the tsc - mtor pathway can function in diabetic hearts . in diabetic hearts , phosphorylation of raptor at both ser722 and ser792 is decreased , and phosphorylation of mtor at both ser2448 and thr2446 is increased . also , 4 e binding protein 1 and p70 ribosomal protein s6 kinase 1 , downstream effectors of mtor , are increased . studies collectively suggest that mtor complex 1 ( mtorc1 ) activation may be detrimental under cardiac energy deprivation , while mtorc1 inhibition is protective because of energy preservation . in addition , it has been revealed that mtorc1 activation may be responsible for cell growth . rheb , a ras homolog guanosine triphosphate - binding protein , is inhibited in response to energy deprivation for autophagy activation . in addition , suppression of autophagy activation by inhibiting beclin-1 counteracts the protective action of rheb protein for energy deprivation . the action of rheb - regulated autophagy has been shown to be protective against nutrient starvation and ischemia in cardiomyocytes through the preservation of atp content and the reduction of misfolded protein accumulation . rheb controls the activation of autophagy partly through atg7 , where atg7 overexpression induces autophagy and suppresses rheb - induced cell death in response to glucose deprivation . in addition , mtorc1 may be involved in regulating autophagy through ulk1/2 regulation , though its exact function remains to be elucidated . under a starvation state , such as in myocardial ischemia , ampk acts as a checkpoint by suppressing cellular growth and promoting autophagy activation in cardiomyocytes . therefore , the ampk - mtor pathway is certainly a crucial regulator of autophagy in such circumstances , as inhibition of ampk reduces autophagy and increases cell death in cardiomyocytes . this phenomenon was also observed in transgenic mice with cardiac - specific expression of a dominant negative ampk . this setting has shown reduced autophagy induction in states of fasting in vivo , which suggests that ampk - induced autophagy may be controlled by inhibiting the expression of mtor in response to ischemia . one study has shown that glycogen synthase kinase ( gsk)-3 , an enzyme involved in gene transcription regulation , protein translation , and apoptosis , as well as hexose metabolism , may be a regulator of the mtor pathway in cardiomyocytes . in addition , inhibition of gsk-3 has been reported to be cardioprotective [ 17 - 20 ] by inhibiting mtor signaling and thus activating autophagy via phosphorylation of tsc2 . the function of gsk-3 also includes the regulation of mtor during both myocardial ischemia and reperfusion . in response to glucose deprivation , cardiomyocytes initiate the nuclear translocation of foxo1 and foxo3 to the nucleus where the transcription of genes responsible for autophagy are activated . foxo3 overexpression in the heart is associated with increased autophagy , which may be related to the development of cardiac atrophy , while genetic deletion of foxo3 resulted in the development of cardiac hypertrophy . under a starvation state , sirtuin 1 ( sirt1 ) , a nad - dependent deacetylase , is up - regulated . sirt1 mediates the deacetylation of foxo1 and upregulation of rab7 , which functions as the center for mediating increased autophagic flux in response to starvation , which in turn maintains left ventricular function during these events . atg13 binds to atg1 and atg17 in response to glucose deprivation , promoting the induction of autophagy at the phagophore assembly site . this complex can be found in yeast ; the mammalian counterpart shows slight differences . during starvation , mtor dissociates and promotes the activation of ulk1 , which up - regulates autophagy by increasing the phosphorylation of matg13 and focal adhesion kinase interacting protein of 200 kd ( fip200 ) . a class iii phosphoinositide 3-kinase ( pi3k ) complex is then recruited to the assembly site and vps34 lipid kinase protein binds to the phagophore via vps15 . this complex contains beclin1/atg6 and atg14 , which control the induction of vps34 lipid kinase protein . it is believed that this lipid kinase is an essential protein for recruiting additional atg proteins , where they complete the autophagosome formation . under nutrient - rich conditions , including obesity , the akt signaling pathway is activated , and akt phosphorylates and activates mtor kinase and the foxo family . it has been shown that inhibition of the tor pathway is responsible for cardioprotection against cardiac dysfunction induced by a high fat diet . activated mtor interacts with ulk1 , the mammalian atg13 , and fip200 complex . 1 ) . high fat diet - induced obesity activates the rheb / mtorc1 pathway and reduces the activation of autophagy in the heart of mice . increased myocardial injury in these mice in response to prolonged ischemia suggests that an increased level of mtorc1 activity may be associated with an increased susceptibility . it has been demonstrated that reactivation of autophagy is a critical mechanism underlying the beneficial effects of mtorc1 inhibition in high fat diet - induced obesity , as shown in the failure of pharmacological mtorc1 inhibition to reduce ischemic injury by inhibiting beclin-1 . physiological inhibition of the rheb - mtorc1 signaling pathway during myocardial ischemia can be impaired in such conditions as obesity and metabolic syndrome , which consequently exacerbates myocardial injury . this rheb - dependent mtorc1 pathway seems to be critical in regulating the activation of autophagy during ischemia in cardiomyocytes and its dysfunction is thereby associated with human diseases . nonobese mice with fructose - induced insulin resistance have shown activation of myocardial autophagy , while ossabaw swine with excessive nutrition have shown inhibition of cardiac autophagy , which may be responsible for myocardial injury . the expression of conjugated atg12-atg5 is increased in obesity and metabolic syndrome , as well as in defective hepatic autophagy of obese individuals , while unc-51-like kinase-1 , beclin-1 , and lc3 conversion , which are indicative of autophagic activity , all decrease in metabolic syndrome , indicating the suppressed formation of nascent and mature autophagosomes . in addition , insulin resistance impairs the action of autophagy as highlighted by the up - regulation of the autophagy inhibitor mtor in metabolic syndrome . on the other hand , sirt1 is responsible for activating autophagy by inhibiting the expression mtor ; its down - regulation may be associated with the inhibition of autophagy in metabolic syndrome . inhibition of autophagy , in turn , leads to accumulation of dysfunctional cellular organelles and proteins that thereby result in apoptosis or cell death . insulin receptors are activated in nutrient - rich conditions , which in turn switches on enzyme class i pi3k . this enzyme acts to modify the lipid phosphatidylinositol in the plasma membrane and leads to tor up - regulation and autophagy inhibition [ 38 - 40 ] . increased numbers of autophagosomes have been observed in patients with left ventricular hypertrophy , hibernating myocardium , aortic valve stenosis , and heart failure . unfortunately , the exact roles of autophagy activation in cardiac diseases have not been fully elucidated . it is still ambiguous whether autophagy is activated to promote cell death in these conditions , or to prevent it . the increased expression of autophagic proteins and occurrence of autophagic vacuoles in chronic myocardial ischemia suggest that autophagy may show cardioprotective effects . this cardioprotective role of autophagy has also been implicated in the autophagic degradation of dysfunctional organelles , misfolded proteins , and the importance of autophagy in nutrient supply and preservation of energy in times of limitation , such as ischemia . some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation , mitochondrial dysfunction , fibrosis , apoptosis , and myocardial autophagy . further research on autophagy is warranted to clarify whether autophagy plays a beneficial role or has a deleterious effect , and to elucidate the exact role of autophagy in obesity - associated cardiac dysfunction .

autophagy is necessary for the degradation of long - lasting proteins and nonfunctional organelles , and is activated to promote cellular survival . however , overactivation of autophagy may deplete essential molecules and organelles responsible for cellular survival . lifelong calorie restriction by 40% has been shown to increase the cardiac expression of autophagic markers , which suggests that it may have a cardioprotective effect by decreasing oxidative damage brought on by aging and cardiovascular diseases . although cardiac autophagy is critical to regulating protein quality and maintaining cellular function and survival , increased or excessive autophagy may have deleterious effects on the heart under some circumstances , including pressure overload - induced heart failure . the importance of autophagy has been shown in nutrient supply and preservation of energy in times of limitation , such as ischemia . some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation , mitochondrial dysfunction , fibrosis , apoptosis , and myocardial autophagy .

scoliosis surgery can often be complicated by postoperative paralytic ileus and superior mesenteric artery ( sma ) syndrome.1234 both , conditions have usually a benign course and resolution of the symptoms should be expected with early instigation of conservative management . their clinical appearance can , however , mask that of an acute colonic pseudo - obstruction ( acpo ) which if left untreated can result in bowel ischemia and perforation with an estimated mortality rate of 40%.5 acpo was first described by the british surgeon sir william heneage ogilvie in 1948 when he reported 2 patients with chronic colonic dilatation associated with malignant infiltration of the celiac plexus.6 in his original report , ogilvie attributed the condition to sympathetic deprivation.6 it is now recognized that a probable explanation of the syndrome is imbalance in the regulation of the colonic motor activity by the autonomic system , which leads to excessive sympathetic stimulation or parasympathetic suppression . ogilvie 's syndrome presents with symptoms , signs and radiographic appearance of acute large bowel obstruction of nonmechanical aetiology . the clinical features include abdominal distension and pain ( 80% ) , as well as nausea with or without associated vomiting ( 60%).57 plain abdominal x - rays demonstrate varying degrees of colonic dilatation with the right colon and cecum being most markedly distended . the clinical examination confirms a dilated , tympanitic abdomen with preserved but hypoactive bowel sounds . the differential diagnosis should include mechanical obstruction , faecal impaction , cecal or sigmoid volvulus , as well as toxic megacolon . we present an adolescent female patient with a thoracic and lumbar scoliosis who underwent posterior spinal arthrodesis and developed ogilvie 's syndrome . we discuss the clinical course and treatment , as well as the final outcome at latest followup . to the best of our knowledge , a 12 years and 8 months old female presented with a double structural thoracic and lumbar scoliosis associated with arnold - chiari 1 malformation and an extensive cervicothoracic syringomyelia . at age 11 years and 11 months she developed acute weakness affecting both hands and feet with associated pins and needles down the arms and legs , as well as altered sensation affecting the right upper limb below the elbow while her bladder and bowel function was normal . the patient underwent an urgent cranio - cervical decompression including a posterior fossa craniotomy and c5/c6 laminectomy with syringostomy and placement of a syringopleural shunt to drain the syrinx [ figure 1 ] . she recovered well following surgery and there were no residual neurological signs or symptoms at the time of presentation in our clinic . preoperative mri ( a ) at onset of neurological symptoms shows herniation of the cerebellar tonsils and a large syringomyelia which extended along the whole of the cervical and into the upper thoracic spine . repeat mri ( b ) after neurosurgical decompression and placement of a syringopleural shunt shows the syrinx to have markedly reduced and no pressure on the cerebellum at the foramen magnum on clinical examination at age 12 years and 8 months , she had a progressive thoracic and lumbar scoliosis extending from t5 to t10 measuring 60 and t10 to l3 measuring 50 respectively . an mri of the whole spine demonstrated adequate decompression of the cranio - cervical junction and a small residual cervical syrinx which was considered to require no further treatment at the time by our neurosurgical colleagues . the patient underwent posterior spinal arthrodesis extending from t4 to l3 at age 12 years and 10 months with the use of segmental pedicle screw and rod instrumentation and autologous iliac crest bone graft [ figure 2 ] . spinal cord monitoring was performed during the procedure recording motor and sensory ( cortical and cervical ) evoked potentials which remained stable throughout . the patient had 3 doses of intravenous ( iv ) cefuroxime ; one at induction to anaesthesia , and 2 after surgery at 8-hourly intervals . preoperative posteroanterior ( a ) and lateral ( b ) radiographs of the spine show a left thoracic and a right lumbar scoliosis . repeat radiographs at latest followup ( c and d ) show a balanced spine in the coronal and sagittal planes with good maintainance of scoliosis correction in the postoperative period , the patient developed prolonged abdominal distension without pain which was considered to be due to paralytic ileus as the result of the major spinal operation , as well as the effect of narcotic analgesic agents delivered during and after surgery . she had no electrolyte abnormalities and her blood tests were normal other than an expected small reduction in haemoglobin . the spinal wound healed uneventfully and the patient mobilized out of bed on postoperative day 2 . at the end of the first week following surgery the abdominal distension began to increase and she started having generalized abdominal pain with associated tenderness in the right iliac fossa . repeat blood tests showed marginal leukocytosis coinciding with the onset of abdominal pain while the remaining parameters including electrolytes , kidney and liver function tests were within normal limits . she was initially managed conservatively maintaining fluid and electrolyte balance and placing a nasogastric tube for aspiration of gastric contents . repeat ultrasounds and a ct scan of the abdomen did not demonstrate evidence of mechanical obstruction , congenital anomaly ( such as a fibrous band or a malrotated bowel ) , or cecal / sigmoid volvulus [ figure 3 ] . during the whole postoperative period our patient was under regular review by our general surgical colleagues . ( a ) abdominal x - ray at 2 weeks after scoliosis surgery showing dilated bowel loops across the whole of the abdomen with a similar appearance on the ct scan ( b ) performed before decision was made for surgical exploration through a laparotomy due to aggravation of the patient 's abdominal distension and absence of clear signs of peritonitis pain a laparoscopy was decided on postoperative day 16 followed by an exploratory laparotomy . at that stage the laparotomy showed the cecum and ascending colon to be grossly inflamed with multiple ragged perforations , no dilatation and gross contamination of the abdomen . multiple loops of small bowel were adherent to the anterior abdominal wall in the right iliac fossa . the remainder of the transverse , descending and sigmoid colon was found to be entirely normal . a limited right hemi - colectomy and ileocecal anastomosis was performed and the patient returned to the intensive care with nasogastric aspirations . she remained intubated for 7 days and was treated with meropenem and vancomycin for 2 weeks as the peritoneal cultures showed a mixed growth of enterococcus and e. coli . she made gradual recovery with good bowel function , returned to feedings over a period of 2 weeks and was discharged on postoperative day 32 . the surgical specimen sent for histopathology included 3 cm of terminal ileum , 5.5 cm appendix and 12 cm of colon . a single large defect was identified at the cecum and multiple defects in the ascending colon above the ileocecal valve . the surgical findings combined with the clinical picture and the pathology report confirmed the diagnosis of ogilvie 's syndrome . at latest followup , 3.2 years after scoliosis surgery our patient was skeletally mature ( risser 5 ) , had no abdominal complaints and was on a normal diet . spinal radiographs showed maintenance of an excellent correction of her scoliosis and no signs of infection , instrumentation failure or nonunion . the most common abdominal complications occurring in patients who undergo scoliosis surgery include postoperative paralytic ileus and sma syndrome.1234 these have a good prognosis and usually respond well to conservative management . post - surgical ileus is expected to settle within 48 - 72 h after the procedure and as the patients become mobile out of bed with fewer requirements for opioid analgesia . sma syndrome requires insertion of a nasogastric tube for gastric decompression , as well as a nasojejunal tube for bowel feedings until the temporary compression to the third part of the duodenum by the sma resolves and the patient gradually returns to oral feeds within a few days . ogilvie 's syndrome has not been previously recognized as a cause for abdominal distension and pain following spinal deformity surgery . our patient had a prolonged prodromal period of gradually increasing painless abdominal distension , un - associated with vomiting , which was not accompanied by any mechanical obstruction to the small or large bowel , typically seen in acpo . the most common predisposing conditions of this syndrome include nonoperative trauma , infections ( pneumonia / sepsis ) and cardiac diseases ( heart failure / myocardial infraction ) , usually in elderly patients who require long treatment in the high dependency unit.5 operative procedures often associated with ogilvie 's syndrome include caesarean section , abdominal and pelvic surgery , urologic / thoracic / neurosurgical and coronary by pass procedures.89 it has also been reported following hip and knee surgery , as well as after lumbar or cervical spinal operations , such as discectomy.1011121314 neurological conditions and the use of medication such as opioids , calcium channel blockers and anticholinergics can also precipitate acpo.7 even though the exact aetiology of this syndrome is not fully clarified , it is considered to occur due to autonomic disturbance of the colonic motor function.15 the predisposing factors produce an autonomic imbalance leading to excessive parasympathetic inhibition which in turn results in colonic atony and features of pseudo - obstruction . our patient had at least 3 risk factors for ogilvie 's syndrome , namely a surgical insult , a neurological factor ( association of scoliosis with arnold - chiari 1 malformation and syringomyelia ) , as well as the use of morphine and other opioids during the postoperative period . the pathological features of acpo include gross dilatation of the colon and cecum without mechanical block which may lead to ischemia and perforation.7 the differential diagnosis includes faecal impaction , colonic or rectal tumours , cecal or sigmoid volvulus and toxic megacolon.5 ct scan is an excellent investigation to diagnose colonic or sigmoid tumors and differentiate between cecal and sigmoid volvulus.16 toxic megacolon should also be considered as part of the differential diagnosis but it is associated with rapid thinning of the colonic wall along with severe toxaemic features , which make it a potentially lethal condition . this is often associated with crohn 's disease , ulcerative and pseudo - membranous colitis but can occur as a complication of any infective or noninfective condition affecting the colon.1718 having excluded a mechanical obstruction and other conditions as part of the differential diagnosis , it is possible to treat a patient with ogilvie 's syndrome conservatively . the management includes keeping the patient nil by mouth , insertion of a nasogastric tube for suctioning to limit swallowed air contributing further to colonic distension , iv fluid administration , correction of underlying electrolyte imbalance , insertion of a rectal tube , as well as minimizing risk factors including discontinuation of medication which can adversely affect bowel motility.719 a trial of iv neostigmine ( a reversible acetylcholinesterase inhibitor which enhances bowel motor activity ) can be given to decompress the colon if mechanical obstruction , ischemia and perforation have been excluded.20 if the symptoms persist an endoscopy ( colonoscopy ) or surgical decompression is warranted , especially if the patient develops fever , abdominal pain / guarding and a high white cell count in addition to abdominal distension and constipation . a cecal diameter of 12 cm or more correlates with higher risk of perforation when the distension has been present for more than 6 days.21 surgical intervention is reserved for patients with signs of bowel ischemia or perforation and those who fail endoscopic and pharmacologic management . in the case of a colonic perforation , sub - total resection ( hemi - colectomy ) with ileostomy or an ileocecal anastomosis is the procedure of choice.22 in retrospect , even though our patient was under close monitoring during her whole postoperative course by our pediatric surgical colleagues the diagnosis of ogilvie 's syndrome was overlooked . the ct scan and the marked delay in diagnosis resulted in bowel perforation and developing peritonitis which required an urgent laparotomy and major bowel reconstructive surgery which could have been life - threatening . the histopathological examination of the surgical specimen obtained during the hemi - colectomy ruled out volvulus or pathologies associated with toxic megacolon and indirectly confirmed the suspected diagnosis of ogilvie 's syndrome . the absence of previous reports in the literature of acpo developing after scoliosis surgery was the main reason why the possibility of this diagnosis was not raised , despite the presence of strong clinical and radiological features suggestive of the condition in the background of co - existing risk factors . postoperative abdominal complications primarily related to paralytic ileus or superior mesenteric artery syndrome are not uncommon following scoliosis surgery and these usually settle with appropriate conservative management . we recommend that surgeons involved in the management of children and adolescents with spinal deformities should maintain a high index of suspicion of the occurrence of ogilvie 's syndrome as a possible cause of prolonged abdominal distension and pain mimicking paralytic ileus following major reconstructive surgery . the key to successful treatment of acpo lies with a ) an early diagnosis , b ) assessment to exclude mechanical obstruction or other causes of pseudo - obstruction , c ) evaluation of signs and symptoms indicating bowel ischemia or perforation , which carries a mortality rate of 40% ( compared to 15% in patients with a viable bowel)5 and requires urgent surgical management , and d ) instigation of appropriate treatment at an early stage when this is more likely to be successful .

we report ogilvie 's syndrome following posterior spinal arthrodesis on a patient with thoracic and lumbar scoliosis associated with intraspinal anomalies . postoperative paralytic ileus can commonly complicate scoliosis surgery . ogilvie 's syndrome as a cause of abdominal distension and pain has not been reported following spinal deformity correction and can mimic post - surgical ileus . 12 year old female patient with double thoracic and lumbar scoliosis associated with arnold - chiari 1 malformation and syringomyelia . the patient underwent posterior spinal fusion from t4 to l3 with segmental pedicle screw instrumentation and autogenous iliac crest grafting . she developed abdominal distension and pain postoperatively and this deteriorated despite conservative management . repeat ultrasounds and abdominal computer tomography scans ruled out mechanical obstruction . the clinical presentation and blood parameters excluded toxic megacolon and cecal volvulus . as the symptoms persisted , a laparotomy was performed on postoperative day 16 , which demonstrated ragged tears of the colon and cecum . a right hemi - colectomy followed by ileocecal anastomosis was required . the pathological examination of surgical specimens excluded inflammatory bowel disease and vascular abnormalities . the patient made a good recovery following bowel surgery and at latest followup 3.2 years later she had no abdominal complaints and an excellent scoliosis correction . ogilvie 's syndrome should be included in the differential diagnosis of postoperative ileus in patients developing prolonged unexplained abdominal distension and pain after scoliosis correction . early diagnosis and instigation of conservative management can prevent major morbidity and mortality due to bowel ischemia and perforation .

there is no debate that asa reduces mortality in secondary prevention of cardiovascular disease ( cvd ) , but an important question is why some patients do not benefit from asa therapy . it was suggested that diabetic patients not treated with aspirin therapy display increased platelet reactivity , and that aspirin treatment in diabetic patients is less effective than aspirin treatment in nondiabetic patients [ 1 , 2 ] . asa - r is not limited to diabetes and is documented in subjects with cardiovascular and kidney disease . despite the absence of a current gold standard to define asa resistance , urine thromboxane and verifynow point - of - care optical aggregometry are clinically validated with cutoff values that predict worse cvd outcomes [ 57 ] . we previously demonstrated that platelets are activated after incubation with increasing glucose concentrations in vitro . chronic hyperglycemia and hyperlipidemia are associated with asa - r , but the role of acute hyperglycemia and hyperlipidemia on asa function in vivo has not been defined . in this study , we investigated the effects of acute glucose and fat ingestion on aspirin function in diabetic subjects with and without cardiovascular disease . we studied 55 subjects with diabetes on asa therapy for at least 2 weeks prior to testing . subjects reported fasting to the clinical and translational research center ( cats ) at 8 am . blood was obtained on arrival and 1 hour after glucose ( n = 49 ) or 4 hours after fat ingestion ( n = 11 ) . the study was approved by our institutional review board , and all patients provided written informed consent prior to testing . clinical cardiovascular disease was defined by prior coronary artery bypass surgery ( cabg ) , percutaneous transluminal angioplasty ( ptca ) , or thrombotic stroke . the study excluded subjects if they met any of the following criteria : bleeding diathesis or a history of gastrointestinal bleeding , hemorrhagic stroke , illicit drug or alcohol abuse , coagulopathy , major surgery within 6 weeks prior to study , platelet count < 100,000/mm , hematocrit < 25% , creatinine > 4 mg / dl , or current use of nonsteroidal anti - inflammatory drugs , anticoagulants , or antiplatelet drugs other than aspirin . blood and urine collection : after an overnight fast , blood was collected from the antecubital vein into vacutainer tubes ( becton - dickinson , franklin lakes , nj ) at 8 am to avoid a potential effect of circadian rhythm on platelet function . all patients were instructed to take their prescribed morning medications prior to blood draw . after collecting the first 2 - 3 ml of free flowing blood for other measurements , the tubes were filled to capacity and gently inverted 3 to 5 times to ensure complete mixing of the anticoagulant . tubes containing 3.2% sodium citrate ( greiner bio - one vacuette north america , inc . , urine samples were collected for measurements of 11-dh - txb2 ( corgenix , bloomfield , co ) and stored at 20c until analysis . verifynow ( accumetrics , ca ) is a turbidimetric optical detection assay designed to measure platelet aggregation that is based upon the ability of activated platelets to bind to fibrinogen . the cartridge contains a lyophilized preparation of human fibrinogen - coated beads , arachidonic acid , preservative , and buffer . the fibrinogen - coated beads aggregate in whole blood in proportion to the number of unblocked platelet gpiib / iiia receptors . the instrument reports aggregation as aspirin resistance units ( arus ) . aspirinworks ( corgenix co. ) is an enzyme - linked immunosorbent assay ( elisa ) . in brief , assay buffer and urine were incubated with a monoclonal antibody followed by the addition of an 11-dh - txb2-alkaline phosphate tracer . urinary 11-dh - txb2 concentrations were determined by measuring colorimetry at 405 nm using an elisa reader and expressed as pg / mg creatinine [ 1 , 7 ] . forty - nine subjects ingested a standard glucose solution ( trutol 75 , nerl diagnostics ) consisting of 75 grams of glucose . for the fat diet , 11 subjects ingested a standardized test meal that consisted , per square meter of body surface area , of 175 ml of heavy whipped cream ( shamrock farms , 99% fat ) . of 700 calories per square meter , 99% ( 70 g ) were derived from fat , < 1% was derived from carbohydrates ( < 1 g ) , or from proteins ( < 1 g ) . the cholesterol content was 25 mg , and the ratio of total polyunsaturated to saturated fat was 0.06 . we recorded asa - r measures at one and two hours after glucose ingestion , and two and four hours after fat ingestion . we report the most prominent changes that we noted at one hour after glucose ingestion and four hours after lipid ingestion . we measured weight , height , waist circumference , fasting lipids , hba1c , uric acid , serum creatinine in all subjects at baseline , and glucose or triglycerides levels after ingestion of the glucose or fat challenge , respectively . aspirin resistance was defined by previously reported criteria : 550 aru by verifynow or 1500 pg 11-dh - txb2/mg creatinine during treatment with 81 mg or 325 mg of daily aspirin . we defined apriori a group of responders with change of at least 10% increase ( calculated as premeasure / postmeasure ) in thromboxane and vn response after glucose or fat challenge . categorical variables were expressed as n ( % ) and continuous variables as mean se . kruskal wallis was used to analyze groups with nonparametric distribution . a one - way analysis of variance ( anova ) for repeated measures was used to compare levels of platelet function between and within diabetic and nondiabetic patients . an unpaired t - test was used to compare the prevalence of aspirin resistance between groups ; p < .05 was considered statistically significant . linear regression was used to explain the changes in measures of asa - r to measures of glucose or triglyceride after the challenge . the majority of our diabetic subjects were obese and had a history of hyperlipidemia , hypertension , and were receiving medical treatment such as statins , beta - blockers , and angiotensin converting enzyme inhibitors for prevention and treatment of cvd . urine thromboxane was significantly increased in all 11 subjects after fat ingestion ( p = .01 ) . we did not find a correlation between the changes in glucose or triglyceride and the changes in 11-dh - txb2 or vn . within subjects that underwent the glucose challenge ( n = 49 ) we defined a group of subjects with at least 10% increase ( calculated as premeasure / postmeasure ) in thromboxane and vn response after glucose challenge ( responders ) and compared their profiles to subjects that did not change their measures of asa - r after the glucose challenge , using an independent t - test . in this analysis , 13 subjects did not change their 11-dh - txb2 measures , while 19 increased it by more than 10% . for vn measures , 14 subjects did not change their asa - r measure , while 10 subjects had an increased response . we did not analyze the data from subjects that had a decrease in txb2 or vn after the glucose ingestion . as demonstrated in table 3 , subjects with an increased response to glucose were more aspirin resistant per 11-dh - txb2 criteria at baseline compared to subjects where asa - r measures did not change . subjects with elevated 11-dh - txb2 or vn measures in response to glucose tended to have a prior history of cvd , greater ldl cholesterol , and longer duration of diabetes . there was no correlation between the change in plasma glucose before and after glucose ingestion and measures of aspirin resistance . after glucose ingestion , two subjects were defined as aspirin resistant per the urine thromboxane criteria and three subjects per vn criteria . after fat ingestion , one subject developed asa - r using 11-dh - txb2 cutoff values and one subject using vn values . there was no significant correlation between the change in 11-dh - txb2 / vn after glucose or fat ingestion . this is the first study to demonstrate that acute ingestion of saturated fat consistently increases in vivo thromboxane production , leading to a state of asa - r . the lack of significance related to the measure of platelet function ( vn ) highlights that the fat load may have increased production / excretion of 11-dh - txb2 . urinary thromboxane is not only a marker of platelet activity , but also a marker of inflammation and oxidative stress . urine thromboxane , as a global index of thromboxane synthesis , originates from other blood elements such as erythrocytes and monocytes and from renal biosynthesis . we previously reported that whole blood incubation with increasing concentrations of glucose increased platelet function by the upregulation of p - selectin expression . the current results suggest that the response to glucose ingestion in vivo is more complex . subjects with chronic hyperglycemia , as assessed by the duration of diabetes , dyslipidemia , and prior cvd , are likely to be asa - r in response to a high glucose load . the state of increased thromboxane production and platelet activity after an acute fat or glucose load may be a mechanism explaining the role of a heavy meal as a trigger for acute myocardial infarction [ 13 , 14 ] . although there is no gold standard for defining asa - r , definitions based on urine 11-dh - txb2 and vn assays have cutoff values that are clinically validated to predict worse cvd outcomes . in a subanalysis of the heart outcomes prevention evaluation ( hope ) study , the odds , over a 5-year period , of the composite outcome of myocardial infarction , stroke , or cvd death in 976 asa - treated patients ( 488 who suffered myocardial infarction , stroke , or cvd death and 488 sex- and age - matched controls ) increased with each increasing quartile urine thromboxane levels . the antiplatelet effect of aspirin measured by verifynow correlated with adverse clinical events in stable patients with cad and is independent of known risk factors including diabetes and prior mi . the prevalence of asa - r in our study was 36% by urine 11-dh - txb2 , and 18% by vn measures ( table 1 ) . in comparison , the prevalence of asa resistance of diabetic subjects on 81 mg of asa in the aspect study was 37% by urine 11-dh - txb2 , and 13% for vn . in another study of subjects with cvd but not diabetes , asa - r prevalence was 23% by 11-dh - txb2 , and 7% by vn . possible mechanism(s ) for the reduced ability of asa to sufficiently protect against intravascular occlusions in diabetes mellitus ( dm ) patients compliant with asa therapy include chronic hyperglycemia , hyperlipidemia , and suboptimal asa dosing , particularly in relation to altered platelet turnover in diabetic patients [ 16 , 17 ] . the activating role of chronic hyperlipidemia on platelet function was demonstrated both in vivo and in vitro . friend et al . found that platelet responsiveness to aspirin is reduced in patients with chronic hyperlipidemia . observed enhanced in vivo formation of the f2-isoprostane 8-epi - pgf2a in chronic hyperlipidemia that correlated with enhanced urine 11-dh - txb2 production . this provides an aspirin - insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation . alternatively , oxidized ldl and oxidized choline glycerophospholipids induce platelet activation and thrombosis in fat fed mice through platelet cd36 . we suggest that rather than acute hyperglycemia per se , it is the mishandling of hyperglycemia and resulting libration of oxygen - free radicals in subjects with chronic diabetes , dyslipidemia , and prior cardiovascular disease leading to increased platelet activation and thromboxane production . the limitations of this study are the small sample size , the absence of a control group , and a cvd cohort without diabetes . the acute response to glucose or fat ingestion may not reflect the chronic condition . although we noted a trend increase in verifynow after fat ingestion , the lack of a significant change is possibly related to our small cohort size . the greater variability in the prechallenge 11-dh - txb2 between the glucose and fat groups is likely related to the small size of the fat challenge group . in summary , our study indicates that saturated fat in the diet increases in vivo thromboxane production . this highlights the importance of low dietary saturated fat intake and aggressive lipid management in diabetic patients on asa therapy .

aspirin has lower antiplatelet activity in diabetic patients . our aim is to study the roles of acute hyperglycemia and hyperlipidemia on aspirin function in diabetic subjects with and without cardiovascular disease . using urine thromboxane ( pg / mg creatinine ) and verifynow ( aspirin resistance measures - aru ) , we investigated diabetic subjects during a 2-hour glucose challenge ( n = 49 ) or a 4-hour fat challenge ( n = 11 ) . all subjects were currently taking aspirin ( 81 or 325 mg ) . after fat ingestion , urine thromboxane increased in all subjects ( mean se before : after ) ( 1209 336 : 1552 371 , p = .01 ) , while we noted a trend increase in verifynow measures ( 408 8 : 431 18 , p = .1 ) . the response to glucose ingestion was variable . diabetic subjects with cardiac disease and dyslipidemia increased thromboxane ( 1693 364 : 2799 513 , p < .05 ) and verifynow ( 457.6 22.3 : 527.1 25.8 , p < .05 ) measures after glucose . we conclude that saturated fat ingestion increases in vivo thromboxane production despite aspirin therapy .

twelve wistar strain male rats , aged 120 days and with a mean weight of 250 to 300 g , were obtained from the breeding center of the anatomical and biological sciences center , shahid beheshti medical university ( sbmu ) tehran , iran . the animals were maintained under natural light and humidity conditions ( temperature 22 ; 12-h light / dark cycles ) in individual cages cleaned daily , fed once a day , and offered water ad libitum . the study was approved by the institutional medical ethics committee of shahid beheshti medical university . on day 0 , the rats were anesthetized by the intramuscular injection of 50 mg / kg ketamine hydrochloride ( rotex , made in germany ) and 5 mg / kg diazepam ( tpico , made in iran ) . their dorsal hair was shaved , and their skin was cleaned with povidone - iodine . the rats were equally divided into experimental and control groups randomly ( six rats in each group ) . four incisional wounds measuring 20 mm in length were made in the dorsolateral regions of each experimental rat and one incisional wound in each control rat . all the incisions were performed in the skin and subcutaneous cell tissue using a scalpel . the depth of the surgical incisions was controlled by removing the epithelial tissue to the extent that the dorsal muscular fascia was exposed . the wounds in the experimental rats were treated with : aloe vera gel ( av ) , thyroid hormone cream ( tc ) , silver sulfadiazine 1% ( s ) , or vehicle ( v ) . all the therapies were initiated on day 0 and repeated daily for 14 consecutive days . an aloe vera plant was obtained from a medical plant garden and sent to the laboratory of anatomical and biological sciences center , shahid beheshti medical university ( sbmu ) for the extraction of aloe vera gel . after washing the leaves thoroughly , the base , apex and margins were cut off carefully to facilitate the slicing of the aloe vera leaves , revealing the transparent mucilage . a greenish gel - like liquid was obtained which was further refined through the use of a strainer . we also prepared a topical t3 cream by dissolving 150-ng of t3 ( sigma , made in spain ) in 20 l of ethanol and then mixed it into the vehicle . the tensile strength of the wounds was measured in both the experimental and control groups on day 14 after surgically inducing the wounds . we cut standardized 5mm - wide skin strips perpendicularly to the incisions with a double - bladed cutting instrument . the specimens were placed in 0.9 percent saline after necropsy and were evaluated within one hour . from each wound , we obtained one strip specimen and placed it in a material testing machine ( zwick , made in germany ) using two griping clamps . the distance between the edges of the clamps was 5 mm and the specimens were loaded uniaxially while the deformation rate was kept constant at 15 mm a minute so that failure and complete load - deformation curves were recorded by transducers coupled to bridges . from these curves , we analyzed the parameters of ( 1 ) ultimate tensile stress ( newtons / square millimeter ) , which was derived from the ultimate load divided by the original unstrained cross - sectional area ; ( 2 ) ultimate tensile strength ( fmax newtons ) , the load that causes a structure to fail ; and ( 3 ) the area under the load - deformation curve ( newton millimeters ) , the amount of work done by the deforming load . we used a one - way analysis of variance and t tests to compare the data related to ultimate tensile stress , fmax , and area under load - deformation curve . an aloe vera plant was obtained from a medical plant garden and sent to the laboratory of anatomical and biological sciences center , shahid beheshti medical university ( sbmu ) for the extraction of aloe vera gel . after washing the leaves thoroughly , the base , apex and margins were cut off carefully to facilitate the slicing of the aloe vera leaves , revealing the transparent mucilage . a greenish gel - like liquid was obtained which was further refined through the use of a strainer . we also prepared a topical t3 cream by dissolving 150-ng of t3 ( sigma , made in spain ) in 20 l of ethanol and then mixed it into the vehicle . the tensile strength of the wounds was measured in both the experimental and control groups on day 14 after surgically inducing the wounds . we cut standardized 5mm - wide skin strips perpendicularly to the incisions with a double - bladed cutting instrument . the specimens were placed in 0.9 percent saline after necropsy and were evaluated within one hour . from each wound , we obtained one strip specimen and placed it in a material testing machine ( zwick , made in germany ) using two griping clamps . the distance between the edges of the clamps was 5 mm and the specimens were loaded uniaxially while the deformation rate was kept constant at 15 mm a minute so that failure and complete load - deformation curves were recorded by transducers coupled to bridges . from these curves , we analyzed the parameters of ( 1 ) ultimate tensile stress ( newtons / square millimeter ) , which was derived from the ultimate load divided by the original unstrained cross - sectional area ; ( 2 ) ultimate tensile strength ( fmax newtons ) , the load that causes a structure to fail ; and ( 3 ) the area under the load - deformation curve ( newton millimeters ) , the amount of work done by the deforming load . data were summarised as meansem . we used a one - way analysis of variance and t tests to compare the data related to ultimate tensile stress , fmax , and area under load - deformation curve . since an increase in the synthesis of collagen occurs in the wound healing process , we used a biomechanical method to examine and compare among the treatments for tensile stress , fmax , and area under load - deformation curve ( table 1 ) . as table 1 indicates , the tensile stress was not significantly different among tc , av and s. averaged ultimate tensile stress was greater in the av , tc and s groups than in the v and control groups , but this difference was not statistically significant . no difference in fmax was observed among the tc , s , v , and control groups . the area under the load - deformation curve was significantly greater in the av group than in the other groups and was not significantly greater in the s and tc groups than in the v and control groups . skin wound healing is a dynamic response to injury that has three overlapping phases : inflammation , granulation tissue formation and remodeling . during the wound healing process , especially the transition from granulation tissue to scar tissue formation , collagen remodeling occurs , that is , the degradation of collagen with the formation of larger collagen bundles and an increase in the number of intermolecular cross - linkages . this process is controlled by several proteolytic enzymes called matrix metalloproteinases that are discharged by fibroblasts , macroghages , epidermal cells and endothelial cells . the tensile strength of a wound can be related to its collagen formation and maturation . on the other hand , the strength of the repaired wound tissue is the result of the remodeling of collagen and the formation of stable intra - and inter - molecular cross - linkages . this study examined and compared the effects of aloe vera leaf gel , thyroid hormone cream , and silver sulfadiazine cream on the healing of skin incisional wounds in rats by biomechanical methods to assay the tensile stress of the wounds . according to the results of the study , fmax and the area under the load - deformation curve significantly increased in the wounds treated with aloe vera as compared with the wounds treated with thyroid hormone and silver sulfadiazine , suggesting that aloe vera was more effective in healing the wounds , which has been observed in other studies . a possible explanation for this increase is that the aloe leaf gel extract infiltrates into the wounds , contributes to the increase of fibroblasts , macrophages , and epidermal cells activities , subsequently facilitates enzyme activity during collagen remodeling , and possibly even aids in the formation of cross linkages as the collagen matures . in other words , aloe vera may have a direct effect on the wound healing process as a whole , which is manifested as an increase in fmax and the area under the load - deformation curve , suggesting an improvement in the tensile strength of the wounds . the results are also in agreement with those of chithra et al . that attributed this improvement in tensile strength to an increase in the aldehyde groups of collagen fibres responsible for forming cross - linkages . subramanian et al . also confirmed the effect of aloe vera on increasing wound contraction and collagen synthesis and attributed this to the mannose-6-phosphate known to be present in aloe vera leaf gel . mannose - containing products have been shown to increase macrophage activity and therefore stimulate fibroblast activity and collagen synthesis . the results indicate that thyroid hormone did not have any significant effect on the healing of the incisional wounds . thus , the results do not provide evidence for safer et al . who found that topical triiodothyronine stimulated epidermal proliferation , dermal thickening , and hair growth . one possible explanation for this discrepancy is the difference in the type of wound between the two studies ; in the present study incisional wounds were under investigation while in the other , excisional wounds . an incision is a cut made into the tissue , mainly for operation , therefore topical medication must infiltrate into the tissue to accelerate the healing process . on the other hand , an excision is a removal skin tissue and topical medication is put on the wound directly , which may contribute more to the healing process . another possible explanation is the difference in the methods of assessing wound healing : safer et al . used a histological approach to assess whether topical triiodothyronine stimulates epidermal proliferation , dermal thickening , and hair growth while in the present study we drew on a biomechanical assessment method to explain the physical characteristics of the skin tissue . the findings of the current study indicate that ssd was not significantly effective on skin incisions , providing more evidence for the studies conducted by mccauley et al . and cooper et al . , in that they explained the inhibitory and cytotoxic effects of ssd and mafenide acetate on human keratinocyte and fibroblast growth [ 25 - 28 ] . leitch et al . also found inhibitory effects of antimicrobial agents on wound contraction in an acute rat wound model . muller et al . compared the impact of ssd with or without aloe vera , nystatin with and without ssd , and placebo on time to achieve 50% and 90% wound healing in excisions of sprague - dawley rats . no difference in the acceleration of wound healing was observed between the control and ssd treatment lesions . in addition , the combination of aloe vera with ssd has been suggested to improve wound healing . such inhibitory effects may be related to the cytotoxic characteristics of ssd on cells synthesizing collagen , proteoglycan , and other products . the results of this study indicate that topical application of aloe vera can lead to significantly rapid wound healing and stronger repaired tissue . we can conclude that aloe vera can effectively be applied as a topical treatment to accelerate the wound healing process of surgically induced incisional wounds in rats as compared with other topical applications such as : thyroid hormone , silver sulfadiazine , and vehicle .

many research studies report the healing effects of aloe vera , thyroid hormone cream and silver sulfadiazine . however , the effects of these therapeutic agents are not well understood and have not been compared in one study . this study aimed at investigating the effects of topical application of an aloe vera gel , a thyroid hormone cream and a silver sulfadiazine cream on the healing of skin wounds surgically induced in wistar rats for determining the treatment of choice . in a randomized controlled trial , twelve male rats , aged 120 days and with a mean weight of 250 to 300 g , were divided randomly into 5 groups based on drug treatments : aloe vera gel ( av ) , thyroid hormone cream ( tc ) , silver sulfadiazine 1% ( s ) , vehicle ( v ) and control . to evaluate the efficacy of each treatment technique , a biomechanical approach was used to assess tensile stress after 14 days of treatment . tensile stress was significantly improved in the aloe vera gel group as compared with the other four groups ( p0.05 ) . while the other treatment options resulted in better healing than the control group , this difference was not significant . we conclude that aloe vera topical application accelerated the healing process more than thyroid hormone , silver sulfadiazine and vehicle in surgically induced incisions in rats .

normal surgical procedures for cataract removal require lens cortical capsular cleavage ( hydrodissection ) using a syringe and cannula , lens nucleus removal using a phacoemulsification tip ( phaco tip ) , and lens cortical removal using an irrigation / aspiration tip ( i / a tip ) . therefore , this requires the insertion and withdrawal of three different surgical instruments in order to complete these three surgical stages . as a result , this can lead to an increased risk of the collapse of the eye . multiple studies that have examined manual hydrodissection and hydrodissection - related complications have reported that there is a significant increase in the intraocular pressure ( iop ) during the procedures.17 furthermore , when using femtosecond laser - assisted cataract surgery ( flacs ) , it has been reported that there is a manual hydrodissection induced capsular block syndrome because of the expansion of the endocapsular volume by the laser - induced intracapsular gas and cortical changes.8 based on these findings , it is suggested that the use of a single instrument for all the three cataract surgical stages would likely improve stability of the iop during hydrodissection and lens removal , including the cortex . moreover , it is also likely that the number of complications would be reduced , as the use of a single instrument would also keep the safety irrigation iop from the phaco tip sleeve which limit is the bottle - height dependent hydrostatic pressure , thereby helping to avoid an excessively high iop and disturbance of the eye.9,10 in the present article , we describe a novel method that only uses the phaco tip for lens cleavage and removal . after completion of the initial steps of cataract surgery ( incision ; 2.7 mm , ophthalmic viscosurgical device injection , and continuous curvilinear capsulorhexis [ ccc ] ) , a dewey phaco tip ( 0.9 mm diameter ; microsurgical technology , inc . , redmond , wa , usa ) with a microsleeve ( alcon laboratories , inc . , when using the phaco tip technique for lens cleavage and removal , once the superficial cortex and epinucleus have been removed to the maximum possible degree , the dewey phaco tip is positioned on the peripheral lens at the capsulorrhexis edge using zero ultrasound energy . aspiration of the intraocular fluid is then performed to induce irrigation flow from the sleeve hole to the cortical capsular layer ( figure 1a ) . by repeating this procedure at several points on the capsulorhexis edge , the irrigation dynamic pressure cleaves the cortical capsular layers of the lens , which makes it possible to rotate the lens ( which is referred to as the irrigation dynamic pressure hydrodissection [ ih ] ) . in this stage , a constellation vision system ( alcon laboratories , inc . ) is used that contains a dewey phaco tip with a microsleeve . the phacoemulsification parameters are set as follows : vacuum system , venturi pump ; vacuum pressure , 200 mmhg ; irrigation pressure , 50 cm h2o ; and ultrasound power , zero . the same parameters are utilized during the second stage of surgery , with the phaco tip used to rotate the lens nucleus circumferentially clockwise and counterclockwise ( figure 1b and c ) several times in order to peel the residual lens cortex from the capsule . consequently , this makes it possible to use the phaco tip to aspirate the majority of the peeled cortex prior to removal of the nucleus . after cortical capsular cleavage and removal of most of the cortex , the lens nucleus is removed during the third stage of surgery using the phaco tip , with the procedure based on the divide and conquer technique ( figure 2a and b).11 during the final stage of the procedure , if needed , any residual cortex is aspirated using the phaco tip ( figure 2c ) followed by removal of the entire lens via the use of only the phaco tip ( figure 2d ) . in order to prevent damage to the capsule when aspirating the cortex using the dewey phaco tip : 1 ) we aspirated only the cortex by peeling it from the capsule , and thus did not aspirate the capsule and 2 ) as the posterior capsule is easily absorbed by phaco tip in cases with wieger s ligament disturbance , infusion misdirection syndrome , etc . , we aspirated the residual cortex after intraocular lens implantation using the i / a tip . subsequently , the posterior chamber intraocular lens is implanted in the bag and the procedure is concluded as per the normal surgical procedure . after completion of the initial steps of cataract surgery ( incision ; 2.7 mm , ophthalmic viscosurgical device injection , and continuous curvilinear capsulorhexis [ ccc ] ) , a dewey phaco tip ( 0.9 mm diameter ; microsurgical technology , inc . , redmond , wa , usa ) with a microsleeve ( alcon laboratories , inc . when using the phaco tip technique for lens cleavage and removal , once the superficial cortex and epinucleus have been removed to the maximum possible degree , the dewey phaco tip is positioned on the peripheral lens at the capsulorrhexis edge using zero ultrasound energy . aspiration of the intraocular fluid is then performed to induce irrigation flow from the sleeve hole to the cortical capsular layer ( figure 1a ) . by repeating this procedure at several points on the capsulorhexis edge , the irrigation dynamic pressure cleaves the cortical capsular layers of the lens , which makes it possible to rotate the lens ( which is referred to as the irrigation dynamic pressure hydrodissection [ ih ] ) . in this stage , a constellation vision system ( alcon laboratories , inc . ) the phacoemulsification parameters are set as follows : vacuum system , venturi pump ; vacuum pressure , 200 mmhg ; irrigation pressure , 50 cm h2o ; and ultrasound power , zero . the same parameters are utilized during the second stage of surgery , with the phaco tip used to rotate the lens nucleus circumferentially clockwise and counterclockwise ( figure 1b and c ) several times in order to peel the residual lens cortex from the capsule . consequently , this makes it possible to use the phaco tip to aspirate the majority of the peeled cortex prior to removal of the nucleus . after cortical capsular cleavage and removal of most of the cortex , the lens nucleus is removed during the third stage of surgery using the phaco tip , with the procedure based on the divide and conquer technique ( figure 2a and b).11 during the final stage of the procedure , if needed , any residual cortex is aspirated using the phaco tip ( figure 2c ) followed by removal of the entire lens via the use of only the phaco tip ( figure 2d ) . in order to prevent damage to the capsule when aspirating the cortex using the dewey phaco tip : 1 ) we aspirated only the cortex by peeling it from the capsule , and thus did not aspirate the capsule and 2 ) as the posterior capsule is easily absorbed by phaco tip in cases with wieger s ligament disturbance , infusion misdirection syndrome , etc . , we aspirated the residual cortex after intraocular lens implantation using the i / a tip . subsequently , the posterior chamber intraocular lens is implanted in the bag and the procedure is concluded as per the normal surgical procedure . in the current study , only a phaco tip was used for lens cleavage and removal during the phacoemulsification surgeries utilized for the cortical capsular cleavage , and cortex and nucleus removal . the unique point of this technique is that it removes the cortex in parallel with the ih , which is carried out prior to the lens nucleus phacoemulsification . as the cortical capsular connection adhesive strength affects the time of the ih , the procedure tends to be faster in cases with a harder versus a softer nucleus . as the dewey tip has a smooth edge that does not cause rupture of the capsule due to attachment , tip placement on the posterior capsule is considered to be safe in cases that have residual cortex after the nucleus removal ( figure 3).12,13 this technique is also unique as it uses a circumferential nucleus rotation approach after the cortical capsular cleavage . this weakens the lens cortical capsular adhesive strength , which makes it possible to remove the majority of the cortex prior to the removal of the nucleus . as the aspiration opening of the phaco tip is larger than that of the i / a tip and the phaco tip can easily absorb the posterior capsule in situations in which there is no tension from the nucleus , in the past , the phaco tip has been previously considered to be unsuitable for cortical removal after the removal of the nucleus . in contrast to the common phacoemulsification approach , our technique can overcome this issue by aspirating the cortex prior to removal of the nucleus . thus , the cortex can be removed without any absorption of the capsule , as the nucleus stretches the capsule centrifugally . modern phacoemulsification machines provide stable irrigation pressure in the endocapsular space , which makes it possible to avoid the risk for capsular tears when removing the nucleus without the residual cortex . the cause of capsular block syndrome has been considered to be due to the ccc block by the lens nucleus and the pressure of the trapped irrigation that occurs between the lens nucleus and the posterior capsule . due to the development of this high pressure , posterior capsule rupture can be elicited during manual hydrodissection . with our technique , however , the cortical removal in parallel with the ih produces space for flow passage around the ccc , thereby contributing to the avoidance of the ccc block during the hydrodissection . in cases undergoing flacs , it is very important to reduce the intracapsular gas prior to hydrodissection in order to avoid these high - pressure complications . thus , when the cortical and intracapsular gas removal is performed in parallel with ih , it ensures that flacs can be performed safely compared to manual hydrodissection . when using the phaco tip technique for lens cleavage and removal , it is not necessary to perform manual hydrodissection using a syringe and cannula or cortical removal using an i / a tip . moreover , avoiding the use of multiple surgical instruments and bottle height - dependent maximum irrigation pressure promotes a stable iop during hydrodissection and lens removal , including the cortex . in addition , the cortical and/or intracapsular gas removal in parallel with ih also contributes to the avoidance of capsular block syndrome . as this approach may be a beneficial option for phacoemulsification surgery , further studies that examine the safety and efficacy of the technique in various other types of cataract cases

use of the phaco tip technique for lens cleavage and removal does not require manual hydrodissection using a syringe and cannula , or cortical removal using an irrigation / aspiration tip . the phaco tip is the only surgical instrument required for this technique . its advantages include maintaining a stable intraocular pressure during cortical cleaving hydrodissection and lens removal , which includes the cortex .

several parameters of the immune system exhibit circadian rhythms which refer to daily oscillations with a period of approximately 24 hours [ 1 , 2 ] . for instance , the number of specific immune cells ( e.g. , monocytes , neutrophils , and lymphocytes ) in circulation and plasma levels of cytokines ( e.g. , tnf- and il-6 ) show ~24-hour daily rhythm that is translated into variations in acute response to infection [ 1 , 2 ] . recent studies reveal that the internal time - keeping system circadian clock is responsible for driving the circadian rhythms evident in the immune system . this review briefly summarizes new studies that provide mechanistic insights into how the immune system is under tight control of the circadian clock . in particular , this review puts emphasis on temporal regulation of cytokines by the circadian clock because cytokines play a central role in shaping immune response as crucial mediators for intercellular communication among immune and nonimmune cells . better understanding of an emerging role of the circadian clock as a novel regulator of cytokines will be greatly helpful to improve timing of conventional treatment and to exploit new drug targets for immune - related diseases such as infection , autoimmunity , and allergy . the circadian clock drives the daily rhythms in behavior and physiology ( e.g. , sleep - wake cycles , body temperature , blood pressure , and hormonal secretions ) that enable organisms to keep track of the time of day according to daily changes in light intensity [ 3 , 4 ] . mammalian circadian clock consists of the central oscillator located in the suprachiasmatic nucleus ( scn ) of the hypothalamus and peripheral oscillators virtually present in all cell types [ 3 , 4 ] . light activates a specific group of photoreceptors in the retina connected to the central scn clock which 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 transcriptional - translational feedback loops that consisted of several clock genes and their protein products . briefly , two transcription factors , clock and bmal1 , activate the transcription of the period ( per ) and cryptochrome ( cry ) genes . the per and cry proteins in turn inhibit their own expression by repressing clock / bmal1 activity . this negative feedback loop , with additional posttranscriptional modifications , generates ~24-hour oscillations of the clock protein levels and activity , which are translated into periodic changes of a variety of clock - controlled genes ( ccgs ) involved in important biological processes , including immune responses . it has been well documented that many parameters in the immune system exhibit circadian rhythms [ 1 , 2 ] . not only the components of the immune system but also the immune functions , such as leukocyte migration / trafficking , and innate immune response also show circadian rhythms [ 1 , 2 ] . recent excellent studies have provided compelling molecular evidence that the circadian clock is responsible for the temporal activities in the immune system [ 58 ] . have recently reported that the central scn clock drives circadian rhythms in the expression of adhesion molecules ( e.g. , icam-1 and vcam-1 ) on endothelial cells or chemokines / chemokine receptors ( e.g. , ccl2 and cxcr4 ) in tissue or leukocytes , which contributes to a time of day - dependent recruitment of leukocytes into the tissues such as the bone marrow and muscle . the circadian activity of sympathetic nervous system driven by the central scn clock likely regulates the expression of adhesion molecules or chemokine / chemokine receptors in a temporal manner , thereby controlling leukocyte migration . nguyen et al . suggest another regulatory mechanism for leukocyte migration by the circadian clock . they found that frequency of ly6c inflammatory monocytes ( an innate immune cell type for the first line of defense against pathogens ) in blood , spleen , and bone marrow exhibited circadian oscillations , which corresponded to the diurnal variations in recruitment of the cells into the sites of inflammation . they suggested that clock / bmal1 heterodimer negatively regulated expression of ccl2 in monocytes , which likely contributed to the circadian oscillations of ly6c inflammatory monocytes . in contrast to the study by scheiermann et al . , this study therefore puts more emphasis on an important role of peripheral immune cell clock in leukocyte migration . they found that clock / bmal1 heterodimer bound to the promoter of toll - like receptor ( tlr9 ) and promoted the expression and function in a circadian manner . consistent with the findings , they showed that mice immunized at the time of enhanced tlr9 responsiveness presented strong innate immune reactions with an improved adaptive immune response . most recently , t cell development has been surprisingly shown to be regulated by the circadian clock proteins . yu et al . reported that clock / bmal1-mediatd rev - erb induction inhibited expression of nf - il3 , a suppressor of th17 cell development , thereby selectively influencing th17 cell development . interestingly , circadian disruption by chronic light - cycle perturbations increased th17 frequency in mouse intestine and worsened dextran - sodium sulfate ( dss)-induced colitis in mice . several other important immune functions have been also shown to be regulated by the circadian clock and the reader is encouraged to consult with excellent reviews for detailed overview of circadian immunity in many aspects [ 58 ] . cytokines are essential to shape immune responses and are indispensable for self - defense against infection . on the other hand , once the cytokine network goes out of control and an excessive amount of cytokines are produced , serious damage , such as sepsis or autoimmunity and allergy , occurs in the host animals . therefore , expression of cytokines should be tightly regulated to maintain homeostasis of the immune system and , indeed , cytokine expression is regulated at multiple levels . recent excellent studies reveal that the circadian clock is also an important regulator of cytokines [ 58 ] . because circadian regulation of cytokines is extensively studied in in vitro and in vivo models of endotoxin lps - induced inflammatory responses in innate immune cells , this review summarizes such studies to describe how the circadian clock regulates cytokine expression at the molecular levels . keller et al . reported that mouse macrophages derived from spleen , lymph nodes , and peritoneal cavity contain intrinsic circadian clockworks that operate autonomously as well as other innate and acquired immune cells . macrophages isolated from mouse spleen stimulated with lps at different time points display circadian rhythms in tnf- and il-6 secretion and the cytokine secretion rhythms persist in constant in vitro culture conditions , suggesting that macrophage - intrinsic circadian clock may govern these oscillations . interestingly , ~8% of the expressed genes in peritoneal macrophages show circadian modulation including the genes involved in lps - immune response pathways such as md-1 and cd180 , which may explain rhythmic secretion of the cytokines upon lps challenge . it has been known since pioneering work of the 1960s and 1970s that mice challenged with lps showed significant circadian - dependent variation in magnitude of response including mortality and cytokine concentrations in serum . showed that the temporal variations in serum il-6 following lps challenge were absent in mice with specific deletion of bmal1 in myeloid cells , suggesting that myeloid cell - intrinsic clockwork provides temporal gating of cytokine responses to lps . bmal1 activates transcription of the nuclear receptor rev - erb and rev - erb , which in turn inhibits bmal1 transcription , forming an accessory feedback loop that stabilizes the circadian clock machinery . because peritoneal macrophages exhibit a profound temporal variation in transcriptional factor rev - erb ( ~20-fold differences across the day ) and the temporal variation of rev - erb was completely suppressed in bmal1-deficient peritoneal macrophages , gibbs et al . investigated whether rev - erb was a key molecule linking the circadian and inflammatory pathways . as expected , rhythmic immune responses to lps were abolished in rev - erb-deficient mice , suggesting a link among bmal1 , rev - erb , and il-6 production in macrophages upon lps challenge . spengler et al . showed that the severity of lps - induced inflammatory response in mice was correlated with the intensity of nf-b activation and that nf-b activation is , in fact , under circadian control based on experiments using nf-b reporter mice . they demonstrated that the core circadian protein clock bound to the p65 subunit of nf-b , acetylated p65 , and upregulated nf-b - dependent transcriptional responses . interestingly , clock acts as a positive regulator of nf-b - responsive genes distinct from the transactivation of circadian genes via e - box elements that i , independent of its circadian function . narasimamurthy et al . reported another mechanism of how the circadian clock controls inflammatory cytokine expression . they showed that cry - deficient macrophages exhibited a marked increase in tnf- and il-6 protein secretions compared with wild - type macrophages , suggesting that cry - deficient macrophages were hypersensitive to lps stimulation . they also showed that cry binds to adenyl cyclase , resulting in enhanced levels of camp and constitutive pka activity and nf-b activity in macrophages . because cry - deficient macrophages constitutively upregulated tnf- and il-6 expression , an important implication of this study is that an arrhythmic clock system may be sufficient to increase the stress levels of cells leading to constant expression of inflammatory cytokines and causing a low - grade chronic inflammatory status . collectively , these findings provide molecular insights into how the circadian clock regulates daily variations in the induction of inflammatory cytokines upon a powerful challenge of lps and how disruption of the clockwork affects the cytokine responses . in particular , these findings clearly demonstrate that certain clock proteins interact with important regulatory pathways for cytokine expression . the results may explain the daily fluctuations in susceptibility to various pathogens to the immune system . however , it remains largely unclear whether the circadian clock is attributed to such circadian pathophysiology . rheumatoid arthritis ( ra ) is one of the representative chronic inflammatory diseases with circadian pathophysiology . patients with ra exhibit bad joint inflammation , pain , and stiffness in the morning hours , which is associated with increased inflammatory cytokine production . recently , hashiramoto et al . showed the link between ra and the circadian clock for the first time . they demonstrated that cry - deficient mice exhibited enhanced arthritis associated with upregulation of inflammatory cytokines including tnf- . their data are largely consistent with the findings that cry may be a suppressor for inflammatory cytokine expression . for instance , in most allergic rhinitis patients , symptoms worsen overnight or early in the morning morning attack and often compromise night - time sleep , which results in poor daytime quality of life . for example , caelius ( 4th or 5th century ad ) noted the frequent nocturnal occurrence of asthma attacks . have recently provided evidence that the circadian clock temporally controls ige / mast cell - mediated allergic reaction in vivo . they showed the time of day - dependent variation observed in ige - mediated immediate type allergic reaction in the skin of wild - type mice ( passive cutaneous anaphylactic [ pca ] reaction ) to be absent in per2-mutant mice ( mper2 mice ) . most recently , they have also shown that the circadian clock present in mast cells primarily contributes to the generation of the daily rhythms observed in pca reaction by temporally regulating fcri ( the high affinity ige receptor ) expression and signaling . thus , allergic reaction also appears to be under tight control of the circadian clock . future studies will ensure that many other chronic inflammatory diseases with circadian pathophysiology are under control of the circadian clock . recent strong molecular evidence shows an involvement of certain clock proteins in the circadian gating of immune responses . importantly , new studies demonstrate direct interaction of certain clock proteins with regulatory pathways for cytokine expression in immune cells , which may contribute to shaping circadian immunity such as temporal variations observed in leukocyte trafficking , t cell development , innate immune defense against pathogens , and autoimmunity / allergy . interestingly , disruption of the circadian clock appears to aggregate chronic inflammatory diseases such as ra via aberrant expression of inflammatory cytokines [ 6 , 7 , 17 ] . the findings may implicate that increased prevalence of human inflammatory diseases including autoimmunity and allergy in industrialized countries may be linked to modern life style chronically disrupting the circadian clock such as night shift work or jet lags . thus , it will be a significant challenge in future how new basic studies on circadian control of immunity , especially on circadian regulation of cytokines , will be translated into prevention and treatment of infection , autoimmunity , and allergy .

several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to circadian rhythms . such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur . however , the mechanisms behind circadian immunity have not been fully understood . recent studies reveal that the internal time keeping system circadian clock plays a key role in driving the daily rhythms evident in the immune system . importantly , several studies unveil molecular mechanisms of how certain clock proteins ( e.g. , bmal1 and clock ) temporally regulate expression of cytokines . since cytokines are crucial mediators for shaping immune responses , this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines . a greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines .

patients with metabolic syndrome , also known as cardiometabolic syndrome or insulin resistance syndrome , are at greater risk of cardiovascular disease regardless of a previous history of cardiovascular events.1,2 this is particularly relevant in patients with type 2 diabetes mellitus , who are at even greater cardiovascular risk.3 in fact , cardiovascular complications are the most common cause of morbidity and mortality in this population.4 the availability of several definitions of metabolic syndrome has created potential confusion concerning its prognostic utility . at present , little data exist about the risk factors associated with metabolic syndrome in diabetic patients.5,6 the aim of this analysis was to identify the risk factors associated with metabolic syndrome in a large sample of patients with type 2 diabetes mellitus in spain according to three diagnostic criteria : world health organization ( who ) , the third report of the national cholesterol education program expert panel on detection , evaluation , and treatment of high blood cholesterol in adults adult treatment panel iii ( ncep - atp iii ) , and the international diabetes federation ( idf ) . the main difference between these diagnostic criteria lies in the way in which the various components for the diagnosis are grouped and combined . the who criteria focus on the presence of diabetes , glucose intolerance or insulin resistance together with the presence of at least two other components from a list of five components . on the other hand , the ncep - atp iii criteria give the same weight to abdominal obesity , hypertension , hyperglycemia , hypertriglyceridemia and low hdl - cholesterol ( three or more of these components must be present for a diagnosis ) . finally , the idf criteria are similar to ncep - atp iii although emphasizing the presence of abdominal obesity with cutoff points tailored to ethnic origin compared with other four components of which at least two or more must be present.7 study design , subjects , and methods have been described previously.7 this is a secondary analysis of the data from a nationwide , cross - sectional , naturalistic , multicenter study carried out in outpatient clinics in spain . included patients had type 2 diabetes mellitus diagnosed according to the american diabetes association ( ada ) criteria and were aged 18 years or older . the local ethical review board of the hospital clnico san carlos ( madrid , spain ) provided approval of the study protocol and the study was conducted in accordance with the principles of the declaration of helsinki . we explored the associations between significant demographic , clinical , and lifestyle variables and the prevalence of metabolic syndrome ( diagnosed according to who , ncep - atpiii , and idf criteria ) by means of a chi - square test for categorical variables and a student s t - test for continuous variables . the sociodemographic and lifestyle variables included in the analysis were age , geographical region , education , smoking status , and physical activity ; the clinical variables were body mass index ( bmi ) , glycosylated hemoglobin ( hba1c ) and fasting plasma glucose ( fpg ) values , diagnosis of dyslipidemia , hypertension , cardiovascular disease , heart failure , left ventricular hypertrophy , or existing comorbidities . all the variables with a p value < 0.1 in the bivariate analysis were included as independent variables in a multivariate logistic regression model . this cut - off point was chosen to ensure that all possibly related variables were included in the logistic regression model . out of the 1345 patients selected , 1259 met the inclusion criteria and participated in the study ( 622 from primary care and 637 from internal medicine settings ) . patients mean age ( standard deviation [ sd ] ) was 64.7 ( 10.7 ) years , and 57.1% of patients were male . physical activity was low in 61.9% of patients , of whom 31.4% had a sedentary lifestyle . mean time ( sd ) from type 2 diabetes mellitus diagnosis was 7 years ( 7.3 ) . the majority of patients were on diet and exercise ( 88.2% ) , and 75.9% of the sample was receiving oral antihyperglycemic medications ( oam ) . in addition , a total of 70.8% of patients had been diagnosed with hypertension , dyslipidemia ( 67.1% ) , or left ventricular hypertrophy ( 12.3% ) . the presence of metabolic syndrome according to the who definition was significantly associated with age , intense and moderate physical activity , dyslipidemia , hypertension , treatment with oam , and hba1c levels 7% . the existence of dyslipidemia , hypertension , and hba1c 7% in patients was related to higher odds ratios for metabolic syndrome . in contrast , older age ( 65 years ) and intense and moderate physical activity attenuated the risk of metabolic syndrome . for ncep - atp iii definition , age , gender , moderate and intense physical activity , elevated fpg levels , dyslipidemia , hypertension , treatment with oam , and the presence of endocrine disorders were independently associated with metabolic syndrome . the risk of metabolic syndrome was elevated in females ( twofold ) , patients with elevated fasting plasma glucose levels ( sixfold ) , dyslipidemia , hypertension , and endocrine disorders . finally , the prevalence of metabolic syndrome as per idf definition was associated with gender , moderate physical activity , insulin treatment , and left ventricular hypertrophy . women ( fourfold ) , patients not treated with insulin , and patients with left ventricular hypertrophy were at higher risk of idf - defined metabolic syndrome than men , patients treated with insulin , and patients without left ventricular hypertrophy , respectively . the risk of having metabolic syndrome for women with type 2 diabetes mellitus was higher by the idf criteria than the ncep - atp iii criteria . an older age ( 65 years ) and intense physical activity appeared to be protective factors against metabolic syndrome according to both who and ncep - atp iii , whereas the presence of dyslipidemia , hypertension , and treatment with oam showed similar increased risk by both diagnostic definitions . finally , moderate physical activity seemed to be associated with reduced risk by ncep - atp iii , idf , and who definitions of metabolic syndrome . previously published data from this study showed that in this population , the prevalence rates of metabolic syndrome according to who , ncep - atp iii , and idf were different ( 71.5% , 78.2% , and 89.5% , respectively).7 further , the data presented here provide evidence that in subjects with type 2 diabetes mellitus , the existence of dyslipidemia , hypertension , and hba1c levels of 7% increases the risk of presenting metabolic syndrome , according to who - defined criteria . for the ncep - atp iii - defined metabolic syndrome , the risk is increased in women , subjects with elevated fpg levels , dyslipidemia , hypertension , and endocrine disorders . for the idf criteria , women , patients treated with insulin , and patients with left ventricular hypertrophy ( although there is some disparity in the degree of physical activity related to the ncep - atp iii , idf , and who definitions , it seems that exercise training would be associated in this study with a decreased risk of metabolic syndrome . this is the first study to show that metabolic syndrome , according to all three definitions ( who , ncep - atp iii , and idf ) , in a large sample of spanish patients with type 2 diabetes , is independently associated with different risk factors ( metabolic and non - metabolic ) depending on the diagnostic criteria used , likely due in part to the differences in the cut - off points . nevertheless , all three criteria provided greater odds ratios for the cardiovascular risk factors studied . in fact , previous studies have reported an increased cardiovascular risk associated with the presence of metabolic syndrome.8,9 this is not surprising since metabolic syndrome contains well - established cardiovascular risk factors such as hypertension and dyslipidemia . in summary , the risk factors associated with the presence of metabolic syndrome in a population with type 2 diabetes mellitus are highly dependent on the criteria used to define metabolic syndrome , supporting the need for a single common clinically and epidemiologically useful definition of metabolic syndrome . the identification and clinical management of the high - risk groups will contribute significantly to metabolic syndrome prevention in patients with type 2 diabetes mellitus .

background : the availability of several definitions of the metabolic syndrome has created potential confusion concerning its prognostic utility . at present , little data exist about the risk factors associated with metabolic syndrome in diabetic patients.aim:to identify risk factors associated with metabolic syndrome in patients with type 2 diabetes mellitus according to three diagnostic criteria : world health organization ( who ) , third report of the national cholesterol education program expert panel on detection , evaluation , and treatment of high blood cholesterol in adults adult treatment panel iii ( ncep - atp iii ) , and international diabetes federation ( idf).subjects and methods : a logistic regression model was used to identify demographic , clinical , and lifestyle variables related with metabolic syndrome ( n = 1259).results : hypertension , dyslipidemia , and glycosylated hemoglobin ( hba1c ) 7% were associated with increased risk of who - defined metabolic syndrome ( odds ratio [ or ] , 2.33 ; 95% confidence interval [ ci ] : 1.603.40 ; or , 1.79 95% ci : 1.252.55 ; and or , 1.58 ; 95% ci : 1.122.22 , respectively ) . the risk of presenting metabolic syndrome according to ncep - atp iii criteria was increased in female patients ( or , 2.02 ; 95% ci : 1.372.97 ) , elevated fasting glucose levels ( or , 5.99 ; 95% ci : 3.5610.07 ) , dyslipidemia ( or , 2.28 ; 95% ci : 1.573.32 ) , hypertension ( or , 2.36 ; 95% ci : 1.593.53 ) , and endocrine disorders ( or , 1.64 ; 95% ci : 1.062.57 ) . for the idf criteria , female patients and patients with left ventricular hypertrophy or insulin treatment were at higher risk of metabolic syndrome ( or , 4.00 ; 95% ci : 2.356.80 ; or , 2.72 95% ci : 1.226.04 ; and or , 1.96 95% ci : 1.243.11 , respectively).conclusions : the risk factors for metabolic syndrome in type 2 diabetes mellitus patients are highly dependent on the criteria used to define the syndrome , supporting the need for a single clinically useful and epidemiologically useful definition .

deep brain stimulation ( dbs ) is commonly accepted as a safe and effective treatment for many neurological diseases including movement disorders , refractory epilepsies , psychiatric diseases and pain disorders.14 dbs of the anterior nucleus of thalamus ( ant ) was recently reported as beneficial for patients with intractable epilepsy in a randomized , controlled , double - blind study.5 many studies have discussed the complications of dbs on classical targets . however , because of limited experience with ant dbs for epilepsy , its technical problems are rarely reported and unclear . in this case report , we describe a patient with a unique complication after ant dbs , whose dbs lead had migrated into ventricle , detected 8 years after implantation . a 57-year - old male was admitted for progressive loss of anti - epileptic effect from bilateral ant dbs during the last 6 months prior to admission . his first seizure developed at the age of 10 . since then , he suffered from chronic epilepsy with generalized tonic - clonic seizures and had regularly taken antiepileptic medications . a huge left frontal lobe meningioma detected due to increasing seizure frequency was removed in 2001 , when he was 43 year of age . after about 6 years of multiple antiepileptic drug treatment by an experienced epileptologist in a tertiary hospital , he was diagnosed with intractable bilateral frontal lobe epilepsy . he was considered to have medically intractable epilepsy and was evaluated with presurgical studies , including video - electroencephalography ( eeg ) , ictal and interictal single - photon emission computed tomography , magnetic resonance imaging ( mri ) , and positron emission tomography . bilateral ant dbs was performed in one hospital in 2007 . according to the medical records and old brain images , minneapolis , mn , usa ) and soletra ( model 7426 ; medtronic inc . , he had undergone replacement of bilateral implantable pulse generators ( ipgs ) in 2011 due to ipg depletion . however , his seizure frequency had increased gradually to three or more times a month , since 6 months before admission . his left ipg battery was found to be depleted at the outpatient clinic 2 weeks before admission . admission was decided to evaluate shortened longevity of the ipg and poor antiepileptic effect of dbs . he had no major head trauma history that could have affected the function of the dbs system . plain x - rays were taken to determine the integrity of bilateral leads and extension lines . brain mri showed that the left dbs lead was not located in the left ant , but in the third ventricle ( fig . the third and lateral ventricles had enlarged significantly and bilateral sylvian fissures had widened without any evident obstructive lesion in the cerebrospinal fluid pathway , compared to the mri performed in 2007 ( fig . we estimated the degree of ventricular enlargement and created fusion images using framelink navigation software ( medtronic inc . , minneapolis , mn , usa ) to identify the direction and degree of lead migration . to make fusion images , postoperative computed tomography ( ct ) scan , taken after the first dbs in 2007 , was merged on the stereotactic mri taken for re - visionary ant dbs in 2015 . other areas in the ct scan , except the dbs lead , were made invisible by controlling the contrast and transparency of the image ( fig . the patient required re - implantation of a new dbs lead in the left ant and replacement of the ipg . we removed the dbs lead and performed a mri - guided , transventricular ant dbs on the left side . postoperative ct scan was taken for detecting any acute complication , and then it was fused with the preoperative stereotactic mri to confirm the location of the electrodes . after verification of the eeg driving response and conducting test stimulations for 2 days , the ipg was replaced . comparison of the brain mris taken in 2007 and 2015 revealed that the evans index , the cella media index and the maximal width of the third ventricle had increased from 0.254 to 0.267 , 0.142 to 0.204 , 7.7 to 14.5 mm , respectively . the ct scan taken after the first dbs in 2007 showed that only the most distal electrode had definite contact with the ant parenchyma ( fig . we fused the ct scan with the recent mri taken in 2015 using the navigation software . the fusion images showed that the left lead had migrated medially into the third ventricle and the right lead had migrated laterally during the intervening 8 years ( fig . rather , it was firmly attached to the burr hole with thick adhesions and new bone formation . after a simple adhesiolysis between the lead and surrounding tissue , the lead was easily removed without much risk of intracerebral hemorrhage as it was in the ventricle , rather than within the thalamic parenchyma . after removing the lead and the extension line , the scan was merged with the preoperative stereotactic mri to confirm the final electrode locations . the fusion image revealed that successful targeting was achieved with sufficient contact to the ant parenchyma ( fig . the patient showed a mechanical , antiepileptic effect after re - implantation of the left ant lead , and a prominent eeg driving response was verified . it receives the mammillothalamic tract and projects to the cingulate gyrus.6 electrical stimulation of the ant to treat epilepsy was introduced by sussman et al.7 and by cooper et al.8 recently , the sante multi - center , prospective , randomized , double - blind study ( electrical stimulation of the anterior nucleus of the thalamus for treatment of refractory epilepsy ) demonstrated the efficacy of ant dbs to reduce epileptic seizures.5 the authors reported paresthesia , implant site pain and infection as the most common device - related adverse effects . initially mislocated electrodes were 8.2% of their cases , but the details were not described.5 in the present case , it was obvious that the lead had spontaneously migrated due to the significant enlargement of the ventricle because the patient had no definite history of trauma and no securing failure was observed near the burr hole site intraoperatively . the ct scan taken immediately after the first dbs in 2007 showed that only the distal part of the left dbs lead had contact with the ant parenchyma ( fig . the targeting was correct , but the contact surface for the electrodes was insufficient . in fusion images the left lead was revealed to have migrated medially into the third ventricle and the right lead had migrated laterally ( fig . we speculate that the left lead probably moved laterally due to laterally acting pressure caused by enlargement of the ventricle . then , the lead pulled out of the thalamic parenchyma , which eventually caused its medially directed migration , while the right lead remained in the laterally moved location in the thalamus . we think that it was caused by a shallow and insufficient lead implantation . a transventricular trajectory is usually avoided in dbs for classical targets , such as the subthalamic nucleus , globus pallidus interna , and ventral nuclei of the thalamus.9 ventricular puncture during the surgery may induce a brain shift due to loss of cerebrospinal fluid , which is a common cause of mistargeting . in addition , a dbs lead is not rigid enough to pierce through the ventricle and may proceed in the wrong direction in a curvelinear shape along the ventricular wall during the implantation.9 moreover , many vascular structures in the ventricles can cause acute hemorrhage.10 therefore , neurosurgeons carefully perform dbs so as not to interrupt the ventricular wall . however , transventricular trajectory is frequently chosen for ant dbs because of its proximity to the ventricle.6 the medial dorsal nucleus of thalamus also has profound projections to the cerebral cortex , which can be affected by a more anteriorly located trajectory , and which may lead to a synergetic effect with ant stimulation.11 during the 8 years , the patient had undergone significant atrophic brain changes ( figs . 2a and 2b ) . because the human brain changes with time , it is important for physicians to understand and predict the absolute or relative changes in electrode locations , which may cause unexpected side effects or loss of benefits.12 according to a longitudinal cross - sectional study , the volume of the cerebral cortex and subcortical structures decrease , and the ventricular volume increases during healthy aging.13 in that study , the volumes of the inferior lateral ( 5.47% ) , lateral ( 4.40% ) , and third ( 3.07% ) ventricles increased significantly , but the size of the fourth ( 0.71% ) ventricle did not change.13 studies have evaluated the influence of aging on structures , such as the subventricular and basal ganglia , the thalamus , and the brain stem region , where most dbs targets are located.1315 the atrophic changes in the brain of a patient with epilepsy are more severe . in a volumetric mri study , both the gray and white matter had more atrophy beyond the known epileptogenic area in the temporal lobe epilepsy ( tle ) patient group , compared to that in a healthy group.16 atrophy progresses more significantly compared to that observed during normal aging in patients with pharmacoresistant tle.17 in the present case , in addition , surgery of the huge frontal meningioma in 2001 , may have contributed the acceleration of atrophic changes of the brain by inducing traumatic injury . therefore , regular brain imaging studies can be helpful to identify possible changes in electrode locations of ant dbs , because many causes , such as aging , epileptic seizure and brain injury , can provoke and accelerate progressive ventricular dilatation and cerebral atrophy . in conclusion , the progressive dilatation of the ventricles and shallow , insufficient implantation of the initial ant dbs may have caused migration of the dbs lead . we recommend regular follow - up imaging studies as well as measuring impedance and battery status of the implanted device , because ventricular dilatation and cerebral atrophy can progress years after ant dbs in an epilepsy patient with injured , atrophied brain .

the long - term ( 5-years ) antiepileptic effect of deep brain stimulation ( dbs ) of the anterior nucleus of the thalamus ( ant ) against refractory epilepsy has been reported . however , experience with ant dbs for epilepsy is limited , and so hardware complications and technical problems related to ant dbs are unclear . we report the case of a 57-year - old male who underwent re - implantation of a dbs lead in the left ant because of lead migration into the third ventricle detected 8 years after the first dbs , and which was caused by the significant enlargement of the lateral and third ventricles . after re - implantation , the patient showed a mechanically - related antiepileptic effect and a prominent driving response of the electroencephalography was verified . we speculate that progressive dilatation of the ventricle and shallow , insufficient implantation of the lead during the initial ant dbs may have caused migration of the dbs lead . because dilatation of the ventricle could progress years after dbs in a patient with chronic epilepsy , regular follow - up imaging is warranted in ant dbs patients with an injured , atrophied brain .

many diverse lines of evidence indicate that schizophrenia is a neurodevelopment disorder ; early - life adverse events such as prenatal stress , obstetric complications , malnutrition , and viral infection may interrupt the normal brain development and increase the susceptibility of schizophrenia later in life [ 14 ] . neurotrophic molecules are believed to be critical in the development and function maintenance of cortical neurons and synapses , such as brain - derived neurotrophic factor ( bdnf ) . bdnf is a key member of the neurotrophin family widely expressed in the brain [ 6 , 7 ] ; it plays an important and unique role in regulating a wide repertoire of functions at different development stages , including neuronal survival , migration , phenotypic differentiation , and axonal and dendritic growth in neonatal individuals [ 8 , 9 ] , as well as synaptic plasticity and behavior in adulthood [ 1012 ] . several lines of evidence have suggested the involvement of bdnf in pathophysiology of schizophrenia in both human and animal studies [ 1315 ] . however , knowledge in understanding of bdnf in pathophysiology of schizophrenia remains limited and poorly defined . one of key pitfalls of schizophrenia research in animal studies is that all experiments usually focused only on a certain period during development . therefore , it is fundamentally and clinically significant to investigate long - term changes of bdnf in animal models of schizophrenia in a development scheme . among a number of schizophrenia animal models , repeated administration of dizocilpine maleate ( mk-801 , a noncompetitive nmda receptor antagonist ) during neonatal period may be a suitable animal model to explore certain remaining issues . this is because the paradigm of this model has been shown to produce schizophrenia - like behaviors weeks after administration , a potential advantage over other models to study long - lasting effects in a development scheme . the aim of the present study is to investigate the long - term bdnf expression profiles in different regions and correlation with timed - pregnant sprague - dawley rats were purchased from the department of laboratory animal science , peking university health science center . female pups were collected and then cross - fostered to one of the lactating dams within 24 h of parturition , which was designated as postnatal day 0 ( pnd 0 ) . animals were housed on a 12 : 12 light / dark cycle ( lights on 08:00 hour ) with ad libitum access to food and water . all procedures were performed in accordance with the national institute of health guide for use and care of laboratory animals and were approved by the peking university committee on animal care and use . on pnd 5 , the pups from each litter were randomly assigned to the mk-801 or saline groups , which were injected subcutaneously with mk-801 or saline for 10 consecutive days . all groups were sex balanced . to avoid potential influence on bdnf levels by behavioral testing , rats were sacrificed and assessed for bdnf levels 24 hours ( pnd 15 ) and 4 weeks ( pnd 42 ) after the last injection . for behavioral testing , all animals were tested for locomotor activity at pnd 42 and pnd 77 . pups ( except those sacrificed on pnd 15 ) mk-801 was obtained from sigma ( st . louis , mo , usa ) and dissolved in saline ( 0.9% nacl ) . based on our preliminary experiment , a dose of 0.25 mg / kg per injection of mk-801 was used in the present study . all rats received injections twice daily beginning at 9:00 and 15:00 , respectively . because locomotor activity has been thought to be an indicator of schizophrenia - like behavior [ 1719 ] , to test the face validity of the mk-801 administration in mimicking schizophrenia , we measured locomotor activity . two tests on pd 42 and pd 77 for each animal were conducted , of which the procedures were adapted from our previous work . briefly , locomotor activity was measured by an automated video tracking system with four activity chambers ( digbehv - lm4 , shanghai jiliang software technology co. ltd , china ) . the chambers were made of black iron ( 45 cm 45 cm 70 cm , length width height ) . all of the chambers were connected to a pc which recorded the locomotion of rat . the video documents ( stored in the computer ) were analyzed by the digbehv analysis software . the analysis resulted in a track record , and locomotor activity was expressed as a total distance traveled for a predetermined period of time . on the testing day , rats were kept in testing room at least for 60 minutes before placing animals in the activity chambers . the bdnf emax immunoassay system ( promega ) was used to measure bdnf protein levels in each brain region according to the manufacturer 's protocol . briefly , on pn15 ( 24 hours after the last injection ) and pn42 ( 4 weeks after the last injection ) , brain tissues of hippocampus and pfc were immediately dissected out and frozen on dry ice . then the dissected brain tissues were homogenized in lysis buffer ( 137 mm nacl , 20 mm tris , 1% np-40 detergent , 10% glycerol , 1 mm methylphenylsulphonylfluoride , 10 mg / ml aprotinin , 1 mg / ml leupeptin , and 0.5 mm sodium orthovanadate ) . homogenates were centrifuged at 10,000 rpm for 10 min in a cold room , and supernatants were used for elisa analysis . a standard curve was made using serial dilutions of known amounts of bdnf ranging from 0 to 500 pg / ml . results for duplicate experiments were averaged , and bdnf values were corrected for the amount of protein in each sample . the sensitivity of the assay was within the range reported by the above - mentioned promega kit and the interassay variation was less than 10% . statistical differences between groups were determined by independent samples t - test . a probability level of p < .05 was considered to be statistically significant . mk-801 treated rats exhibited significantly increased locomotor activity compared with saline - treated controls on both pnd 42 ( t = 2.63 , df = 17 , and p = .018 ) and pnd 77 ( t = 2.43 , df = 20 , and p = .025 ) ( figure 1 ) . protein content of bdnf was significantly increased , but with different patterns in pfc and hippocampus . in pfc , the bdnf expression was significantly upregulated in mk-801 treated rats ( t = 6.19 , df = 16 , and p < .001 ) at early time point of pnd 15 . however , this early increase of bdnf expression was only transient , and it went back to normal control baseline on pnd 42 ( t = 1.19 , df = 19 , and p > .05 ) and pnd 77 ( t = 0.54 , df = 17 , and p > in contrast to the developmental pattern in pfc , bdnf expression in the hippocampus was not influenced by neonatal mk-801 administration ( t = 0.30 , df = 16 , and p > however , there was a significant late increase of bdnf expression on pnd 42 ( t = 3.89 , df = 16.9 , and p = .001 ) and pnd 77 ( t = 3.28 , df = 17 , and p = .01 ) ( figure 2(b ) ) . the major findings of present study are ( 1 ) exposure of the developing brain to mk-801 , neonatal blockade of nmda receptor , resulted in the locomotor hyperactivity in adolescence and in adult of rats ; ( 2 ) bdnf levels in brain tissues were affected by neonatal mk-801 administration with patterns of age - dependent , long - lasting , and brain regional specificity ; ( 3 ) the postpubertal emergence of the hippocampal bdnf upregulation was concomitant with the behavioral abnormality of the animals . the above findings altogether indicate that altered bdnf expression in this experimental animal model for schizophrenia may be correlated with the development of schizophrenia - like behavior and pathophysiology . it has been demonstrated that schizophrenia is usually diagnosed during adolescence , a period experiencing dramatic changes in behaviors ; interestingly bdnf expression in human brain changes during development and maturation . therefore it is necessary and important to include different time points in the current study . we chose pfc and hippocampus in the current study , because these two brain areas are most implicated in schizophrenia [ 23 , 24 ] . abnormal bdnf expression has been observed in these two areas , and conditional knockout of bdnf in the forebrain induced impaired locomotor activity in rodents . locomotor hyperactivity is routinely used as indicator of schizophrenia - like behavior [ 1719 ] and has been found in adolescent or adult animals experienced neonatal nmda receptor blockade [ 16 , 26 ] . our finding showed the feasibility of assessing bdnf levels in such a developmental rat model long after the drug administration . however , on pnd 42 , the upregulated bdnf levels in pfc returned to normal level , while the bdnf expression in hippocampus significantly increased and sustained from pnd 42 to pnd 77 . we did not assess the locomotor activity on pd15 , since the preweaning animal is not suitable for behavioral assessment of schizophrenia model . a previous clinical observation showed that bdnf protein was increased in hippocampus and unchanged in pfc of schizophrenia patients . since the above tested brain samples of all patients received antipsychotic treatment before death , the association of the altered bdnf expressions with schizophrenia pathology or antipsychotic drug effects remains unknown . furthermore , it is not known whether the expression of bdnf in schizophrenia patients changes at different ages . the current study demonstrates that the bdnf levels in mk-801 treated rats persisted from pnd 42 to pnd 77 , suggesting that the abnormal expression patterns of bdnf observed in schizophrenia patients might not be affected by age during adolescence and early adulthood . interestingly , the abnormal bdnf expression occurred between pnd 15 and pnd 42 , adolescence in rats . this is consistent with clinical observations that schizophrenia is usually diagnosed at late adolescence or early adulthood . this plausible coincidence of schizophrenia age onset and the emergence of the bdnf increase hints at the association of bdnf expression and the etiology of schizophrenia . additionally , there is evidence that bdnf protein levels may cause changes in strength of synaptic transmission in hippocampus , and upregulated bdnf levels in hippocampus can induce other schizophrenia - like behavior . thus , it is possible that the locomotor hyperactivity is related with the increased bdnf in hippocampus but not pfc in the current study . the increase of bdnf levels at pfc is probably a protective response to mk-801 administration induced cytotoxic insults [ 26 , 30 ] . the fact that hippocampus is spared from acute responses to mk-801 treatment suggests that the alterations of bdnf in adolescence and adulthood were not remnants of acute responses . therefore , the bdnf changes at adolescence and adulthood may have different roles and mechanisms with that of neonatal stage , which needs further investigations . it could be seen from the current study that the alterations of bdnf expression and locomotor activity both persisted from pnd 42 to pnd 77 . the plausible association between changes in behavioral performance and bdnf expression indicates that regulation of bdnf expression may be related with pathophysiology of schizophrenia . it has been reported that bdnf levels in serum are abnormal in patients with schizophrenia [ 31 , 32 ] ; it would be interesting and important to have information on circulation , bdnf levels in our future studies . the correlations between behavioral deficits and bdnf alterations are incompletely understood from this study ; a more thorough behavioral profile needs to be performed in the future . bdnf protein levels alone may not give a complete account of bdnf / trk b signaling , and the function of bdnf / trk b signaling may vary among subregions of hippocampus . mrna and protein may have different developing trajectories , and different transcripts of bdnf may have different development trajectories ; more studies for different mrna transcripts of bdnf need to be carried out . there may be multiple neurotrophic molecules and signaling pathways involved in this model ; interaction and a network regulation need to be aware , and investigated as well . in summary , our present study demonstrates that there are sustained behavioural deficit and bdnf alterations in the rat model of schizophrenia induced by neonatal mk-801 administration . these findings suggest that altered expression of bdnf might attribute to schizophrenia and provide evidence that the patterns of abnormal bdnf expression may vary at different developing stages . further experiment needs to elucidate the mechanisms underlying the age - associated changes of bdnf and the potential roles of bdnf on abnormal behavior , which may lead to a better understanding of the pathophysiology of schizophrenia .

neonatal blockade of n - methyl - d - aspartic acid ( nmda ) receptors represents one of experimental animal models for schizophrenia . this study is to investigate the long - term brain - derived neurotrophic factor ( bdnf ) expression profiles in different regions and correlation with schizophrenia - like behaviors in the adolescence and adult of this rat model . the nmda receptor antagonist mk801 was administered to female sprague - dawley rats on postnatal days ( pnd ) 5 through 14 . open - field test was performed on pnd 42 , and pnd 77 to examine the validity of the current model . bdnf protein levels in hippocampus and prefrontal cortex ( pfc ) were analyzed on pnd 15 , pnd 42 , and pnd 77 . results showed that neonatal challenge with mk-801 persistently elevated locomotor activity as well as bdnf expression ; the alterations in bdnf expression varied at different developing stages and among brain regions . however , these findings provide neurochemical evidence that the blockade of nmda receptors during brain development results in long - lasting alterations in bdnf expression and might contribute to neurobehavioral pathology of the present animal model for schizophrenia . further study in the mechanisms and roles of the bdnf may lead to better understanding of the pathophysiology of schizophrenia .

although cerebral hyperperfusion syndrome ( chs ) is well documented after carotid endarterectomy and carotid artery stenting , only a few cases have been described after intracranial stenting . after the stenting versus aggressive medical therapy for intracranial arterial stenosis and vitesse stent ischemic therapy trials demonstrated the inferiority of intracranial stenting compared to aggressive medical treatment , this procedure has been largely abandoned . cerebral hyperperfusion is defined as a > 100% increase in cerebral blood flow ( cbf ) compared to the baseline and it is generally associated with postprocedural hypertension . chs has an estimated incidence of 0.4%2.7% after ce and usually presents with ipsilateral headache or migrainous phenomena , seizures , or intracerebral hemorrhage ( ich ) . i would like to report an unusual case of chs following middle cerebral artery ( mca ) stenting . a 71-year - old man presented to us with fluctuating motor aphasia of 3 h duration . magnetic resonance imaging of the brain showed multiple acute infarcts in the left mca territory and he was started on antiplatelets and statins . by the next day morning , he had developed global aphasia and transient right - sided weakness . his blood pressure ( bp ) was 150/90 mm hg and he was taken up for a four - vessel digital subtraction angiography which showed a possible dissection with a thrombus in the distal left mca [ figure 1 ] . after obtaining consent , a 4 mm 15 mm solitaire ab neurovascular modeling device ( ev3 , irvine , usa ) was placed across the lesion into the superior mca division with good recanalization . postprocedure , the patient was sedated and ventilated , but had severe hypertension , exceeding 240/140 mm hg which was difficult to control even with multiple antihypertensives . the next morning , a routine computed tomography ( ct ) brain ( 12 h later ) showed two discrete intracerebral hematomas ( ich ) in the left frontal and temporal areas [ figure 1 ] . transcranial doppler ( tcd ) showed elevated mean flow velocities of > 130 cm / s in the left mca . coagulation parameters were normal . on examination , now he had a dense right hemiplegia and global aphasia . two weeks later , a repeat ct showed resolution of the ich and no fresh infarcts . the patient had a residual wernicke 's aphasia and right hemiplegia at follow - up even 6 months later . ( a ) top left panel shows an irregularity in the left middle cerebral artery m1 segment , suggestive of dissection . ( c ) bottom panels ; computed tomography scan images showing left temporal and frontal intracerebral hematomas risk factors for chs include age > 75 years , preexisting hypertension , high - grade stenosis with poor collateralization , decreased cerebrovascular reactivity , and increased peak flow velocities . reperfusion of ischemic territories can also lead to reperfusion injury , wherein oxidant production , complement activation , and increased microvascular permeability result in an impaired blood chs is a devastating complication because of the high morbidity and mortality of nearly 60%80% associated with this condition . after cerebral revascularization , the advent of severe headache , seizures , or focal neurological deficits after cerebral revascularization should be presumed to signify chs unless proved otherwise . tcd studies are helpful in monitoring elevated peak systolic velocities in the intracranial arteries as a marker of impending chs . in about 15% of patients , in such patients , near - infrared spectroscopy may be a useful option to monitor cbf . all critical care physicians should be aware of this entity for better monitoring and prevention of this postprocedural complication in the icu .

cerebral hyperperfusion syndrome ( chs ) is a rare complication following cerebral revascularization . it presents with ipsilateral headache , seizures , and intracerebral hemorrhage . it has mostly been described following extracranial carotid endarterectomy and stenting and it is very unusual after intracranial stenting . a 71-year - old man with a stuttering stroke was taken up for a cerebral angiogram ( digital subtraction angiography ) , which showed a dissection of the distal left middle cerebral artery . this was recanalized with a solitaire ab stent . after 12 h , the patient developed a right hemiplegia and aphasia . computed tomography brain showed two discrete intracerebral hematomas in the left hemisphere . this is the first reported case of chs following intracranial stenting from india .

the demand of esthetics among the patients has led to the introduction of tooth - colored materials . nowadays , composites are the most promising tooth - colored materials that have replaced silicates and acrylics . composite resin bonds to enamel by means of acid - etching and to dentin with the help of dentin bonding agents . adhesion to dentin is not as reliable as adhesion to enamel , because of the morphologic , histologic , and compositional differences between them . to overcome the challenges in dentin bonding , various advancements have been made . the ideal bonding system should be biocompatible , should have sufficient bond strength to resist failure as a result of masticatory forces , bond indifferently to enamel and dentin , and be easy to use . in the search of the ideal bonding agent , various dentin bonding systems were introduced in market but were more complicated and time consuming as they involved various clinical steps . during the past few years , the trend has been to move one step further by combining the etching , priming , and bonding with an attempt to develop fifth- , sixth- , and the seventh - generation adhesives . the seventh - generation adhesives are the acidic primers and the rationale behind these systems is to superficially demineralize dentin and to simultaneously penetrate it to the depth of demineralization with monomers that can be polymerized in situ . the aim of this study was to compare the tensile bond strength of three seventh - generation self - etch adhesives , because higher the actual bonding capacity of an adhesive , the longer the restoration will survive in vivo . although clinical trials are the ultimate tests for the dental restorations , they can not differentiate the true reason for failure due to the simultaneous impact of diverse stresses on the restoration , whereas laboratory testing can evaluate the effect of single variable while keeping the other variables constant . sixty recently extracted intact caries - free permanent mandibular molars were collected , cleaned of debris , blood , and calculus , and were then stored in the normal saline . the teeth were drilled in the deepest part of the central fossa of the occlusal surface of each tooth with the help of round diamond bur ( sf 21 , prime and dental , mumbai ) up to the depth of 1.5 mm in order to standardize the depth of cavity . all the teeth were ground on the orthodontic trimmer until the drilled hole depth to expose the flat dentinal surface . this was followed by polishing of the flat dentinal surfaces with 600 grit silicon carbide paper ( 3 m products ) to produce a uniform smear layer . after finishing , the teeth materials used in the study the teeth were then placed on the glass slab with the flat dentinal surfaces facing the glass slab and stabilized at the periphery with the wax sheet . rectangular aluminium molds of dimension 2.5 2 2.5 inches were placed in the position over the wax sheet bearing the teeth . a thin mix of self - cure acrylic resin ( dpi products ) was placed in the molds to embed these teeth . a piece of adhesive tape was firmly attached on the occlusal surface to define the area of bonding . all the self - etch adhesives were applied according to manufacturer 's instructions on the specified area of the tooth . group 1 : adper easy bond ( 3 m espe , st paul , mn , usa ) was applied as one coat on the dentinal surface , left undisturbed for 20 seconds , dried with a strong blast of air for 5 seconds , and was further light cured for another 10 seconds . group 2 : g bond ( gc corp , tokyo , japan ) was applied as one coat on the dentinal surface , left undisturbed for 5 seconds , dried with a strong blast of air for 5 seconds , and was further light cured for another 10 seconds . group 3 : xeno v ( dentsply , detrey , germany ) was applied as one coat on the dentinal surface , left undisturbed for 20 seconds , dried with a strong blast of air for 5 seconds , and was further light cured for another 20 seconds . a split brass mold of diameter 3 mm and height 5 mm was used to form and hold the restorative resin onto the dentin surface . after the placement of first increment , a stainless steel wire loop was placed so that the composite stabilized it perpendicular to the surface and each increment was light cured for 20 seconds . the split brass mold and the adhesive tape were removed from the specimen 10 minutes after irradiation . the bonded specimens were stored in normal saline and placed in the incubator at 37c and after 24 hours , the specimens were removed from the incubator and tested in tensile mode in universal testing machine ( lloyd 's machine ) . the equipment was adjusted to operate at 1 mm / min , as different cross head speeds may influence the bond strength values . for the tensile bond strength measurement , the wire protruding out of the composite cylinder was gripped into the superior cross head and the aluminium mold was held in the inferior cross head of the universal testing machine . tensile loading was done until the dislodgement of the composite cylinder from the dentinal surface occurred . the breaking load was measured and the results of the debonding force were tabulated in the values of force ( newton , n ) . the tensile bond strength was calculated by dividing the debonding force ( n ) by the debonding area ( mm ) . the mean values of bond strength were calculated for each experimental group and the data were analyzed by one way analysis of variance ( anova ) . post hoc comparisons were carried using tukey 's test with the statistical significance set at = 0.05 . the mean values of tensile bond strength and the standard deviations are shown in table 2 . for group i ( adper easy one ) , the bond strength measured was 12.41 mpa , whereas the mean tensile bond strength obtained for group ii ( g - bond ) was 10.09 mpa and that obtained for group iii ( xeno v ) was 8.67 mpa . mean debonding force and mean tensile bond strength of each experimental group means and standard deviation of the three groups were calculated as debonding force is a continuous dat . to compare all these three groups , as p values came out to be statistically significant in all the three groups , tukey 's b test was applied to see multiple comparisons . post hoc tests and tukey 's hsd test were applied to evaluate the difference in the mean bond strength of the experimental groups statistically . the comparisons revealed differences in the mean bond strength of three self - etch adhesives containing different solvents and the difference between all the three groups was statistically significant ( p<0.05 ) . the concept of adhesive restoration has been essentially the most noteworthy development in ever progressing science . thus , during the evolution of dentin bonding agents , attempts were made to achieve good bonding with enamel and dentin under difficult oral conditions and to ease out the technique . in this process , the recent development is combining etchant , primer , and bonding agent in one component to form seventh - generation dentin bonding agents which are commonly known as self - etch adhesives . these self - etching adhesives can be used to etch both ground enamel and dentin simultaneously and they bond equally well to superficial and deep dentin . ideally , the adhesives should be formulations based on hydrophobic monomers and high molecular weight , without additives such as solvents and water . however , due to the necessity for adhesive to penetrate into microporosities of the dentin , substrate inherently wet , hydrophilic resinous diluents , and solvents were incorporated into the adhesive . thus , the liquid to be spread uniformly over a solid surface , the surface tensile of liquid must be less than the energy free surface of the substrate . the low viscosity of primers and/or adhesive resins is partly due to the dissolution of the monomers in a solvent and will improve ability of diffusion into the microretentive tooth surface . in fact , high values of bond strength to dentin , similar to those achieved in enamel , were obtained after the development of hydrophilic monomers and their association with organic solvents . also , during bonding , if the collagen network is allowed to collapse , the spaces between the collagen fibrils disappear and the adjacent fibrils come into intimate contact with each other . in the absence of water or other hydrogen forming substances , the collagen peptides may form intermolecular hydrogen bonds with the nearest neighboring collagen peptides which may contribute to the further collapse of the network by causing the shortening of the fibrils and leading to the increase in the stiffness . the addition of water and 2-hydroxymethyl methacrylate ( hema ) can break these intermolecular bonds with mass action , thereby softening the network and allowing it to re - expand . thus , the present study was designed to in vitro compare the tensile bond strength of three recent seventh - generation bonding agents , hema - rich , hema - free , and containing three different solvents : ethanol ( adper easy one , 3 m espe ) , acetone ( g - bond , gc asia , corp ) , and butanol ( xeno v , dentsply ) which were bonded with the same microhybrid composite ( charisma , heraeus kulzer ) . the study was planned to be conducted in vitro as it can help to evaluate the effect of single variable while keeping the other variables constant . the results of tensile bond strength measurement of three groups were tabulated and compared and the statistical analysis was done using one step anova test and post hoc tukey 's hsd test . the results showed that the group i ( adper easy one ) with tensile bond strength of 12.41 mpa performed better than the other two groups ; group ii ( g - bond ) with bond strength of 10.09 mpa and group iii ( xeno v ) with bond strength of 8.67 mpa . adper easy one showed higher tensile bond strength than g - bond and tetric n - bond self - etch , and the result was statistically significant ( p<0.05 ) . the inferior bond strength of g - bond and xeno v in comparison with adper easy one can also be contributed to absence and presence of hema . adper easy one contains hema ( 2-hydroxyl ethyl methacrylate ) which is absent in case of g - bond ( hema - free ) and also in xeno v ( hema - free ) . the hydrophilicity of hema makes it an excellent adhesion - promoting monomer and by enhancing wetting of dentin , hema significantly improves bond strength . in order to attain high bonding strengths to dentin , it is essential for the dentin substrates to have good penetrability and diffusibility . in addition , the resin penetration into tubules can effectively seal the tubules and intertubular dentin and the resin infiltration can only occur if the mineral phase of dentin is removed by acidic conditioners . however , acidity of conditioner not only removes mineral from the dentinal matrix , but may also protonate collagen , changing the charges on the peptides and extracting noncollagenous proteins . however , once collapsed , it can be re - expanded with hydrophilic monomers such as hema . the higher bond strength following hema may be due to the fact that the demineralized collagen is kept wet and does not collapse as much as dentin that is dried with air blast . also , the moist dentin may permit a more porous collagen network , which permits greater infiltration of adhesive monomers than do surfaces that are air dried and hence collapse . furthermore , adper easy one contains ethanol as a cosolvent as compared with acetone present in case of g - bond . ethanol removes water from these spaces causing the hydrogel to collapse , thus enlarging the interfibrillar spaces and allowing more resin infiltration . it is speculated that the significantly higher bond strengths obtained when ethanol was used may be due to its hansen 's triple solubility parameters of the hydrogen bonds which is 19.4 ( j / cm ) and is higher than that of dried collagen , 18.2 ( j / cm ) . the higher hansen 's triple solubility parameter of ethanol allows dehydration and stiffening of the matrix without allowing interpeptide h - bonding to collapse it . acetone has a high dipole moment and forms much lower hydrogen bonds due to which it is not able to expand the shrunken demineralized collagen . it has a high vapor pressure of 184 mm hg at 20c as compared with that of ethanol ( 43.9 mm hg at 20c ) . as the solvent evaporates , the viscosity of the bonding system increases , which decreases the ability of the bonding system to penetrate around the exposed collagen fibers and the opened dentinal tubules producing poor and incomplete hybrid layers . also , acetone has a boiling temperature of 56.5c as compared with that of ethanol ( 78.3c ) , which requires careful observation and handling of the product if the optimum ratio among the components is to be maintained . when g - bond and xeno v were compared with each other , it was observed that group iii ( 8.67 mpa ) exhibited lower tensile bond strength as compared with group ii ( 10.09 mpa ) and the result was statistically significant ( p<0.05 ) . this result can be attributed to the fact that xeno v has the lowest ph among the three self - etch adhesives . mild self - etching appears most promising , especially with regard to bond stability . g - bond and adper easy bond both have ph > 2 which makes them mild self - etch adhesives , whereas xeno v has ph < 2 which makes it intermediatory strong self - etch adhesive . in the light of bonding durability , mild self - etch adhesives have unique property that all hydroxyapatite are not removed from the interaction zone , and much calcium is available for additional chemical interaction with specific adhesive monomers . so , the bonds are stable , even in the aqueous environment and the mechanism is supposed to prolong the clinical lifetime of the restorations . also , the preservation of hydroxyapatite around the collagen in mild self - etch adhesives may protect the collagen against hydrolysis and thus prevents the early degradation of the bonds . under the circumstances of the present ex vivo study , adper easy one showed highest tensile bond strength when compared with the other two seventh - generation bonding agents : g - bond and xeno v. thus , comparison of contemporary adhesives revealed that the hema - rich and ethanol - water - based self - etch adhesives are the golden standard in terms of adhesion durability . a further understanding of factors that contribute to the durability of adhesives and their bonding characteristics is needed .

aim : this study evaluated the effect of 2-hydroxymethyl methacrylate ( hema ) and the type of solvent on the tensile bond strength of the following three self - etch adhesives : adper easy one ( hema - rich adhesive ) which contained ethanol , g - bond ( hema - free adhesive ) which contained acetone , and xeno v ( hema - free adhesive ) which contained butanol as a solvent.material and methods : intact mandibular molars were mounted in self - cured resin and the occlusal surfaces were ground with # 600 sic paper . adhesives were applied on the prepared dentinal surfaces and the resin composite was condensed in the split brass mold ( 5 3 mm ) placed over the adhesive surface . the specimens were stored in normal saline and placed in incubator at 37c . after 24 hours , the specimens were tested in tensile mode at a crosshead speed of 1 mm / min . statistical analysis was done using one way anova and tukey 's hsd test.results:the mean bond strengths of adper easy one , g - bond , and xeno v were 12.41 mpa , 10.09 mpa , and 8.67 mpa , respectively.conclusions:comparison of contemporary adhesives in this ex vivo study revealed that the ethanol - based hema - rich self - etch adhesive is better than hema - free self - etch adhesive that contained acetone and butanol as the solvents , when compared in terms of bond strength .

for a given province , year , maternal age group , and the estimated number of live patients with congenital t. cruzi infection were computed as the total number of live newborns ( f ) , times the probability of a woman s being infected with t. cruzi ( p ) , times the probability of transmitting t. cruzi to the live newborn ( t ) . province and age - specific numbers of live births and maternal seroprevalence rates of infection are needed to provide a countrywide annual estimate . the total number of live births in 1991 ( 694,776 newborns ) , according to the mother s age group and province ( 4 ) , changed very little during the 1990s . we categorized births uniformly within each maternal 5-year age class because data on births of single - year age classes were not available ; we did not count the very small number of births in other countries or with unspecified birthplace . the probability of a woman s being infected with t. cruzi varies with age ; however , it may be estimated from the seroprevalence for t. cruzi in men of the same age group because no evidence of a gender - related excess risk of infection has been detected ( 5,6 ) . for argentina , the available province - specific seroprevalence rates of t. cruzi infection for young men drafted into military service in 19651969 ( when they were 21 years of age ) and annually from 1981 to 1993 ( when they were 18 years ) showed quite different temporal trends ( 7 ) . each recruit age class was a randomly selected birth cohort ; unhealthy persons were excluded after blood samples were taken . to reconstruct maternal seroprevalence rates in 1993 , we assumed a closed , steady - state population between year of diagnosis and 1993 . this assumption meant that a ) the fraction infected in each birth cohort remained stable because most t. cruzi infections were acquired during childhood , and specific treatment of infected adults was uncommon except for male recruits and legal immigrants ; and b ) men and women ages 1550 had similar age - specific death and emigration rates because most findings of t. cruzi potential differences in cohort - specific rates of recruitment or loss of infected women through differential migration associated with t. cruzi infection were ignored , although internal migrations may modify the expected number of cases , depending on the interplay between fertility , t. cruzi infection , age at migration , and source and destination of migrants . we tentatively assumed that the chance of being pregnant and having an uneventful pregnancy was not affected by infection with t. cruzi , but present evidence is controversial . the province - specific maternal prevalence of t. cruzi infection in 1993 comprised the partial contributions of mothers who were 18 years old in 1993 ( born in 1975 ) and to whom we assigned the seroprevalence rate of 18-year - old men assessed in 1993 , and so on through mothers ages 30 years in 1993 ( born in 1963 ) and to whom we assigned the seroprevalence rate of 18-year - old men assessed in 1981 . for mothers > 30 years of age in 1993 , we assigned the rate from 19651969 data to 1967 and assumed that the prevalence followed a linear trend between 1967 and 1981 . the few 14- to 17-year - old mothers were assigned the 18-year - olds seroprevalence assessed in 1993 . tierra de fuego was excluded from calculations because the time series had numerous missing data . the probability of congenital transmission from pregnant women seropositive for t. cruzi has been extremely variable ( range 0.0050.117 ) among countries and geographic areas ( 13 ) , and its determinants are little known ( 9,10 ) . from the latest review ( 3 ) , we estimated the median t as 0.025 ( interquartile range 0.020.04 ) . we assumed that t was not modified by the mother s age ( 9,10 ) because most mothers were in the indeterminate or chronic phase of infection in which the parasitemia levels are low and age independent . the national system of epidemiological surveillance reported ( 11 ) a total of 1,080 congenital cases of t. cruzi in 19942001 ( annual mean 135 ; standard deviation 35 ) , with no significant time trend and very large asynchronic variations among and within provinces ( figure 1 ) . as demonstrated for leishmaniasis surveillance in argentina ( 12 ) , inconsistencies among provincial , national , and chagas surveillance reports of congenital cases were frequent and led to substantial underreporting . nationwide and province - specific numbers of reported cases of congenital trypanosoma cruzi infection notified to the ministry of health of argentina . mean coefficient of variation among provinces over time , 266% ; range 39% to 283% . for the city and province of buenos aires , we used the 19942001 data corrected by the chagas national surveillance system . an example of the calculations for the province of buenos aires is given in the appendix . the expected annual number of congenital cases peaked in chaco ( 153 cases ) and the province of buenos aires ( 96 cases ) ; the latter had rare domiciliary triatomine infestations and a large number of immigrants from chagas - endemic provinces during 1947 to the 1970s . santiago del estero , with high seroprevalence and fertility rates but very low human population , ranked 3rd ( 90 cases ) . the ratio between our conservative estimate of congenital cases in 1993 ( 846 cases ) and official notifications in 1994 and 19942001 ( 135 cases ) was 6.3 : 1 . a very rough calculation that used countrywide averages ( f = 687,051 ; p = 0.019 ; t = 0.025 ) yielded 326 congenital cases , or 38% of the above estimate . ( a ) numbers of expected ( in 1993 ) and reported ( mean of 19942001 ) cases of congenital trypanosoma cruzi infection . ( b ) ranked ordering of provinces according to numbers of expected ( in 1993 ) and total reported cases ( 19942001 ) of congenital t. cruzi infection ; spearman s correlation coefficient ( r ) = 0.711 , n=24 , p<0.0001 . 1 , catamarca ; 2 , chaco ; 3 , chubut ; 4 , city of buenos aires ; 5 , cordoba ; 6 , corrientes ; 7 , entre rios ; 8 , formosa ; 9 , jujuy ; 10 , la pampa ; 11 , la rioja ; 12 , mendoza ; 13 , misiones ; 14 , neuquen ; 15 , province of buenos aires ; 16 , rio negro ; 17 , salta ; 18 , san juan ; 19 , san luis ; 20 , santa cruz ; 21 , santa fe ; 22 , santiago del estero ; 23 , tucuman . ( c ) relationship between seroprevalence rates of t. cruzi infection in military recruits in 1993 and mean rural parity in 1991 ( r=0.541 , n=23 , p<0.01 ) . the city of buenos aires , which does not have a rural area , was excluded from analysis . extreme differences between observed and reported mean numbers of congenital cases occurred in chaco and santiago del estero , followed by formosa , tucuman , and mendoza ( figure 2a ) , suggesting strong underreporting . santa fe , jujuy , salta , and the province of buenos aires reported most cases . the ranked province - specific total numbers of cases estimated for 1993 and reported officially from 1994 to 2001 were significantly correlated ( figure 2b ) and thus provided a qualitative hierarchic ordering of provinces in terms of the likely burden of congenital cases . additional calculations tend to support our rough estimates . a pilot control program in a public maternity facility , where 37.8% of all births in tucuman took place , detected 32 congenital cases over 28 months ( mean 13.7 cases per year ) ( 13 ) . if we assume this was a random sample , the annual number of congenital cases projected to the whole province was 36.2 cases , which is roughly close to the expected number of 46.7 cases . schmuis ( 1 ) estimated that 1,593 congenital cases of t. cruzi occurred annually in argentina around 1985 , on the assumptions that the maternal seroprevalence equaled the overall seroprevalence of t. cruzi in blood banks ( 6.96% ) ; that t = 0.03 ; and that no age - specific variations in fertility and prevalence of infection occurred . when we used data on the seroprevalence of t. cruzi among 131,909 pregnant women ( 4.4% ) from 15 argentine provinces in 2000 , and among 153,266 women ( 5.7% ) from 20 provinces in 2001 ( sonia blanco , unpub . data ) , where f = 700,000 and t = 0.025 , a similar calculation yields 770 and 997 estimated congenital cases for 2000 and 2001 , respectively . however , because mean rural parity in 1991 was positively and significantly associated with t. cruzi seroprevalence in military recruits in 1993 at a province level ( figure 2c ) , fertility and maternal infection also may be positively associated at the individual level in rural settings . therefore , the use of average , province - wide fertility rates would underestimate both the number of newborns from infected women and the occurrence of congenital cases . discussionthe congenital transmission of t. cruzi appears to be a sizeable public health problem in argentina , where it has already surpassed the number of vector - mediated acute cases by a factor of 10 , and probably elsewhere in the region . despite a long - term decreasing trend in the human prevalence of t. cruzi , for which we need increased prevention measures , infected women of reproductive age available data favor a short - term policy of antenatal diagnosis of pregnant women for t. cruzi infection and follow - up of their newborns . increased international migrations from t. cruzi endemic latin american countries suggest the need for an increased awareness among obstetricians , neonatologists and pediatricians . effective , nontoxic drugs that may be administered to prospective mothers or pregnant women to reduce the likelihood of congenital transmission are clearly needed . example of the calculations involved in the estimate of the number of congenital cases of trypanosoma cruzi infection for the province of buenos aires , 1993

trypanosoma cruzi , the causative agent of chagas disease , infects 1018 million people and may be transmitted to the newborn . using various data sources , we estimated that nearly 850 congenital cases occurred in argentina in 1993 , or 6.3 expected cases per each reported case in 1994 and in 19942001 . the congenital transmission of t. cruzi constitutes a sizeable public health problem in the region .

a malformation is a primary anatomical defect resulting from abnormal development of an organ or a tissue . it may be isolated , occurring in an otherwise normal child , or multiple , affecting several body systems . its prevalence in maxillofacial region is rare , but when present , it is associated with severe hemorrhage resulting in significant morbidity and mortality . arterio - venous malformation ( avm ) is an abnormal communication between an artery and a vein , which can be congenital or acquired . avms can have a spectrum of effects on the patient ranging from disfigurement to life - threatening morbidity ; therefore , it is considered a difficult clinical problem . very little is understood about the underlying pathogenesis of these lesions , and thereby , interventions frequently involve considerable risk with suboptimal outcomes . a review of fatal outcomes due to unawareness of presence avm in dental field has shown most exsanguination results due to dental extractions , tooth eruption , or even incision . one of the most common signs of these patients , especially in the mixed dentition period , is hyper mobility of the teeth with spontaneous hemorrhage from the surrounding gingival sulcus . bleeding is the most common sign that a vascular malformations manifests within the maxillofacial region ; therefore , vascular malformations may be considered in differential diagnosis of gingival bleeding with inconclusive dental radiographs . vascular malformation can be classified as low flow capillarysalmon patchport - wine stainnaevus anaemicus and naevus oligaemicusmixed vascular malformationsreticulate vascular naevusklippel trenaunay syndromevenous malformationsblue rubber bleb naevus syndromemaffucci 's syndromezosteriform venous malformationsgorham 's diseaseother multiple vascular malformation syndromeslymphatic malformationsmicrocysticmacrocystic rapid flow ( arteriovenous malformations ) capillarysalmon patchport - wine stainnaevus anaemicus and naevus oligaemicusmixed vascular malformationsreticulate vascular naevusklippel trenaunay syndromevenous malformationsblue rubber bleb naevus syndromemaffucci 's syndromezosteriform venous malformationsgorham 's diseaseother multiple vascular malformation syndromeslymphatic malformationsmicrocysticmacrocystic naevus anaemicus and naevus oligaemicus mixed vascular malformations reticulate vascular naevus klippel trenaunay syndrome blue rubber bleb naevus syndrome zosteriform venous malformations other multiple vascular malformation syndromes lymphatic malformations rapid flow ( arteriovenous malformations ) lisa m. buckmiller has reported that 60% of vascular malformations occur in the head and neck . most lesions in this region occur in the scalp and skin , and actual involvement of the mandible or maxilla is very rare . in particular , the prevalence of lesions in the maxilla is half as likely as in the mandible . congenital malformations are extremely rare and may be caused by environmental factors e.g.- ionizing radiation ; or genetic factors e.g.- chromosomal syndromes , or combination of two . the acquired form is associated with trauma leading to broken blood vessels . on healing , an artery communicates with a vein and the normal blood flow is inverted . as a result of increase in blood pressure in the affected area , the vessels dilates , appearing to be a cavernous hemangioma or an aneurysm . vascular malformation can be classified as low flow capillarysalmon patchport - wine stainnaevus anaemicus and naevus oligaemicusmixed vascular malformationsreticulate vascular naevusklippel trenaunay syndromevenous malformationsblue rubber bleb naevus syndromemaffucci 's syndromezosteriform venous malformationsgorham 's diseaseother multiple vascular malformation syndromeslymphatic malformationsmicrocysticmacrocystic rapid flow ( arteriovenous malformations ) capillarysalmon patchport - wine stainnaevus anaemicus and naevus oligaemicusmixed vascular malformationsreticulate vascular naevusklippel trenaunay syndromevenous malformationsblue rubber bleb naevus syndromemaffucci 's syndromezosteriform venous malformationsgorham 's diseaseother multiple vascular malformation syndromeslymphatic malformationsmicrocysticmacrocystic naevus anaemicus and naevus oligaemicus mixed vascular malformations reticulate vascular naevus klippel trenaunay syndrome blue rubber bleb naevus syndrome zosteriform venous malformations other multiple vascular malformation syndromes lymphatic malformations rapid flow ( arteriovenous malformations ) lisa m. buckmiller has reported that 60% of vascular malformations occur in the head and neck . most lesions in this region occur in the scalp and skin , and actual involvement of the mandible or maxilla is very rare . in particular , the prevalence of lesions in the maxilla is half as likely as in the mandible . congenital malformations are extremely rare and may be caused by environmental factors e.g.- ionizing radiation ; or genetic factors e.g.- chromosomal syndromes , or combination of two . the acquired form is associated with trauma leading to broken blood vessels . on healing , an artery communicates with a vein and the normal blood flow is inverted . as a result of increase in blood pressure in the affected area , the vessels dilates , appearing to be a cavernous hemangioma or an aneurysm a 12-year - old female patient reported to the department of periodontics , people 's college of dental science and research centre , bhopal , with a history of swelling in the upper lip and gums since last six years . patient gave history of trauma during playing six years back , which resulted in laceration of upper lip , for which a local doctor was consulted . this was followed by appearance of swelling in the upper lip which increased gradually in size and was constant since the last two years . patient also gave a history of swelling and spontaneous bleeding from the gums , because of which she refrained herself from oral hygiene maintenance . intra oral examination showed generalized gingival hyperplasia with maxillary arch with a typical bluish purple gingiva at the interdental areas of 11 and 21 ; associated with grade i mobility also , localized gingival enlargement was present in relation with mandibular incisors and canine [ figures 13 ] . no abnormalities were detected on general systemic examination , and hematological investigations which included a coagulation profile . pre operative frontal view pre operative right lateral view pre operative left lateral view periodontal treatment which was initiated with phase i therapy using hand instruments resulted in spontaneous brisk bleeding which was difficult to control . the bleeding site was suctioned and severe hemorrhage was controlled by digital pressure which took no less than 20 to 25 minutes . because of the severe nature of hemorrhage encountered , some type of vascular abnormality was suspected and the patient was referred to physician for opinion . ultra sonography of the upper lip was performed which showed marked thickening of upper lip with multiple dilated vascular channels in the submucosal layer of upper lip . dilated and enlarged arteries were seen with marked increase in systolic and diastolic flow predominantly on left side of midline . angiography is the corner stone of diagnosis of vascular lesions which helps in visualizing exact angioarchitecture of the lesion essential for treatment planning . a transfemoral angiography was performed which confirmed the diagnosis of a small high flow av malformation measuring ( approx . the arterial feeders were from right internal maxillary artery and venous drainage via bilateral ophthalmic vein into bilateral cavernous sinuses and partly via bilateral facial vein into bilateral jugular vein . the patient underwent a surgery in a private clinic where the mass associated with upper lip was excised using circumferential excision and the defect was closed . the patient did not turn up for further recall and reported back after two years for periodontal treatment . intraoral examination revealed gingival enlargement was still present , and also a recurrence of the malformation of lip was noted as the central nidus of the lesion present in the midline of the upper lip was not removed . after consultation with the physician and oral surgery department , it was decided to undertake periodontal treatment after embolization of the lesion . local anesthesia was administered to the patient and the osseous topography of the bone was determined using bone sounding . gingivectomy and gingivoplasty were performed at the same time , so as to achieve the normal topography of gingiva . bleeding points were marked using pocket marker so as to outline the course of incision . 15 scalpel blade from the distal most tooth apical to the bleeding points marking the course of the pocket and directed coronally to a point between the base of the pocket and crest of bone . the incision was beveled at 45 degree to the tooth surface , so as to recreate normal festooned patter of gingiva . taking into consideration the bleeding encountered and the extent of gingival enlargement , the surgery was performed sextant wise , the bleeding during the surgery was relatively less as compared to initial phase due to embolization of the lesion . the intrasurgical bleeding was controlled using pressure pack and postoperative bleeding was controlled by cold compression . post embolization of the vascular lesion present with the upper lip and following gingivectomy procedure , the patient was followed - up for a period of one year and no recurrence was noted [ figures 79 ] . post operative frontal view after one year post operative right lateral view after one year post operative left lateral view after one year ultra sonography of the upper lip was performed which showed marked thickening of upper lip with multiple dilated vascular channels in the submucosal layer of upper lip . dilated and enlarged arteries were seen with marked increase in systolic and diastolic flow predominantly on left side of midline . angiography is the corner stone of diagnosis of vascular lesions which helps in visualizing exact angioarchitecture of the lesion essential for treatment planning . a transfemoral angiography was performed which confirmed the diagnosis of a small high flow av malformation measuring ( approx . the arterial feeders were from right internal maxillary artery and venous drainage via bilateral ophthalmic vein into bilateral cavernous sinuses and partly via bilateral facial vein into bilateral jugular vein . the patient underwent a surgery in a private clinic where the mass associated with upper lip was excised using circumferential excision and the defect was closed . the patient did not turn up for further recall and reported back after two years for periodontal treatment . intraoral examination revealed gingival enlargement was still present , and also a recurrence of the malformation of lip was noted as the central nidus of the lesion present in the midline of the upper lip was not removed . after consultation with the physician and oral surgery department , it was decided to undertake periodontal treatment after embolization of the lesion . local anesthesia was administered to the patient and the osseous topography of the bone was determined using bone sounding . gingivectomy and gingivoplasty were performed at the same time , so as to achieve the normal topography of gingiva . bleeding points were marked using pocket marker so as to outline the course of incision . 15 scalpel blade from the distal most tooth apical to the bleeding points marking the course of the pocket and directed coronally to a point between the base of the pocket and crest of bone . the incision was beveled at 45 degree to the tooth surface , so as to recreate normal festooned patter of gingiva . taking into consideration the bleeding encountered and the extent of gingival enlargement , the surgery was performed sextant wise , the bleeding during the surgery was relatively less as compared to initial phase due to embolization of the lesion . the intrasurgical bleeding was controlled using pressure pack and postoperative bleeding was controlled by cold compression . post embolization of the vascular lesion present with the upper lip and following gingivectomy procedure , the patient was followed - up for a period of one year and no recurrence was noted [ figures 79 ] . post operative frontal view after one year post operative right lateral view after one year post operative left lateral view after one year emphasis on a comprehensive classification is still a priority in literature , and yet there remains a great deal of misinformation . a well accepted classification system was published by mulliken , glowacki and finn et al . , avm , first described by hunter in 1757 , are abnormal communications between an artery and a vein , which bypass the capillary bed . avms are a group of conditions that can have a spectrum of effects on the patient ranging from disfigurement to life - threatening morbidity . these are high - flow lesions of unclear aetiology , but tend to behave aggressively with unpredictable growth and tissue destruction . in various studies published , a traumatic origin was found in approximately 90% of cases . although avm of the oral and maxillofacial region is a rare entity , its knowledge is imperative for the periodontist , oral surgeons , and radiologists in dental fraternity . the most common complaint by the patient is chronic intermittent bleeding , which may often occur resulting from minimal oral trauma such as eruption of a tooth or brushing . other relevant clinical signs could be facial color and/or temperature asymmetry , audible bruit , palpable thrill , discolored mucosa , and persistent or recurrent oral infection may also be present . the symptoms can be local or general , so a periodontist can play an important role in the diagnosis of the vascular lesions , which otherwise may go undiagnosed . since treatment and prognosis are different for each type of anomaly , it is extremely important that these lesions be diagnosed correctly . angiographic and ultrasound tests are widely used to provide the diagnosis and the exact location of the fistula . angiography is currently the gold standard for the determination of location and flow characteristics of vascular lesions .

arterio - venous malformation ( avm ) is an abnormal communication between an artery and a vein . the incidence of its occurrence in oral and maxillofacial region is rare , and if present , the most common sign is gingival bleeding . a 12-year - old female patient presented with an extra oral swelling in relation with upper lip . intra oral examination showed non tender gingival swelling with spontaneous bleeding associated with maxillary arch . on initiation of phase i therapy using hand instruments , spontaneous brisk bleeding was encountered which was difficult to control . because of severe nature of hemorrhage encountered , some type of vascular abnormality was suspected . ultrasonography followed by angiography confirmed avm in relation with upper lip . embolization of lesion was followed by gingivectomy procedure and no recurrence was reported during one year of follow - up . thus , proper recognition and therapeutic intervention is essential to avoid serious complications and potentially tragic outcome in such situations .

stem cell therapy is considered as a promising therapy for degenerative disease treatment , especially articular cartilage injury as well as osteoarthritis . however , the mesenchymal stem cells ( mscs ) are considered as most suitable candidates . mscs are multipotential cells capable of differentiation into bone , cartilage , fat , and some other cells . mscs could be isolated from bone marrow , adipose tissue , cord blood , banked umbilical cord blood , umbilical cord , wharton 's jelly , placenta , and pulp . however , mscs from bone marrow [ 1012 ] and from adipose tissue [ 1315 ] are two common stem cell sources for treating cartilage degeneration . cartilage degeneration or cartilage injury is a common clinical problem and easily leads to osteoarthritis . osteoarthritis is a chronic degenerative process characterized by the degeneration of cartilage , bone bud formation , cartilage reorganization , joint erosion , and loss of joint function . currently , cartilage injury was treated primarily with drugs [ 1720 ] or injection of hyaluronic acid [ 21 , 22 ] to reduce the symptoms , pain , and inflammation control . however , these therapies 's efficiencies were limited and often failed to prevent the degeneration of the joints . mscs from adipose tissue , also known as stem cells isolated from fat tissue ( adipose - derived stem cells this stem cell source was used to treat many diseases such as liver fibrosis , sciatic nerve defects , systemic sclerosis , ischemia , skeletal muscle injury , passive chronic immune thrombocytopenia , and infarcted myocardium . recently , they have been extended to treat cartilage injuries as well as osteoarthritis such as dogs [ 3133 ] , rabbits , horses , rat , mice , and goats . i and ii clinical trials using adscs transplantation are performed to treat osteoarthritis and cartilage degeneration ( nct01300598 , nct01585857 , nct01399749 ) . pak ( 2011 ) showed that all adsc grafted patients improved the cartilage regeneration . among all of adsc transplantation cases , svf transplantation has some advantages such as saving time ( from isolation to transplant faster about 2 - 3 hours ) , being inexpensive , and reducing the risk of cell culture . although many studies have demonstrated the benefits of svf / adsc transplantation in cartilage injury treatment , especially knee articular cartilage , so far a little comprehensive studies aim to evaluate the safety and efficiency of svf transplantation for articular cartilage treatment . therefore , this study aims to evaluate the safety and efficiency of svf transplantation combined with prp in the treatment of cartilage injury in the mouse model . firstly , adipose tissue was collected from abdominal fat tissue of ten consenting healthy donors . about 4080 ml of fat was collected by syringe and stored in 100 ml sterile bottle . svf cells are separated from the fat using the extraction kits ( adistem , australia ) according to the manufacturer 's guideline . briefly , fat is washed 3 times with saline solution to eliminate red blood cells . then , the fat was incubated with a solution adiextract ( adistem , australia ) . the sample was centrifuged to collect svf as pellet at the bottom of the tube . to prepare platelet - rich plasma ( prp ) , 50 ml of peripheral blood was taken from a large vein ( arm veins ) . blood was centrifuged 1,700 rpm for 10 minutes to get platelet - enriching plasma . this plasma is activated with activator solution ( adistem , australia ) . then , prp was mixed with svf to make the cell suspension . finally , this suspension was stimulated by the led light ( light monochromatic low energy , adlight , adistem , australia ) for 30 minutes before using for treatment . cell number and percentage of viable cells were determined by automatically nucleus - based cell counter ( nucleocounter , chemometec ) . total cell numbers were counted after permeabilization of the membrane by reagent a ( lysis buffer , chemometec ) and neutralized with a solution of reagent b ( neutralized buffer , chemometec ) . cell suspension is loaded into the counting chamber containing propidium iodide dye . for counting dead cells , suspension cells were mixed with only reagent b solution and loaded into the counting chamber . survival rate is calculated as follows : ( total cell number the number of dead cells ) : the total number of cells 100% . the existence of adsc in svf determined by flow cytometry . the process summarized as follows : cells were washed twice in physiological saline of dulbecco - modified pbs ( d - pbs ) supplemented with 1% bovine serum albumin ( sigma - aldrich , st louis , mo ) . cells were stained for 30 min at 4c with the monoclonal antibody anti - cd44-pe , anti - cd90-pe , and anti - cd105-fitc ( bd biosciences , franklin lakes , new jersey offers ) . , we should identify the gene expression levels related to the process of causing tumors and test the ability to form tumors in vivo . about gene expression , rna was isolate by trizol according to the manufacturer 's instructions ( sigma - aldrich , st louis , mo ) . adsc cells analyzed the expression of genes related to markers of cancer cells or embryonic stem cells , oct-3/4 and nanog by real - time kit sybr rt - pcr one tube - one step ( sigma - aldrich , st . the used primers were oct-3/4 , forward primer : f : 5-ggaggaagctgacaacaatgaaa-3 , reverse primer r : 5-ggcctgcacgagggttt-3 ; nanog , forward primer : f : 5-acaactggccgaagaatagca-3 ; reverse primer r : 5-ggttcccagtcgggttcac-3 ; gapdh , forward primer : f : 5-gggctgcttttaactctggt-3 ; reverse primer : r : 5-tggcaggtttttctagacgg-3. the tumorigenicity of adsc was evaluated in mice nod / scid ( nod.cb17-prkdcscid/j , charles river laboratories ) . all mice manipulation was according to guideline of laboratory and approved by the local ethics committee of stem cell research and application , university of science ( vnu - hcm , vn ) . mice were injected subcutaneously at a concentration of 10 , 10 , and 10 cells , respectively in three groups ( each group with 3 mice ) . the formation of tumors in mice was followed for 3 months . to evaluate the efficiency of svf transplantation in articular cartilage injury the nod mouse / scid mice were anesthetized with ketamine ( 40 mg / kg ) , then joint destruction by fine needle 32.5 g. normal mice were used as a positive control ( uninjured ) . nine mice randomly divided into the treatment group ( 5 mice ) and negative control group ( 4 mice ) . six hours after injury , the mice were treated . in the treatment group , 200 l containing 2 10 svf in prp ( the treatment group ) or pbs ( the negative control group ) was injected into the knee joint via two doses , with a 10 min interval between injections . the mice were recorded the movement on the table daily . at the 45th day , all mice were anesthetized , and their hind limbs were cut and used for histological analysis and further experiments . the samples were fixed in 10% formalin , decalcified , sectioned longitudinally , and stained with hematoxylin and eosin ( he ) ( sigma - aldrich , st louis , mo ) . using he stained slides , three parameters were examined such as the area of injured cartilage ( % ) , the area of neo - cartilage ( % ) , and the number of neocartilage cell layers . the injured cartilage area was determined as the percentage of lost mature cartilage compared to the control . data was analyzed using statgraphics software ( v7.0 ; statgraphics graphics system , warrenton , va ) . mscs have the large differentiative potential , easily differentiate into bone , cartilage , and adipocyte . similar to mscs from other sources , adsc have the ability to differentiate into fat cells , bone , and cartilage and transdifferentiate into neurons and muscle [ 3945 ] . the isolated adsc relatively complex , consuming time , so adscs were mainly used as svf ( containing adsc ) without culture . this study aims to evaluate the safety and efficiency of svf transplantation resuspended in prp in mouse model . in the first experiment , we have successfully isolated 0.32 0.15 10 svf cells from 1 gram of fat with a survival rate of 90.90% 8.57% ( n = 10 ) . adsc populations were identified based on the expression of cd44 , cd90 , and cd105 of them ( figure 1 ) . these results were similar to many other authors on adsc markers [ 43 , 4652 ] . two genes oct-3/4 and nanog were assessed by real - time rt - pcr method and ssea-3 , and ssea-1 was assessed by flow cytometry . the results showed expression of oct-3/4 , nanog , ssea-3 , and ssea-1 much lower than embryonic stem cells ( figure 2 ) . in fact , nanog and oct-3/4 participate in the process of self - renewal of embryonic stem cells [ 54 , 55 ] . moreover , these proteins related to the tumorigenicity process in mature germ cells , carcinoma oral squamous cell , lung cancer , breast cancer , and gliomas . the svf and prp injection under the skin mouse nod / scid could not form teratomas . with these experiments , we concluded that the svf plus prp has a promising therapy with a high safety for transplantation experiments . in the next experiment the results showed that the svf plus prp transplantation significantly improved the articular cartilage injury compared to control . in the treated group , mice exhibited a reduction of the time required that mice could move on the table by injured hind limb compared to control . in the control group , mice can move by injured legs after 38.5 4.30 days , while in the treated group , mice could move by injured legs after 29.4 4.32 days . about histological analysis , in the treated group , an average area of the cartilage damage was 62.60% , and there was 35.5% of neocartilage formation after 45 days ( n = 5 ) . while in the control group , average area of cartilage lesions was 53.13% , but only 15.5% of neocartilage formation after 45 days ( figure 3 ) . the grade of cartilage injury between two experimental groups was different due to the effects of the dissimilar force from needle . after 45 days , results showed that 35.5% of neocartilage formed in treated group , while only 15.5% of neocartilage formed in the negative control group . this suggested that svf and prp gave benefit effects on the enhancement as well as trigger the neocartilage forming . more importantly , the articular cartilage in both of groups completed at the same level after 45 days with 12 cell layers . these results demonstrated that the svf and prp could participate in the process of self - renewal of joint cartilage at the joint microenvironment . this result was similar to the previous publications about svf plus prp transplantation in the treatment of cartilage injury in dog [ 3133 ] , rabbits [ 34 , 61 ] , horses [ 14 , 61 ] , rat , mice , and goats . for example , in joint injured mice model by collagenase , ter huurne et al . ( 2011 ) showed that the level of damage nearly 50% reduction in adsc transplanted mice compared to control after 42 days . specifically , knee injury went down to 25% in treated mice compare to 88% in controls . ( 2007 ) showed that autologous adscs could reestablish the joint surface in rabbits , in which 100% of rabbits ( 12/12 ) had the occurrence of neocartilage , while only 8% rabbit ( 1/12 ) in the control had the appearance of neocartilage ( p < 0.001 ) . in fact , similar to mscs derived from bone marrow , adsc had anti - inflammatory properties [ 63 , 64 ] and inhibition of graft versus host disease ( gvhd ) . the transplantation of adsc could successfully treat graft versus host disease with steroid - resistant form [ 66 , 67 ] . all of these roles could add more effects to trigger rapid cartilage regeneration in this study . besides , in this study , ingredients from prp also had important roles in stimulated grafted cells as well as endogenous cells growth and differentiation . there are at least six known growth factors such as platelet - derived growth factor ( pdgf ) that promotes blood vessel growth , cell division , and forming the skin ; transforming growth factor - beta ( tgf- ) that promotes cell division mitosis and bone metabolism ; vascular endothelial growth factor ( vegf ) that promotes the blood vessel formation ; epidermal growth factor ( egf ) that promotes cell growth and differentiation , angiogenesis , and collagen formation ; fibroblast growth factor-2 ( fgf-2 ) that promotes the growth of cell differentiation and angiogenesis ; and insulin - like growth factor ( igf ) that is a regulator in all cell types of the body [ 68 , 69 ] . prp injection also showed that improvements in knee injury and osteoarthritis score , including pain and symptom relief [ 70 , 71 ] . combining effect of svf and prp has a positive effect on the stimulation of proliferation , differentiation , and regeneration of cartilage in a mouse model . however , svf also has a few limitations , notably the relatively low presence of adscs in the svf . therefore , svf cultured to enrich adsc before being transplanted may be essential , especially a little obtained fat cases . some side effects such as fever and muscle pain as well as the tumorigenicity in human being when using svf and prp could not be checked in this research .

stromal vascular fraction ( svf ) combined with platelet - rich plasma ( prp ) is commonly used in preclinical and clinical osteoarthritis as well as articular cartilage injury treatment . however , this therapy has not carefully evaluated the safety and the efficacy . this research aims to assess the safety and the efficacy of svf combined with prp transplantation . ten samples of svfs and prps from donors were used in this research . about safety , we evaluate the expression of some genes related to tumor formation such as oct-4 , nanog , ssea3 , and ssea4 by rt - pcr , flow cytometry , and tumor formation when injected in nod / scid mice . about efficacy , svf was injected with prp into murine joint that caused joint failure . the results showed that svfs are negative with oct-4 , nanog , ssea-3 , and ssea-4 , as well as they can not cause tumors in mice . svfs combined with prp can improve the joint regeneration in mice . these results proved that svfs combined with prp transplantation is a promising therapy for articular cartilage injury treatment .

in the recent years , an increasing number of scientists studied oxidative stress ( os ) as a possible link between oral and systemic diseases . many of these studies are related to periodontal disease , by far the most common link being oral infection . oxidative stress plays a major role in the pathogenesis of many systemic and oral diseases . there is substantial evidence that links some oral diseases , such as periodontal disease , to systemic conditions such as cardiovascular diseases , metabolic syndrome , or diabetes mellitus . diabetes mellitus , a chronic disease , considered epidemical by world health organization ( who ) , is by now recognized as a risk factor for periodontal disease . reactive oxygen species ( ros ) or free oxygen radicals are products of normal cellular metabolism and are produced in case of oxidative processes . many biochemical pathways strictly associated with hyperglycemia , such as glucose autooxidation , polyol pathway , prostanoid synthesis , and protein glycation , can increase ros production . furthermore , endothelial cell exposure to elevated levels of glucose can lead to ros production . this might be one of the reasons why alterations of periodontal tissues occur in type 2 diabetes subjects ( t2d ) , even in the absence of dental plaque and calculus which are the main etiologic factors of periodontal disease . the aim of this study was to investigate oxidative stress that occurs in the periodontium of subjects with type 2 diabetes mellitus without signs of periodontal disease and to establish a possible link between this systemic condition and the morphologic changes in periodontal structures . the present study was conducted on two groups of patients ; one consisted of ten diabetic patients without signs of periodontal disease and the other one consisted of eight systemically and periodontally healthy subjects as controls . diabetic subjects were recruited from the patients that addressed to the department of odontology and periodontology , faculty of dental medicine , umf tg - mures , for different dental problems , and controls were selected from the patients that addressed to the emergency department , faculty of dental medicine , umf tg - mures , for the same reasons . all diabetic subjects included in the present study had records of at least 4 to 5 years of diagnosed t2d , were on medication with oral antidiabetic drugs , and all had well - controlled t2d ; none was insulin treated and none used any antioxidant agent . subjects aged 30 to 58 , nonsmokers , without any inflammatory disease or use of anti - inflammatory drugs in the last three months prior to the study . this study was approved by the ethical committee of umf tg - mures , and all the patients included in the study signed for informed consent . from each subject biopsy specimens biopsy specimens were harvested from a dental - periodontal unit in the posterior region of dental arches . from the biopsy specimens harvested from all subjects , one fragment was sent for histopathology study , while the other was stored at 80c until os evaluation . histopathological examination was performed using formalin - fixed , paraffin - embedded tissue fragments following standard protocols . the 4 - 5 micron thick tissue sections were stained with hematoxylin - eosin stain and also digitally archived using zeiss miraxscan system . from conserved tissue biopsies we determined the levels of malondialdehyde ( mda ) as a marker for os and glutathione ( gsh ) as a marker of defense antioxidant mechanism , using the fluorometric methods according to conti et al . and ellman . statistical analysis was performed using microsoft excel , graph - pad instat , and ncss 2007 software , and values of p < 0.05 were considered statistically significant . mean age of patients in study group was 44.7 7.66 and 44.125 6.728 in controls , with a nonsignificant difference between groups ( p = 0.8696 ) . the mean mda value in diabetic tissues was 3.578 ( 2.834.960 ) , significantly higher than in controls , where the mean mda value was 0.406 ( 0.210.9 ) . statistical comparison between the two groups yielded a p < 0.0001 ( figure 1 ) . the mean gsh value in diabetic subjects was 2.48 ( 0.983.9 ) , significantly lower than 9.788 ( 6.813.2 ) in controls , with p < 0.0001 ( figure 2 ) . histological alterations in tissue sections obtained from diabetic patients were present in both the epithelium and the lamina propria of the gingival mucosa . the epithelium displayed variable amounts of acanthosis and parakeratosis , with reduced quantities of acute inflammatory infiltrate composed mostly of polymorphonuclear leucocytes ( segmented granulocytes ) throughout its thickness and in superficially located microabscesses . a diffuse polymorphous inflammatory infiltrate consisting of lymphocytes , plasma cells , and , to a lesser extent , granulocytes was present in the mildly fibrotic lamina propria , displacing collagen fibers and surrounding ectatic blood vessels and exteriorized erythrocytes ( figures 3 and 4 ) . the hypothesis of the study was that diabetes mellitus can increase os at periodontal tissues level , contributing to periodontal disease development . our results showed that tissue mda and gsh levels differ significantly in diabetics without signs of periodontal disease compared to controls . in our study , as mda ( the final result of lipid peroxidation ) is considered a biomarker of os , elevated tissue mda levels can support the hypothesis of os implication in pathogenesis of periodontal disease in diabetic patients . it is considered the most important nonenzymatic antioxidant agent , having an important role in antioxidant defense mechanism and in regulation pathways that insure whole body homeostasis [ 79 ] . in our study this can stem from an adaptation of glutathione turnover as a response to os caused by systemic condition , namely , diabetes mellitus . the microscopic changes are in concordance with previously published data and with those of other authors , confirming the fact that the presence of a metabolic condition such as diabetes mellitus and associated hyperglycemia can induce alterations of marginal periodontal structures , increasing the chance of periodontal disease occurrence [ 1115 ] . oxidative stress ( os ) can be defined as an imbalance between the production of some highly reactive molecule species and the antioxidant defense mechanism . reactive oxygen species ( ros ) or free oxygen radicals are products of normal cellular metabolism ; however , their unbalanced increased levels disrupt normal cellular function . the most common free oxygen radicals are hydroxyl ( ho ) , nitric oxide ( no ) , superoxide ( o2 ) , hydrogen peroxide ( h2o2 ) , and peroxynitrite ( onoo ) . ros can react with different amino acids , generating a large range of products , from modified and less reactive enzymes to denatured , nonfunctional proteins . an important structural modification of protein molecules is nitrosylation , with peroxynitrite being responsible for this change . tyrosine nitration not only compromises protein function but may also have serious consequences in cell regulation . enzymes such as superoxide dismutase ( sod ) were identified as specific targets for nitrosylation . several studies have shown a decreased superoxide dismutase activity in the gingival tissue of parodontopathic patients compared to parodontopathic diabetic patients . the diabetic with periodontal disease has a lower activity of the prooxidative enzyme myeloperoxidase in the gingival crevicular fluid , compared to nondiabetics . reaction between mononuclear phagocytes and age ( advanced glycation end products ) induce the regulation of cytokine expression and os . these periodontal infections amplify the magnitude of macrophage response to age , leading to cytokine and os production . many studies have shown a decreased sod activity in the gingival tissue of periodontotic patients compared to parodontotic diabetic patients . patients with diabetes and periodontal disease have a lower activity of the prooxidative enzyme myeloperoxidase in the gingival crevicular fluid , compared to nondiabetics . also , it was proven that there is a relationship between proinflammatory biomarkers and os in case of periodontal disease . the clinical relevance of our study is that mda and gsh levels can predict the evolution of periodontal disease in subjects with type 2 diabetes mellitus . further research should include smokers with t2d and periodontal disease , as smoking is a common habit in romanian population and its effect on oral mucosa needs to be taken into consideration . one topic that remains to be explored is how antioxidant periodontal therapy can influence periodontal alterations in diabetic patients . diabetic subjects have higher mda levels in their periodontal tissues , suggesting an increased lipid peroxidation in case of diabetes mellitus . in periodontal tissues from diabetics , decreased levels of glutathione suggest an alteration of local antioxidant defense mechanism . these results are in concordance with the histological changes that we found in periodontal tissues of diabetic subjects . the results of our study confirm the hypothesis of os implication , as a correlation between periodontal disease incidence and diabetes mellitus . these results can be a starting point for further research on the efficiency of different antioxidant agents for prevention and treatment of periodontal disease in diabetic patient .

objective . to investigate oxidative stress ( os ) and histological changes that occur in the periodontium of subjects with type 2 diabetes mellitus without signs of periodontal disease and to establish if oxidative stress is a possible link between diabetes mellitus and periodontal changes . materials and methods . tissue samples from ten adult patients with type 2 diabetes mellitus ( t2d ) and eight healthy adults were harvested . the specimens were examined by microscope using standard hematoxylin - eosin stain , at various magnifications , and investigated for tissue levels of malondialdehyde ( mda ) and glutathione ( gsh ) . results . our results showed that periodontal tissues in patients with t2d present significant inflammation , affecting both epithelial and connective tissues . mean mda tissue levels were 3.578 0.60 sd in diabetics versus 0.406 0.27 sd in controls ( p < 0.0001 ) , while mean gsh tissue levels were 2.48 1.02 sd in diabetics versus 9.7875 2.42 sd in controls ( p < 0.0001 ) . conclusion . diabetic subjects had higher mda levels in their periodontal tissues , suggesting an increased lipid peroxidation in t2d , and decreased gsh tissue levels , suggesting an alteration of the local antioxidant defense mechanism . these results are in concordance with the histological changes that we found in periodontal tissues of diabetic subjects , confirming the hypothesis of os implication , as a correlation between periodontal disease incidence and t2d .

medical errors in hospitals kill more people every year than aids , breast cancer and auto accidents combined . widespread consensus exists that all of health care facilities can reduce patient injuries by concentrating on safety by implementing technical changes , such as electronic medical record systems , or by improving staff awareness of patient safety risks . who has defined patient safety as activities or measures taken by an individual or a health care organization to prevent , remedy or mitigate the occurrence or reoccurrence of a real or potential ( patient ) safety event ; a large part of safety problems in health care facilities are related to errors . an error is a failure to perform a planned action as intended or implementation of an incorrect plan . errors may be defined as doing the wrong thing ( commission ) or failing to do the right thing ( omission ) , at either the planning or execution phase . there is a worldwide growing consensus to take action to reduce the occurrence of apparently common , serious medical errors . achieving this goal involves identifying errors in practice and undertaking initiatives to avoid and prevent them . medical errors and therefore medical injuries can happen at all stages of the complicated process of care . the lack of standard taxonomy in addition to different complicated issues in large part explains why so little is known about the prevalence of adverse outcomes and effective prevention of medical injuries . in health care , as in other organizations , anything which can not be measured is difficult to improve . in response to this important issue , agency for healthcare quality and research ( ahrq ) have developed a set of indicators , namely patient safety indicators ( psis ) , which provide information on potential of hospital complications and adverse events following surgeries , procedures , and childbirth . the most important characteristic of psis is that readily available and inexpensive hospital discharge data have been identified as a useful source of information on aes . ahrq has published the three modules as a series : the first module prevention quality indicators , the second module inpatient quality indicators and the third module that focuses on potentially preventable complications and iatrogenic events for patients treated in hospitals . the psis are measures that screen for adverse events that patients experience as a result of exposure to the health care system ; these events are likely amenable to prevention by changes at the system or provider level . the psis are valid indicators and used in a variety countries and health care facilities worldwide . , one of four psis was recently adopted by the centers for medicare and medicaid services to compare quality and safety across hospitals . they used this measure to determine how well it identifies true cases of postoperative wound dehiscence . rosen and itani described psis as specifically designed to screen for potentially preventable adverse events that patients experience as a result of exposure to the acute - care setting . the psis are based on icd-9-cm codes and therefore only require information from hospital administrative discharge data , making them readily available , cost - efficient , and easy to use . borzecki and colleagues suggested that psis are indicators which were designed to identify inpatient complications that are clinically significant and potentially preventable . in iran there has recently been a growing interest in patient safety initiatives and considerable efforts have been taken to achieve them . one of these is the implementation of patient safety friendly hospital pilot project in partnership with who . this pilot project led to positive results and some hospitals in iran succeeded to be awarded patient safety friendly hospital certification . regardless of the problems and considering the initiatives , this study through psis can enforce other efforts and concerns in patient safety . as carol et al . , said , the intended purpose of the psis is to detect potential aes , prioritize areas of action and to provide a starting point for further analysis to reduce preventable errors through system or process changes . the psis can be used to help hospitals identify potential adverse events that might need further study ; provide the opportunity to assess the incidence of adverse events and in - hospital complications using administrative data found in the typical discharge record ; include indicators for complications occurring in hospitals that may represent patient safety events . alzahra hospital is a referral hospital which provides services to patients from isfahan and other provinces near isfahan . this hospital is the most important educational hospital in the isfahan province . in this study nine selected measures were investigated using inpatient medical record data of hospitalized patients in the first half of fiscal year 2010 in alzahra hospital . this study was a retrospective study aimed to detect psis developed by ahrq in alzahra hospital , a tertiary care academic medical center in isfahan . data gathering was done using medical record data of hospitalized patients in a six month period , from october 2010 to march 2011 . the ahrq - psis are based on applying computer algorithms to secondary diagnosis and procedure codes from hospital discharge abstracts to identify potential adverse events during the hospital stay . the codes for diagnosis and procedure were applied to the patient record after a review by the medical record coding unit based on standard administrative coding guidelines . in the first step , considering the inadequate system of recording medical error in iran 's health care facilities , for assuring , existence of data , practicality and feasibility of study , a preliminary report of hospital information system ( his ) including principal and secondary diagnosis codes were provided , a series of interviews were done with some experts such as hospital medical records personnel , superior nurses of clinical departments , physicians and surgeons . based on these interviews and his report , finally from 20 psis , 9 indicators were selected for calculating ; i.e. psi 1 ( complications of anesthesia ) , psi 5 ( foreign body left during procedure ) , psi 7 ( selected infections due to medical care ) , psi 9 ( postoperative hemorrhage ) , psi 14 ( postoperative wound ) , psi 15 ( accidental puncture or laceration ) , psi 16 ( transfusion reaction ) , psi 17 ( birth trauma injury to neonate ) and psi 20 ( obstetric trauma health information technology experts was involved in data reviewing . selected psis or the number of adverse events per 1000 populations at risk , were calculated . for estimating measures excel software and his software were used . calculation of psis rates was done based on definition of each indicator notified by ahrq . thus psis were calculated as : psi 1 ( complications of anesthesia ) : cases of anesthetic overdose , reaction , or endotracheal tube misplacement per 1000 surgery discharges . psi 5 ( foreign body left during procedure ) : discharges with foreign body accidentally left in during procedure per 1000 discharges . psi 7 : selected infections due to medical care cases of secondary icd-9-cm codes 9993 or 00662 per 1000 discharges . psi 9 ( postoperative hemorrhage ) : cases of hematoma or hemorrhage requiring a procedure per 1000 surgical discharges . excludes mdc 14 . psi 14 ( postoperative wound ) : cases of reclosure of postoperative disruption of abdominal wall per 1000 cases of abdominopelvic surgery . excludes obstetric admissions . psi 15 ( accidental puncture or laceration ) : cases of technical difficulty ( e.g. , accidental cut or laceration during procedure ) per 1000 discharges . excludes obstetric admissions . psi 17 ( birth trauma injury to neonate ) : cases of birth trauma , injury to neonate , per 1000 live born births . cesarean ) : cases of obstetric trauma ( 3 or 4 degree lacerations ) per 1000 cesarean deliveries . in this study from 20 provider - level psis published by ahrq , 9 indicators were calculated . totally 25,164 discharge data were investigated of which 794 ( 3.1% ) were dead and 24,370 ( 96.8% ) were discharged ; 13,257 ( 52.6% of total accepted patients ) cases were surgical discharges [ table 1 ] . frequency and percentage of investigated discharge data selected ahrq - psis ( based on research methodology ) were investigated in all of patient discharge data . and the rate of each psi was calculated and the results are as shown in table 2 . since the medical error report from the institute of medicine has attracted public attention toward patient safety issues , many studies on medical errors have been conducted and reported , including several from the medical informatics and patient data . applying these measures can lead to identifying errors in practice and undertaking initiatives to avoid or prevent them . this study indicated that , almost all of nine calculated measures , have improper status than optimum base promulgated by ahrq and values reported in the other studies . the first indicator , complications of anesthesia ( psi 1 ) , was calculated as 2.2 ( per 1000 ) , whereas in an empirical analysis conducted by an ahrq project team using florida state inpatient database this indicator was estimated as 0/75 . of course , considering the newly introduced nature of safety actions in iran and specifically in this hospital , this value is somewhat expectable . the next studied indicator was foreign body left during procedure ( psi 5 ) which estimated 0.31 ; this indicator in the same review was presented as 0/07 . psi 14 was defined as cases of reclosure of postoperative disruption of abdominal wall per 1000 cases of abdominopelvic surgery excludes obstetric admissions . this measure in our study was calculated as 3/7 which is higher than ahrqs estimate and must be improved . as per the zhan and miller study , postoperative wound dehiscence is a serious surgical complication which is associated with an additional 9 days of hospitalization , $ 40,000 in excess charges , and 10% in hospital - attributable mortality . postoperative wound dehiscence may be prevented through appropriate surgical technique , optimizing modifiable patient risk factors prior to elective surgery , and close monitoring of perioperative conditions . webster et al . , pointed that surgeon experience level and technical factors have also been shown to affect the rate of wound dehiscence . selected infections due to medical care ( psi 7 ) or health care - associated infections is another important measure in patient safety issue . rates of infections due to medical care have risen over the past decade and this malpractice now kills as many people as aids , breast cancer , and auto accidents combined . health care - associated infections are one of the most frequent adverse events in health care . this indicator ( psi 7 ) rate was calculated in our study as 3.8 , compared to ahrq estimation in 2006 which was reported as 2.4 , it must be improved . as sheng pointed the average increased length of hospital stay due to hospital - acquired infections ( hais ) was about 20 days . on the basis of the same research hai burden costs about us$10,000 to health care facility , the next investigated indicator was postoperative hemorrhage or hematoma ( psi 9 ) which was estimated at 2.2 per 1000 . the postoperative hemorrhage or hematoma indicator is intended to capture cases of hemorrhage or hematoma following a surgical procedure . in a study conducted by carol in united states accidental puncture or laceration ( psi 15 ) also is another potentially preventable complication of health care system . this indicator in two other studies conducted by carol and by haytham et al . , was reported as 0.32 and 0.31 , respectively , which are consistent with this study finding . birth trauma injury to neonate which was clarified as ( psi 17 ) was estimated in this study as 1.7 . this measure in other studies was reported as 0.667 , which is lower than our study finding . another study points that major birth trauma occurs in 3% of all live - born infants , although in a study carried out in iran this rate was reported as 41.16 per 1000 vaginal deliveries . in the same study , induction of labor , premature rupture of membranes , academic degree of attending physician at delivery , higher birth weight , and gestational age associated with fetal injuries were introduced as risk factors of birth trauma . in two psis 16 ( transfusion reaction ) and 20 ( obstetric trauma cesarean delivery ) there were not recorded any codes . while carol has reported these two indicators as 0.0004 and 0.593 another study conducted by ahrq this contradiction may be associated to not reporting malpractices in the patient 's medical record in our studied hospital . this may be due to a fact that physicians also strongly oppose public reporting of information on medical errors perhaps because of worries about malpractice lawsuits , and also economic and legal consequences . the assessment and reporting of quality medical outcomes has become a key factor of health care improvement and efforts in cost reduction . despite of , all studied measures were an underestimate of actual rate , but , in almost all calculated psis alzahra hospital have a worse situation comparing other health care facilities measures which were studied in literature review . observed gap may be attributed to this hospital being young in safety and patient safety actions in iran . however the more important problem is that , all of malpractices and events occurring in medical practices are not reported completely . this condition may be associated with problems such as lacking internal systems to identify events , a culture of non - reporting due to fear of publicity and fear of liability , a lack of enforcement and bureaucratic burdens . despite the fact that calculated measures are underestimate but , considering the initial aim of this study , i.e. sensitizing hospital managers to adverse events importance , detect potential adverse events , prioritize areas of action , it is suggested the alzahra safety managers should be more active in safety and improving quality performance . they should firstly have a serious concern to reporting malpractices and events occurred during medical practice , and then have a more tendency to postoperative wound dehiscence ( psi 14 ) and selected infections due to medical care ( psi 7 ) . generally it should be pointed that in spite of objections to psis , these indicators are useful starting points for improving health care quality and patient safety . so these can provide an accessible , low cost , and efficient means of detecting aes in hospitals . hence it is suggested that such studies will be conducted in the other hospitals and inpatient care services , because conducting and publishing these studies can increase awareness of errors in , and injuries due to , medical management ( aes ) .

introduction : medical errors in hospitals kill more people every year than aids , breast cancer and auto accidents combined . widespread consensus exists that health care organizations can reduce patient injuries by improving the environment for safety from implementing different alternatives from technical and managerial improvements to considering medical record data . considering the preventability of medical errors , the agency for healthcare quality and research ( ahrq ) developed patient safety indicators ( psis ) . this study analyzes the psis calculated in alzahra hospital of isfahan.materials and methods : this study was conducted retrospectively using the inpatient medical record data of hospitalized patients in a six month period , from october 2010 to march 2011 . an experienced team in the fields of medical record , health management and health information technology was involved in data reviewing . based on a prior consultation and reviewing , some psis were selected . indicators were calculated considering ahrq guidelines . excel software and hospital information system software were used.results:across all studied medical records of patients , out of 25,164 discharges , below measures were calculated.-8 foreign body cases ( psi 5 ) ( 0.31 per 1000).-30 postoperative hemorrhage or hematoma cases ( ps i9 ) ( 2.2 per 1000).-5 accidental puncture or laceration cases ( psi 15 ) ( 0.3 per1000).-8 complications of anesthesia cases ( psi 1 ) ( 2.2 per 1000).-96 selected infections due to medical care cases ( psi 7 ) ( 3.8 per1000).-17 cases of postoperative wound dehiscence ( psi 14 ) ( 3.7per1000).-1 birth trauma injury to neonate case , and ( psi 17 ) ( 1.7 per 1000).- 18 obstetric trauma cesarean delivery cases ( psi 20 ) ( 40 per 1000 ) were flagged by studied psis developed by ahrq.conclusion:comparing with the reported rates by other studies and ahrq study in 2006 , all of calculated indicators have inadequate condition ; i.e. these are far from empirical estimated rates . the hospital administrators should be more sensitive to this issue and perform some improvement programs .

the online version of this article ( doi:10.1007/s13555 - 015 - 0073 - 6 ) contains supplementary material , which is available to authorized users . mastocytosis comprises a heterogeneous spectrum of diseases characterized by a range of local and systemic symptoms . the current world health organization ( who ) classification , updated in 2008 , differentiates one exclusively cutaneous form from the systemic forms of mastocytosis [ 13 ] . cutaneous mastocytosis ( cm ) is a condition classified according to clinical symptoms and identified by an abnormal accumulation of mast cells limited to the skin . clinically , cm is divided into three main variants : maculopapular cm ( or urticaria pigmentosa ) , characterized by disseminated small patches , papules , and plaques ; diffuse cm , affecting large areas of the skin with yellow - red erythroderma - like , diffuse doughy - firm swellings and solitary mastocytoma , partly characterized by blistering and found predominantly in children . the much rarer forms are defined as the plaque form , the nodular form , and telangiectasia macularis eruptiva perstans . these disorders do not represent independent variants in the who classification and are assigned to maculopapular cm [ 14 ] . cm has been diagnosed in patients with disseminated bullous lesions , plaques , nodules , and other clinical presentations such as localized mastocytosis , solitary and multiple mastocytomas , and some other unusual morphologies [ 4 , 5 ] . we present a 3-year - long follow - up of a child with skin lesions of various morphologies and sizes , continuous blistering , and frequent flushing during the first 6 months of his life . successful treatment was achieved with a short methylprednisolone course and subsequent intermittent h1 receptor antagonist and topical treatments . a 6-month - old male infant was referred with different types of skin lesions , persistent blistering , and frequent spontaneous flushing since birth . intermittent courses with oral h1 blockers and topical antibiotics and corticosteroids had been administered without improvement . on admission , vital signs and chest and abdomen examinations were unremarkable , while hepatosplenomegaly and lymphadenopathy were absent . a variety of skin lesions ( reddish - brown , partially with peau dorange appearance , macules , papules , plaques , and nodules ) , sized 465 mm , were distributed on the neck , trunk , buttocks , and extremities . tense bullae , erosions , and crusts were revealed to overlay plaque surfaces ( figs . 1 , 2a ) . oral mucosa was not affected . within the first 2 days , we observed several flushing episodes , unprovoked by any triggering factors.fig . 1one of the multiple reddish - brown plaques with peau dorange appearancefig . 2 a nodular lesion on the neck , b darier s sign one of the multiple reddish - brown plaques with peau dorange appearance a nodular lesion on the neck , b darier s sign laboratory findings did not disclose hematologic , biochemical , or liver function abnormalities . serum tryptase level ( stl ) was 11.8 ng / ml ( reference range < 11.4 ng / ml ) . a biopsy taken from an elevated plaque with vesiculation revealed melanin in the basal / suprabasal layer , subepidermal bulla , dense mast cell infiltration , and some eosinophils in the dermis ( fig . toluidine blue and giemsa stainings showed metachromatic granules in the cytoplasm of the infiltrating cells ( fig . . the pediatric consultation did not reveal systemic symptoms.fig . 3 a subepidermal bulla and dermal infiltration ( h&e ; 200 ) , b cd117-positive mast cell infiltration ( 400)fig . 4 a toluidine blue ( 200 ) and b giemsa ( 400 ) staining of mast cell dermal infiltration a subepidermal bulla and dermal infiltration ( h&e ; 200 ) , b cd117-positive mast cell infiltration ( 400 ) a toluidine blue ( 200 ) and b giemsa ( 400 ) staining of mast cell dermal infiltration the patient was initially treated with methylprednisolone 0.6 mg / kg once daily ( o.d . ) intramuscularly ( 3 days ) , oral levocetirizine 1.25 mg o.d , 2% topical fusidic acid , and 0.1% betamethasone valerate cream . subsequently , the dose of methylprednisolone was tapered , given orally ( 0.5 mg / kg o.d [ 4 days ] , 0.5 mg / kg every other day [ 2 weeks ] , 0.5 mg / kg twice a week [ 2 weeks ] ) and stopped . after 10 days , levocetirizine was replaced with ketotifen 0.05 mg / kg twice daily for eight more weeks and the cream was replaced with 1% hydrocortisone cream for a month . parents were counseled on the avoidance of triggering factors for mediator release . at the last follow - up ( 3.5 years of age ) , only a few pale - brownish macules were seen with no blistering or isolated flushing episodes . all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation ( institutional and national ) and with the helsinki declaration of 1964 , as revised in 2013 . informed consent was obtained from the parent for the child being included in the study and for the publication of the patient photographs . the diversity of cm skin manifestations is evident when reviewing the literature . with regard to cutaneous lesions , our case seems to belong to the maculopapular and nodular cm , showing a range of lesions of various sizes and morphologies . such varied lesions are encountered more often in pediatric than in adult cm where a more uniform presentation of small patches and papules is common [ 15 ] . the bullous form of mastocytosis is a rare , morbid condition typically encountered in young children . episodic blistering has been reported in maculopapular cm , which usually occurs after stroking or rubbing of the lesional skin and rarely appears spontaneously . there are also reports of nodular forms with occasional blistering as well as predominant bullous variants of cm . in fact , the long - living bullous manifestations are characteristic of the diffuse cm [ 35 ] . it is interesting that in our case , the varied skin lesions , not corresponding to diffuse cm , were associated with an uninterrupted bulla formation for half a year and no improvement with h1 receptor blockers or topical corticosteroids / antibiotics . in our case , the flushing episodes were very frequent , spontaneous , and not induced by any precipitating factor ( ambient temperature , food , exercise , stress , medication , etc . ) . no other signs of internal organ involvement were revealed except for an stl of 11.8 ng / ml . this is not indicative of systemic mastocytosis , where the stl reference value is > 20 ng / ml . this slightly elevated stl might relate to flushing as a single symptom of the mast cell mediator release . it is observed more often in patients with systemic involvement , but may also occur in those with purely cutaneous manifestations [ 16 ] . in our case , the diagnosis of cm was made based on clinical manifestations , darier s sign , and histopathological and immunohistochemical findings ( anti - c - kit / cd117 with a high specificity and sensitivity for mast cells ) . it is widely accepted that growth and differentiation and proliferation of mast cells are controlled by the tyrosine kinase receptor c - kit ( cd117 ) and its ligand stem cell factor . it is also controlled by other cytokines such as il-4 , il-6 , il-10 , and il-13 [ 1 , 2 ] . recent genetic studies have identified new proteins ( lin28b ) that are of interest in mast cell disease . counseling of patients / parents is important to avoid mediator release precipitating factors and treat mast cell mediator release symptoms . cm remissions have been reported following treatments with anti - mediator drugs such as h1 and h2 receptor antagonists and cromolyn sodium ( oral and topical ) . topical / intralesional corticosteroids , phototherapy , and topical calcineurin inhibitors may be useful [ 810 ] . in our case , considering the previous therapy failure , we applied a short course of methylprednisolone , combined with an h1 receptor blocker ( levocetirizine ) and topical mid - potency corticosteroid . this was followed by intermittent h1 receptor blocker ( ketotifen ) and topical hydrocortisone courses . the 3-year - long follow - up demonstrated that our approach to a refractory , though not severe , clinical form of cm can be to the patient s benefit . of note , neither low - dose h2 receptor blockers ( for pediatric use ) nor sodium cromoglycate are available in bulgaria . systemic and topical corticosteroids have demonstrated good therapeutic results in some cases of bullous mastocytosis , as reported in the literature [ 11 , 12 ] . childhood cm usually has a benign course and most of the cases resolve by puberty [ 2 , 3 ] . with proper treatment and family education on avoiding triggering factors , gradual resolution of both skin lesions and mast cell - mediated symptoms may be observed . despite the lack of systemic involvement therefore , follow - up with rigorous evaluation and relevant management is required for each individual case . r. yankova , t. abadjieva , and v. belovezhdov declare that they have no conflict of interest . all procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation ( institutional and national ) and with the helsinki declaration of 1964 , as revised in 2013 . informed consent was obtained from the patient s parents for the child being included in the study and for the publication of the patient photographs . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and the source are credited .

backgroundmastocytosis is a rare disorder with diverse clinical manifestations . in cutaneous mastocytosis the mast cell infiltration is limited to the skin , but is often associated with systemic symptoms due to the release of mast cell mediators.case reportwe report a 6-month - old male infant who had skin lesions of various morphologies ( macules , papules , plaques , and nodules ) and sizes , persistent blistering and frequent flushing episodes for half a year . vital signs and physical examinations were unremarkable . no abnormalities in the laboratory tests were found except for a serum tryptase level ( stl ) of 11.8 ng / ml . the histological and immunohistochemical examinations confirmed the diagnosis of cutaneous mastocytosis . the patient was first treated with methylprednisolone , oral levocetirizine , and topical fusidic acid / betamethasone cream . subsequently the treatment was tapered and stopped within 9 weeks . the child s symptoms improved and were successfully controlled with intermittent courses of ketotifen and topical hydrocortisone over 3 years.conclusionchildhood cutaneous mastocytosis usually has a favorable prognosis , but in some cases the disease can progress with skin manifestations necessitating a more active systemic and topical treatment.electronic supplementary materialthe online version of this article ( doi:10.1007/s13555 - 015 - 0073 - 6 ) contains supplementary material , which is available to authorized users .

different species of cobras defend themselves by spitting venom towards the face of whom they perceive as an aggressor . although rare , this event can lead to ocular envenomation with potentially serious injuries . reported consequences range from periocular soft tissue swelling , hyperemia , extensive conjunctivitis , and corneal epithelial erosion to corneal opacity , uveitis , and hypopion , and even cranial nerve vii involvement [ 2 , 3 , 4 , 5 , 6 ] . previous reports have highlighted the importance of an emergency therapeutic approach with multiple drugs to avoid severe complications such as necrosis of the eye [ 3 , 6 ] . however , in most cases a strict follow - up with early observation after the trauma is not available . hereby , we describe the first case of eye involvement secondary to cobra spit in the volta region in ghana with a close follow - up and an early resolution with a simple and affordable therapy . a 65-year - old male farmer presented to the eye clinic of the comboni hospital in sogakope ( volta region , ghana ) 1 h after having suffered an attack from a cobra that had spat venom in his eyes . the snake had been killed and identified as a naja nigricollis , while the man 's eyes and face had been promptly irrigated with tap water by his coworkers . upon examination , the patient 's uncorrected visual acuity was 20/40 in the right eye and 20/70 in the left eye . the latter showed diffuse punctate corneal epithelial defects , conjunctival injection , and mild chemosis ( fig . the patient 's left eye was treated solely with vitamin a ophthalmic ointment ( kerato vita ; bruschettini , genova , italy ) applied underneath a pressure patch . he was then instructed to come back for follow - up visits during the next 7 days . these further examinations allowed an appreciation that on day 1 after injury the epithelial defect had healed completely ( fig . 2 ) . in addition , the patient 's left uncorrected visual acuity had improved to 20/40 , and he no longer complained of any symptoms . during the following week , he did not develop any sequelae . direct ocular exposure to cobra venom spitting has been reported previously in a few dozen humans [ 2 , 3 , 4 , 5 , 6 ] . cobras spread the venom over the entire face of the aggressor by rapidly moving their head , therefore enhancing the chance of hitting at least 1 eye . as a consequence , various degrees of ocular and periocular injuries have been reported [ 2 , 3 , 4 , 5 , 6 ] . cobra venom contains bioactive proteins such as neurotoxins , necrotoxins , and proteolytic enzymes that may damage ocular and periocular tissues and potentially produce a systemic effect [ 3 , 6 ] . this is why prompt and copious irrigation of the involved eyes is considered a mandatory maneuver . additionally , in most cases topical antibiotics , mydriatics , and cycloplegics are prescribed , while topical antivenom and heparin are rarely used . administration and prescription of these types of drugs may be limited due to their poor availability in a rural setting . the therapy of choice should obviously depend on the severity of the presenting case and the possibility of performing a close follow - up . in this case , 2 main factors were determinant in selecting the treatment . firstly , our patient only showed mild symptoms such as punctate epithelial erosions and mild conjunctival involvement in the absence of any periocular swelling and intraocular inflammation . in addition , we had the rare possibility of closely monitoring the patient for a week following the injury . based on these observations , it appears that in the absence of major intraocular reactive signs to the venom , a simple re - epithelization therapy may be sufficient to obtain early recovery . our findings also support the general conviction that irrigation of the involved eyes is of crucial importance . since such a simple procedure could be sight saving , we believe that a public education campaign should be issued on possible cobra spitting injuries to the eyes . the subject has given informed consent and the report has been approved by the institute 's committee . none of the authors received any sponsorship or funding arrangements relating to this study and none of the authors have any conflicts of interest .

purposeto report the first case of ophthalmia due to contact with cobra venom in the volta region , ghana.methodsan ointment containing vitamin a was applied to treat the patient 's unilateral defects in the corneal epithelium and the consequent diminished visual acuity.resultshealing of the corneal epithelium and improvement of visual acuity were observed after only 1 day.conclusionsthis case suggests that consequences of cases of cobra venom spitting in the eyes can be minimal if immediate treatment is provided .

we report the case of a 64-year - old man , who had been under immunosuppressive treatment for many years after a pulmonary transplant , who presented with diffuse viral warts on the neck and chin that had been present for 11 months ( fig . cryotherapy sessions were conducted over the course of 9 months without success but with increasing intolerance to the related pain . imiquimod had not been suggested due to its theoretical contraindications relating to the risk of a graft rejection and a graft - versus - host disease . a photodynamic therapy ( pdt ) test session was carried out on the most prominent warts in the submental region , with a very clear improvement after 1 week ( fig . two more sessions were conducted within a 10-day interval , using 2 fields of light each time , thus covering the entire surface of the neck ( right and left sides ) . three hours after an application of 5-aminolevulinic acid ( metvix ) under an occlusive and opaque dressing , a red light of 634 nm was delivered , with a 37 j / cm light intensity for the duration of 9 min . a spray bottle filled with spring water , in combination with an integrated cooling fan , was used to decrease pain during illumination . the painful sensation lasted 12 h after illumination , whereas erythema and swelling decreased after 23 days . viral wart treatments include local keratolytic application , topical retinoids , cryotherapy , intralesional injection of bleomycin , imiquimod , laser co2 , pulsed dye laser and intralesional immunotherapy . the benefit - risk ratio in organ - transplanted patients is currently being evaluated . pdt has proven to be successful in the treatment of actinic keratosis and basocellular carcinoma . at present several studies show that protoporphyrin ix accumulation after 5-aminolevulinic acid application is not specific to tumour cells . hpv - infected cells also accumulate protoporphyrin ix in a specific manner , as compared to the surrounding healthy cells [ 4 , 5 ] , as demonstrated by in vivo fluorescence spectroscopy . pdt therapeutic effects are due to anti - inflammatory and anti - proliferative properties activated through the release of cytotoxic radicals that destroy keratinocytes via selective apoptosis . numerous clinical studies have demonstrated the efficiency of pdt in the treatment of viral warts of the hands and feet , ( recalcitrant [ 9 , 10 , 11 , 12 , 13 ] or not ) , including periungual warts . several studies have shown that pdt is efficient in treating plane warts [ 14 , 15 ] , including those on the face . treated verrucae vulgares on the hands and feet with a clear clinical improvement in 68.3% of the patients . this improvement was confirmed by a placebo - controlled study led by bastuji - garin et al . . in addition , wang et al . successfully treated 42% of recalcitrant viral warts , and chong and kang reported complete healing of recalcitrant foot verrucae vulgares after only 3 pdt sessions . schroeter et al . treated periungual warts with full clinical success in 90% of patients after a mean of 4.7 sessions . some authors suggested the use of a keratolytic pre - treatment ( urea 10% , salicylic acid 10% , for 1 week ) to enhance the treatment 's efficiency , with complete healing in 75% of viral warts . in the immunosuppressed subject , granel - brocard et al . reported the therapeutic effect of pdt on recalcitrant warts . it is a safe , noninvasive technique , which yields effective therapeutic results in multiple series of patients [ 17 , 23 ] . the risk of secondary infection after pdt is insignificant , and the cosmetic results are excellent . the technique is particularly interesting in slow - healing subjects and acts selectively , allowing healthy surrounding skin to remain intact and functional . the use of one or several fields of light enables treatment of many lesions at the same time , thus limiting the risk of wart spread and recurrence between sessions . the drawbacks are pain and local side effects such as erythema and swelling , which is generally mild and well tolerated ( table 1 , table 2 , table 3 ) . immunosuppressed patients often present with extensive viral warts . controlling the spead of these warts is of great importance because they can potentially be a source of neoplasia . our case report shows that pdt can be very efficient in the treatment of verrucae vulgares in immunosuppressed organ - transplanted patients . the technique is easy to implement , resulting in minimal side effects and reproducible results . we think that pdt should be considered as a gold standard in the treatment of facial verrucae vulgares in immunodepressed patients . all authors certify that they have no conflicts of interest , including specific financial interests and relationships and affiliations relevant to the subject of this manuscript .

a 64-year - old man with a pulmonary transplant developed diffuse verrucae vulgares of the neck . after the failure of multiple cryotherapy treatments , 3 sessions of photodynamic therapy resulted in rapid therapeutic clinical success . this moderately painful and well - tolerated treatment is reproducible and can be very useful in treating papillomavirus infections in the immunosuppressed patient .

the exercise of metal / metal oxide nanoparticles as a frontier between the homogeneous catalysis and heterogeneous catalysis in organic synthesis has invoked tremendous interests in the recent times . the interesting features inherited with these small particle sizes are their large surface area along with more edges and corners and distinct electronic , optical , magnetic , thermal , and chemical properties [ 35 ] . the crucial role of nanoparticles in organic transformations is their excellent catalytic activity , straightforward recoverability , better selectivity , criteria of evolution , and their versatile role in green chemistry [ 610 ] . thus , the domain of metal nanoparticle catalysis [ 1113 ] should offer opportunities for mining new chemical reactions [ 1416 ] which include the synthesis of biologically important and synthetically challenging natural products . in the context of green chemistry , organic synthesis in solvent - free reaction condition [ 1821 ] has occupied a significant position in the recent years since solvent - free reaction condition involves the best reaction medium with no medium . one of the key motifs present in the biopolymer rna [ 2326 ] is uracil , a nucleobase of the pyrimidine family which participates in various functions in our life processes . uracil derivatives also have several potent medicinal properties such as bronchodilators and anticancer [ 28 , 29 ] , antiallergic [ 30 , 31 ] , antiviral [ 32 , 33 ] , antihypertensive , and adenosine receptor antagonists [ 34 , 35 ] . recently , our research group reported a greener protocol for the synthesis of bisuracil derivatives . some of the n - substituted bisuracil analogues have been screened for bioactivities against several diseases . to explore the possible applications of the metal / metal oxide nanoparticles in organic synthesis , we have been focusing on the advancement of a protocol termed nose ( nanoparticles - catalyzed organic synthesis enhancement ) [ 3941 ] chemistry in our laboratory . to the best of our knowledge , there has been no report on nano - rod - shaped al2o3 catalyzed n , n - diformylation of bisuracil derivatives . recently , we reported n - formylation of amines catalyzed by nano - al2o3 under solvent - free reaction condition . this work inspired us to focus on nano - al2o3 catalysis for the n , n - diformylation of bisuracil analogous . therefore , in this paper , we wish to account for the same ( scheme 1 ) . nano - al2o3 draws our attention due to its crystalline size and shape , abrasive and insulating properties , less toxicity , large surface area , basic surface characteristics , high resistant towards bases and acids and excellent wear resistance [ 4044 ] . rod - shaped nano - al2o3 ( the average particle diameter is 8.12 nm and average length 25.5 nm , sbet = 185.63 m g , = 3.98 g cm , and purity is 99.99% ) were purchased from sigma aldrich and used as received . the chemicals and reagents were purchased from sigma - aldrich , merck , m / s s.d . fine chemicals pvt . ltd . , and loba chemie , and used without further purification . ir spectra were recorded as kbr pallets in a nicolet ( impact 410 ) ft - ir spectrophotometer . h and c nmr spectra were recorded in a 400 mhz nmr spectrophotometer ( jeol , jnm ecs ) using tetramethylsilane ( tms ) as the internal standard , and coupling constants are expressed in hertz . elemental analyses were carried out in a perkin - elmer chn analyser ( 2400 series ii ) . mass spectra were recorded with a waters q - tof premier and an acquity uplc spectrometer . reactions were monitored by thin - layer chromatography using aluminium sheets with silica gel 60 f254 ( merck ) . in a two - neck round bottom flask ( 50 ml ) , nanorod - shaped basic al2o3 ( 7.0 mol% , 7.12 mg ) were taken , and then 1 g ( 1.0 mmol , 414 mg ) and formic acid ( 98% , 6.0 mmol , 0.23 ml ) were added . after that , it was allowed to stir on a pre heated oil bath at 40c for the required time ( the progress of the reaction was judged by tlc ) . the reaction mixture was brought to room temperature after its completion , and ethyl acetate ( 3 10 ml ) was added and then centrifuged ( 3,000 r.p.m ) to recover the nanocatalyst . having done this , the reaction mixture was washed with water and brine , dried over anhydrous na2so4 , and concentrated in a rotary evaporator , and finally the crude product was purified by column chromatography ( 30% ethyl acetate : hexane as an eluent ) . the recovered catalyst was washed with hot ethanol ( 3 10 ml ) to remove the organic impurities , decanted , dried in an oven at 80c for 6 h , and reused for evaluating the performance in the next run in the reaction as shown in scheme 2 . with the previously reported catalyst characterizations in hand , to begin with , reaction of 6,6-diamino-1,1,3,3-tetramethyl-5,5-(benzylidene)bis[pyrimidine-2,4 ( 1h , 3h)-dione ] ( 1a , 1 mmol ) with formic acid ( 6 mmol ) was chosen as the model reaction ( scheme 2 ) . initially , the reaction was carried out without using catalyst under solvent - free reaction condition at 40c and 80c which did not yield any product ( table 1 , entries 1 and 2 ) . various solvents were also tested under the mentioned condition , but they all failed ( table 1 , entries 311 ) to provide any product . these negative results suggested that we look for an effective catalyst in the present study . next , various lewis acid - base catalysts ( table 1 , entries 1214 ) along with the nanocatalysts ( table 1 , entries 1518 ) were surveyed to observe the influence on rate and yield of n , n - diformylation of 1a which were not fruitful . interestingly , nanorod - shaped basic al2o3 stood out as a choice of catalyst at 7 mol% loading ( table 1 , entry 15 ) under solvent - free reaction condition at 40c . during the course of our experiment , we observed that at higher temperature ( table 1 , entry 19 ) and at lower / higher catalyst loading the yield of the products was poor ( table 1 , entries 2022 ) . thus , the yield of n , n - diformylation product of bisuracil derivatives is highly dependent upon the temperature and catalyst loading . with this supportive optimized reaction condition in hand , a series of bisuracil derivatives ( entries 111 ) bearing different aliphatic , aromatic , and heterocyclic moieties were examined to explore the scope and limitations of this reaction and the outcomes are presented in table 2 . it is clear from table 2 that bisuracil derivatives carrying both electron donating and electron withdrawing groups in benzene ring underwent n , n - diformylation reaction smoothly producing good yields ( table 2 , entries 18 ) . however , longer reaction time was required for bisuracil derivatives substituted with furan and alkyl groups ( table 2 , entries 911 ) . it is worth mentioning that 6-amino-1,3-dimethyluracil when treated with formic acid under the current condition gave n , n - diformylation product in lower yield ( 26% , 9 h ) . the reactions were found to be clean , and no side products were formed . to test the recyclability ( vide scheme 2 ) of nano - al2o3 , it was separated from the reaction mixture by adding ethyl acetate ( 10 ml ) , centrifuged at 3,000 rpm , to pellet out the catalyst . the separated particles were washed with hot ethanol ( 3 10 ml ) to remove the organic impurities , decanted , dried in an oven at 80c for 6 h , and reused for further reactions . the efficiency of the catalyst was found to be unaffected up to 4th run , and after that , its action started to decrease as shown in table 3 . the tons were also retained from fresh up to the 5th cycle , and after that it decreased considerably . the recovered catalyst was also investigated through powder xrd and it was compared with the fresh nano - al2o3 ( figure 1 ) . in the powder xrd of the recovered catalyst after 6th run ( figure 1 ) , the intensity of the peaks ( 4 0 0 ) and ( 1 0 0 ) weakened and became broad . it might be due to the blockage of the pores of the catalyst which caused a decrease in effective active sites and also due to the dislocation of the crystal planes after each run which in turn decreased the yield . the sem micrograph of the fresh nano - al2o3 previously reported by us was also compared with the recycled one ( figure 2 ) under the present study . as indicated in figure 2 , the recycled nano - al2o3 revealed the aggregation of the particles responsible for reducing its surface area and hence deactivated the catalyst after 4th run which caused the lower yield of product . in conclusion , we have demonstrated a novel method for synthesis the n , n - diformylation of bisuracil derivatives in good yield under solvent - free reaction condition at 40c catalyzed by recyclable nano - al2o3 rods . nano - al2o3 catalyzed organic transformations we believe that this work would find wide applications for new chemical transformations , including those which enable the synthesis of complex natural products and derivatives .

a feasible nose ( nanoparticles - catalyzed organic synthesis enhancement ) protocol has been developed for n , n - diformylation of bisuracil derivatives using nano - al2o3 rods as an efficient , inexpensive , and recyclable catalyst under solvent - free reaction condition at 40c . the catalyst was reused up to the 4th cycle without affecting the rate and yield of the n , n - diformylation products appreciably .

the meeting was introduced by edwin l. cooper , a very communicative and scientifically participative professor , who illustrated the main aims of the journal ecam , evidence - based complementary and alternative medicine , and roused everyone to contribute publishing scientific - based evidences on homeopathy and other complementary / alternative medical approaches . he described how the journal born in los angeles ( ucla ) sustained by important collaboration in kanazawa and japan , with assistance from oxford university press . professor cooper illustrated the electronic submission of all contribution types and hastened peer reviewing that results in free access to electronic publication before the appearance of a hard copy issue . professor paolo bellavite opened the conference by discussing the historical background of homeopathy , and then developed into a session of open - ended questions . what can be concluded through meta - analysis ? is it possible to imagine the future of the homeopathic approach by either exceeding and/or incorporating the different doctrines ? 1 ) ; they shape a triangle whose vertices are ( from the top ) as follows : complexity and individuality , similarity and dilutions . daily medical practice and clinical studies lie on the sides of the triangle and within its area , sustained and supported by other scientific trials : from phase i clinical trials to phases ii iv trials , from basic research on the similia principle to electromagnetic properties of water passing through the paradox of very high dilution . taken together , this could increase the area of the triangle , which determines the acceptance of homeopathic medicine . similarity : healing is achieved by taking a drug that proved by healthy individuals have yielded symptoms and signs very similar to those of the patients . similarity : healing is achieved by taking a drug that proved by healthy individuals have yielded symptoms and signs very similar to those of the patients . the published homeopathic clinical trial and meta - analysis review was very detailed ( as many as 80 studies were reviewed ) . results varied , and the following observations were extensively discussed during the course of the conference : ( i ) homeopathic research requires more rigorous trials ; ( ii ) clinical studies on asthma , allergies and other respiratory pathologies yielded the best results ; and ( iii ) classic homeopathy requires more specific trail methodology . special attention was given to a recent famed meta - analysis from the lancet ( 1 ) which addressed the prejudice toward homeopathy , primarily due to the choice of trials that were analyzed . homeopathic trails must employ more rigorous methodologies : they frequently lack in randomization criteria , placebo use and laboratory markers . the speaker stressed efficacy in homeopathy , which could be evidenced both referring to complex therapeutic method ( the use of individualized therapy ) and to specific drug effects on specific pathology . provings , i.e. homeopathic pathogenetic trials ( htps ) , contributed by professor giuseppina pitari . milestones of homeopathic medicine , htps suffer about large methodological variability : different aims , different described outcomes , placebo usage , supervising , poor remedy description , multivariegated symptoms collections , lack of data analysis , etc . a possible methodology was described and some indications were discussed on study design ( double - blind placebo - controlled trial ) ( 2 ) , doses and potency of the drug , description of the potentized substance detailing its toxicological effects , time of observation . carlo m. rezzani concluded the session by describing a research project ( ciflicol ) on clinical report cases : an electronic case sheet can be drawn up and sent to a worldwide database , continuously updated ( www.hmssrl.com ) . the intriguing discussion about placebo solution preparation was flowed into the description of the world of high dilutions. the most characteristic and controversial principle of homeopathy is that the potency of a remedy can be enhanced by dilution , in a procedure known as dynamization or potentization. paolo bellavite discussed about basic researches showing limits , successes and possible hypotheses . life has evolved around water , into water , because of water : special water properties permit hydrophobic interaction , very few water molecules go with biological compounds keeping its imprint , water clusters activated during homeopathic dynamization can reach a cellular receptor and trigger specific responses . papers on animal or in vitro models showed the effects of very diluted and potentized on human basophils , chicken embryos , rat duodenum , mouse blood , etc . hormetic effect were reviewed : stimulus or molecule different doses trigger opposite effects on the same receiver system . as paolo bellavite clearly showed as a system 's ( cells , organs and organisms ) starting conditions can be crucial to treatment results and as some drug effects can be paradoxical , thus supporting the possible use of similia principle as curative efficient approach ( 3 ) . at the end of the conference the speaker expounded coherence of homeopatic medicine towards the dynamic complexity of diseases . homeodynamic conditions make possible the organized complexity of life and a pharmacological complex information mimicking disease via high homeopathic dilutions are reported to be effective both in humans and animal / in vitro models . methodological problems in clinical trials can be overcome drawing up a specific approach to clinical homeopathic research with a large approved consensus .

verona 's school of homeopathic medicine ( www.omeopatia.org ) organized a day of full immersion in the field of homeopathy , focusing on the validity of this much - debated discipline . there is widespread consensus in the medical community that evidence - based medicine is the best standard for assessing efficacy and safety of healthcare practices , and systematic reviews with strict protocols are essential to establish proof for various therapies . students , homeopathic practitioners , academic and business representatives , who are interested in or curious about homeopathic practices attended the conference .

an 83-year - old male suffering from severe symptomatic aortic valve stenosis and , being a high surgical risk , received an implant of a biological aortic prosthesis ( corevalve 29 ) through the femoral artery . during the evaluation 1a ) showed sinus rhythm with an incomplete right - bundle branch block and left anterior hemiblock . the echocardiogram showed signs of calcifications in the aortic valve with a peak gradient of 90 mmhg and a medium gradient of 60 mmhg . the left ventricle showed good global and segmental contraction and the coronography showed insignificant irregular coronary vessels . during the expansion process of the prosthetic valve in the aortic root , we observed a previously unregistered complete heart block , which lasted for 23 min . 1b ) showed how atrioventricular conduction immediately restarted after the complete block , with a slight widening of the qrs . the patient was hospitalized and monitored for seven days , without presenting any further heart block or arrhythmia . when arriving at the emergency room , the vital signs were normal and the ecg was similar to the one taken at the time of discharge . fortunately , the patient was wearing an ecg holter monitor that day , which revealed a wide qrs complex tachycardia of 300 beats per minute ( bpm ) lasting 43 min ( fig . an electrophysiological study was performed , which revealed an hv interval of 64 ms . we induced , through ventricular stimulation , a 300 bpm ventricular tachycardia ( fig . 2a ) with a left - bundled branch block and left axis , with similar morphology to the syncope - registered ecg . the post pacing interval after entrainment by right ventricular apex stimulation was + 20 ms ( fig . the conclusion was that the cause of the syncope was due to a bundle - branch reentry . radio - frequency was applied on the right - bundle branch , with a qrs widening from 130 ms to 150 ms ( fig . the hv interval after the ablation was of 67 ms , and the wenckebach av point was 180 bpm . the insertion of metallic materials close to the prosthetic overlays , in particular within the first millimeters of the interventricular septum under the aortic root , can harm the conduction system . approximately 45% of the patients with a corevalve prosthesis develop signs of a left - bundle branch block . only 510% of the patients develop a right - bundle branch block , as seen in our patient . lastly , approximately 2530% of the patients with a core valve prosthesis need a pacemaker implantation . furthermore , it is also known that aortic valve diseases , valve surgery and conduction impairments may cause bundle - branch reentry tachycardia . bundle - branch reentry tachycardia is a macroreentrant tachycardia that uses the right and left branches as reentry components in its circuit . non - ischemic dilated myocardiopathies , bundle - branch reentry tachycardia may amount to 40% of the induced ventricular tachycardias . it has also been noted that aortic valve surgery may trigger bundle - branch reentry tachycardia . bundle - branch reentry tachycardia may be seen at an early stage , normally four weeks after surgery and the ventricular function tends to be regular . ventricular tachycardias that set at a later stage are usually related to periannular scars or underlying myocardiopathies . as far as we are aware , this is the first case of a bundle - branch reentry tachycardia after trans - catheter implantation of a prosthetic aortic valve . if our patient had not been wearing the ecg holter at the time of the syncope , we would have not been able to register the tachycardia and would have implanted a pacemaker . especially , taking into account the paroxysmal complete block that the patient experienced during the implant of the valve and the widening of the qrs . with regard to the electrophysiological study , we wish to outline the utility of the return cycle for the diagnosis of the bundle - branch reentry tachycardia in patients with difficulties at the his registry . we believe that the implantation of a pacemaker is not required at the onset of syncope in patients who have undergone a trans - catheter implantation of an aortic valve , and developed a bundle - branch block . in these cases , an electrophysiological study is suggested in order to exclude the presence of a bundle - branch reentry tachycardia .

an 83-year - old male suffering from severe symptomatic aortic valve stenosis received an implant of a biological aortic prosthesis through the femoral artery without complications . seven days after dischargement he experienced a syncope . the patient was wearing an ecg holter monitor that day , which showed a wide qrs complex tachycardia of 300 beats per minute . the electrophysiological study revealed a bundle - branch reentry ventricular tachycardia as the cause of the syncope . radio - frequency was applied on the right - bundle branch . twelve months later , the patient has remained asymptomatic .

chronic pain is defined as pain lasting over a period of at least 3 months.1 patients with chronic pain are frequently seen in departments of hand surgery.2 whereas a large proportion of patients benefit from surgical interventions , some continue to suffer from pain regardless of such therapeutic measures.3 depending on the nature of the damaged anatomical structures , pain occurs postoperatively with different frequencies and for different durations . from research on complex regional pain syndrome ( crps ) type 1 , it is , however , known that often there is no correlation between the type of initial lesion and the severity of subsequent pain and that psychological factors may be predictive for the course of pain.4 there is a large and well - established branch of pain research showing that in terms of the risk of post - surgical pain , psychological and social factors play a crucial role.5 in the case of patients undergoing spine surgery , block et al have suggested that psychological factors may have a greater impact on outcome than medical ones , including type of surgery , chronicity , and previous spine surgery . the accuracy of pre - surgical psychological screening predicting overall outcome was 82%.6 an increasing number of studies also suggest an influence of psychological distress in hand surgery . a recent study of 66 patients with crps type 1 showed that anxiety is associated with poorer outcomes of this condition , including pain level , although patients with crps type 1 of the upper and lower limb were combined.4 a study of 121 patients with distal radius fractures reported that pain anxiety and pain catastrophizing were significantly associated with delayed functional recovery and increase in perceived disability , although the level of pain was not reported as a separate outcome.7 a further study of 120 patients with hand injuries showed that depressive symptoms were a significant predictor of pain intensity between 10 and 14 days after minor hand surgery ( e.g. , surgery for carpal tunnel syndrome , trigger finger , and benign hand tumor).3 one prospective and one retrospective study on 83 and 89 patients , respectively , who underwent decompression of carpal tunnel , found low mental health scores to be correlated with poorer response to surgery and higher level of scar pain.8,9 taken together , it follows from the assessment of the currently available literature that more prospective studies are needed to gain more clarity about a potential association of anxiety and depressive symptoms with pain level as an outcome in hand surgery patients . in theory , general pain research offers sufficient grounds for a link of anxiety and depressive symptoms with chronic pain . basically , pain perception is a function of the brain , which alerts the individual about potential tissue damage . this somatosensory function is always influenced by limbic - affective ones , coloring the experience of pain as emotionally aversive . this affective aspect is a function of brain structures that are also involved in anxiety and depressive disorders.10,11 thus , it is not surprising that anxiety and depression along a spectrum of severity ( i.e. , yet at subsyndromal levels ) are supposed to have an impact on pain experience . in hand surgery clinics , a wide range of treatment options are available that can roughly be categorized according to operative and conservative interventions . both these approaches have their clear indications and treatment standards.12 regarding the treatment process , the operative procedure is perceived by patients as more severe and less controllable , but possibly more suggestible.13 to the extent that pain conditions differ between the two procedures , we distinguished in our analysis between operatively and conservatively treated patients . accordingly , we hypothesized that anxiety and depressive symptoms would affect pain levels at 4-month follow - up in both the treatment groups , but with different effects . the study protocol was approved by the local ethics committee ( kek - nr.117/12 ) . regarding diagnoses , there were no selection criteria , that is , all patients were invited to participate in the study , regardless of their specific hand surgical problems . in particular , patients were not selected based on their pre - surgical pain level , so that patients with and without pre - surgical pain were included . all patients included in the study underwent an initial , as well as a follow - up interview 4 months later . they took place in a separate room on the occasion of the consultation with the two hand surgeons ( ev and bj ) . the decision regarding the necessary hand surgery intervention operative or conservative was taken by the two surgeons according to current western standards.12 the chosen procedures were strictly based upon the type of lesion and anatomical circumstances of each patient . therefore , a random allocation to the intervention groups was not intended , nor was it possible . specific treatments to reduce pain were transcutaneous electrical nerve stimulation ( tens ) , lymph tapes , anti - inflammatory treatments by iontophoresis , laser , or sonography , and passive and active joint mobilization depending on the injury , stretching , and massaging of soft tissues and muscles . surgical treatment included procedures such as debridement of infected tissues , repair of skin , nerves , vessels , tendon , bones , joints , and reconstruction after trauma . in elective surgery , there were neurolyses of median and ulnar nerves ; arthroplasties of carpometacarpal , metacarpophalangeal , or interphalangeal joints ; arthrodeses and arthroscopies of radiocarpal joint , skin , and soft tissue tumor resections , as well as tendon transfers or reconstructions . during the initial consultation with the patient , a pain history was taken followed by the patient completing a self - rated psychometric questionnaire , namely , the hospital anxiety and depression scale ( hads).14 the hads is a screening instrument for determining the level ( i.e. , the severity ) of anxiety ( hads - a ) and depression symptoms ( hads - d ) , but it can not confirm a psychiatric diagnosis of an anxiety or depressive disorder . the hads is a valid and reliable instrument to assess depressive and anxiety symptoms in populations with somatic diseases with a cronbach s alpha between .68 and .93 for hads - a and between .67 and .90 for hads - d.15 the anxiety and depressive symptom subscales each comprise seven items that are rated on a likert scale from 0 to 3 total ( scores 021).15 the test takes about 8 minutes to complete . our outcome measure ( dependent variable ) was the level of pain at a 4-month follow - up . all patients were asked to rate their pain level with a visual analog scale ( vas ) ranging from 0 ( no pain ) to 10 ( highest pain imaginable).16 we used independent t - test , mann whitney u test , and chi - square test to compare the two patient groups on demographic and clinical characteristics . multiple regression analyses were carried out controlling for age , sex , pain level at the initial assessment and hads scores ( independent variables ) . the study protocol was approved by the local ethics committee ( kek - nr.117/12 ) . regarding diagnoses , there were no selection criteria , that is , all patients were invited to participate in the study , regardless of their specific hand surgical problems . in particular , patients were not selected based on their pre - surgical pain level , so that patients with and without pre - surgical pain were included . all patients included in the study underwent an initial , as well as a follow - up interview 4 months later . they took place in a separate room on the occasion of the consultation with the two hand surgeons ( ev and bj ) . the decision regarding the necessary hand surgery intervention operative or conservative was taken by the two surgeons according to current western standards.12 the chosen procedures were strictly based upon the type of lesion and anatomical circumstances of each patient . therefore , a random allocation to the intervention groups was not intended , nor was it possible . specific treatments to reduce pain were transcutaneous electrical nerve stimulation ( tens ) , lymph tapes , anti - inflammatory treatments by iontophoresis , laser , or sonography , and passive and active joint mobilization depending on the injury , stretching , and massaging of soft tissues and muscles . surgical treatment included procedures such as debridement of infected tissues , repair of skin , nerves , vessels , tendon , bones , joints , and reconstruction after trauma . in elective surgery , there were neurolyses of median and ulnar nerves ; arthroplasties of carpometacarpal , metacarpophalangeal , or interphalangeal joints ; arthrodeses and arthroscopies of radiocarpal joint , skin , and soft tissue tumor resections , as well as tendon transfers or reconstructions . during the initial consultation with the patient , a pain history was taken followed by the patient completing a self - rated psychometric questionnaire , namely , the hospital anxiety and depression scale ( hads).14 the hads is a screening instrument for determining the level ( i.e. , the severity ) of anxiety ( hads - a ) and depression symptoms ( hads - d ) , but it can not confirm a psychiatric diagnosis of an anxiety or depressive disorder . the hads is a valid and reliable instrument to assess depressive and anxiety symptoms in populations with somatic diseases with a cronbach s alpha between .68 and .93 for hads - a and between .67 and .90 for hads - d.15 the anxiety and depressive symptom subscales each comprise seven items that are rated on a likert scale from 0 to 3 total ( scores 021).15 the test takes about 8 minutes to complete . our outcome measure ( dependent variable ) was the level of pain at a 4-month follow - up . all patients were asked to rate their pain level with a visual analog scale ( vas ) ranging from 0 ( no pain ) to 10 ( highest pain imaginable).16 we used independent t - test , mann whitney u test , and chi - square test to compare the two patient groups on demographic and clinical characteristics . multiple regression analyses were carried out controlling for age , sex , pain level at the initial assessment and hads scores ( independent variables ) . within a period of 6 months , 132 consecutive patients could be included in the study . table 2 gives an overview of the diagnoses and treatments of the patients . between the first interview and the 4-month follow - up , the operatively treated patients , those in the conservatively treated group were significantly older , reported greater pain intensity at the 4-month follow - up , and had greater levels of anxiety symptoms . degenerative disorders were significantly more frequent , whereas injuries and compression neuropathy were less frequent in conservatively treated patients , who , moreover , used less paracetamol compared with operatively treated patients . after controlling for age and sex , pretreatment pain level was found to be a significant predictor for an increased level of pain at the 4-month follow - up ( p0.001 ) in both the patient groups . controlling for age , sex , and initial pain level in patients who were conservatively treated , depressive symptoms were found to be a significant predictor for an increased pain level at the 4-month follow - up ( b=0.38 , p=0.001 ; table 3 ) . for every point increase in the hads - d score , there was a 0.38-point higher level of pain intensity at the 4-month follow - up . accordingly , a 3-point increase in the hads - d score corresponded to a 1.14-point increase on the pain vas . usually , a one- or two - point change / difference on the pain vas is considered to be clinically relevant . to better illustrate this : the difference in pain scores between a patient with a normal level of depressive symptoms ( hads - d score=7 ) and a patient with moderate depressive symptoms ( hads - d score=13 ) would exceed two units on the vas , indicating clinical relevance . depression accounted for 1.8% of the unique variance in pain intensity at the 4-month follow - up . in patients who were operatively treated , anxiety symptoms showed a trend for being a predictor of the level of pain ( b=0.12 , p=0.09 ; table 4 ) , explaining 0.4% of the unique variance in pain intensity at the 4-month follow - up . for every point increase in the hads - a score , there was a 0.12-point higher level of pain intensity at the 4-month follow - up . in concordance with our hypothesis , this prospective study of 132 subjects showed that symptoms of anxiety and depression may predict the level of pain in patients undergoing hand surgery treatment . in conservatively treated patients , depressive symptoms were a significant predictor of elevated pain levels at the 4-month follow - up . in operatively treated patients , these results are in agreement with other recent studies in hand surgery patients , although prospective studies are still few in number.4,79 the differing patterns of correlations in conservatively and operatively treated patients suggest different pain conditions in the two patient groups . as expected , this is also reflected by differences in some patient characteristics that suggest two distinct diagnostic populations ( table 1 ) . as shown in table 2 we are aware that this heterogeneity across hand surgical diagnoses represents a certain limitation in terms of the generalization of our results . to determine the association of anxiety and depressive symptoms with the outcome of specific hand surgery diagnoses , future cohort studies with larger sample sizes , the currently available literature draws attention to the relevance of psychosocial factors as predictors of pain persistence , pointing out at the same time that the development of chronic pain is always multicausal . accordingly , in recent years , the bio - psychosocial model has established its firm role in understanding the pathogenesis of chronic pain.17 this multicausal model assigns the relevance of biological aspects , as well as psychosocial aspects , and analyzes their inherent pathophysiological relationships . furthermore , modern experiments in animal models provide physiological evidence in support of the hypothesis that psychological stressors intensify and prolong pain responses in the peripheral and central nervous system via alterations in neuroendocrine pathways and substrates.1821 we mention several limitations of our study . due to the rather small effects , our results are to be interpreted carefully . however , as illustrated , the association between depressive symptoms and pain levels may be considered clinically meaningful . the rather small variance in pain scores explained by depressive and anxiety symptoms implies that there must be additional , perhaps even more important factors explaining the pain levels at 4-month follow - up . however , other important concepts such as quality of life , self - esteem , allostatic stress load , positive affects , or well - being would be predictors of interest to be investigated in future studies . furthermore , we did not assess anxiety and depressive symptoms at follow - up , so we can not draw any conclusions based on the course of psychological symptoms . nevertheless , all together , this study motivates to take more care about patient s psychological conditions in hand surgery . obviously , future studies will have to examine the extent to which concomitant treatment of psychological symptoms can improve the outcome of hand surgical treatments . findings of interdisciplinary pain centers offering multimodal therapeutic approaches suggest that such an effect can be expected.22

the aim of this prospective study was to examine to what extent anxiety and depressive symptoms predict the level of pain at 4-month follow - up in hand surgery patients . a total of 132 consecutive patients ( mean age : 51.517.1 years , 51.9% female ) of a tertiary center for hand surgery participated in this study . the patients underwent conservative or operative treatment , depending on the nature of their hand problem . the initial pain assessment included psychometric testing with the hospital anxiety and depression scale . ninety - nine patients underwent operative treatment and 33 patients were conservatively treated . at 4-month follow - up , the amount of pain was measured with a visual analog scale ( 010 ) . after controlling for age , sex , and pre - surgical pain intensity , depressive symptoms were a significant predictor for increased pain levels at follow - up in conservatively treated patients . in operatively treated patients , anxiety symptoms showed a trend for being a predictor of pain level at follow - up . the findings support the assumption that psychological factors may have an impact on pain outcome in patients presenting to hand surgery clinics .

salmonella typhi is a gram - negative bacilli which causes typhoid fever in human . this bacterium may survive in phagosome to escape the immune system . some complications of typhoid fever are perforation of ileum , bacteremia , and endovascular infection [ 1 , 2 ] . general therapy of typhoid fever is antimicrobial agents , such as chloramphenicol , ampicillin , and cotrimoxazole ( trimethoprim - sulfamethoxazole ) . cotrimoxazole is commonly used for typhoid fever therapy in adults and children , including carrier , as an alternative to ampicillin and quinolone . curcumin is a major active compound of curcuma ( curcuma domestica ) , which is widely used as traditional therapy for fever and gastrointestinal problems in asia . it may bind to vitamin d receptor and stimulates expression of an antibacterial protein called cathelicidin [ 46 ] . combination between antimicrobial agent and herbal medicine has become a recent trending topic , but there is not enough research to prove that this combination is beneficial to treat typhoid fever . this study was preceded by an exploration study to ensure antimicrobial effect of both curcumin and cotrimoxazole toward s. typhimurium . male balb / c mice underwent acclimatization in laboratory for seven days with free access to meal and water . animals were randomized into groups and were treated with curcumin , cotrimoxazole , or both . every mouse was matched to inclusion criteria and did not show any sign of illness prior to infection . we used s. typhimurium from laboratory of microbiology , faculty of medicine , brawijaya university , malang , indonesia . bacteria were cultured on bismuth sulfite agar and confirmed as s. typhimurium by using macconkey agar , triple sugar iron imvic test , and vitek2 ( biomerieux ) . curcumin was given orally in three different doses for different groups and was emulsified with carboxymethyl cellulose ( sigma - aldrich ) . we used doses as follows : 100 mg per body weight per day , 150 mg per body weight per day , and 200 mg per body weight per day . emulsified curcumin was given orally using nasogastric tube for three or five days , according to each therapeutic group . we used the same dose for all therapeutic groups ( 1.56 mg per day ) divided into two . cotrimoxazole was given orally using nasogastric tube every twelve hours for three or five days , according to each therapeutic group . according to ulhaq et al . , systemic infection of s. typhimurium begins on the seventh day after initial infection and we confirmed this statement from our exploration study . every specimen was incubated for twenty - four hours and we counted the black colony using colony counter . each colony count was converted using the following formula to determine bacterial count inside each specimen : ( 1)(colony count)(dilution)(first dilution concentration)(specimen weight ) . ileum is the part of intestine which has peyer 's patch as main entry of s. typhimurium infection . we found from our exploration study that s. typhimurium has spread via bloodstream into extraintestinal organs such as spleen and liver on the seventh day after infection . we found very different results of curcumin single therapy and curcumin - cotrimoxazole combination therapy . according to figure 1 curcumin significantly reduced colonization of bacteria in both intraintestinal and extraintestinal organs after therapy for five days ( p < 0.05 ) . figure 2 shows significant difference after curcumin - cotrimoxazole combination therapy compared to curcumin single therapy . after three days using the lowest dose of curcumin ( 100 mg / kg ) , we still found bacteria in ileum . interestingly , after five days of combination therapy , we found that cotrimoxazole could not eliminate extraintestinal bacteria compared to cotrimoxazole single therapy . we found higher colony count when we increased the dose of curcumin in curcumin - cotrimoxazole combination therapy ( p < 0.05 ) . after five days of therapy , we found significant difference between colonization in ileum from curcumin single therapy and curcumin - cotrimoxazole combination therapy . we also found significantly different outcomes from curcumin - cotrimoxazole combination therapy after three days and five days , especially in intestine . there was also significant difference in the extraintestinal colonization between curcumin single therapy and curcumin - cotrimoxazole combination therapy for five days ( p < 0.05 ) . the bacteria will colonize gastrointestinal tract , especially ileum , and penetrate into blood vessel to spread systematically [ 11 , 12 ] . most bacteria will be killed by gastric acid , so high load of bacteria is needed to reach intestine and manifest clinically . curcumin is an active compound which is widely known as anti - inflammatory , anticancerous , and recently , antimicrobial agent . . showed that antimicrobial mechanism of curcumin correlates with its ability to bind with vitamin d receptor ( vdr ) as a potential ligand . this condition promotes expression of cathelicidin antimicrobial peptide ( camp ) and kills the bacteria . moreover , curcumin may increase mrna expression of camp ; thus it may increase cathelicidin level in tissues . cathelicidin is a small peptide with some structural similarities with other antimicrobial proteins , such as defensin . it has wide spectrum of action toward both gram - positive and gram - negative bacteria and also toward some fungi and parasites . cathelicidin intercalates and infiltrates into bacterial membrane to alter membrane 's integrity , but some bacteria are known to have intrinsic resistance toward cathelicidin . these bacteria , such as enterococcus faecalis , streptococcus pyogenes , salmonella enterica , and proteus mirabilis , may synthesize certain proteinase to degrade cathelicidin . regardless of this , we proved that curcumin still stands a chance against s. typhimurium as an antimicrobial agent . those two substances consecutively inhibit anabolism of folic acid . as an alternative to ampicillin and chloramphenicol , after three days of therapy using 200 mg / kgbb of curcumin , we found that there was a high load of bacteria that colonized the distal part of ileum . this decrease could not reach zero even with the highest dose of curcumin given in this study . we conclude that curcumin has antimicrobial effect toward s. typhimurium after five days of therapy , and we supposed that lower dose of curcumin might instead promote bacterial growth . detailed mechanism of this condition still needs further research . according to ukil et al . and jurenka , curcumin wields anti - inflammatory effect when given in a dose of at least 50 mg / kg until 100 mg / kg [ 8 , 15 ] , but there was no literature precisely showing its antimicrobial effect in vivo . from this study we found that curcumin can not be used as a single therapy for treating s. typhimurium infection . but we can not exclude the possibility that curcumin may show better antimicrobial effect in higher dose , given the pattern of decreased colonization as the dose increases . we could not use a higher dose than 200 mg / kg due to our limited supply of curcumin . administration of cotrimoxazole together with low dose of curcumin could not kill the bacteria in ileum even after five days of therapy . this condition raised an assumption that low dose of curcumin may alter cotrimoxazole 's antimicrobial effect in intestine . we found an increasing number of colonizations in both spleen and liver as we increased the dose of curcumin . we have confirmed effectivity of cotrimoxazole in intraintestinal organs and spleen , although we still found bacterial growth inside liver . through this finding , we assumed that curcumin may interact with cotrimoxazole and lowers cotrimoxazole 's effectivity in killing microbes in extraintestinal organs . a research conducted by lamont showed that curcumin addition into therapy with ciprofloxacin in infection of s. typhi and s. typhimurium may increase survival rate of the bacteria . curcumin intervenes the ciprofloxacin 's antimicrobial mechanism and alters the environment to become more suitable for bacterial growth . curcumin increased bacterial proliferation by protecting the bacteria from antimicrobial effect of ciprofloxacin , both in vitro and in vivo via filamentation inhibition and reversed downstream effect of ciprofloxacin . we also found similar effect from combination therapy between patent antimicrobial agent ( cotrimoxazole ) and curcumin . we found that curcumin lowers the effectivity of antimicrobial effect of cotrimoxazole , but further research is needed to explain the molecular mechanism . curcumin has been known to have antimicrobial properties and to be widely used as adjunctive herbal therapy , especially in asia . we found that curcumin indeed wields antimicrobial effect toward s. typhimurium , but curcumin lowers antimicrobial effects of cotrimoxazole when these two compounds are given together . according to this , we conclude that combination therapy of curcumin and cotrimoxazole , especially in typhoid fever , needs to be reconsidered .

typhoid fever is a disease caused by salmonella typhi and commonly treated by an antimicrobial agent such as cotrimoxazole . on the other hand , herbal usage has risen as an adjunctive therapy to treat many diseases . curcuma ( curcuma domestica ) is a commonly used herb which consists of curcumin as its major active compound . curcumin has been known for its antimicrobial effect , but there is no proof regarding the usage of curcumin and cotrimoxazole together . this research was conducted by using typhoid fever model in mice infected by salmonella typhimurium . each animal was treated with curcumin , cotrimoxazole , or both . ileum , spleen , and liver of each animal were isolated and cultured . we found that curcumin - cotrimoxazole combination therapy lowered the antimicrobial effectivity of cotrimoxazole in both intraintestinal and extraintestinal organs . we conclude that curcumin - cotrimoxazole combination therapy in typhoid fever has to be reconsidered .

hemophagocytic lymphohistiocytosis ( hlh ) is a systemic disease characterized by hemophagocytic syndrome accompanied by fever , hepatosplenomegaly , jaundice , cytopenia , low fibrinogen level , high ferritin level , and hypertriglyceridemia . familial hlh is a group caused by the mutation of the gene encoding perforin ( prf1)1 ) or unc13d gene2 ) , stx11 gene3 ) , or others . secondary hlh is a group that develops as a result of strong immunological activation after either infection , malignancy , or rheumatoid disorders . according to the hlh-2004 diagnostic guideline , diagnosis of hlh such diagnosis is supported by hemophagocytosis in the bone marrow or other tissues such as spleen , liver , or lymph node4 ) . however , in atypical cases that do not fulfill the diagnostic criteria of hlh , histiocytes or macrophages found in the cerebrospinal fluid ( csf ) can be helpful in the diagnosis . this report describes a rare hlh case who presented with prolonged fever and seizures , whose brain pathology but not bone marrow pathology showed hemophagocytosis . the institutional review board of seoul national university hospital approved this study ( e-1307 - 039 - 501 ) . a 5-year - old boy visited seoul national university children 's hospital ( snuch ) in august 2010 with fever for six weeks and intermittent seizure for five weeks . the patient had visited another hospital five weeks ago with fever and generalized - tonic - clonic seizures . on initial csf examination , no specific abnormalities were found : four white blood cell ( wbc)/mm , protein 15 mg / dl , glucose 65 mg / dl . t2 weighted brain magnetic resonance imaging ( mri ) showed high signal intensity at the right internal capsule area ( fig . initially he was treated with antiviral agents and antiepileptic drugs ( aeds ) under the assumption of encephalitis . neutropenia developed one week after admission , and left cervical lymph node enlargement was found three weeks after admission . laboratory findings showed anemia and thrombocytopenia with increased reticulocyte count , elevated aspartate aminotransferase , alanine aminotransferase , and c - reactive protein . ferritin level was 15,671 ng / ml , fibrinogen level was 139 mg / dl , and triglycerides level was 285 mg / dl . peripheral blood cell morphology showed left - shifted neutrophils , atypical lymphocytes , toxic neutrophils , and vacuolated neutrophils . epstein - barr virus ( ebv ) igg antibody was positive , while igm antibody was negative . his follow - up brain mri done on the day of admission showed decreased size of focal lesion with high signal intensity at the anterior limb of right internal capsule ( fig . 1b ) . by the second hospital day , he showed altered mentality with anisocoric pupil and sluggish light reflexes . 1c ) . to control intracranial pressure , emergent craniotomy with decompressive right temporal lobectomy was performed . under the suspicion of hlh , bone marrow examination was done , which showed hypercellular marrow with increased number of megakaryocytes . ebv polymerase chain reaction was found to be negative . on brain pathology , there was perivascular and leptomeningeal lymphohistiocytic infiltration with hemophagocytosis and some red neurons with parenchymal hemorrhage . cd68 immunohistochemistry revealed perivascular and leptomeningeal histiocytic infiltration , which were consistent with hlh ( fig . 2 ) . there was no mutation detected on the gene analysis of prf1 and unc13d . the etiology is not confirmed but secondary hlh might be more possible given his age and clinical course . under the diagnosis of hlh , the patient was treated with chemotherapy of hlh-2004 regimen4 ) suggested by the histiocyte society which is based on etoposide , dexamethasone , cyclosporine a , and intrathecal chemotherapy with methotrexate and prednisolone in selected patients . in addition , csf analysis and intrathecal chemotherapy was done at two days after the initiation of the hlh-2004 regimen due to brain involvement of hlh . csf findings showed one wbc / mm , and the protein level of csf was 126 mg / dl . intrathecal methotrexate and hydrocortisone were administered four times in total . in the last follow - up csf analysis ( done after the 4th intrathecal chemotherapy ) , csf protein level was decreased to 93 mg / dl and wbc level was 2/mm . after eight weeks of initial therapy , his mentality improved but left side hemiplegia persisted with motor power grade iii . there was no evidence of hlh reactivation for over 28 months after completion of chemotherapy , and his ferritin improved significantly ( fig . now he is being followed up with aeds for seizure controls and his left hemiplegia is much improved . until now , there was one report about neuropathologic findings of central nervous system ( cns)-involved hlh patients confirmed with autopsy specimen5 ) . in addition , there was a report of hlh which involved only cns with pathological confirmation , without other systemic symptoms6 ) . most recently , there was a report of two cns - involved hlh cases in korea7 ) . in current case , hlh was diagnosed on the basis of clinical features and lab findings . the unique finding of this study was that bone marrow pathology did not show the features of hlh , but the pathology of brain showed hemophagocytosis , supporting the diagnosis . the patient 's initial ferritin level was 15,671 ng / ml , in accordance with the result of a recent report which showed ferritin levels above 10,000 ng / ml are specific and sensitive for hlh8 ) . elevated protein level of csf also supported the diagnosis of hlh9 ) . on the basis of the present report , we suggest that the diagnostic criteria of hlh-2004 may need some updating . in some cases , the diagnostic criteria can not be fulfilled even if hlh is strongly suspected clinically . a recent study showed that hemophagocytosis of bone marrow specimen has 83% sensitivity and 60% specificity only10 ) , and another report showed hlh diagnosed after repetitive bone marrow biopsy11 ) . furthermore , some laboratory exams ( e.g. , soluble cd25 and nk - cell activity ) are not available in many hospitals , making the diagnosis more difficult . in these circumstances , if hemophagocytosis is confirmed at organs other than bone marrow , liver and lymph node , it can be helpful in the diagnosis of hlh . hlh is known to be a fatal disease that has a high mortality rate if the diagnosis is delayed . therefore , the confirmation of hemophagocytosis in other organs may be helpful in the diagnosis of hlh when other clinical findings support . cns involvement is common in hlh , and the manifestation is highly variable : seizure , hemiplegia or tetraplegia , ataxia , cranial nerve palsy , signs of increased intracranial pressure , and coma . thus , when a patient shows unexplained neurologic manifestations , hlh should also be considered in the differential diagnosis . however , reports showed that some hlh patients do not have neurological symptoms or signs but do have neuroradiological abnormal findings . hlh with cns involvement has been reported in up to 50% of patients , and they have worse outcome with a poorer 5-year survival rate13 ) . csf analysis is included in the hlh-2004 guideline , and the brain mri is also recommended when reactivation or new onset of hlh . in addition , the present authors suggest that the brain mri should be considered at the initial diagnosis . in conclusion , this paper reports a case of successfully treated hlh , which presented with sustained high fever and seizure . the patient 's brain pathology showed hemophagocytosis , although bone marrow did not represent the hallmark of hlh . from the experience of the present case , it is recommended that the diagnosis of hlh can be assisted with pathologic confirmation of tissues other than bone marrow , liver , and lymph node if the patient 's clinical findings support hlh . additionally , neuroradiologic study and csf analysis should be considered at initial diagnosis of hlh because it can reveal the hlh involvement of brain even in the cases without neurological symptom .

hemophagocytic lymphohistiocytosis ( hlh ) is characterized by fever , splenomegaly , jaundice , and pathologic findings of hemophagocytosis in bone marrow or other tissues such as the lymph nodes and liver . pleocytosis , or the presence of elevated protein levels in cerebrospinal fluid , could be helpful in diagnosing hlh . however , the pathologic diagnosis of the brain is not included in the diagnostic criteria for this condition . in the present report , we describe the case of a patient diagnosed with hlh , in whom the brain pathology , but not the bone marrow pathology , showed hemophagocytosis . as the diagnosis of hlh is difficult in many cases , a high level of suspicion is required . moreover , the pathologic diagnosis of organs other than the bone marrow , liver , and lymph nodes may be a useful alternative .

in january 2015 , two sisters aged four ( sibling 1 ) and six ( sibling 2 ) with asymptomatic , consanguineous ( first cousin ) parents were referred to our ophthalmology department for evaluation of bilateral high astigmatism . both siblings suffered since birth from poor vision in both eyes and photophobia since birth . on ophthalmological examination , autorefractometer measurements for sibling 1 and sibling 2 were od 3.75 2 179/os 3.75 2.75 177 and od 2.25 7.75 166/os 3.75 5.75 174 , respectively . reliable visual acuity measurements could not be obtained in sibling 1 , whereas best - corrected visual acuity for sibling 2 was 20/32 . blue sclera and mild globular protrusion of the cornea were observed bilaterally in both siblings . slit - lamp examination of the cases revealed that both corneas were globular in shape with peripheral corneal thinning . corneal topography and pachymetry maps were obtained using a scheimpflug imaging ( pentacam , oculus optikgerte gmbh , wetzlar , germany ) [ fig . 1 ] . maximal keratometry ( kmax ) indices for sibling 1 and sibling 2 were 52.9 d ( od)/53.5 d ( os ) and 54.4 d ( od)/55.4 d ( os ) , respectively . the corneal thickness values for sibling 1 and sibling 2 were 241 ( od)/291 ( os ) and 286 ( od)/305 ( os ) , respectively . corneal topographic images of the left eye of sibling 1 showing limbus - to - limbus corneal thinning the two siblings had in common the features of keratoglobus , blue sclera , atypical faces , hearing loss , and hypermobile joints [ fig . 2 ] . therefore , they were referred to the genetic department for systemic evaluation . on general assessment both siblings had flat midfaces , large eyes , frontal bossing , mild hypertelorism , calvarial thickening , and absent frontal sinuses , suggesting a diagnosis of marshall syndrome [ fig . 3 ] . these siblings had also mandibular hypoplasia , hyperextensible joints , and metaphyseal widening of long bones , suggesting a diagnosis of stickler syndrome . otoacoustic emission test was performed to evaluate hearing loss and was found abnormal in both siblings . other detailed clinical characteristics of marshall syndrome , stickler syndrome , and our cases are presented in table 1 . we tentatively diagnosed the sisters as having an overlapping marshall / stickler phenotype based on clinical and radiological findings . frontal and profile views of sibling 1 ( top ) and 2 ( bottom ) absence of frontal sinus is seen in x - ray graphy of sibling 2 clinical features of marshall syndrome , stickler syndrome , and overlapping phenotype of our cases written informed consent was taken for photography and genetic analysis . we could study only the exon 49 and exon 52 regions of the col11a1 gene , and the results were negative . protective eyeglasses were prescribed for both siblings , and avoidance of contact sports was highly recommended owing to the high risk of perforation . to our knowledge , this is the first report describing congenital keratoglobus with blue sclera in two siblings with overlapping marshall - stickler phenotype . in the past , it is proposed that the existing phenotypic overlap suggests that marshall and stickler syndromes are probably allelic expressions of the same locus . although jun et al . demonstrated the expression of the col11a1 gene in human donor corneas , corneal disease associated with marshall - stickler syndrome due to col11a1 mutation has not yet been reported . the altered collagen due to col11a1 mutation may weaken collagen fibers in the cornea , which could play a role in the development of keratoglobus in these cases . furthermore , thinning and breakdown of the collagen is the main histological finding in cases of blue sclera . in practice , there are difficulties in obtaining whole genome analysis due to size and complexity of the col11a1 gene and also to the high cost of these investigations . only the exon 49 and exon 52 regions of the col11a1 gene were identified and found to be mutation negative . furthermore , we could not screen the col2a1 gene in relation to some forms of stickler syndrome . khalifa et al . pointed out that dominant and recessive mutations in the col11a1 gene cause marshall and stickler syndromes . in this report , our cases were the offspring of unaffected consanguineous parents , suggesting autosomal recessive inheritance . our cases also showed bilateral involvement . in the literature , keratoglobus with blue sclera was reported in association with connective tissue disorders . these disorders are ehlers - danlos type vi , marfan syndrome , rubinstein taybi syndrome , and osteogenesis imperfecta . until now , keratoglobus with blue sclera has not been reported in association with marshall / stickler phenotype . as a connective tissue disorder , marshall - stickler syndrome might be in the differential diagnosis of keratoglobus with blue sclera . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed . the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s ) has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal . the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .

we aimed to describe congenital keratoglobus with blue sclera in two siblings with overlapping marshall / stickler phenotype . two sisters ( ages four and six ) with bilateral high astigmatism were evaluated by slit - lamp microscopy . corneal topography and pachymetry maps were also obtained . slit - lamp examination revealed that both corneas were globular in shape with peripheral corneal thinning . pachymetry maps showed diffuse corneal thinning . two siblings had in common the features of keratoglobus , blue sclera , atypical face , hearing loss , and hypermobile joints . we tentatively diagnosed the sisters as having an overlapping marshall - stickler phenotype based on clinical and radiological findings . marshall - stickler syndrome may exist in the differential diagnosis of keratoglobus with blue sclera .

with the abundance of dna sequence information currently available , researchers are now looking to comprehensively identify and characterize the proteomic products of the genetic blueprint . the most widespread and high - throughput methodology being used to address this goal is mass spectrometry ( ms ) . using ms to perform large - scale experiments generates substantial amounts of peptide and protein mass spectra . the informatics issues involved in dealing with these volumes of data can be overwhelming even within an individual laboratory . this matter , together with a lack of open standard formats , has contributed towards the general shortage of publicly available ms - based proteomic data . however , there is increasing recognition within the community , granting bodies and publishing agencies ( 1 ) that published proteomic data can , and should , be fully accessible . open access policies such as these allow the community to review and comprehensively re - examine the data upon which experimental conclusions are based . from the researcher 's ; perspective , the long - term archiving of proteomic data at a centralized repository not only increases the data usability and visibility but also decreases the risk of data loss . in addition , the availability of large collections of ms data can benefit the field in a wider sense , for example , by enabling informaticians to develop better algorithms or construct spectral libraries . several databases already exist to store and disseminate proteomic data including pride ( 2 ) , peptideatlas ( 3 ) , tranche ( 4 ) , the gpm ( 5 ) , and human proteinpedia ( 6 ) . peptidome ( 7 ) aims to complement these resources ; the major goals of the peptidome project are to : build and maintain a robust database in which to efficiently store tandem ms data at a level of detail appropriate for both ms professionals and the wider biological community , develop simple deposit procedures that minimize the burden of submission while supporting well - annotated data deposits from the research community , exchange data with established ms repositories , offer user - friendly tools that enable users to query , locate , analyze and review the data of interest . build and maintain a robust database in which to efficiently store tandem ms data at a level of detail appropriate for both ms professionals and the wider biological community , develop simple deposit procedures that minimize the burden of submission while supporting well - annotated data deposits from the research community , exchange data with established ms repositories , offer user - friendly tools that enable users to query , locate , analyze and review the data of interest . the information captured in the online database is designed to represent the final results based upon the submitter 's ; interpretation of the raw ms / ms spectra . this is intended to provide a quick overview for mass spectrometrists and accessibility for other non - specialists . the original submitted files are the true record , and will always be available for download . proteins and peptides. proteins contain links to their member peptides , and peptides know which proteins they are members of . spectra through peptide identifications ( pepidents ) , thus allowing more than one interpretation of a spectrum , and providing storage for post - translational modifications and identification scores . a schematic overview of peptidome . proteins and peptides. proteins contain links to their member peptides , and peptides know which proteins they are members of . spectra through peptide identifications ( pepidents ) , thus allowing more than one interpretation of a spectrum , and providing storage for post - translational modifications and identification scores . a study is a collection of related samples and provides a focal point for , and description of , the whole experiment . a sample contains all the data related to the biological material , which may be derived from one or more ms instrument runs . each sample record contains a list of identified proteins and a list of identified peptides . each protein points to a sublist of peptides by which it was identified , and each peptide is linked to the protein(s ) that it is a member of . these pepidents denote any post - translational modifications as well as any identification scores for the match between a given spectrum and a peptide . note that this allows a spectrum to have more than one peptide associated with it . a sample also contains descriptive information about the biological material , protocols used to generate the data , instrumentation and informatics parameters . both studies and samples are accessioned objects ; each record is assigned a unique and stable peptidome accession number that may be cited in a manuscript describing the data . the accession consists of a number and a letter prefix indicating whether the record is a peptidome study ( psexxx ) or peptidome sample ( psmxxxx ) . our goal is to make data submission procedures as straightforward as possible , while encouraging a high level of experimental annotation . to minimize the burden of data submission there are four components that are required for a complete submission : a metadata file that describes the overall experiment , each associated biological sample , the instruments and protocols used to generate the data and the relationship of the corresponding data files . this information is provided by completing a metadata spreadsheet ; templates and example spreadsheets are provided within the peptidome submission guidelines from a link on the petidome homepage.raw data files contain the original ms and ms / ms information from the instrument . peptidome currently accepts any of the standard xml formats ( mzdata , mzxml or mzml ) that contain both the ms and ms / ms data from a single fraction . in addition , text formats ( .mgf , .pkl , .sqt , .dta ) are also accepted , but not preferred . proprietary binary data directly from the manufacturers ( e.g. .raw or .wiff ) are not accepted.output files from any peptide identification program . these files contain matches of the ms / ms scans to the peptides . currently , peptidome supports dat files from mascot , asn.1 or xml formatted files from omssa , and any search engine output files that have been converted to pepxml format ( e.g. x!tandem or sequest ) . if manual identification was used to interpret the spectra , or the search engine output formats are not supported by peptidome , the submitted results table must include references to spectrum files and additional information that is usually extracted from the search engine output files , e.g. charge state and identification scores.results tables that describe the submitter 's ; view of the final , processed results according to whatever criteria they use to determine acceptability . results tables list the proteins discovered in each sample in the study . for each protein , the peptides should be listed , and for each peptide , the matching spectrum files should be listed . if the matching spectrum file list is omitted , then every spectrum matched to that peptide / protein in the peptide identification output files is assumed to be correct . similarly , if the results table contains only proteins , then all associated peptides and spectra will be gleaned from the peptide identification output files . peptidome supports post - translational modification annotations in the unimod i d ( 8) format . fixed modifications for given residues are listed separately and are assumed to apply to all residues of that type . in the modified peptide strings , each residue is followed by a unimod i d in parenthesis if it is modified and fixed modifications need not be listed . a metadata file that describes the overall experiment , each associated biological sample , the instruments and protocols used to generate the data and the relationship of the corresponding data files . this information is provided by completing a metadata spreadsheet ; templates and example spreadsheets are provided within the peptidome submission guidelines from a link on the petidome homepage . raw data files contain the original ms and ms / ms information from the instrument . peptidome currently accepts any of the standard xml formats ( mzdata , mzxml or mzml ) that contain both the ms and ms / ms data from a single fraction . in addition , text formats ( .mgf , .pkl , .sqt , .dta ) are also accepted , but not preferred . proprietary binary data directly from the manufacturers ( e.g. .raw or .wiff ) are not accepted . currently , peptidome supports dat files from mascot , asn.1 or xml formatted files from omssa , and any search engine output files that have been converted to pepxml format ( e.g. x!tandem or sequest ) . if manual identification was used to interpret the spectra , or the search engine output formats are not supported by peptidome , the submitted results table must include references to spectrum files and additional information that is usually extracted from the search engine output files , e.g. charge state and identification scores . results tables that describe the submitter 's ; view of the final , processed results according to whatever criteria they use to determine acceptability . results tables list the proteins discovered in each sample in the study . for each protein , the peptides should be listed , and for each peptide , the matching spectrum files should be listed . if the matching spectrum file list is omitted , then every spectrum matched to that peptide / protein in the peptide identification output files is assumed to be correct . similarly , if the results table contains only proteins , then all associated peptides and spectra will be gleaned from the peptide identification output files . there are many different methods for ms quantification , with new ones being invented all the time . therefore , for peptide and protein quantification , each quantification value with a single number per protein , peptide and/or spectrum per sample is denoted , where the units ( if applicable ) and methodology used to quantify the sample are required in the metadata annotation . when all submission files are assembled , they can be transferred to peptidome via ftp . a curator will collect the files and manually curate and validate them before depositing in the database . some journals require accession numbers for ms proteomic data before acceptance of a paper for publication . thus , ideally , data should be deposited in peptidome before a manuscript describing the data is sent to a journal for review . a reviewer url can be generated and disclosed to journal editors ; this url grants anonymous , confidential access to private data during the manuscript review period . all submissions undergo both syntactic validation and manual review by a curator before being uploaded to the peptidome database , thus enforcing good quality data deposits . when any issues , such as mangled formats or missing components , are identified , a curator will work with the submitter until the problems are resolved . early exemplar submissions in peptidome were gathered from selected data in peptideatlas ( 3 ) , with the metadata manually enriched from publications associated with those experiments . submissions are processed using custom software to upload the metadata and results into the database . the spectra files are not loaded into the database , instead they are converted to a custom format , based upon hdf5 ( available from http://www.hdfgroup.org/hdf5/ ) , that is both more compact and allows faster retrieval of individual spectra than the original xml format . proteins are linked with the corresponding entries in ncbi entrez in a best effort fashion . this flexibility allows submitters to reference novel proteins that are not yet in the mainstream databases , and to use custom protein databases . peptidome protein links are updated in an ongoing process , in order that they remain up - to - date . the data in peptidome may be browsed by studies or samples , and the individual samples may be examined from the identified proteins and peptides down to the individual spectra as shown in figure 2 . figure 2.a series of screenshots showing navigation from a top level list of studies ( 1 ) , to its list of samples ( 2 ) , to the protein list for a sample ( 3 ) , to the list of peptide identifications for that protein ( 4 ) and finally to three individual spectra for different peptide identifications ( 5 ) . a series of screenshots showing navigation from a top level list of studies ( 1 ) , to its list of samples ( 2 ) , to the protein list for a sample ( 3 ) , to the list of peptide identifications for that protein ( 4 ) and finally to three individual spectra for different peptide identifications ( 5 ) . metadata for all public studies and samples , and the associated proteins for each sample , are loaded into ncbi 's ; powerful entrez search and linking system ( 9 ) . this facilitates cross - linkage with other ncbi resources like entrez protein , pubmed and taxonomy . the entrez interface also allows users to search peptidome using simple free text or complex fielded queries . additionally , all original data , including spectra files , output results and supplementary data are available for bulk download via anonymous ftp at ftp://ftp.ncbi.nih.gov / pub / peptidome/. peptidome was recently established at ncbi with the goal to enhance proteomic research by providing a high - quality mass spectra repository . we are now accepting submissions and invite researchers to deposit their tandem ms data sets with us so that we can disseminate them to the wider community . currently , the peptidome team is working to expand and improve existing indexing , linking , searching , exploring and retrieving functionalities . additional advanced data mining and visualization tools for the convenience of proteomic researchers are under design and development . funding for open access charge : intramural research program of the national institutes of health , national library of medicine .

peptidome is a public repository that archives and freely distributes tandem mass spectrometry peptide and protein identification data generated by the scientific community . data from all stages of a mass spectrometry experiment are captured , including original mass spectra files , experimental metadata and conclusion - level results . the submission process is facilitated through acceptance of data in commonly used open formats , and all submissions undergo syntactic validation and curation in an effort to uphold data integrity and quality . peptidome is not restricted to specific organisms , instruments or experiment types ; data from any tandem mass spectrometry experiment from any species are accepted . in addition to data storage , web - based interfaces are available to help users query , browse and explore individual peptides , proteins or entire samples and studies . results are integrated and linked with other ncbi resources to ensure dissemination of the information beyond the mass spectroscopy proteomics community . peptidome is freely accessible at http://www.ncbi.nlm.nih.gov/peptidome .

for human hair and skin , lipids play an integral role in protecting and maintaining key properties and structure . oxidative insult leads to compromised lipid function and is linked to a wide range of consumer complaints , including brittleness , splitting , dryness , and decreased luster . hair can contain up to 9% lipids by mass , comprising two general types : sebaceous lipids , which contribute to waterproofing , lubrication , and sheen ; and endogenous lipids , which are associated with chemical diffusion , cell cohesion , and physico - mechanical properties such as strength . however , advances in this field have yet to be fully applied to the cosmetic sciences . this paper reports the preliminary development of redox lipidomic techniques for the characterization and profiling of selected lipids and their oxidation products in human hair . light , straight brown virgin hair was sourced from de meo brothers , ny usa . approximately 10 mg was divided into three regions : root , middle , and tip . the lipids were extracted by soxhlet ( 8 h in chloroform / methanol 2:1 , then 18 h in fresh chloroform / methanol 2:1 at 18 c ) , washed with chloroform , methanol , and then concentrated . a portion of the lipid extracts was treated with 9% hydrogen peroxide and 1% ammonium persulfate for an hour and then dried . the following maldi matrices were trialed : 9-aminoacridine ( 9-aa ) from sigma - aldrich at 10 mg / ml in 60:40 isopropanol : acetonitrile ; saturated -cyano-4-hydroxycinnamic acid ( chca ) from bruker daltonics in a 1:2 mixture of acetonitrile with 0.1% trifluoroacetic acid ; and 2,5-dihydroxy benzoic acid ( dhb ) from bruker daltonics at 10 mg / ml in a 1:2 mixture of acetonitrile with 0.1% trifluoroacetic acid . lipid analysis was performed on a bruker daltonics ultraflex iii maldi - tof / tof . matrix solutions and sample were mixed 1:1 , and 1 l was spotted on a polished steel target plate and allowed to dry . for calibration , peptide calibration standard ( bruker daltonics ) and lipid standard , mono- , di- , and tri - glyceride mix ( sigma - aldrich ) were prepared according to the manufacturer 's instructions . an initial evaluation of varying matrices was performed to determine the optimal matrix for matrix - assisted laser desorption ionization ( maldi ) mass spectrometric ( ms ) analysis . the lipid profiles of each of the matrices trialed appeared quite different ( data not shown ) . a range of lipids were detected with both dhb and chca in both positive and negative modes . chca was selected as the matrix of choice on the basis of facilitating good lipid coverage across the full mass range of interest and the best resolution of the lipid / peptide standard used for calibration . several classes of internal hair lipids were identified including ceramides , diglycerides , and cholesteryl esters . an example of the structural assignment of a ceramide , n-(tetracosanoyl)-dihydroceramide , is shown in [ figure 1 ] . ms / ms spectrum of ceramide n-(tetracosanoyl)-dihydroceramide , with characteristic fragment ions highlighted peroxide treatment of the lipid extract revealed significant changes in the lipid profile [ figure 2 ] . from these profiles , the loss of characterized lipids can be observed , in addition to a wide range of new observed ions correlating to damage products . in negative mode , no discernable changes were seen in the lipid profiles . in positive mode the range of lipids found from m / z 700 to 1000 ( including phosphocholines , di- and tri - glycerides ) seemed to be primarily present in the root region with the exception of one phosphocholine seen in the tip region . ms spectra of peroxide treated lipid extract of the root region of human hair in both positive and negative modes this proof - of - principle study has demonstrated the validity and utility of redox lipidomic approaches for evaluating lipid damage in human hair . while the small sample number utilized in this initial study made it hard to determine exact lipid differences between the three regions of the hair , peroxide treatment of extracted hair lipids revealed ion peak shifts and disappearances within the di- and tri - glyceride regions . the cholesterol and cholesterol derivatives regions appeared to be the most affected , indicating higher susceptibility to oxidative damage . this preliminary evaluation has demonstrated that redox lipidomic - based approaches can be applied to the detection of molecular - level damage to important lipids in human hair , allowing pinpoint characterization of the damaging effects of treatments such as peroxide bleaching . the next key steps will include the systematic characterization of oxidative products , and correlation of specific modifications and relative abundances with damage protocol . significant potential exists for applying and expanding our approach to both fundamental and applied hair and skin research , as well as personal care product advances , though development of lipid damage tracking technologies .

lipids are an amazingly diverse group of biomolecules with an array of biological functions including protecting and maintaining key properties and structure . oxidative insult in the form of uv , hydrothermal , or other damage leads to compromised lipid function and can be linked to a wide range of consumer complaints . this proof - of - principle study applied and evaluated redox lipidomic approaches for the characterization and profiling of selected lipids and their oxidation products in human hair . it was observed that cholesterol and cholesterol derivatives regions appeared to be the most susceptible to oxidative damage and this leads to further experiments , including the systematic characterization of oxidative products , and correlation of modifications with damage protocol .

semiconductor gas sensors offer good advantages with respect to other gas sensor devices due to their simple implementation , low cost and good reliability for real - time control systems [ 1 - 3 ] . among them , zno , wo3 and sno2 have widely been studied . tungsten oxide ( wo3 ) is a wide band gap , n - type semiconductor that has interesting physical and chemical properties [ 5 - 9 ] . wo3 is a good photochromic , electrochromic , thermochromic and catalytic material [ 9 - 12 ] . as gas adsorption occurs at surface level , an increase in the active surface area of the semiconductor oxide would enhance the properties of materials used as gas sensors [ 4,13 - 15 ] . nanostructured mesoporous materials have been widely studied in the development of gas sensing and catalytic systems , due to their large , controllable pore size and high surface area [ 1,13,16 - 18 ] . nanocasting is a novel methodology for preparing nanoparticles by using mesoporous materials as a template to accommodate different oxides . in this synthesis pathway , the surface and voids of a preformed mesoporous solid the subsequent mineralization of these precursors and removal of the former solid templates may lead to mesostructures with other compositions and crystalline frameworks . while using in chemical sensors , the sensing material should be aligned and connected between the electrode structures , so that the change of their properties is converted into electrical signal , when exposed to the measurand . several approaches have been reported in the literature for placement of the nanomaterials between the electrodes , but most of them do not offer selective settlement of particles or need expensive apparatus and high vacuum . using electric field is one of the most versatile techniques known till date for selective and inexpensive assembly of nanoparticles . in this research , we applied a nanocasting route for synthesis of ultrafine wo3 nanoparticles . in the first step , mesoporous silica ( sba-15 structure ) was prepared using a soft template , and in the second step , this material was used as a hard template in nanocasting of wo3 nanoparticles . also , alternating electric field was used to manipulate the sensing material between electrodes , in order to fabricate gas sensor . polypropylene oxide block copolymer was used as soft template and tetraethyl orthosilicate ( teos ) as silicate source . in the first step , 6 gr of the copolymer , 180 cc distilled water and 30 gr hcl ( 35% wt ) were mixed together , and the solution was stirred for 6 h at 35c . in the second step , teos was added to this acidic solution and stirred for 24 h at the same temperature and then heated at 100c for another 24 h as a hydrothermal treatment . small volume of nh3 was added in order to increase the ph up to 7 . then , the product was dried at room temperature in air atmosphere and calcined at 550c for 4 h. the solid product of this process is mesoporous sio2 , which will be used as nanotemplate in production of wo3 nanoparticles . the synthesis of wo3 nanoparticles was carried out as follows : equal amounts of phosphotungstic acid hydrate and mesoporous sio2 were dissolved in ethanol , stirred vigorously for 1 h , dried at room temperature at air atmosphere and heated at 570c for 5 h. the sio2 hard template was removed by hf ( 2% wt ) , and the product was collected by centrifugation . the product was washed both with water and ethanol for three times and dried at room temperature . for sensor fabrication , wo3 nanopowders were deposited on an alumina substrate between electrodes , via low frequency ac electrophoretic deposition [ 21 - 23 ] . for this purpose , a suspension of 1 gr / l wo3 nanoparticles in acetone was prepared and ultrasonicated for 15 min to become stable and homogenous . deposition was done by applying a voltage of 25 v and a frequency of 1 khz . the sensor was calcined for 1 h at 58c in an electric furnace and air atmosphere . synthesized powders were characterized by x - ray diffraction ( xrd , siemens d500 , cu k radiation ) and transmission electron microscopy ( hrtem , jeol2000 and tem , phillips ) . response of the sensors toward various concentrations of no2 was measured using a normal set - up . the gas response was calculated as ra / rg , where ra and rg represent samples resistances without and with the presence of gas , respectively . tem image of mesoporous sio2 and hrtem image of wo3 nanoparticles are shown in fig . the results revealed that wo3 replica was constructed by hexagonally packed nanoparticle array in the two - dimensional sba-15 structure of sio2 . these nanoparticles were randomly oriented in the mesostructured framework and rather uniform in diameter ( 5 nm ) due to the confined growth in the channels of the mesoporous silica template . the d spacing has been measured to be 3.8 , which is in accordance with ( 001 ) planes in monoclinic wo3 crystal structure . a tem image of mesoporous sio2 ; b hrtem image of a single wo3 nanoparticle bet measurements showed a surface area of about 700 m /gr for mesoporous sio2 template that was reduced to 43 m /gr for wo3 nanoparticles . 2 , indicating that wo3 is fully crystalline with monoclinic crystal structure , which is in a good agreement with tem results . the results show that sio2 peaks were removed after washing with hf and pure wo3 has remained . xrd pattern of synthesized wo3a before and b after removing the silicate template in ac electric field , the nanomaterials align in a highly uniform way and orientate along the electric field direction by the electrophoresis force . as it can be seen from the sem images in fig . 3a and 3b , nanoparticles assemble along the direction of electric field , connect end to end and bridge the electrode gap . based on the sem images , ac electrophoresis has the potential for the precise manipulation of nanoparticles , which would be useful in making micro / nano electronic devices . sem image of wo3 nanoparticles between the electrodes optical microscopy image of fabricated sensor via ac electrophoretic deposition is shown in fig . , wo3 particles have connected the electrodes , by bridging over them as a result of ac electrophoresis forces . optical microscopy image of fabricated gas sensor , the particles have connected the electrodes together the sensing properties of fabricated sensor exposed to dilute no2 were investigated in a dynamic mode switching from air to the specific concentration of the target gas and again back to the base air in each cycle . figure 5a and 5b show the response transients and sensitivities of synthesized wo3 nanoparticles at 200c . 5a ) is an indication of sensor quality and is a direct consequence of extremely small particle size and high specific surface area . the sensor needed a rather long time to reach its original level after switching back to the air . sensitivity values ( defined as the ratio of sensor resistance in target gas over its resistance in base air ) presented in fig . a response transients to different concentrations of no2 at 200c , b corresponding sensitivities sensing test results prove that the synthesized nanoparticles are sensitive to low concentrations of no2 , which may be a consequence of ultrafine particle size that leads to higher active surface . application of electric field for deposition of particles also improves the sensing properties of the fabricated gas sensor , thanks to precise placement of particles side by side and establishment of a good connection between the electrodes facilitating the charge transfer between electrodes . ultrafine wo3 nanoparticles rather uniform in diameter ( 5 nm ) were synthesized efficiently by nanocasting route . ac electrophoresis was applied to deposit wo3 nanoparticles between electrodes in order to fabricate the gas sensor . the sensing measurements showed that the synthesized particles are sensitive even to very low concentrations of no2(100 ppb ) , which is a result of very small particle size combined with application of proper deposition method .

ultrafine wo3 nanoparticles were synthesized by nanocasting route , using mesoporous sio2 as a template . bet measurements showed a specific surface area of 700 m 2/gr for synthesized sio2 , while after impregnation and template removal , this area was reduced to 43 m 2/gr for wo3 nanoparticles . hrtem results showed single crystalline nanoparticles with average particle size of about 5 nm possessing a monoclinic structure , which is the favorite crystal structure for gas sensing applications . gas sensor was fabricated by deposition of wo3 nanoparticles between electrodes via low frequency ac electrophoretic deposition . gas sensing measurements showed that this material has a high sensitivity to very low concentrations of no2 at 250c and 300c .

it is produced starting from whole or minced meat marinated for 12 hours at 4c with red or black pepper , salt , onion powder or pieces , sliced tomato or tomato sauce , olive oil , lemon juice , vinegar , milk or milk powder , yogurt and eggs ( vazgecer et al . , 2004 ) . after that , the kebab is shaped like a cone around a skewer then frozen for distribution to mass caterers and administration to final consumers . dner kebab in a block is cooked vertically on roller grill skewers . during cooking , the cooked part is cut away using a long bladed or circular knife and stuffed into pita bread along with sliced tomatoes , onions , lettuce and served with other typical oriental sauces like hummus or tabbouleh . dner kebab chemical - physical characteristics are variable : humidity varies from 48 to 69% , ph ranges from 5.7 to 6.0 and the water activity varies between 0.94 and 0.95 ( kilic , 2009 ) . on the basis of regulation ( ec ) no 853/2004 ( european commission , 2004 ) , dner kebab could be classified as a meat preparation which means fresh meat , including meat that has been reduced to fragments , which has had foodstuffs , seasonings or additives added to it or which has undergone processes insufficient to modify the internal muscle fiber structure of the meat and thus to eliminate the characteristics of fresh meat . as such it is included in the guidance document describing the food categories in part e of annex ii to regulation ( ec ) no 1333/2008 on food additives ( european commission , 2008 ) . the annex also lists the additives authorized for use in the preparation of this food . the aim of this study was to ascertain if dner kebabs sold on the italian market as meat preparations comply with the labelling requirements of relevant eu legislation . the labels listed different additives commonly used in dner kebab ingredients , including e 621 ( monosodium glutamate ) . this additive is not authorized for use in meat preparations so a histological evaluation was performed to assess whether dner kebabs belong to the meat preparation food category and whether the use of additive e 621 complies with the eu regulation on additives . nine labels of dner kebab ( produced with calf , turkey and chicken meat ) marketed in the province of modena , were collected to evaluate the mandatory information included in article 9 of regulation ( eu ) no 1169/2011 together with the mandatory requirements of regulation ( ec ) 853/2004 for meat preparations 4 of regulation ( eu ) 1169/2011 ( european commission , 2011 ) , mandatory food information defined by the community legislator falls into three categories : the identity , composition and properties of the food ; the protection of consumers health and safe use of food ; the nutritional characteristics . the checklist aimed at evaluating only the first two categories , and not the nutritional labelling . as it can be observed in table 1 , the section of mandatory identity information in the checklist included the name of the food , the list of ingredients , the quantity or categories of certain ingredients , the net quantity of the food , the name or business name and the address of the food business operator ( fbo ) responsible for the information , the identification mark and the lot identification . the section of mandatory food information on protection of consumers health in the checklist included the indication of ingredients or substances causing allergies ( or intolerances ) , the date of minimum durability or the use by date , any special storage conditions and/or conditions of use and the instructions for use . to verify if dner kebab could be classified in the meat preparations food category and consequently establish if some ingredients listed in the label were authorized , eight frozen dner kebab samples were taken and a visual assessment and histologic examination were performed to verify potential changes in the meat muscle fibre structure . samples were fixed in 10% buffered formalin at ph 7 - 7.6 for 24 hours , embedded in paraffin wax , sectioned at 5 m , longitudinally and transversely , and stained with haematoxylin and eosin ( h&e ) for histological examination . were produced with calf , turkey and chicken meat . at macroscopic visual assessment , the dner kebabs were frozen meat blocks wrapped in a transparent film . at histological examination , these appeared diffusely eosinophilic , arranged in parallel , with peripheral elongated nuclei near the sarcolemma and typical cross streaks in most fields were observed ( figure 1 ) . in cross - sections , the cells were round or polygonal in shape with peripheral nuclei ( figure 2 ) . furthermore , they were leaning against each other , with little or moderate interposed space , sometimes occupied by connective tissue of probable endomysial / perimysial or fascial origin . as a whole , the tissue was moderately swollen , but the structure of the muscle fibres was intact . only in a few areas the tissue present signs of fragmentation , judged as artefacts caused by cutting several parts of partially thawed samples . some of these aspects , such as fibre swelling , may have been caused by osmotic changes due to kebab preparation . focal roundish greyish material , of probable exogenous origin , was visible among the muscle cells or inside the fibrous tissue at low and high magnification . the mandatory food information evaluated from a legislative perspective in this study concerned the identity , composition and properties of dner kebabs , the protection of consumers health and the safe use of the product . regarding the mandatory information on identity , composition and properties , a high number of minor legislative non - conformities were found , emphasizing a scant knowledge of eu regulations or poor attention to regulation requirements ( for example non conformities on the name of the food , the list of ingredients , the quantity of certain ingredients or categories of them , the net quantity , the name or business name and the address of the fbo responsible for the information , the batch identification ) ; details are reported in table 1 . some important hygienic - sanitary conditions for the protection of consumer s health and the safe use of the product were inadequate . for example , in two of the nine labels analysed , the production plant whose approval number appeared on the labels was not authorized to produce meat preparations or meat products . none of the mandatory information on the minimum durability date and/or the use by date was expressed correctly . in one case , the minimum durability date was not printed in italian . for frozen meat preparations , the date of freezing ( or the date of first freezing ) must be specified and none of the labels complied with this rule . furthermore the legislator established that if the product needs particular precautions , considering its nature , information must be given on the conditions of storage and use . as the product is frozen , storage conditions should be specified , but six of the nine labels did not comply with this requirement . in addition , the instructions for use must be reported in such a way as to enable appropriate use of the food . this aspect is relevant for the fbo due to the peculiar cooking technique of kebab ( progressive exposure to heat from the outer part to the centre of the meat block ) . the outcome of this procedure is that during cooking , that is generally long , the heart of kebab is subjected to a heat treatment in a temperature range of 25 - 45c . this may give rise to the replication of any pathogens present in the raw product ( kilic , 2009 ) . dner kebabs have often been identified as vehicles for foodborne pathogens such as clostridium perfringens , salmonella spp . and staphylococcus aureus ( kayisoglu et al . , 2003 ; food standard agency , 2005 ; ziino et al . , 2013 ) . evaluation of kebab labels must address the problem of information on the proper storage conditions for the product unsold at the end of the day that is regulated by national agencies ( food standard agency , 2005 ; nsw food authority , 2012 ) . the fbo preparing dner kebabs for consumption must provide information to consumers on any allergenic substances that may be present . the indication of substances or products that may cause allergies or intolerances was absent in five of the nine labels examined , thereby limiting the possibility for the fbo to communicate useful information to consumers with food allergies . the dner kebab labels analysed in this study listed different additives commonly used in dner kebab ingredients , including e 621 ( monosodium glutamate ) . our microscopic and macroscopic examination showed that the kebab samples analysed can be classified as meat preparations for which the use of additive e 621 is not authorized . in conclusion , our study disclosed several systematically deficient regulatory requirements in dner kebab labelling , both for extrinsic defects ( not related to food composition ) and for aspects concerning the protection of consumers health that may influence the safety of dner kebabs .

the aim of this study was to assess whether dner kebabs sold in italy comply with legal labelling requirements . a checklist of eu labelling requirements was drawn up and nine labels of dner kebab marketed in the province of modena were collected to evaluate the mandatory information laid down in article 9 of regulation ( eu ) no 1169/2011 together with the mandatory requirements of regulation ( ec ) 853/2004 for meat preparations . the study showed that different additives are commonly used in dner kebabs , including e 621 ( monosodium glutamate ) . this additive is not included among the ingredients authorized for the meat preparation food category . eight frozen dner kebab samples were taken and a visual assessment and a histologic examination were performed to verify potential changes in the meat s inner muscle fibre structure that could allow the product to be considered among meat preparations or meat products . the dner kebab labels showed several systematically deficient regulatory requirements in both extrinsic defects ( not related to food composition ) and aspects concerning the protection of consumers health . histological examination showed that the tissue was moderately swollen , but the muscle fibre structure was intact . kebab can be reasonably classified as a meat preparation thereby precluding the use monosodium glutamate ( e 621 ) as an ingredient .

the number of endoscopic procedures has increased considerably due to the wide use of screening upper and lower endoscopy . the complexity of endoscopic procedures has also increased due to the wide adoption of interventional techniques such as endoscopic submucosal dissection and peroral endoscopic myotomy . more advanced techniques have in turn increased the need of sedation.1 the use of propofol for sedation during endoscopic procedures has increased in recent years,2 mainly because of its favorable pharmacokinetic profile compared with traditional endoscopy sedation drugs such as benzodiazepines and opioids.3,4 propofol ( 2,6-diisopropyl - phenol ) is a phenolic derivative with satisfactory sedative , hypnotic , antiemetic , and amnesic properties . propofol is highly lipophilic and thus can rapidly cross the blood - brain barrier , resulting in an early onset of action ( the drug can induce unconsciousness within periods as short as 30 seconds).5 the depth of sedation increases in a dose - dependent manner . as an additional advantage , regardless of the depth or length of the sedation period , propofol has a short recovery profile ( recovery occurs within 10 to 20 minutes after discontinuation).5 propofol has a short half - life ( 4 minutes vs. 30 minutes for midazolam).5,6 with regard to side effects , although propofol is generally associated with good hemodynamic stability , it can induce a dose - dependent decrease in blood pressure and heart rate . to date , no pharmacological antagonist has been developed . in the united states , propofol is generally administered by anesthesia specialists , despite the evidence that endoscopists can administer or supervise the administration of propofol safely without the involvement of an anesthesia specialist.7,8,9,10,11,12 the administration of propofol by anesthesia specialists for routine endoscopic procedures is controversial because it adds significantly to the cost of endoscopic procedures without an established improvement in outcomes.13 on the other hand , the administration of propofol by endoscopists or supervision of its administration by endoscopists is controversial because anesthesiologists claim that it is unsafe.14 concerns about the safety of endoscopist - directed propofol ( edp ) have been voiced that propofol should be given only by healthcare professionals trained in the administration of general anesthesia.14 here we discuss about the safety and drawbacks of edp for routine endoscopic procedures . according to the american society of anesthesiologists ( asa ) , sedation and analgesia comprise a continuum of states ranging from minimal sedation ( anxiolysis ) through general anesthesia.15 it is important to recognize this continuum as summarized in table 1 . a change in the level of sedation from conscious sedation to general anesthesia may occur inadvertently with a relatively small alteration in the dose of sedative drugs used.16 propofol possesses relatively little analgesic effect , and its amnesic effect is less pronounced than that of midazolam.7,10 local pain occurs in 30% of patients during administration of propofol . this can lead to a fall in systemic vascular resistance and cardiac contractility and consequent hypotension.17 propofol can reduce cardiac output without a concomitant change in heart rate.18,19 respiratory depression can also occur with propofol use . slow administration of propofol boluses has not been shown to attenuate these cardiorespiratory effects although using propofol as an infusion may do this . propofol can also give rise to myoclonic jerks and convulsions ; these are usually very transient and occur as the sedative effects of propofol are wearing off.20,21 the metabolism of propofol is different in the elderly and the dose should be reduced in these patients . impaired cardiac function also potentiates the effects of propofol but impaired renal or hepatic function does not affect propofol activity to a significant extent.21 in patients with cirrhosis , use of propofol for elective upper endoscopy does not precipitate encephalopathy.21 safety literature has been developed primarily in the united states , switzerland , and japan ( table 2).1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30 in the united states , edp has been restricted largely to the states without nursing practice acts or laws prohibiting propofol administration by nonanesthesiologists . the largest volume of data has been collected by heuss et al.11 and kulling et al.31 in switzerland , tohda et al.32 in japan , walker 's group in medford , oregon , and the group at indiana university hospital in the united states.20 heuss et al.11 reported that the administration of propofol under the supervision of the gastroenterologist is safe for conscious sedation during endoscopic procedures . they observed 82,620 endoscopic procedures and there were no severe adverse effects.11 cohen et al.22 reported that propofol could be safely and effectively administered under the direction of a gastroenterologist . hypotension ( > 20 mm hg decline in either systolic or diastolic blood pressure ) developed in 218 patients ( 27% ) , and hypoxemia ( oxygen saturation < 90% ) occurred in 75 patients ( 9%).22 all episodes of hypotension and hypoxemia were transient , and there was no need of assisted ventilations . rex et al.,14 in a safety review of 646,080 edp sedation cases ( 223,656 published and 422,424 unpublished ) , noted that endotracheal intubation and death occurred in 11 and 4 cases , respectively . there were no patients with permanent neurologic sequelae , although one patient had a tonic - clonic seizure , and one had a transient ischemic attack ( blindness ) , both of which resolved without sequelae.14 they concluded that edp appears to result in a lower mortality rate than traditional sedation with benzodiazepines and opioids , and to have a comparable rate to that of general anesthesia administered by anesthesiologists.14 the four deaths observed after edp administration occurred in patients with asa iii or higher who were undergoing nonroutine medical procedures.14 three of the patients had serious underlying medical conditions . the results suggest that such patients should be sedated by an anesthesiologist ; however , nonanesthesiologists have successfully used propofol for patients with higher asa classes , despite the higher risk associated with sedating these patients . the current controversy surrounding performance of edp and the cost of anesthesia specialists for endoscopy anesthesiologist - administered propofol for truly routine procedures in average - risk patients would be very costly and may be unjustified , because there were no deaths or permanent sequelae among such patients or procedures . combining propofol with an additional drug ( benzodiazepine / opioid / ketamine ) allows the dose of propofol administered to be reduced without reproducible effect on recovery time.33,34 administration of ' balanced propofol sedation ' seems to be associated with less need for assisted ventilation , although this has not been demonstrated in head - to - head comparisons . it is clear , however , just from an observational standpoint , that balanced propofol sedation allows more moderate levels of sedation compared with single - agent propofol.1,7 during upper endoscopy , single - agent propofol titrated only to moderate sedation is frequently accompanied by coughing and gagging.7 these responses during upper endoscopy tend to cause endoscopists to administer additional propofol to drive patients into deep sedation . although this has been reported safe in the literature , the need for mask ventilation seems to be greater when single - agent propofol is used . balanced propofol sedation , or combination therapy , has several distinct advantages for edp.5,7,32 first , it maintains a reversible drug component , because antagonists to both opioids and benzodiazepines are available . second , it simplifies the administration of propofol , because even low doses of an opioid or a benzodiazepine result in reduction of the total dose of propofol by more than 50% . third , administration of propofol is smoother because boluses are not only smaller but also given less often . prospective studies have indicated that the actual incidence of deep sedation using balanced propofol sedation targeted to moderate levels is lower than when opioids and benzodiazepines are used without propofol.15,35 a randomized controlled trial in which single - agent propofol titrated to deep sedation was compared with balanced propofol sedation ( targeted to moderate sedation ) using fentanyl and propofol , midazolam and propofol , or fentanyl , midazolam , and propofol showed that the combination regimens could be successfully targeted to moderate sedation and that satisfaction was kept at a high level compared with single - agent propofol , with no lengthening of the time for recovery.1,5,36 in fact , patients who received combination therapy actually recovered faster than those who received single - agent propofol , presumably because they were recovering from only moderate sedation . continuous propofol - infusion is an alternative procedure for deep sedation with intermittent bolus application of propofol . continuous infusion of propofol may be theoretically associated with a less need for user interventions , maintenance of a more consistent level of sedation , and probably a lower total drug dose required . additionally , the avoidance of high peak propofol plasma concentrations , which occurred during bolus application , may reduce the intensity of the hypotensive effect of propofol . furthermore , a rapid lightening of the sedative effect with subsequent patient movements may be avoided by only minimal fluctuations of the plasma propofol concentration under continuous infusion . however , according to reported studies , continuous infusion of propofol holds no relevant advantages . neither the total dose of propofol required nor the sedation efficacy or the frequency of side effects are improved by infusion versus bolus administration . bennett et al.37 compared incremental bolus with continuous infusion of propofol for deep sedation during dentoalveolar surgery after induction with a bolus of midazolam / fentanyl , and found no significant differences in efficiency , safety , and recovery . however , in the continuous infusion group , a statistically higher maintenance dose of propofol ( 7.3 mg / kg / hr vs. 6.03 mg / kg / hr , p<0.05 ) was needed to maintain anesthesia.37 in a study by klein et al.,38 18 children who underwent 40 elective oncology procedures were randomly assigned to intermittent bolus administration or continuous propofol infusion . adequate sedation and examiner satisfaction were comparable between the two groups.38 riphaus et al.39 reported no difference in total propofol dose between the bolus group and the infusion group . arterial blood pressure < 90 mm hg was documented in two patients in the bolus group and 7 patients in the infusion group ( p=0.16).39 recovery time was significantly shorter in the bolus group compared with the infusion group ( 195 minutes vs. 236 minutes , p<0.001 ) whereas the quality of recovery was identical in the two groups.39 repeated bolus administration as well as continuous infusion of propofol allow nearly identical good controllability of endoscopic sedation and are associated with similar sedation efficacy and patient 's safety . however , the patient 's recovery time under continuous sedation is significantly slower and hypotension tends to occur more often . therefore , repeated bolus administrations of propofol might be more helpful at routine upper endoscopy . currently , both diagnostic and therapeutic endoscopy are well tolerated and accepted by both patients and endoscopists due to the implementation of sedation in most clinics worldwide . accordingly it is crucial for endoscopists to be very familiar with the use of propofol or a combination of drugs . however , the controversy regarding the administration of sedation by an endoscopist or an anesthesiologist continues . until now , there have been no randomized control trials comparing propofol - induced sedation administered by an endoscopist or by an anesthesiologist . currently , most of sedation drugs are administered during endoscopy by an endoscopist . however , a few death cases are reported every year in korea . edp is a trend that can not be gone against , but proper monitoring and familiarity with the adverse events are needed . for the convenience and safety of sedative endoscopy , it would be important that edp be generally applied to endoscopic procedures , and for more safety , an anesthesiologist may automatically take care of particular patients at high risk of suffering from propofol side effects .

concerns about the safety of endoscopist - directed propofol ( edp ) have been voiced that propofol should be given only by healthcare professionals trained in the administration of general anesthesia . here we discuss the safety and drawbacks of edp for routine endoscopic procedures . currently , both diagnostic and therapeutic endoscopy are well tolerated and accepted by both patients and endoscopists due to the application of sedation in most clinics worldwide . accordingly , propofol use is increasing in many countries . it is crucial for endoscopists to be very familiar with the use of propofol or a combination of drugs . however , the controversy regarding the administration of sedation by an endoscopist or an anesthesiologist continues . until now , there have been no randomized control trials comparing sedation induced by propofol administered by an endoscopist or by an anesthesiologist . it might be difficult to perform this kind of study . for the convenience and safety of sedative endoscopy , it would be important that edp be generally applied to endoscopic procedures , and for more safety , an anesthesiologist may automatically take care of particular patients at high risk of suffering from propofol side effects .

among patients who underwent tka because of primary knee osteoarthritis from october 2006 to october 2009 , we included only patients who had bmd measured with unilateral tka at preoperation , and one , three , six , and 12 months after the operation . tka was performed with patients who had a radiographic kellgren - lawrence grade iii8 ) or greater and wanted the operation due to severe knee pain . we excluded patients who had undergone a contralateral tka ( seven cases ) within one year after tka or who had any neurological issues ( cerebral infarction , 1 case ; parkinson disease , 3 cases ; peroneal nerve injury , 1 case ) or took medicine ( steroid , 32 cases ; osteoporosis drug , 41 cases ) . a total of 48 consecutive patients ( 11 males and 37 females ) were included in this study . the mean age of the patients was 63 years ( range , 53 to 76 years ) . the 40 cases of the nonoperative side were kellgren - lawrence grade ii or less . eight cases had kellgren lawrence grade iii or more , but did not receive tka . bmd of both hips was measured at baseline and at one , three , six , and 12 months follow - up . the femoral neck , trochanter , and total area of the hip were measured in the proximal femur . bmd was measured using dual energy x - ray absorptiometry ( dexa ; lunar ppx - l , medison , wi , usa ) . the in vivo coefficients of variation for bmd were 1.4% for the lumbar spine , 2.1% for the femoral neck , 2.1% for ward 's triangle , 1.1% for the greater trochanter , and 1.0% for the total proximal femur . we used a leg holding device provided by the manufacturer to gain high - quality anteroposterior scans of the hips . the least significant change ( lsc ) was calculated for each skeletal variable studied using the formula cv% 2 1.41 , which would represent a significant statistical difference at the 95% confidence level.9 ) spss ver . repeated measured analysis of variance ( anova ) was performed for testing changes of bmd at each measurement time on the operative side and nonoperative side . a paired t - test was performed for testing the difference in changes of bmd between the operative side and nonoperative side at each time point ( baseline , one , three , six , and 12 months ) . among patients who underwent tka because of primary knee osteoarthritis from october 2006 to october 2009 , we included only patients who had bmd measured with unilateral tka at preoperation , and one , three , six , and 12 months after the operation . tka was performed with patients who had a radiographic kellgren - lawrence grade iii8 ) or greater and wanted the operation due to severe knee pain . we excluded patients who had undergone a contralateral tka ( seven cases ) within one year after tka or who had any neurological issues ( cerebral infarction , 1 case ; parkinson disease , 3 cases ; peroneal nerve injury , 1 case ) or took medicine ( steroid , 32 cases ; osteoporosis drug , 41 cases ) . a total of 48 consecutive patients ( 11 males and 37 females ) were included in this study . the mean age of the patients was 63 years ( range , 53 to 76 years ) . the 40 cases of the nonoperative side were kellgren - lawrence grade ii or less . eight cases had kellgren lawrence grade iii or more , but did not receive tka . bmd of both hips was measured at baseline and at one , three , six , and 12 months follow - up . the femoral neck , trochanter , and total area of the hip were measured in the proximal femur . bmd was measured using dual energy x - ray absorptiometry ( dexa ; lunar ppx - l , medison , wi , usa ) . the in vivo coefficients of variation for bmd were 1.4% for the lumbar spine , 2.1% for the femoral neck , 2.1% for ward 's triangle , 1.1% for the greater trochanter , and 1.0% for the total proximal femur . we used a leg holding device provided by the manufacturer to gain high - quality anteroposterior scans of the hips . the least significant change ( lsc ) was calculated for each skeletal variable studied using the formula cv% 2 1.41 , which would represent a significant statistical difference at the 95% confidence level.9 ) spss ver . 18.0 ( spss inc . , chicago , il , usa ) was used for statistical analysis . repeated measured analysis of variance ( anova ) was performed for testing changes of bmd at each measurement time on the operative side and nonoperative side . a paired t - test was performed for testing the difference in changes of bmd between the operative side and nonoperative side at each time point ( baseline , one , three , six , and 12 months ) . in this study , the authors classified two categories from each subject , one was bone density of the proximal femur that underwent tka ( ipsilateral side ) , and the other was bone density of the proximal femur that did not undergo tka ( contralateral side ) . there were no statistically significant differences in mean baseline bmd of the femur neck , trochanter , or total area between the ipsilateral and the contralateral side . ( femur neck , p = 0.153 ; trochanter , p = 0.184 ; total area , p = 0.169 ) . on the ipsilateral side , bmd in the femur neck was measured as 0.672 0.075 g / cm after postoperative three months , and these values were significantly lower than baseline bmd . bmd in the trochanter was measured as 0.620 0.107 g / cm after postoperative one month and 0.624 0.093 g / cm after postoperative three months , and these values were significantly lower than baseline bmd . g / cm after postoperative three months , and these values were significantly lower than baseline bmd . on the contralateral side , bmd in the femur neck was measured as 0.683 0.058 g / cm after postoperative three months , and these values were significantly lower than baseline bmd . g / cm after postoperative three months , and these values were significantly lower than baseline bmd . g / cm , and these values were significantly lower than baseline bmd ( table 1 ) . however , when the lsc was not included in the calculation , only bmds in the femoral neck and total area after postoperative three months were significantly lower than baseline bmd . no statistical differences in changes of bmd were observed between the two groups at each measurement time ( table 2 ) . the changes ( % ) of bmd after postoperative one year are shown in table 3 . severe complications in elderly patients with a hip fracture included pneumonia , thromboembolism , and death . known risk factors for hip fracture include falls , proximal femoral geometry , vitamin d level , muscle strength , and bmd.10,11 ) among these , decrease in bmd is an important factor . melton et al.12 ) reported that the more bmd decreased , the greater the risk of femur neck fracture as the square of bmd change , and greater the risk of trochanteric fracture as the cube of bmd change . if a certain area of an object under loading shows a change in material property or mechanical property or microstructure , the transmission of stress is changed . changes of the knee , such as osteoarthritis or tka would have an effect on the mechanical properties of surrounding regions.13,14 ) many studies have reported that knee osteoarthritis influences bone strength of the proximal femur and patients with osteoarthritis usually have increased bmd in the femur neck.15 - 18 ) in our study , preoperatively , bmd of the hip on the operative side was lower than on the nonoperative side in accordance with the study reported by ishii et al.7 ) however , no statistical differences were observed . soininvaara et al.6 ) reported that preoperative bmd of the proximal femur on the operative side was significantly lower than that of the contralateral side in all region of interests . considering the results , degree of exercise restriction due to pain and limited range of motion of the joint , degree of osteoarthritis , pain scale before operation , dominant - leg , individual demands in daily life , and discordance between bmd of the left- and right - hip were considered compositively.19 - 22 ) also , according to the results of our analysis , the fact that 83% of the nonoperative side showed kellgren - lawrence stage ii or less ( 83% ) should be considered , and there was a limit to the application of the result to severe osteoarthritis of both knees . regarding discordance between bmd of the left- and right - hip , many studies have reported that the difference was not statistically significant , and bmd measurements of both hips were meaningless.22 ) however , some studies have reported that measurement of bmd of both hips has an effect on diagnosis according to who osteoporosis diagnostic criteria , asserting the need for measurement of bmd in both hips.22 ) however , in our study , we analyzed changes of bmd on each side and differences of the change in bmd between the operative side and nonoperative side . therefore , discordance between bmd of the left- and right - hip was not our concern . bmd in the femoral neck and total area showed a significant decrease after postoperative three months on both the nonoperative side and the operative side . however , bmd at twelve months after operation showed similar values compared to preoperative levels , but lower than baseline , and followed predicted rates of age related loss.17,21,23,24 ) we believe that an early decrease of bmd occurred with decreased activity and weight load due to postoperative pain , and less recovery of general condition and nutritional state before postoperative three months and recovery to baseline bmd after six months were due to their restoration . age - related loss of bmd after postoperative one year differs according to ethnic group . dennison et al.23 ) reported that women aged 60 - 75 years showed a bmd loss of 1.43% naturally . young et al.24 ) reported that changes of bmd in white people was 0.35%-0.96% in the femur neck , 0.32%-0.95% in total , and 0.36%-1.14% in the trochanter . in our study , for change in bmd after tka at postoperative one year , recovery of bmd after the operation at one year was not sufficient to reach a baseline state and followed age related loss . this differed from the report by ishii et al.,7 ) which indicated that early intervention by tka might also be protective against later hip fracture . we checked the difference in bmd of both hips in order to determine whether tka can affect proximal bmd differently between the operative side and nonoperative side . according to our results , there was no significant difference in change of bmd between the operative side and nonoperative side . we suggest that changes in general condition , nutritional state , and degree of weight bearing did not influence bmd of either hip differently . in addition , factors directly and indirectly related to tka , such as less recovery of range of motion and decrease of periprosthetic bmd , did not influence either hip differently . in considering these results , a decrease in postoperative bmd is not a direct cause of ipsilateral femoral neck stress fracture after tka.1 - 5 ) we deem there could be another cause , such as the occurrence of femoral neck microfracture intraoperatively because of hammering or forceful manipulation in osteoporotic patients . a constrained type design would be a cause that would demand increased range of motion and result in increased bending and shearing force on the hip joint . first , the number of patients was only 49 of 871 cases who underwent an operation during the research period . second , our study may include more ambulating patients and patients who showed good results , who visited the hospital regularly and accepted measurements of bmd five times for a set period . we suggest that further study is needed , with inclusion of a larger number of cases , and additional analysis together with bone quality , such as the microstructure . although tka has an effect on bmd in both the femur neck and trochanter after postoperative one month and three months , it does not affect the ipsilateral side and contralateral side differently . therefore , we thought that a temporary decrease in bmd after tka was not the direct cause of ipsilateral femoral stress fracture , but the indirect cause of ipsilateral femur neck stress fractures after tka . therefore , there is a need to conduct a variable study on the causes of ipsilateral femoral neck stress fracture after tka .

backgroundthis study investigated the effects of total knee arthroplasty ( tka ) on bone mineral density ( bmd ) of the proximal femur in patients who underwent the procedure.methodsforty-eight patients scheduled to undergo unilateral tka because of primary knee osteoarthritis were included in this study , which was conducted at a medical center between october 2006 and october 2009 . in these 48 patients , 96 hips were evaluated . measurement of bmd was performed preoperatively and one month , three months , six months , and one year after unilateral tka . repeated measured analysis of variance and paired t - tests for comparison of two repeated samples were used to compare differences between time points ( preoperation , one , three , six , and 12 months ) and between the operative and nonoperative sides.resultspreoperatively , bmd of the femoral neck , trochanter , and total hip on the operative side were lower than on the nonoperative side ; however , there was no statistical difference . bmd of both femoral neck areas was significantly lower than preoperative bmd at one month and three months after tka . bmd of both trochanter areas was significantly lower than preoperative bmd at one month and three months after tka . bmd of both total hips was significantly lower than preoperative bmd at three months after tka . however , no statistical differences of changes in bmd were observed between the operative and nonoperative sides at each measurement time.conclusionsaccording to our results , tka was found to affect both proximal femurs during the acute period . however , tka did not affect a change in bmd of the proximal femur during one year postoperative .

a rpbphp2 gene was kindly provided by eric giraud ( institute for research and development , france ) . ifp1.4 gene was de novo synthesized by genscript company , based on the available protein sequence . the dna sequence was optimized with proprietary optimumgene algorithm ( gensript ) , taking into account the codon usage bias ( human cells ) , gc content , cpg dinucleotides content , mrna secondary structure , and other parameters . the genes encoding a bacteriophytochrome rpbphp2 and an ifp1.4 protein were amplified using polymerase chain reaction ( pcr ) as the bglii - ecori or psti - hindiii fragments and inserted into the bglii - ecori sites of a pbad / his - b vector or the psti and hindiii sites of a pbad / his - c vector , respectively ( invitrogen ) . biliverdin synthesis in bacteria was facilitated by co - transformation with a ppl - bv plasmid , which was obtained after digestion with bamhi and subsequent ligation of the ppl - pcb plasmid . site specific mutagenesis was performed using a quickchange mutagensis kit ( stratagene ) . for simultaneous mutagenesis at several positions , including a site - specific saturated mutagenesis ( i.e. , all 20 amino acids were encoded using the mixture of primers ) , an overlap - extension method was applied . random mutagenesis was performed with a genemorph ii random mutagenesis kit ( stratagene ) , using conditions that resulted in the mutation frequency of up to 16 mutations per 1,000 base pairs . after the mutagenesis , a mixture of mutants was electroporated into the lmg194 host cells ( invitrogen ) containing the ppl - bv plasmid . lmg194 bacteria were grown overnight in lb medium with an addition of 2% glucose to repress synthesis of both proteins . next morning , the bacterial cells were centrifuged and re - suspended in rm medium with 0.002% arabinose , 0.001 mm iptg , 100 m 5-aminolevulinic acid ( ala ) , and 50 m fecl3 . the cells were then grown up to 24 hours either at 37c or 37c followed by 25c , depending on the experiment . for facs screening , protein mutants were expressed in bacteria at 37c followed by an overnight incubation at 25c . the next morning , bacteria were washed with phosphate buffered saline ( pbs ) and then diluted with pbs to an optical density of 0.02 at 600 nm . a moflo xdp cell sorter ( beckman coulter ) , equipped with the standard ar , kr , ar - kr mixed - gas lasers ( coherent ) and a 592 nm solid - state laser ( mpb communications ) , was used . typically , about 10 sizes of each library were facs - sorted , using a 676 nm kr laser line for excitation and a 700lp nm emission filter for positive selection . the brightest collected nir bacterial cells were rescued in a soc medium at 37c for one hour , and then plated on petri dishes made of rm / agar supplemented with ampicillin and kanamycin . the next day , the expression of proteins in bacterial colonies on the dishes were induced with 0.002% of arabinose and 0.001 mm of iptg . the dishes were left for 4 - 6 hours at 37c and then incubated at room temperature overnight . fluorescence of the colonies was analyzed the next day using a leica mz16f fluorescence stereomicroscope equipped with the 650/45 nm excitation and 690lp nm emission filters ( chroma ) , and a ccd camera . a mixture of several selected mutants was then utilized as a template for the next round of mutagenesis . rpbphp2 mutants and ifp1.4 protein with polyhistidine tags were expressed in lmg194 bacterial cells , as described above , and then purified using ni - nta agarose ( qiagen ) . the excitation and emission spectra were measured using a fluoromax-3 spectrofluorometer ( jobin yvon ) . for absorbance measurements , the first approach was based on a direct measurement of the protein concentrations with a bca protein essay kit ( pierce ) , followed by the calculation of extinction coefficients using a beer lambert bouguer equation . the second approach , which has been introduced in the original ifp1.4 paper , was based on a comparison of absorbance values for the protein at the main peak ( 692 nm or 694 nm ) with the absorbance value at the 391 nm peak assuming the latter to have the extinction coefficient of the free bv which is 39,900 mcm . for determination of quantum yield , fluorescence signal of irfp was compared to that of the equally absorbing ifp1.4 and nile blue dye ( quantum yield is 0.27 in an acidic ethanol ) . ph titrations were performed using a series of buffers ( 100 mm naoac , 300 mm nacl for ph 2.55.0 , and 100 mm nah2po4 , 300 mm nacl for ph 4.59.0 ) . to study protein maturation , lmg194 bacterial cells were grown at 37c overnight in a lb medium supplemented with ampicillin , kanamycin , and 2% of glucose . the next morning , the cells were centrifuged , resuspended , and cultured in rm medium with 0.002% arabinose , 0.001 mm iptg , 100 m ala , and 50 m fecl3 for 1 hour . then , the cells were washed and cultured in rm medium supplemented with 0.001 mm iptg , 100 m ala , and 50 m fecl3 ( no arabinose was added this time ) at 37c . fluorescence intensity of the cell suspension was measured every hour initially and after longer time periods later . a pshuttle - cmv vector ( stratagene ) was utilized to construct plasmids for mammalian expression of both irfp and ifp1.4 proteins . the fp genes were pcr - amplified and inserted into the bglii and sali sites of the vector , thus generating pshuttle - cmv - irfp and pshuttle - cmv - ifp1.4 plasmids . hek293 and hela cell lines were grown in dulbecco s modified eagle media ( dmem ) containing 10% fetal bovine serum ( fbs ) , penicillin - streptomycin , and 2 mm glutamine ( invitrogen ) . plasmid transfections were performed using an effectene reagent ( qiagen ) according to the manufacturer s protocol . for adenoviral infection , hela cells were grown in 60 mm petri dishes until ~80% confluence and then infected with 310 pfu per dish . for facs analysis of hela cells co - transfected with egfp and nir fps , 488 nm ar and 676 nm kr laser lines and the respective 530/40 nm and 700lp nm emission filters were used . to quantify cells fluorescence , a mean fluorescent intensity of the double - positive population in the nir channel was divided by a mean fluorescent intensity of the same population in the green channel , thus normalizing the nir signal to the transfection efficiency . cells were imaged using an olympus ix81 inverted epifluorescence microscope equipped with 200w metal halide arc lamp ( prior ) , a 100 1.4 na oil immersion objective lens ( uplansapo , olympus ) , and standard cy5.5 filter set ( 665/45 nm exciter and 725/50 nm emitter ) ( chroma ) . photobleaching measurements of cytoplasmically expressed nir fps in live hela cells were performed similarly to the purified proteins with the 100x objective substituted with a 60 1.35 na oil immersion objective lens ( uplansapo , olympus ) . normalization of the curves was made the same way as for the purified proteins . for protein degradation assay , hek293 cells transfected with nir fps were treated with 1 mm of puromycin 48 hours post - transfection . to achieve brighter fluorescence signal , cells were kept with 25 m of bv during the whole experimental course , starting 2 hours before the addition of the puromycin . to study bv binding and bv influence on protein stability , hela cells were harvested 2 days post adenoviral infection and lysed by 3 freezing - thawing cycles . the lysates were clarified by centrifugation , and the total fluorescence was measured using the fluoromax-3 spectrofluorometer ( jobin yvon ) . the adenovirus serotype v based particles containing the irfp or ifp1.4 genes were created using an adeasy xl adenoviral vector system ( stratagene ) according to the manufacture s recommendations and then purified using a cesium chloride gradient centrifugation , as described . the viral titers were assessed by an adeno - x rapid titer kit ( clontech ) . albino c57bl/6 mice ( female 6 - 8 weeks old , b6(cg)-tyr / j , jackson laboratory ) were intravenously injected with 210 infectious units of an adenovirus . belly fur was removed using a depilatory cream , and the mice imaging was performed with an ivis spectrum instrument ( caliper lifesciences ) in epifluorescence mode equipped with 675/30 nm and 720/20 nm filters for excitation and emission , respectively , starting the second day after an infection . 250 nmol of bv were iv injected on the day 5 post - infection , and the mice imaging started 1 hour later . quantitative measurements of fluorescence signal were made with a living image software 4.0 ( caliper lifesciences ) . for an ex vivo liver imaging , livers were dissected 1 hour after mice were injected with 250 nmol of bv . all animal experiments were performed in an aaalac approved facility using protocols approved by the albert einstein college of medicine animal usage committee . bacterial plasmids encoding several far - red gfp - like fps were kindly provided by benjamin glick ( university of chicago , usa ) and dmitry chudakov and konstantin lukyanov ( both from institute of bioorganic chemistry , russia ) . the recombinant gfp - like fps were expressed in the lmg194 bacterial cells and then purified using the ni - nta agarose ( qiagen ) . the purified fps were diluted to the equal concentrations of 16 m , calculated based on the extinction coefficients at the chromophore absorbance maxima . the 5 l volume of each fp was placed 15 mm deep inside into one of two available bores in a xfm-2 phantom mouse ( caliper lifesciences ) . the bores were located at 7.0 mm and 18.1 mm distance from the imaging surface . images were taken in 23 different combinations of the far - red and nir excitation and emission channels using an epifluorescence mode of the ivis spectrum instrument . a signal - to - background ratio was calculated for each wavelength combination for each fp , using the phantom mouse without protein sample inside as a background reference .

the ability of non - invasive monitoring of deep - tissue developmental , metabolic , and pathogenic processes will advance modern biotechnology . imaging of live mammals using fluorescent probes is more feasible within a near - infrared optical window ( nirw)1 . here we report a phytochrome - based near infra - red fluorescent protein ( irfp ) with the excitation / emission maxima at 690/713 nm . bright fluorescence in a living mouse proved irfp to be a superior probe for non - invasive imaging of internal mammalian tissues . its high intracellular stability , low cytotoxicity , and lack of the requirement to add external biliverdin - chromophore makes irfp as easy to use as conventional gfp - like proteins . compared to earlier phytochrome - derived fluorescent probes , the irfp protein has better in vitro characteristics and performs well in cells and in vivo , having greater effective brightness and photostability . compared to the far - red gfp - like proteins , irfp has substantially higher signal to background ratio in a mouse model owing to its infra - red shifted spectra .

early enteral feedings are known to improve outcomes in critically ill intensive care unit ( icu ) patients having difficulty with volitional intake . maintenance of gut integrity by enteral nutrition leads to less bacterial translocation and decreased systemic inflammatory response . thus , enteral feeding has become an important means of providing nutritional support to seriously ill patients . placement of the feeding tube through the pyloric ring and past the ligament of treitz into the proximal jejunum is critical to reduce the risk of gastroesophageal regurgitation and microaspiration , which may improve tolerance of enteral nutrition . conventionally , simple insertion of a feeding tube in the stomach was performed expecting spontaneous transpyrolic migration of the tube , associated with a low success rate of approximately 515% . fluoroscopic positioning has also been used for enteral feeding tube placement ; however , positioning frequently fails because of functional gastric outlet obstruction , gastric dysmotility , gastric distention , and distortion of the duodenal loop . although this fluoroscopy imaging procedure is universally performed , it requires transportation of severely ill patients to the radiology suite and nursing and respiratory support , possibly increasing risk of complications during transport . endoscopic placement of feeding tubes was successfully used after other methods , such as fluoroscopy , failed . more recently , a transnasal endoscopic method using a thin endoscope was developed , and reports demonstrate that the procedure duration is significantly shorter without radiation exposure and the need for transport to radiology . as previous reports have shown , an 8493% correct tube positioning rate can be achieved by transnasal endoscopy . in our department , we started utilizing transnasal endoscopy for intestinal feeding tube placement , placing enteral tubes for 40 patients between march 2008 and february 2009 . although we achieved a high success rate comparable to previous reports , we experienced several cases of failure , which was corrected with repeated endoscopy . based on these experiences , we modified our method by adding a double - check transnasal endoscopy through the other nasal passage , which we used on 14 patients from march 2009 to march 2010 . our novel double - check method enabled instant replacement in cases of incorrect positioning , avoided repeated abdominal plain x - ray , and allowed us to achieve a 100% success . in this report double - check transnasal endoscopic feeding tube placement , which we found to be a helpful adjunct , in icu patients . double - check method with a conventional method , in terms of time of procedure and successful rate ( no requirement of replacement 24 h later ) . forty eight consecutive critically ill icu patients at our hospital who were placed with bowel feeding tubes using nasal endoscopes between march 2009 and march 2010 were included in our review . six cases were excluded where time was spent investigating certain complications , such as suspected bleeding or difficulty of placement . all patients received adequate cardiopulmonary monitoring including the blood pressure , oxygen saturation , and pulse rate during endoscopic procedures . we performed the endoscopic feeding tube insertion only when the patients conditions met the following criteria ; systolic blood pressure < 150 mmhg and > 90 mmhg ; o2 saturation > 96% ; heart rate < 120 bpm and > 50 bpm . patients were divided into two groups : the cases in the initial period without re - endoscopy ( 28 cases ) and the latter cases with all endoscopies were performed at the bedside in the icu by one or two physicians . the tip of the endoscope ( xp260n , olympus corporation , tokyo , japan ; outer diameter 5.9 mm ) was passed under direct vision into one of the nasal foramen . after panendoscopic examination and cannulation of the duodenum , the tip of the endoscope was inserted into the descending part or horizontal part of duodenum , and the guidewire ( create medic , fs-20 t , 052-3500 t , tokyo , japan ) for ileus tube ( argyle , new enteral feeding tube ) was inserted through the endoscope channel as far as possible under direct observation . then , the endoscope was removed , leaving the guidewire ; the feeding tube was advanced along the guidewire , and the guidewire was then pulled out . for double - check re - endoscopy following placement of the feeding tube , the same endoscopy was inserted again through the other nasal foramen , and the correct tube position was verified by visualizing the tube passing the pyloric ring ( fig . 1 ) . 100 ml of contrast medium ( gatsrographin ) was injected into the tube immediately after placement and an abdominal x - ray was performed 24 h later to estimate the location of the tube tip and assess regurgitation of the contrast medium into the stomach and intestinal motility . successful placement of the nasoenteral feeding tube tip was defined as insertion into the second part of the deodenum or further down and passage of the contrast agents to the ileum , confirmed by plain abdominal x - ray 24 h later . forty eight consecutive critically ill icu patients at our hospital who were placed with bowel feeding tubes using nasal endoscopes between march 2009 and march 2010 were included in our review . six cases were excluded where time was spent investigating certain complications , such as suspected bleeding or difficulty of placement . all patients received adequate cardiopulmonary monitoring including the blood pressure , oxygen saturation , and pulse rate during endoscopic procedures . we performed the endoscopic feeding tube insertion only when the patients conditions met the following criteria ; systolic blood pressure < 150 mmhg and > 90 mmhg ; o2 saturation > 96% ; heart rate < 120 bpm and > 50 bpm . patients were divided into two groups : the cases in the initial period without re - endoscopy ( 28 cases ) and the latter cases with all endoscopies were performed at the bedside in the icu by one or two physicians . the tip of the endoscope ( xp260n , olympus corporation , tokyo , japan ; outer diameter 5.9 mm ) was passed under direct vision into one of the nasal foramen . after panendoscopic examination and cannulation of the duodenum , the tip of the endoscope was inserted into the descending part or horizontal part of duodenum , and the guidewire ( create medic , fs-20 t , 052-3500 t , tokyo , japan ) for ileus tube ( argyle , new enteral feeding tube ) was inserted through the endoscope channel as far as possible under direct observation . then , the endoscope was removed , leaving the guidewire ; the feeding tube was advanced along the guidewire , and the guidewire was then pulled out . for double - check re - endoscopy following placement of the feeding tube , the same endoscopy was inserted again through the other nasal foramen , and the correct tube position was verified by visualizing the tube passing the pyloric ring ( fig . 1 ) . 100 ml of contrast medium ( gatsrographin ) was injected into the tube immediately after placement and an abdominal x - ray was performed 24 h later to estimate the location of the tube tip and assess regurgitation of the contrast medium into the stomach and intestinal motility . successful placement of the nasoenteral feeding tube tip was defined as insertion into the second part of the deodenum or further down and passage of the contrast agents to the ileum , confirmed by plain abdominal x - ray 24 h later . no significant differences between any of the variables were seen . the success rate of the patient group without double - check was 82.1% ( 23/28 ) , with the tip of the catheter placed into the distal duodenum in 7 patients ( 25% ) and into the jejunum in 21 patients ( 28% ) . in 5 cases ( 14% ) , the tip of the feeding tube was misplaced in the stomach and bulbus of the duodenum . plain x - ray taken 24 h later revealed remaining contrast agents in the stomach . the mean procedure time required was 12.4 2.6 min ( ranging seven to 30 min ) . the second group of patients receiving the double - check technique consisted of 9 males and 5 females . successful placement of the feeding tube was achieved in 100% patients , as verified by plain abdominal x - ray examination 24 h later . in one case , double - check endoscopy revealed an incorrect position of the feeding tube , and replacement was undertaken immediately . the average procedure time ( including the first placement and replacement of endoscope ) was 13.1 2.3 min ( ranging 10 to 17 min ) . in all patients , contrast agents passed to the ileum 24 h later , as verified by portable plain x - ray ( fig . 2 ) . after april 2010 , we have placed the feeding tube by double - check method for all patients ( more than 40 patients ) who required transnasal endoscopic feeding tube placement . we have not experienced any misplacement in all these patients after 24 h later with 100% successful rate since the introduction of double - check procedure . this report demonstrates our experiences with transnasal enteral feeding tube placement and verification / correction using double - check endoscopy . transnasal endoscopic placement of feeding tubes has been applied widely and been found to be effective , as it can be performed at the bedside without the need to transport or reposition the patient . at this moment , we routinely perform no fluoroscopy is used to identify the exact position of the guidewire or feeding tubes . endoscopic placement of feeding tubes has the additional advantage of providing valuable information on the upper gastrointestinal tract , as icu patients frequently have upper gastrointestinal - tract pathology . also , endoscopic placement enables insertion of the tubes to the efferent loop after gastrectomy . however , we believe that availability of rapid tube reinsertion after inadvertent displacement or replacement can compensate for this delay . first reported that endoscope position control for enteral feeding tubes with transnasal re - endoscopy has the potential to substantially save costs . of note , the second removal of the endoscope must be conducted with maximal attention , as we experienced looping of the feeding tubes or misplacement in the stomach at the first insertion . recent advances in endoscopic technology have led to the production of very thin endoscopes with instrument channels , which enable exiting the intestinal tube through the instrument channel . these new endoscopes can potentially allow advancement of the guidewire and the nasoenteral feeding tube deeper into the duodenum and jejunum . contraindications ( exclusion criteria ) are severe coagulopathy , history of nasopharyngeal trauma or surgery , and the potential need for a therapeutic endoscopic procedure . reported complications of this new technique may be similar to those of conventional transnasal endoscopic feeding , including nasopharyngeal erosion , aspiration , diarrhea , metabolic derangement , and epistaxis . we acknowledge that our study has been too small and underpowered to conclude that the novel however , as far as our experience was concerned , both procedures were associated with minimal complications and stable vital signs , although the background disease of the patients varied in this study . in conclusion , our double - check method has major advantages over and is more secure and reliable than the current method of endoscopic placement .

enteral feeding has become an important means of providing nutritional support to seriously ill patients . placement of the feeding tube through the pyloric ring and past the ligament of treitz into the proximal jejunum is critical to reduce the risk of gastroesophageal regurgitation and microaspiration . we started utilizing transnasal endoscopy for intestinal feeding tube placement , placing enteral tubes for 40 patients between march 2008 and february 2009 . although we achieved a high success rate comparable to previous reports , we experienced several cases of failure , which was corrected with repeated endoscopy . based on these experiences , we modified our method by adding a double - check transnasal endoscopy through the other nasal passage . after april 2010 , we have placed the feeding tube by double - check method for all patients ( more than 40 patients ) who required transnasal endoscopic feeding tube placement . we have not experienced any misplacement in all these patients after 24 h later with 100% successful rate since the introduction of double - check procedure . we describe our experience with double - check transnasal endoscopic feeding tube placement , which we found to be a helpful adjunct , for patients in intensive care unit .

the frequency of preterm delivery contributes a relatively small proportion of total births ( 511% ) [ 1 , 2 ] , while it is associated with excess of 70% of the total perinatal mortality in developed countries , when excluding deaths related to congenital anomalies [ 3 , 4 ] . moreover , preterm delivery prevention is well recognized as a major strategy for immediate and long - term costs reduction after discharge from the hospital and childhood morbidity [ 57 ] . because of multifactorial ( social , behavioral , and biological ) causes in preterm delivery , efforts in prevention measures have not been successful so far . furthermore , occurrence of spontaneous preterm birth increases 1222% in recent reports [ 9 , 10 ] . therefore , various tocolytic agents have been used to postpone preterm uterine contractions for at least 48 hours which allow maximal effect of antenatal steroid administration to assist in fetal lung maturation and maternal transportation to a center with neonatal intensive care unit ( nicu ) . from early 1960s , progesterone as a tocolytic agent was used for the preventing of preterm birth ; however , relationship between progesterone withdrawal and the onset of labor is a considerable debate [ 13 , 14 ] . progesterone can affect preterm labor reducing contractility and inflammatory processes [ 1519 ] . although previous studies reported that serum level of progesterone following its vaginal administration is lower comparing to intramuscular administration , optimal route of progesterone administration in women undergone preterm labour is yet being considered . moreover , there are controversial documents about the benefit of vaginal progesterone on spontaneous preterm birth . we designed randomized clinical trial study for clarification of the effect of vaginal progesterone on spontaneous preterm birth . after approving trial protocol of study in ethics and research , committee of beheshti university of medical sciences and registration of clinical trial in iranian registry of clinical trial ( irct : code no . 7291 ) , composed of specialized antenatal clinics caring for preterm labour , women were enrolled in the study for a period of 3 years from 2007 to 2010 . an rct study was carried out during a 3-year period , from march 2007 through march 2010 on all singleton pregnancies at 24 and < 34 weeks complicated with preterm labor attending labor ward in mahdieh tertiary care hospital affiliated to shahid beheshti university of medical sciences in tehran , iran . the aim was to assess the efficacy of maintenance vaginal suppository of cyclogest therapy in patients with cervical length less than 15 mm by vaginal ultrasound that acute preterm labor was successfully controlled by intravenous magnesium sulfate . the criteria used for the diagnosis of acute preterm labor included persistent uterine contractions ( e.g. , at least four every 20 minutes or eight every 60 minutes ) , cervical dilation of 1 to 3 cm , effacement exceeding 50 percent , a change in cervical dilation , or effacement detected by serial examinations [ 21 , 22 ] . gestational age was assigned based on the last menstrual period ( lmp ) if it was confirmed by ultrasound or ultrasound alone when lmp was unknown . intrauterine growth restriction ( iugr ) was defined as birth weight less than the fifth percentile . exclusion criteria were preterm premature rupture of membranes , premature termination for obstetric indications and fetal anomaly , vaginal bleeding , polyhydramnios , fetal anomalies , suspected chorioamnionitis or intrauterine growth retardation ( iugr ) , and concomitant cardiovascular disease of woman ( e.g. , preeclampsia , gestational or chronic hypertension ) . all these patients after admission to the labor ward initially received intravenous magnesium sulfate , a 6 gr loading dose followed by maintenance dose of 2 gr / hour , to stop uterine contractions . all patients were given betamethasone ( 12 mg ) and repeated after 24 hours and intravenous ampicillin ( 2 gr ) every 6 hour until the results of group b streptococci vaginal cultures were received . the patients were weaned from intravenous magnesium sulfate after uterine contractions were stopped for 24 hours . the patients were assigned for maintenance vaginal suppository of cyclogest 400 mg every night or without using any drug randomly which was continued until labour or 37 weeks of gestation . permuted blocks were scheduled to be given a participant number randomly corresponding to a specific treatment ( either active or no drug packs ) . during treatment procedure , all study personnel and participants were blinded except statistician who did not have any contact with study participants . weekly vaginal sonography to assessment of cervical length was performed for all patients . until time of delivery , women were followed up for primary outcomes which were recorded such as duration of pregnancy , gestational age of delivery , type of delivery , duration of stay in hospital , and intrauterine fetal death . moreover , neonatal death , neonatal unit admission , and duration of neonatal unit care were compared between two groups . statistical analysis on collected data wilcoxon signed paired test was used for before - after analysis of these dependent samples , and differences were considered statistically significant when the p value was < 0.05 . student t - test and occasionally the mann - whitney test were used for comparison of continuous variables . linear regression was recruited if the association of two continuous variables was analyzed . calculation of p < 0.05 and odds ratios ( ors ) with 95% confidence intervals ( cis ) were estimated as a significant difference . because of withdrawal of consent or being not traceable after moving out of study area , 38 women were lost to followup in both groups . therefore , primary outcome of 72 patients and controls was available for analysis . there was no significant difference in demographics and clinical characteristics of the groups ( table 1 ) . mean gestational age at the time of delivery ( 36.2 1.4 versus 34.1 1.5 ; p value = 0.039 ) and mean time of postponing delivery ( 4.0 1.5 versus 1.4 0.2 ; p value = 0.048 ) were significantly higher in patients who used vaginal progesterone ( table 2 ) . however , the mean of cervical length and dilatation were not changed comparing groups after treatment . necessity to cesarean section was more probable in control group ( 19 patients ; 26.5% ) rather than cases ( 16 patients ; 22.2% ) , but this difference was not meaningful . there was no record for adverse events which need medical care comparing two groups . neonatal mean weight was 2950.6 420.3 in progesterone group and 2628.0 385.1 in no - drug group ( p value < 0.001 ) . only eight babies fulfilled criteria of low birth weight , in contrast to 26 born in no - drug group ( p < 0.001 ) . the number of neonates admitted in nicu had significant difference between groups ( 8.3% versus 23.6% ; p value < 0.001 ) . however , the p value for the formal test of correlation between the type of treatment and neonatal death was not significant ( p = 0.082 ) . preterm birth remains a significant cause of early neonatal mortality and specific morbidity associated with prematurity [ 17 , 24 ] . based on this study finding , vaginal progesterone may increase the demur time of delivery if such efficacy confirmed by further investigation vaginal progesterone can eliminate risk of hospitalization in the first year of life , learning difficulties [ 25 , 26 ] , behavioral problems [ 27 , 28 ] , and burden of economic consequences [ 5 , 29 ] . there is this hypothesis , suppression of uterine contractile activity [ 15 , 16 , 30 ] through inhibition of the calcium - calmodulin - myosin light chain kinase system [ 16 , 30 , 31 ] is the main role of progesterone in continuation of pregnancy [ 3133 ] . moreover , negative effect of progesterone on prostaglandin production and interaction at the fetoplacental unit may be a probable mechanism for clogging preterm birth [ 15 , 18 , 19 ] . although the results of this study were the result of 400 mg vaginal progesterone gel use , with ethical limitation moreover , the route of progesterone administration may affect pharmacokinetics and peak blood concentrations time ( 3 to 8 hours for 100 mg vaginal progesterone ) . the potential lack of delayed local absorption and marginal blood peak level can be proved by high - concentration use of vaginal gel . however , there were similar effects of both intramuscular and vaginal progesterone in several systematic reviews of randomized controlled trials . similarly to date , the optimal dose of vaginal preparations ( ranging from 90 to 400 mg daily ) [ 20 , 34 ] and optimal time to commence therapy ( 24 to 28 weeks of gestation ) [ 20 , 35 , 36 ] vary considerably across studies . obviously , selection of proper dosage and timing for this study was resultant of all previous lucrative studies . there is more limited information available relating to definitive health outcomes of vaginal progesterone in women presenting with symptoms or signs of threatened preterm labour ; therefore , an ongoing trial ( by matrinez et al . ) assessing this role will contribute information in the future as well as our studied parameters . although we observed significant advantages of vaginal progesterone for the remainder of pregnancy on gestational age at the time of delivery and time of postponing delivery of women with spontaneous preterm labour , this finding may not be repeated in women with other risk factors like short cervix , past history of spontaneous preterm birth , and multiple pregnancies [ 3739 ] . during followups , there was no report received from women complaining from sideeffects of vaginal progesterone ( headache , nausea , breast tenderness , and coughing ) in consistence with previous 2-year followup report of northen et al . ; but long - term side effects on mothers and infants should be considered in further investigations [ 42 , 43 ] . based on this randomized clinical trials finding , application of vaginal progesterone has advantages in both maternal and neonatal indexes , while the exact mechanism remains unclear .

vaginal progesterone has a potential beneficial effect in postponing of preterm labor by suppression of prostaglandins cascades . although different studies evaluated the use of progesterone for preterm birth , the exact effect of which on prolongation of pregnancy remains unclear . seventy two women who underwent preterm labor were managed by magnesium sulfate . then they were randomly assigned to continue pregnancy either by applying vaginal progesterone ( 400 mg ) until delivery or without using any drug . gestational age mean at the time of delivery ( p = 0.039 ) and postponing delivery mean time ( p = 0.048 ) were significantly higher in progesterone group . comparison of neonatal outcomes between two groups of patients showed meaningful benefits of progesterone in increasing of neonatal weight , reduction of low birth weight babies , and lowing neonate admitted in nicu .

we report a case of a 31-year - old female presenting with bilateral painful parotitis , a lump in the right groin , and prolonged pyrexia who was diagnosed with kikuchi - fujimoto disease ( kfd ) on lymph node biopsy . very few cases of kfd presenting with bilateral painful parotid swelling and inguinal lymphadenopathy have been reported in the literature . our case illustrates the importance of diagnosing kikuchi 's disease in a patient presenting with bilateral parotitis and pyrexia of unknown origin ( puo ) , which is an unusual presentation of the disease . a 31-year - old female with a history of travel to malaysia 6 weeks prior presented with a 3-week history of high - grade fever with chills . she had a history of watery , nonbloody diarrhea 3 days prior and occasional cough . she denied any history of breathlessness , chest pain , diabetes mellitus , or hypertension . on examination , the patient had prominent bilateral parotid swelling measuring roughly 5 by 4 cm which was soft , tender and nonfluctuating [ figure 1 ] , and mild right inguinal lymphadenopathy . viral markers and multiple blood cultures were negative . in view of clinical features of persistent fever with leukopenia , serological tests for cytomegalovirus igm antibody and epstein barr virus igm were done , which were also negative . routine investigations for pyrexia of unknown origin on admission the patient was started on injection amoxicillin - clavulanate ( dose 1.2 g twice a day ) and symptomatic treatment . a computerized tomogram ( ct ) scan ( chest and abdomen ) showed multiple mildly enlarged nonenhancing , nonnecrotic discrete lymph nodes in the sub - mental and bilateral deep cervical regions and upper abdominal lymphadenopathy , suggestive of a granulomatous etiology . a biopsy of the cervical lymph node showed brownish fragment of 2 cm on gross examination and histiocytic necrotizing lymphadenitis with no evidence of acid - fast bacillus or malignancy on microscopy . tuberculosis ( tb ) mycobacterial growth indicator tube and gene expert mycobacterium tuberculosis rif done from the lymph node were negative . kfd or histiocytic necrotizing lymphadenitis was first described by kikuchi and fujimoto in japan in 1972 . women are affected more often than men , with a ratio of 3:1 . the most common clinical manifestation is cervical lymphadenopathy ( 80% ) . lymph nodes are usually described as mildly tender , firm , and 23 cm in diameter . less common symptoms include headache , malaise , weight loss , arthralgias , and night sweats . parotidomegaly , as seen in our patient , may be present , but is uncommon . our case was unusual as our patient presented primarily with bilateral massive parotid enlargement and right inguinal lymphadenopathy on a background of puo . very few cases have reported the presentation of kfd with parotid involvement and inguinal lymph node involvement . kfd can masquerade as a single , rapidly - growing , parotid tumor in a middle - aged male . it has presented as puo in a 9-year - old boy as well as a 72-year - old male . in a series of 21 patients of kfd evaluated by positron emission tomography - ct , most commonly involved lymph nodes were cervical followed by axillary whereas inguinal nodes were least commonly involved . the differential diagnosis of bilateral parotid enlargement includes infectious parotitis , chronic autoimmune parotitis ( mikulicz disease , sjogren syndrome , and lymphoepithelial lesion of godwin ) , and idiopathic causes ( such as sarcoidosis and chronic nonspecific parotitis ) . sjgren syndrome presents as recurrent or chronic swelling of one or both parotid glands with no apparent cause , frequently associated with other autoimmune diseases . a close mimic of kfd is tb . in any patient from a tb endemic area such as india , presenting with classical clinical features of fever , weight loss , and lymphadenopathy , one should wait for a 6-week culture before making a diagnosis . kfd is a rare self - limiting cervical lymphadenitis , often a diagnosis of exclusion . supportive measures , including nonsteroidal anti - inflammatory drugs ( nsaids ) and antipyretics , can be used for symptomatic relief . the course of the illness is usually 13 months , but longer follow - up may be appropriate as a 4% relapse rate has been reported . monitoring for the development of systemic lupus erythematosus ( sle ) these , however , were the results of single case reports with no follow - up studies . recognizing the significant limitations of the data , antibiotics or antivirals are not recommended . there is a single case report describing intravenous immunoglobulin treatment ( 0.4 g / kg per day for 3 days ) in a patient with severe disease . our patient was given oral steroids ( oral prednisolone 10 mg thrice a day for 7 days followed by a taper over next 2 weeks ) in view of persistent malaise and low - grade fever despite being on nsaids . her fever and malaise improved within 72 h. over a course of 4 weeks , her parotid enlargement decreased and leucopenia normalized . at 6 months ' follow - up , she is stable without any signs of relapse or progression to sle . kfd is an under - diagnosed , yet important cause of fever and lymphadenopathy in the young population . biopsy is recommended to establish a definitive diagnosis and also to rule out other more sinister causes such as malignancy , lymphoma , and tb .

kikuchi - fujimoto disease ( kfd ) is an under - recognized disease most commonly presenting with cervical lymphadenopathy , fever , and cytopenias in young females . bilateral parotid enlargement is usually caused by infections ( e.g. , mumps ) and autoimmune conditions ( e.g. , sjogren syndrome ) . parotid enlargement , inguinal lymphadenopathy , and pyrexia of unknown origin are uncommon presenting features of kfd and should be suspected in the appropriate setting .

granulomas are focal accumulations of epithelioid cells , typically with a rim of lymphocytes and fibroblasts , representing a delayed - type hypersensitivity reaction in response to antigenic stimulation . this stimulation is usually triggered by exposure to antigen that can not be degraded or in cases of immune dysfunction . liver granulomas have been reported in 215% of unselected liver biopsies , with the etiology varying according to geography . in the us , 75% of cases are result in sarcoidosis , mycobacterial infection , primary biliary cirrhosis and drug - induced liver injury . in other countries , such as iran , mycobacterium tuberculosis and visceral leishmaniosis account for 60% . studies have shown that 615% of granuloma findings are idiopathic [ 1 , 2 ] . few histological features associated with certain diseases include caseous necrosis in acid fast bacilli containing granulomas , or ova in schistosoma mansoni . a 38-year - old male sudanese immigrant pronounced brain dead after a motor vehicle accident became an organ donor for liver and kidneys . his serology came back positive for hepatitis b core antibody and surface antibody , hbsag negative , hepatitis c and hiv negative . gross appearance of donor liver gave suspicion of granulomas based on surface heterogeneity ( fig . his liver biopsy at the donor hospital was consistent with < 5% macro and micro steatosis , no fibrosis but significant for the presence of having multiple granulomas ( fig . the initial slide review by the pathologist found multiple granuloma , and requested re - biopsy from the donor liver . the re - biopsy result found parasitic disease in the hepatocyte that later found to be schistosomiasis ( fig . lack of data regarding the behavior of this disease in the recipient , the biopsy result caused us to decline the liver due to the parasitic liver disease . schistosomiasis is a chronic enteral parasitic disease caused by trematode worms of the genus schistosoma . it is estimated that over 258 million people are affected yearly , with most of its disease burden in africa , south america , the caribbean , the middle east and asia . at the present time , due to increased global mobility , schistosoma may be encountered in non - endemic areas . over 90% of the cases of schistosomiasis are currently found in sub - saharan africa , where more than 200 000 deaths occur yearly due to the disease . schistosomiasis is the most prevalent parasitic disease in sudan due to the wide river basin areas and large irrigated agriculture along the nile rivers . once infection occurs , the adult worms reside in veins releasing eggs that are either shed into the environment through feces or urine , or are retained in host tissues where they induce inflammation and then die . when schistosoma eggs are trapped in tissues , they activate an immunologic reaction leading to the development of granuloma and fibrosis . hepatic schistosomiasis leading to severe fibrosis is a well - recognized cause of chronic liver disease and portal hypertension . it results from the host s granulomatous cell - mediated immune response to the ova antigen and progressing to irreversible fibrosis . multiple factors influence the development and pathology of schistosomiasis including the type of immune response developed by the host , host genetic background , intensity and number of infections . most schistosomiasis is caused by schistosoma hematobium , s. mansoni and s. japonicum ; however , s. mansoni and s. japonicum tend to cause hepatobiliary disease , while s. hematobium mainly affects the urinary tract . due to the life cycle of schistosoma , the acute phase of infection is usually asymptomatic , the only chronic sequelae identified via tissue biopsy is necrotic eggs with granuloma formation . strategies such as living donation , split liver transplantation , domino liver transplantation and the extensive use of marginal donor grafts have been implemented in many countries . as a result of this , there are an increasing number of unusual diseases from asymptomatic donors , including schistosomiasis . reports have shown schistosomiasis transmission through liver grafts from deceased donors with no consequences for graft or recipient survival . a retrospective study in brazil highlights cases of living donor liver transplantation ( ldlt ) with schistosomiasis diagnosed on post - reperfusion liver biopsy showing granulomatous reaction with s. mansoni eggs in transplant recipients . also describe the first intentional transplant with schistosomiasis , where known schistosoma eggs in feces were found in a donor . after treatment with praziquantel , ldlt with a graft was performed with no donor or recipient complications after 2 years post - operatively . chronic changes caused by schistosomiasis , leading to granuloma formation to a parasite s egg , might be only a sign of a distant infection . donor organs from endemic areas who have negative fecal examinations and normal liver function tests may be considered for partial liver donation . while organ shortages remains a major limitation to liver transplantation , expansion of the donor pool criteria to include patients presented in this case report might allow expansion and allocation of donor livers .

abstracta shortage of donor organs is a major limitation to liver transplantation . expansion of donor pool criteria to include patients with schistosomiasis diagnosed on liver biopsy might allow the allocation of more transplant livers . schistosomiasis is a chronic parasitic disease affecting millions in endemic areas including sub - sahara africa that might lead to the development of granulomas as a response to the parasite s ova and might cause chronic liver disease and portal hypertension . due to increased mobility globally , schistosomiasis may be encountered in non - endemic areas . currently , the usage of donor livers with known schistosomiasis is not universally defined .

the first step in development of the model was validation of peer - reviewed literature . scientific knowledge of the monoamines ( serotonin , dopamine , norepinephrine , and epinephrine ) has grown significantly since 1990 . along with this growth in knowledge , in contrast to earlier writings it is now known that monoamines do not cross the blood - brain barrier . urinary monoamine levels are not a direct assay of the peripheral or central nervous system monoamine levels . interpretation of urinary monoamine assays is more complex than simply determining if urinary serotonin and dopamine levels found on assay are high or low . under normal conditions , significant amounts of serotonin and dopamine filtered at the glomerulous do not make it to the final urine . serotonin and dopamine ( herein referred to as monoamines ) found in the final urine are newly synthesized in the kidneys.1,2 the monoamines and their amino acid precursors are filtered at the glomerulous then enter the proximal tubules of the kidneys . they are transported by organic cation transporters out of the proximal tubules into the proximal convoluted renal tubule cells . the monoamines filtered at the glomerulous are metabolized in the proximal convoluted renal tubule cells . very little of these monoamines filtered at the glomerulous are found in the final urine of normal subjects . monoamine amino acid precursors filtered at the glomerulous are synthesized in the proximal convoluted renal tubule cells into new monoamines , which are then detected in the final urine.2 serotonin and dopamine exist in two states : the endogenous state found when no additional amino acid precursors are being administered , and the competitive inhibition state found when the amino acid precursors of both serotonin and dopamine are being administered.3 prior to discussing the dual - gate lumen model , the following discussion of the three - phase urinary response is put forth based on previous peer reviewed literature.2 literature notes : urinary monoamine neurotransmitter testing prior to initiation of serotonin and dopamine amino acid precursors is of no value . there is no correlation between baseline testing and urinary neurotransmitter phases once the patient is taking amino acid precursors . it is not necessary or even useful to measure baseline urinary neurotransmitters in treatment.2,4 urinary monoamine neurotransmitters are neurotransmitters that are synthesized by the kidneys and excreted into the urine or secreted into the system via the renal veins.1,2,5 with simultaneous administration of serotonin and dopamine amino acid precursors , three phases of urinary neurotransmitter response have been identified on laboratory assay of the urine ( figures 1 and 2 ) . the three phases of response apply to both serotonin and dopamine . in all the life forms tested that have kidneys along with serotonin and catecholamine systems , , it would appear that the three phases of urinary response to neurotransmitters were present in previous writings but were not identified as such . for example , a 1999 article notes that administration of l - dopa can increase urinary dopamine levels ( phase 3 ) and decrease urinary serotonin levels ( phase 1).2,6 to determine the phase of serotonin and dopamine with certainty requires two urinary monoamine neurotransmitter assays to be performed with the subject simultaneously taking a different amino acid dosing of dopamine and/or serotonin amino acid precursors on each test and comparing the results.1,2 in phase 1 , monoamine neurotransmitters synthesized by the kidneys are excreted into the urine instead of being secreted into the system via the renal vein where they are needed ( figures 1 and 2 ) . increasing the amino acid dose in phase 1 will correct the problem of urinary monoamine excretion into the urine at the expense of secretion into the system . the amino acid precursor dosing of serotonin and dopamine , where the individual patient is in phase 1 varies widely in the population . the level at which the urinary serotonin is no longer in phase 1 ranges from 37.5 mg of 5-htp per day to 3,000 mg of 5-htp per day . the level at which the urinary dopamine is no longer in phase 1 ranges from no l - dopa ( with the use of l - tyrosine only in some subjects ) to 540 mg of l - dopa per day in the subjects not under treatment for parkinsonism or restless leg syndrome.1,2 by increasing the amino acid dosing of serotonin and dopamine precursors above the dosing of phase 1 , the phase 2 response is observed ( figures 1 and 2 ) . in phase 2 , urinary monoamine levels are low ( < 475 micrograms dopamine per gram of creatinine or < 80 micrograms serotonin per gram of creatinine , the neurotransmitter creatinine ratio compensates for dilution of the urine ) , and the inappropriate excretion of neurotransmitters into the urine has ceased . when in phase 2 , serotonin and/or dopamine is being primarily secreted into the system and not excreted into the urine . the model used to explain phase 2 is , inappropriate excretion of neurotransmitters has now ceased as the amino acid precursor dosing is increased and systemic levels are not increasing appropriately.1,2 as serotonin and dopamine amino acid precursors are increased above the phase 1 and the phase 2 levels , all subjects enter the phase 3 response ( figures 1 and 2 ) . further increases in the amino acid dosing lead to increases in urinary dopamine and serotonin neurotransmitter levels if they are in phase 3 . phase 3 represents appropriate secretion into the system and appropriate excretion of excess neurotransmitters synthesized by the kidneys into the urine.1,2 prior to this writing there has been no peer - reviewed publication setting forth an internal renal model to explain the etiology of the three - phase response of urinary serotonin and dopamine . this model is based on analysis of in excess of 75,000 monoamine assays ( serotonin , dopamine , norepinephrine , and epinephrine ) from more than 7,500 human subjects with samples obtained either in the endogenous state or the competitive inhibition state under conditions covered in previous writings on the three - phase response.1,2 the urinary phase of serotonin and dopamine was determined for assay samples obtained in the competitive inhibition state . knowledge gained through large - scale phase interpretation in correlation with peer - reviewed renal literature is the basis for the model . urine samples were collected 6 hours prior to bedtime with 4:00 pm being the most frequent collection time point . the urine samples were collected after a minimum of one week at a specific dose of the precursor being consumed . samples were shipped to dbs laboratories ( duluth , mn , usa ) under the direction of one of the authors ( dr t uncini , hospital - based dual board certified laboratory pathologist ) . urinary dopamine and serotonin were assayed utilizing commercially available radioimmunoassay kits ( 3 cat ria ib88501 and ib89527 , both from immuno biological laboratories , inc . , the dbs laboratory is accredited as a high complexity laboratory by clia to perform these assays . when in the three - phase response , the two systems become completely intertwined to the point that changes in one system will affect not just that system but the other system as well.2 with administration of the dopamine precursor l - dopa and the serotonin precursor 5-htp there is no biochemical feedback regulation in the synthesis of dopamine and/or serotonin , respectively . there is a direct proportion between the amount of l - dopa and 5-htp administered and the amount of dopamine and serotonin synthesized.1,2 the three - phase response occurs only in the competitive inhibition state . it is the response of the newly synthesized renal serotonin and dopamine found in the urine to the manipulation of serotonin and/or dopamine amino acid precursor dosing . with each simultaneous urinary assay of serotonin and dopamine in the competitive inhibition state , a three - phase model for serotonin and dopamine serotonin and dopamine may be in any one of the three phases simultaneously , with one exception . urinary serotonin and dopamine are never found in phase 1 simultaneously.1,2 in figure 1 , increasing or decreasing one or both amino acid precursors of serotonin or dopamine in the competitive inhibition state allows for determination of the urinary phase of both serotonin and dopamine.1,2 the following renal model is the basis for conceptualization of the dual - gate lumen model . while numerous transport and cell wall crossing mechanisms exit in the proximal convoluted renal tubule cells , primary transport out of the proximal convoluted renal tubule cells for the newly synthesized serotonin and dopamine is via the organic cation transporters ( oct ) . newly synthesized serotonin and dopamine exit the proximal convoluted renal tubule cells primarily by one of two routes . they are either transported across the basolateral membrane via the basolateral transporter ( an oct transporter ) or transported across the apical membrane via the apical transporter ( an oct transporter).7,8 for the purpose of this model , the basolateral membrane transporter ( oct ) is deemed as being dominant . newly synthesized serotonin and dopamine , not transported across the dominant basolateral membrane , are transported out of the proximal convoluted renal tubule cells by the apical transporters and detected in the final urine as waste . in reviewing urinary assays of serotonin and dopamine in the competitive inhibition state , the interpreter is viewing monoamines not transported by the basolateral monoamine transporters ( organic cation transporters ) . while numerous other renal functions and interactions have been described , these forces are viewed as minor to insignificant in comparison to the dominating force of the basolateral and apical transport on the newly synthesized monoamines . models of organic cation transporters of serotonin and dopamine have been defined in the past . one such model was the gate - lumen - gate model.913 the gate - lumen - gate model and other models do not explain the phenomenon observed under the three - phase urinary response when both serotonin and dopamine are in the competitive inhibition state . it is purposed that the basolateral monoamine transporter is a dual - gate lumen transporter ( figure 3 ) . the transporter has a serotonin gate and a dopamine gate at the transporter entrance , which function independently of each other . primary forces affecting transport through the basolateral monoamine transporter and the apical monoamine transporter are the status of the basolateral monoamine transporter serotonin and dopamine gates , and lumen saturation . the serotonin and dopamine gates at the entrance of the basolateral monoamine transporters can be either partially closed ( impeding transporter lumen access by the monoamines ) or open ( with no impedance ) . correlations of the three - phase model and dual - gate lumen model considerations are as follows . in phase 1 the monoamine gate is partially closed impeding access to the transporter lumen . in phase 2 and phase 3 the monoamine gate is open giving full access of the monoamine to the transporter lumen . in phase 1 and phase 2 basolateral monoamine transport through the lumen opening and closing of a gate is not solely dependent on changes in associated monoamine levels . the opening and closing of the gates is dependent on the total amount of serotonin and dopamine presenting at the transporter . in the competitive inhibition state , a serotonin gate or a dopamine gate in phase 1 ( partially closed ) can be opened or closed by adding or subtracting the total amount of amino acid precursors administered . this causes an increase or decrease in the total amount of serotonin and dopamine presenting at the transporter . as the gate opens , more monoamine has access to the transporter and is transported , causing a drop in the amount of monoamine transported by the apical transporter and found in the final urine . in phase 2 the transporter effectively transports most of the monoamine through the lumen leading to a very small amount of monoamine being transported by the apical transporter and found in the final urine . in phase 3 the gate is open and the transporter is saturated . increases or decreases in the total amount of the monoamine presenting at the transporter will lead to an increase or decrease in the amount of monoamine found in the final urine . when both serotonin and dopamine are in phase 3 , increasing the amino acid precursor dosing of one monoamine will cause increased transport of the associated monoamine at both the basolateral and apical transporters . due to competitive inhibition , transport of the other monoamine will decrease at the basolateral transporter and increase at the apical transporter . administration of one amino acid precursor with both serotonin and dopamine in phase 3 leads to an increase in apical transport of both monoamines with associated increase of urinary levels of both on assay . assay of the urinary monoamines , serotonin and dopamine , in the competitive inhibition state is an assay of the newly synthesized serotonin and dopamine of the kidneys not transported by the basolateral monoamine transport . the two primary forces affecting transport across the basolateral membrane and responsible for the three - phase response are the status of the basolateral monoamine transporter gates and the saturation of the lumen . proper assay interpretation in the competitive inhibition state is a determination of the states of serotonin and dopamine phases relative to the basolateral monoamine transporter status . it is not the intent of this writing to explore all known aspects of the basolateral monoamine transporter , apical monoamine transporter properties , or renal properties in the context of the three - phase response . the model presented here is intended to be used as a foundation and reference point for continuing discussion , further studies , refinement of the model , and future investigation of renal and urinary serotonin and dopamine response to amino acid manipulation in the competitive inhibition state .

the three - phase response of urinary serotonin and dopamine in subjects simultaneously taking amino acid precursors of serotonin and dopamine has been defined.1,2 no model exists regarding the renal etiology of the three - phase response . this writing outlines a model explaining the origin of the three - phase response of urinary serotonin and dopamine . a dual - gate lumen transporter model for the basolateral monoamine transporters of the kidneys is proposed as being the etiology of the three - phase urinary serotonin and dopamine responses.purposethe purpose of this writing is to document the internal renal function model that has evolved in research during large - scale assay with phase interpretation of urinary serotonin and dopamine.patients and methodsin excess of 75,000 urinary monoamine assays from more than 7,500 patients were analyzed . the serotonin and the dopamine phase were determined for specimens submitted in the competitive inhibition state . the phase determination findings were then correlated with peer - reviewed literature.resultsthe correlation between the three - phase response of urinary serotonin and dopamine with internal renal processes of the bilateral monoamine transporter and the apical monoamine transporter of the proximal convoluted renal tubule cells is defined.conclusionthe phase of urinary serotonin and dopamine is dependent on the status of the serotonin gate , dopamine gate , and lumen of the basolateral monoamine transporter while in the competitive inhibition state .

saponins contain a steroidal or a triterpenoid aglycone to which one or more sugar chains are attached . these chemical structures determine their biological properties as natural nonionic detergents which have cytotoxic , hemolytic , molluscicidal , anti - inflammatory , antifungal , antiyeast , antibacterial , and antiviral activities [ 24 ] . they are used in the pharmaceutical industry because some forms are the starting point for the semisynthesis of steroidal drugs . saponins can be classified into two groups based on the nature of their aglycone skeleton : steroidal ( consisting of a c27 spirostane skeleton comprising a six - ring structure ) and triterpenoid ( consisting of a c30 skeleton comprising a pentacyclic structure ) . the biological properties of saponins depend on the structure of the aglycone and/or the number of sugar units involved . the therapeutic potential of saponins against eukaryotic cells is associated with their cell membrane - permeabilizing properties by complexing with cholesterol . our previous studies with a series of synthetic saponins showed their potential as anticancer drugs . saponins , having surface - active properties , might insert into the lipid bilayer , bind to cholesterol , form domains enriched with cholesterol - saponin complexes , and finally lyse cells . on the other hand , the absence of cholesterol in the membrane structure does not inhibit pore formation by saponins [ 9 , 10 ] . in our previous study , we suggested that saponin might disturb the permeability of the bacterial outer membrane . about 90% of the surface of naturally cholesterol - free gram - negative bacteria cell - wall we concluded that saponin might interact with the lipid a part of proteus lpss and thereby increase the permeability of bacterial cell wall . lipid a - saponin complexes might promote antibiotic ( colistin , ampicillin ) uptake to inherently resistant bacteria cells . the potentially antibacterial effect of saponins from clinical point of view is associated with a comprehensive investigation of its antibacterial effect and minimal cytotoxic properties in eukaryotic cells . we previously showed that colistin or ampicillin in the presence of 15 g / ml saponins reduced the numbers of cells of the laboratory strains p. mirabilis s1959 and r45 . an important medical problem is the elimination of pathogenic gram - positive and gram - negative bacterial strains . several types of actions are published , such as bacteriophage treatment , inhibition of bacterial adhesion , and increasing the permeability of bacterial cell walls . the aims of the present study are testing the saponin abilities to induce hemolytic and cytotoxic effects against eukaryotic cells , studies of saponin influences on growth of clinical e. coli strains , testing of saponin abilities to interfere with antibiotic action against e. coli cells . louis , mo , usa . the main aglycone ( sapogenin , 2035% ) moiety is quillaic acid , a triterpene of predominantly 30 carbon atoms of the -oleanane type . the aglycone is bound to various sugars , including glucose , glucuronic acid , galactose , xylose , apiose , rhamnose , fucose , and arabinose . cho - k1 cells were cultured at 37c in a humidified 5% co2 atmosphere in plastic dishes in mccoy 's 5a medium supplemented with 10% heat - inactivated fetal calf serum , 2 mm l - glutamine , and antibiotics ( 100 units / ml penicillin and 100 g / ml streptomycin ) . saponin at final concentrations of 12 to 100 g / ml was added to 500 l of the cho - k1 cell suspension ( 1.5 10/ml of complete mccoy 's 5a medium ) onto plates . cho - k1 cells were treated with saponin for 72 hours at 37c in 5% co2 . mtt reagent was added to each plate , and after 6 h of incubation in hera cell , 1 ml of sds ( 10% in 0.01 n hcl ) was added to dissolve the water - insoluble formazan salt . one hour later , the od650 nm - od570 nm difference was measured . cho - k1 cells were treated with saponin at different concentrations ( 6 , 12 , 24 , and 50 g / ml ) for 72 hours . after treatment , the frequencies of early apoptotic , late apoptotic , and necrotic cells were evaluated with the annexin v - fitc apoptosis detection kit i ( bd pharmingen , usa ) described elsewhere . briefly , the cells were washed two times with cold pbs and then resuspended in a 1 binding buffer at a concentration of 1 106 cells / ml . an aliquot of 125 l of the cell suspension was incubated with 5 l of annexin v - fitc and 5 l of propidium iodide ( pi ) at room temperature for 15 min in the dark . a computer system ( cellquest pro , becton dickinson ) was used for data acquisition and analysis . a cell gate containing cho - k1 was established on the basis of forward and side light scatter . four different populations of cells were detected with the annexin v - fitc kit : normal cells that are annexin negative and pi negative and express no fluorescence , early apoptotic cells that are annexin positive and pi negative and express green fluorescence , late apoptotic / necrotic cells that are annexin positive and pi positive and express green and orange fluorescence , and necrotic cells that are annexin negative and pi positive and express orange fluorescence . blood was obtained from healthy young male donors . the red blood cells ( rbcs ) were washed three times and resuspended in sterile pbs to give about 15 10 cells per ml and further processed . the erythrocytes were incubated with saponin in a range of 0.550 g / ml for 1 h at 37c . after centrifugation of the nonhemolysed erythrocytes ( 1400 rpm , 15 min ) , the absorbance of the released hemoglobin in the wavelength range of 400600 nm was measured . the percentage of hemolysis was determined by comparing the absorbance of hemoglobin at 435 , 540 , and 575 nm released from the rbcs in the presence of saponin . the positive control ( 100% hemolysis ) was determined by the amount of hemoglobin released from 15 10 rbcs after 10 min of incubation with water . six strains of e. coli isolated from patients at the department of microbiology , holy cross cancer center in kielce , poland , were included in this study . louis , mo , usa ) was diluted in lb medium or minimal m9 medium described elsewhere . the reaction mixtures contained saponin at concentrations of 0.112 g / ml and a bacterial suspension of e. coli strains at 10 cells / ml in each probe in final volumes of 300 l of proper medium . bacterial viability was expressed in terms of colony - forming units ( cfu / ml ) . additionally , the antimicrobial susceptibility of the clinical e. coli strains to ampicillin , streptomycin , and ciprofloxacin at 25400 g / ml was prospectively tested in the presence of saponin at 12 g / ml in lb medium by the cultivation methods . the data were analyzed using the statistica software package ( statsoft , tulsa , ok , usa ) . all the values in this study are expressed as the mean sd of three experiments . if no significant differences between variations were found as assessed by the snedecor - fisher test , the differences were compared by the anova test . figure 1 shows the percent viability of the cho - k1 cells after 4-day treatment with saponin at concentrations ranging from 12 to 100 g / ml measured by the mtt assay . it was found that saponin at concentrations 25 and 50 g / ml caused 70% and 50% cell killing , respectively . table 1 shows the level of apoptosis measured by flow cytometer with the annexin v - fitc kit and propidium iodide staining according to . saponin dose - depended lyses of cho - k1 cells were observed , as in mtt test ( figure 1 ) . the number of early and late apoptotic cells was detected after incubation with saponin in a concentration range of 1250 g / ml . the flow cytometric analyses of the cho - k1 cells population showed that saponins at concentrations of 1250 g / ml significantly increased the percentage of early apoptotic cells up to 30.88% . the increase in the number ( 6.21% ) of late apoptosis was notice at the dose of 12 g / ml of saponin . the necrosis of cells varied and did not excite 2.52% at saponin dose 50 g / ml . in addition to cho - k1 cell line , the human red blood cells ( rbcs ) were used as hemolysis marker . figure 2 shows the amount of hemoglobin released from rbcs that was determined by the absorbance at 435 , 540 , and 575 nm in the presence of saponin at concentrations ranging from 3 to 100 g / ml . we observed a statistically significant , dose - depended increase in hemolysis at concentrations from 25 up to 100 g / ml . the proportion of pick at 435 , 540 , and 575 nm was similar . this may suggest that porfirine rings and iron molecules are not released from hemoglobin , and observed hemolysis is the effect of rbcs wall destruction . this indicates that critical amount of saponin molecules 25 g / ml is required to destabilize cell wall of erythrocytes . figure 3(a ) shows the effect of saponin at concentrations ranging from 1 to 12 g / ml on the growth of the six clinical e. coli strains incubated for 18 h at 37c in lb medium . it is worth to notice that we observed statistically significant increases in cfu of the multidrug resistant- ( mdr- ) e. coli strains in the presence of saponin at a concentration of 6 and 12 g / ml in lb medium , in contrast to growth of bacterial strains in m9 medium which was influenced by saponin presence ( figure 3(b ) ) . in next experiment , dose of 12 g / ml of saponin in lb medium was used for testing antibiotic action against e. coli cells . figure 4 shows the effect of the presence of saponin and ampicillin , streptomycin , or ciprofloxacin at concentrations ranging from 25 to 400 g / ml on the growth of the clinical e. coli strains incubated for 18 h at 37c in lb medium . the addition of saponin caused in strains 3 and 6 that ciprofloxacin was less effective ( figure 4 compares open circle and open triangle ) . having a similar effect , increases of amount of cells were observed with ampicillin or streptomycin and saponin mixtures in all strains tested ( black or gray circle and triangle , figure 4 ) . the presented results indicate that saponin enhances clinical e. coli cells growth in the presence of antibiotics . medically desired situation is the concentration of saponins with antibacterial properties that has minimal cytotoxic activity against eukaryotic cells . saponins possess detergent - like properties and might increase the permeability of bacterial cell membranes without destroying them . in theory , this activity might facilitate antibiotic influx through the bacterial cell wall membrane . in the presented studies , we compared saponins ' activities against prokaryotic and eukaryotic cells . we used commercial saponin from quillaja saponaria , which is one of the major sources of industrial triterpenoid saponins . saponins extracts from quillaja saponaria have been in practical use as foaming agents in beverages or emulsifiers in foods . in our investigations , we analyzed the activity of saponin from quillaja saponaria against cho - k1 cell line . the saponin extracts increase the number of early apoptotic cells in a dose - dependent manner . effect of saponin on membrane receptors for apoptosis was shown also by others . in our studies , we also have shown that saponin at concentrations higher than 12 g / ml has significantly cytotoxic effect on cho - k1 cells . similar effect was observed with human erythrocytes at dose 25 g / ml of saponins . interestingly , lower doses do not lyse of rbc at all . that may indicate a defined amount of saponins intercalating to cell wall membranes of erythrocytes needed to lyse it . to analyze the antibacterial properties of saponin , we use saponin at 12 g / ml taking into consideration its minimal cytotoxic effect against eukaryotic cells . saponin does not inhibites e. coli growth in minimal m9 and luria broth . in contrary , we observed statistically significant increases in cfu / ml of six tested mdr e. coli strains in the presence of saponin at a concentration of 12 g / ml . this effect was not observed on bacterial growth in m9 minimal medium . our study of analysis of susceptibility of clinical e. coli strains against ampicillin , streptomycin , and ciprofloxacin in presence of saponin at a concentration of 12 g / ml confirmed that saponins enhance bacteria growth , even in antibiotic presence . in conclusion , we presented varied potencies of saponins against eukaryotic and prokaryotic cells . the biological properties of chemical substances potentially useful in clinical use should be characterized by their defined activity in correlation with the optimal concentration .

saponins are detergent - like substances showing antibacterial as well as anticancer potential . in this study , the effects of saponins from quillaja saponaria were analyzed against prokaryotic and eukaryotic cells . multidrug - resistant clinical e. coli strains were isolated from human urine . as eukaryotic cells , the cho - k1 cell lines were applied . antibacterial effect of ampicillin , streptomycin , and ciprofloxacin in the presence of saponins was measured by cultivation methods . properties of saponins against cho - k1 cells were measured by the mtt test , hemolysis assay and flow cytometry . saponin from quillaja saponaria has a cytotoxic effect at concentrations higher than 25 g / ml and in the range of 1250 g / ml significantly increases the level of early apoptotic cells . saponin at dose of 12 g / ml enhances the six e. coli strains growth . we postulate that saponins increase the influx of nutrients from the medium into e. coli cells . saponins do not have synergetic effects on antibacterial action of tested antibiotics . in contrary , in the presence of saponins and antibiotics , more cfu / ml e. coli cells were observed . this effect was similar to saponins action alone towards e. coli cells . in conclusion , saponins was cytotoxic against cho - k1 cells , whereas against e. coli cells this effect was not observed .

meatus was normal in 3 , hypospadiac in 2 , and epispadiac in one patient . the most common associated anomaly was bifid scrotum ( 5 cases ) , and other common anomalies consisted of bladder duplication ( 3 cases ) , imperforate anus ( 2 cases ) , and hypospadias ( 2 cases ) . phalloplasty was performed for all but one . all the patients with urethral duplication have to be evaluated carefully because of the high incidence of other systemic anomalies . duplication of the penis or diphallus is a rare anomaly that occurs once in every 5 to 6 million live births . approximately 100 cases have been reported since the first case reported by wecker in 1609 . neugebauer in 1898 and nesbit and bromme in 1933 reviewed cases in the literature[3 , 4 ] . the extent of duplication and the number of associated anomalies vary greatly , ranging from a double glans arising from a common shaft with no other anomaly to complete duplication of the phallus accompanied by multiple anomalies , such as ectopic scrotum , bifid scrotum , hypospadias , imperforate anus , bladder exstrophy , colon duplication , double bladder , and vertebral deformities . embryologically a diphallus deformity arises from either " separation " of the pubic tubercle , wherein each phallus will have only one corporal body and urethra , or " cleavage " of the pubic tubercle wherein each phallus will have two corporal cavernous bodies and urethras . diphallus has been classified in different ways , such as glandular , bifid , concealed , complete , hemidiphallus and triple penis . schneider classified diphallus in three groups : diphallia of glans alone , bifid diphallus , complete diphallia , and recently a fourth category of pseudodiphallia has been added . we herein discuss our six diphallic patients and associated anomalies . patients were classified according to scheneider classification : ( glans diphallia , bifid diphallia , and complete diphallia ) . meatus was normal in 3 , hypospadiac in 2 patients and epispadiac in one patient . the most common associated anomaly was bifid scrotum ( 5 cases ) , and other anomalies consisted of duplicated bladder ( 3 cases ) , imperforate anus ( 2 cases ) , and hypospadias ( 2 cases ) . all associated anomalies were also repaired . in the following , patients are described separately : case 1 : this 2-day old neonate with 2500 kg body weight presented for evaluation of complex genitourinary and ano - rectal malformation . physical examination revealed imperforate anus , complete diphallia , hypospadias and normal testes but bifid scrotum . the first procedure done on the patient was a loop colostomy , which showed duplication of recto - sigmoid colon ( fig . diphallus and duplicated colon and bladder patient 's karyotype was 46xy . abdominal ultrasonography ( us ) showed normal kidneys and ureters but duplicated bladder . a cystogram with retrograde filling through both urethras demonstrated two bladders without reflux and no connection between them ( fig . characteristic results in our six patients ivp = intravenous - pyelography ; vcug = voiding cystourethrography ; psarp = posterior sagittal ano - recto - plasty ; us= ultrasonography case 2 : the four - year old boy was admitted in our hospital for uro - genital evaluation . 2 ) . the scrotum appeared to be normal and contained one testis in each side . us and cystography showed two independent bladders lying side by side and each one emptied through a separate urethra ( fig . 2 ) . hernia repair and cysto- urethro - phalloplasty were performed in two stages . diphallus and duplicated bladder in cystogram case 3 : this 12-year old boy , one of four children in a family , was referred to our clinic for diphallus and inability for normal urination . he had a history of bladder exstrophy operation during neonatal period and infancy in another hospital . physical examination revealed complete diphallus , neither of which had a meatus , scrotum was bifid and contained normal sized testes ( fig . 3 ) . diphallia after bladder exstrophy repair radiographic study of different organs revealed lumbo - sacral hemivertebrae . intravenous - pyelography ( ivp ) and kidney scan showed a single kidney , with extravasated dye over the phalluses . case 4 : this 1-year old boy presented with complete diphallus . on physical examination he had normal meatus on each phallus ; scrotum was bifid and contained normal sized testes . ivp showed normal kidneys and ureters . on us and retrograde cystourethrogram he had two separate bladders , without any interconnection . case 5 : a 14-year old boy , the last of six children from an economically poor family . he had complete bifid diphallia with one normal and another hypospadiac meatus , scrotum was bifid and contained normal testes ( fig . ivp , voiding cystourethrography ( vcug ) revealed normal kidneys , ureters and bladder but duplicated urethra , which was normal in the left but hypospadiac in the right side . his karyotype was 46xy , so the right hypospadiac phallus was excised and the left normal one repaired . case 6 : this 9-month old boy was referred to our clinic for urogenital abnormalities and imperforate anus . he had a history of colostomy due to ano - rectal malformation in another center . physical examination revealed a well baby with complete diphallus , both sides ' normal meatuses , bifid scrotum , normal sized testes , imperforate anus and divided colostomy . u / s , ivp , vcug and ureterography showed normal kidneys , ureters , bladder and other organs , but duplicated urethra and ended loop rectum . posterior sagittal ano - recto - plasty ( psarp ) was performed , and one month later right phallus was excised and scrotoplasty carried out ( fig . diphallus may happen in clitoris which is also very rare , as reported by jeffcoate , but we did not have any in our series.scheneider classified diphallus in three groups : diphallus of glans alone , bifid diphallus , and complete diphallus . we had five complete and one bifid diphallia in our series but no glans diphallia , mutlu et al had no complete diphallus in their cases we had normal type in 3 cases , epispadiac in one case and hypospadiac type in 2 patients . the scrotum may be normal or bifid , our patients had bifid scrotum in 5 cases and only one patient had normal type . we had bifid scrotum , hypospadias , duplicated bladder , imperforate anus , bladder exstrophy , colon duplication , inguinal hernia and kidney agenesis . intestinal anomalies are mostly associated with complete diphallia , and imperforate anus[10 , 15 ] . there are multiple embryological explanations for diphallus ; we could not find any exact etiological factor in our study . all the patients with penile duplication ( diphallus ) have to be evaluated carefully because of the high incidence of other systemic anomalies and all can be repaired surgically .

backgrounddiphallus is an extremely rare anomaly . numerous associated genitourinary , gastrointestinal and other anomalies have been described with diphallus . these patients need several investigations , and finally surgical intervention.cases presentationin this report we discuss six patients with diphallus which evaluated retrospectively . five patients had complete diphallia , and one had bifid diphallus . meatus was normal in 3 , hypospadiac in 2 , and epispadiac in one patient . the most common associated anomaly was bifid scrotum ( 5 cases ) , and other common anomalies consisted of bladder duplication ( 3 cases ) , imperforate anus ( 2 cases ) , and hypospadias ( 2 cases ) . phalloplasty was performed for all but one.conclusionall the patients with urethral duplication have to be evaluated carefully because of the high incidence of other systemic anomalies .

cerebral palsy ( cp ) comprises a group of movement and posture disorders resulting from nonprogressive , permanent damage to the immature brain1 . motor impairment is the main manifestation of cp , with consequent effects on the biomechanics of the body2 . children with cp exhibit impaired muscle coordination , difficulties in the organization of sensory information , and functional limitations3 . approximately half of all children with cp have upper limb dysfunction4 , which includes weakness , associated mirror movements , decreased velocity , overactive reflexes , muscle contractures , altered biomechanics , disuse , sensory impairment , and hypertonia5 , 6 . these upper limb impairments lead to difficulties in reaching , grasping , and manipulating objects . deficiencies in one or more of these basic functions hinder the performance of activities of daily living and therefore exert a negative impact on independence and quality of life7 . adequate treatment planning is imperative and requires extensive knowledge of all upper limb dysfunctions . a clinical assessment combined with objective , quantitative upper limb measures can provide the necessary insights7 . however , most measures are subjective and use a straightforward scoring system . the main disadvantage of qualitative outcome measures is that they provide a subjective description of upper limb performance based on the opinion of the rater , who visually scores the range and quality of movement during the execution of tasks . moreover , some outcome assessments have been criticized for not being sensitive enough to detect clinically meaningful changes in upper limb function following an intervention8 . in a recent study , santos et al . reported that no consensus has been reached on the most appropriate scale or on which scale has greater clinical applicability in this population9 . thus , quantitative measures are needed to provide a more detailed , objective description of upper limb movement patterns . such measures can provide an objective description of upper limb performance based on technical measurements and calculations ( e.g. , joint angles , movement duration , and velocity ) . three - dimensional ( 3d ) movement analysis is a powerful tool for quantitative assessment of movement in all degrees of freedom7 . a number of authors have recommended the use of kinematics for objective , quantitative analysis of upper limb movements in children with cp10 . motion analysis is considered the gold standard for evaluating lower limb function during gait in individuals with cp11 . upper limb motion analysis is more technically challenging due to the noncyclical nature of upper limb use and the complexity of shoulder joint motion12 . in addition to joint kinematics , spatiotemporal variables , such as duration , velocity , smoothness , and trajectory of movement , can provide important quantitative information on the quality of upper limb motion13 . the aim of the present study was to perform a review of the literature on objective upper limb movement measures for children and adolescents with cp with a focus on describing methods for the assessment of kinematics , spatiotemporal variables , and/or angular joint movements . methodological reflections are included in this report to promote standardization of a protocol for 3d analysis of upper limb movements in children and adolescents with cp . a systematic review of the literature was performed with searches in the virtual health library network and the medline , pedro , lilacs , scielo and pubmed databases using combinations of the following key words : upper limb , three - dimensional analysis , kinematics , and cerebral palsy . the articles retrieved were evaluated by two blinded researchers using the following inclusion criteria : 1 ) type of study , controlled clinical trial ; 2 ) outcome , 3d or kinematic evaluation of the upper limbs of children / adolescents with cp ; and 3 ) publication between 2010 and 2015 . the selected articles were evaluated , scored , and qualified using the physiotherapy evidence database ( pedro ) scale , which has 11 items . item 1 is not scored , whereas the other 10 items receive a score of either 0 or 1 . the purpose of this scale is to evaluate the methodological quality ( table 2table 2.characteristics of the studies included in reviewarticlen of subjectssample characteristicsinterventionkinematic processingkinematic analysis112children 611 yearscerebral palsy(hemiplegic , diplegic , quadriplegic)eg : 6 without trunk restraintcg : 6 with trunk restraintsystem : positional data ( x , y , z ) recorded with an optotrak 3020 ( 100 hz ; northern digital , waterloo , on , canada ) for 5 to 8 seconds.markers : fingertip , thumb , first metacarpal head , radial styloid , mid - forearm , lateral epicondyle , ipsilateral and contralateral acromions , sternum , and lateral iliac spine.trials : 7 to 13 trials ( bad trials discarded).kinematics analysis : trajectories and angles . results : smoother arm trajectories and greater elbow extension were observed at the post - intervention assessment in most children , but deterioration in elbow extension for reaches was observed at follow - up . trunk displacement was reduced at the post- intervention assessment and at follow - up.220children 410 yearscerebral palsy ( hemiplegic)eg : 10 bimanual treatmentcg : 10 unimanual treatmentsystem : 3-d kinematic analysis with eight infrared cameras ; all markers digitized at a rate of 120 hz with a low pass filter ( 6 hz ) using vicon software.markers : reflective markers placed at mid - point of both wrists . trials : 7 to 10 trials.kinematic analysis : time . bimanual coordination using normalized movement overlap time and goal synchronization.movement strategies : experimental setup with a loop handleresults : significantly greater reduction in goal synchronization time in the experimental group.316children 814 yearscerebral palsy(hemiplegic and quadriplegic)eg : 8 lycra arm splint usage for three monthscg : 8 no interventionsystem : seven - camera vicon 370 motion analysis system ( oxford metrics , oxford , uk ) operating at 50 hz.markers : 3d position of markers throughout movement trials analyzed using customized model developed with vicon body buildersoftware ( oxford metrics , oxford , uk).trials : three successful trials of each task analyzed.kinematics analysis : time and jerk . the 3d movement substructures of the wrist joint center ( wjc ) were calculated from 3d positional data using a custom jerk analysis computer software ( labview , national instruments corporation , austin , tx , usa).movement strategies : reach forwards , reach forwards to an elevated position , reach sideways to an elevated position , and hand to mouth and down.results : significant improvements in the experimental group regarding movement time , normalized jerk , and jerk index in the primary and secondary movements . 416children 815 yearscerebral palsy ( hypertonic)eg : 8 - lycra arm splint usage combined with goal directed training for three monthscg : 8 - no interventionsystem : seven - camera vicon 370 motion analysis system ( oxford metrics , oxford , uk).markers : reflective markers placed on upper limb and trunk ; 3d position of markers throughout movement trials analyzed using a customized model developed with the vicon bodybuilder software ( oxford metrics , oxford , uk).trials : three successful trials of each task analyzed.kinematics analysis : angle - range of motion . the movement trials were analyzed using a customized model developed with the vicon bodybuilder software ( oxford metrics , oxford , uk).the data were filtered using a woltring spline with a mean standard square error ( msse ) of 20 . movement strategies : reach forward to an elevated position , reach sideways to an elevated position , supination/ pronation , and hand to mouth.results : significant improvements from baseline angles.58children 815 yearscerebral palsy ( hypertonic)eg1 : 4 - botulinum toxin injectioneg2 : 4- muscle lengthening surgery system : vicon optoelectronic system with six cameras.markers : rigid supports provided with three markers ( tripods ) used to measure trunk , arm , forearm , and hand motions.trials : four successful trials of each segment.kinematics analysis : angle - range of motion ( rom ) and mean angles for the trunk / table , arm / trunk , forearm / arm , and hand / forearm . recommendations from the international society of biomechanics.movement strategies : hand to mouth and moving a cup on a table.results : significant rom and mean angle changes between the pre- and post - therapeutic conditions ( homolateral analysis).eg : experimental group ; cg : control group ) of randomized controlled clinical trials , giving priority to internal validity ( whether the results published in the study have sufficient information ) as well as clinical and statistical relevance , so that interpretation of the findings is clear and other researchers can reproduce the study . all divergences regarding classification of the studies analyzed based on the pedro scale were discussed and evaluated by two blinded raters until a consensus was reached on the score of each study . thus , five articles addressing 3d analysis of the upper limbs of children and adolescents with cerebral palsy ( fig . 1fig . 1.flowchart of studies included in the review ) were considered methodologically adequate ( minimum of three points on the pedro scale ) and were included in the present systematic review ( table 1table 1.pedro scale scores of each study ) . flowchart of studies included in the review all studies selected were controlled clinical trials and employed one or more upper limb evaluation methods . the methods and results of the 3d analysis the following information was extracted from each study : authors and year of publication , sample size , sample characteristics , methods employed , and outcomes ( table 2 ) . current clinical methods of upper limb evaluation are performed in terms of function , motor control , sensory impairment , dexterity , tone , and degree of fixed versus dynamic deformity as well as both passive and active range of motion . in higher functioning children , the quality of upper limb movement during functional tasks is determined using available clinical scales19 . a strategy level assessment. a large number of kinematic variables are used to reflect the characteristics of the reaching motion . by quantifying specific kinematic variables , key components can be identified and the influence of motor impairment on the reaching motion can be carefully analyzed . consequently , specific kinematic parameters with large effect sizes can provide therapists with a sensitive way to measure the effectiveness of treatment and analyze the influence of different levels of motor dysfunction on upper arm control during activities that require various degrees of accuracy . a better understanding of this information can offer insights for the evaluation of treatment and the progression of a wide variety of motor disorders , such as those that occur with cp20 . the samples in the studies analyzed in the present systematic review were predominantly made up of children with spastic hemiparetic cerebral palsy , which confirms an observation made by body21 . children with hemiparesis have limitations regarding the use of the affected upper limb and two - hand coordination , which exerts a negative impact on activities of daily living and participation at school , in the community , and in family life . mean age ( eight years ) was also a common factor in the studies analyzed . as the present review was restricted to clinical trials , all studies had two groups : an experimental group subjected to a particular intervention and a control group that did not undergo the intervention . analyzing the kinematic variables , it is clear that there is no consensus on the data collection , processing , and analysis procedures or the reporting of the results . the vicon optoelectronic motion analysis system ( oxford metrics , oxford , uk ) was used in four of the five studies , but the number of cameras employed differed . the optotrak 3020 ( 100 hz ; northern digital , waterloo , on , canada ) was employed in the other study . differences among the studies also occurred with regard to placement of the makers ( five segments were included , the trunk , scapula , humerus , forearm , and hand , and four joints were considered , the scapulathoracic ( scapula ) , humerothoracic ( shoulder ) , elbow , and wrist joints , and the number of trials . in the present review , a variety of mechanical models , numbers of segments , joint degrees of freedom , and marker configurations were encountered , with no consensus on a standardized assessment pattern . only the study conducted by fitoussi et al . 18 used the recommendations on the international society of biomechanics ( isb ) regarding the definition of joint coordinate systems and rotation sequences22 . this observation was also described in a study by ellen jaspers in 2011 , who reported that most studies on upper limb ( up ) kinematics in typically developing children and children with cp have not yet incorporated the isb guidelines . moreover , there is no general consensus on which tasks should be assessed23 . in the following section on kinematic analysis , characteristics are presented for the different tasks , including spatiotemporal characteristics , joint kinematics ( joint angles ) , trajectories of movement , and jerk analysis as well as contextual influences of interventions . the differences in spatiotemporal characteristics between the experimental group and control group during reach to touch and reach to grasp were studied in articles by hung ya - ching el al.15 and elliot et al16 . schneiberg et al.14 compared the differences between pre - intervention and post - intervention assessments for three - dimensional arm and trunk trajectories and elbow angles and overall trend analysis ; the effect size for time period indicated smoother arm trajectories and greater elbow extension at the post - intervention assessment in most children . the other articles analyzed used kinematic evaluation focused on angular data of different joint segments and also found satisfactory results with the treatment protocol offered . in the studies analyzed , the evaluation of kinematics was effective for a discussion of the findings , but we believe that the methodogical differences between the studies likely inconsistent results and therefore , exert an impact on the clinical interpretation . we suggest , based on the present review , that authors of future clinical trials should try to use standardized patterns . standardization of the protocol for 3d upper limb movement analysis will provide the foundation for comparable , reproducible results and eventually facilitate the planning of treatment interventions for children and adolescents with cerebral palsy . several clinical trials involving children and adolescents with cerebral plays have benefitted from the use of objective measurements of upper limb movements , with spatiotemporal and angular parameters used in the majority of them . however , there is a lack of consensus regarding the biomechanical model and which tasks to analyze . the findings of the present systematic review underscore the need for standardization of 3d upper limb movement analysis .

[ purpose ] the aim of the present study was to perform a review of the literature on objective measures of upper limb movements in children and adolescents with cerebral palsy and describe the methods used to investigate upper limb kinematics in this population . [ materials and methods ] an extensive database search was performed using the keywords kinematics , upper limb , and cerebral palsy . a total of 146 papers were identified , but only five met the inclusion criteria . [ results ] no consensus was found regarding the data collection , processing , and analysis procedures or reporting of the results . [ conclusion ] standardization of the protocol for 3d upper limb movement analysis will provide the foundation for comparable , reproducible results and eventually facilitate the planning of treatment interventions .

in the yoga sutras , yoga is defined as union of mind , body and spirit . these days it is assuming importance in improving mental health and quality of life in the treatment of a number of disorders . for example , a rash of psoriasis may not bother some people while it may make some feel depressed and more ill . for example , with some mental illnesses one may not eat , or take care of oneself , and this can cause physical problems . who defines quality of life as individuals perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals , expectations , standards and concerns . quality of life means a good physical and mental condition , consisting of two elements : the ability to cope with everyday tasks ( the biopsychosocial level ) and the patient 's satisfaction from his activities at all levels as well as control over the disease and symptoms connected with the treatment method being applied . the most important and frequently used generic health - related quality of life assessment is the sf-36 comprising of 36 questions providing functional health and well - being scores . the sf-12 is a multipurpose short - form survey with 12 questions , all selected from the sf-36 . the questions are combined , scored , and weighted to create mental and physical functioning and overall health - related - quality of life . the present study evaluates the changes in quality of life following short - term lifestyle modifications based on yoga . to study the effect of short - term yoga therapy program on quality of life in patients suffering from psychosomatic ailments . the study was done in svyasa arogyadhama , bangalore in the month of july 2011 . it was based on the data collected on 94 subjects who were diagnosed for psychosomatic ailments based on history and previous investigations and who attended integrated approach to yoga therapy ( iayt ) . ethical clearance was obtained from institutional ethical committee of svyasa and written informed consent was obtained from all subjects . all subjects , more than 18 years of age and who understood english were included . subjects from psychiatry section of arogyadhama , who came for rehabilitation and who were severely ill , with complications and uncontrolled disease were excluded from the study . the subjects were a heterogeneous group , having hypertension , bronchial asthma coronary artery disease , diabetes mellitus , obesity , neurological disorder , chronic backache and arthritis and they were divided into different departments according to their ailments . in no subject , the physical condition prevented from participation in yoga therapy . all subjects underwent iayt , which included physical postures ( asanas ) , voluntary breathing ( pranayamas ) , meditation , internal cleansing processes ( kriyas ) and lectures on practice of yoga and derived special techniques in their respective sections . these procedures were offered daily and each session lasted for 1 h. all subjects were given self - administered sf-12 questionnaire with no time limit and their doubts were cleared then and there on the first day of their admission and again after 1 week of yoga practice at arogyadhama . the quality of life was assessed by sf-12 questionnaire and thereby calculating physical and mental composite scores ( pcs and mcs ) before and after the yoga therapy . pcs and mcs were computed using the rating on 12 questions from 0 to 100 , where a 0 score indicates the lowest level of health and 100 indicates the highest level . the study was done in svyasa arogyadhama , bangalore in the month of july 2011 . it was based on the data collected on 94 subjects who were diagnosed for psychosomatic ailments based on history and previous investigations and who attended integrated approach to yoga therapy ( iayt ) . ethical clearance was obtained from institutional ethical committee of svyasa and written informed consent was obtained from all subjects . all subjects , more than 18 years of age and who understood english were included . subjects from psychiatry section of arogyadhama , who came for rehabilitation and who were severely ill , with complications and uncontrolled disease were excluded from the study . the subjects were a heterogeneous group , having hypertension , bronchial asthma coronary artery disease , diabetes mellitus , obesity , neurological disorder , chronic backache and arthritis and they were divided into different departments according to their ailments . in no subject , the physical condition prevented from participation in yoga therapy . all subjects underwent iayt , which included physical postures ( asanas ) , voluntary breathing ( pranayamas ) , meditation , internal cleansing processes ( kriyas ) and lectures on practice of yoga and derived special techniques in their respective sections . all subjects were given self - administered sf-12 questionnaire with no time limit and their doubts were cleared then and there on the first day of their admission and again after 1 week of yoga practice at arogyadhama . the quality of life was assessed by sf-12 questionnaire and thereby calculating physical and mental composite scores ( pcs and mcs ) before and after the yoga therapy . pcs and mcs were computed using the rating on 12 questions from 0 to 100 , where a 0 score indicates the lowest level of health and 100 indicates the highest level . the mean sd of age of the study group was 46.18 16.58 years . about 55.3% of the subjects were females and rest 44.7% were males . in the whole study group , there was a statistically significant improvement in both pcs ( p < 0.001 ) and mcs ( p < 0.001 ) with minor variations in patients of various departments [ table 1 ] which are as follows : comparison of pcs and mcs before and after 1-week yoga in different departments a significant improvement was seen in pcs in patients of all departments - neurology / spinal disorders ( p < 0.001 ) , pulmonology / cardiology ( p < 0.001 ) , metabolic disorders ( p < 0.001 ) , endocrinology ( p < 0.001 ) , others ( rheumatology / gastroenterology / promotion to positive health ) ( p < 0.001 ) . similar results were observed in mcs with statistically significant improvement seen in patients of neurology / spinal disorders ( p < 0.001 ) , pulmonology / cardiology ( p < 0.001 ) , metabolic disorders ( p < 0.001 ) , endocrinology ( p < 0.001 ) , others ( rheumatology / gastroenterology / promotion to positive health ) ( p < 0.001 ) . the study intervention was a short - term ; iayt comprised of daily practice of asanas , pranayamas , meditation , kriyas and lectures on practice of yoga and derived special techniques and diet . the results showed that even a short - term that is , just 7 days of yoga practice showed a significant improvement in both pcs and mcs . this implies that yoga improved not only the physical wellbeing of the subjects but also improved the mental state . these benefits were observed over a wide range of chronic diseases , which implies that yoga intervention has an effect regardless of the diagnosis . according to yoga sutra , the body and mind can not be separated . this logic indicates that all physical benefits resulting from the practice of yoga are coupled with mental benefits such as development of inner consciousness , positivity , awareness , and appreciation of nature , combining to offer a whole - body therapy . the physical benefits of yoga are linked to the release of -endorphins and the shift caused in neurotransmitter levels linked to emotions such as dopamine and serotonin and implicit dominance of the parasympathetic nervous system . yoga stimulates an under active parasympathetic nervous system and increases the inhibitory action of a hypoactive gaba system in brain pathways and structures that are critical for threat perception , emotion regulation , and stress reactivity . a 30 min session of yogic stretching and breathing exercises produces a marked augmentation in perceptions of physical and mental energy . such exercises also increase feelings of alertness and enthusiasm , and make subjects feel distinctly less sluggish and sleepy than before the session began . a simple and inexpensive essentially educational intervention based on yoga improves subjective well - being . as the study does not have a control group , the effect of yoga therapy on quality of life can not be generalized . the present study suggests that a short - term integrated yoga therapy can improve the overall general well - being of subjects irrespective of their disease . hence , daily practice of yoga on regular basis will improve the quality of life . to conclude , yoga could be prescribed as a supplement to conventional therapy of a psychosomatic disease .

objective : the aim was to study the effect of short - term yoga therapy program on quality of life in patients suffering from psychosomatic ailments.methods:sample size and study period : all the subjects coming to svyasa arogyadhama in month of july 2011 for yoga therapy for various psychosomatic ailments and were free of any primary psychiatric illness and volunteering to participate were enrolled in the study after taking informed consent . their physical condition was healthy enough to practice yoga as judged clinically . all subjects ( n = 94 ) who were enrolled in the study underwent integrated approach to yoga therapy , which included asanas , pranayamas , meditation , kriyas and lectures on practice of yoga and derived special techniques in their respective sections . the quality of life was assessed by sf-12 questionnaire and thereby calculating physical and mental composite scores ( pcs and mcs ) before and after 1 week of yoga therapy . data thus obtained was analyzed using paired t-test.results:a significant improvement ( p < 0.001 ) was seen in the study group in both pcs ( from mean sd of 37.50 9.58 to 43.7 8.73 ) and mcs ( from 45.87 9.57 to 53.35 7.9 . ) with minor variations in patients of various departments.conclusion:a short - term yoga therapy program leads to a remarkable improvement in the quality of life of the subjects and can contribute favorably in the management of psychosomatic disorders .

soft tissue sarcomas ( sts ) are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm and account for about 1% of all malignant tumors , with the genitourinary ( gu ) tract accounting for 2.1% of sts [ 1 , 2 , 3 ] . they represent between 1 and 3% of all renal cancer cases and have a poor prognosis [ 4 , 5 ] . low - grade fibromyxoid sarcoma ( lgfs ) is a rare indolent but metastasizing sts , with deceptively benign - appearing histological features . the most common tumor locations are the shoulder area , thigh and inguinal area and the primary tumor presents as a painless growing mass . the treatment of choice for lgfs consists of surgery . radiation and chemotherapy are used in addition to surgery in the treatment of recurrent and metastatic tumor depending on the situation . a 48-year - old male patient consulted the urology department of our hospital , reporting a recent episode of left renal colic pain . past medical history is significant for surgical removal of parathyroid glands due to hyperparathyroidism , accompanied by recurrent kidney stone formation , which was treated by sessions of extracorporeal lithotripsy ( eswl ) . laboratory tests ( blood count , blood biochemistry ) were within normal limits , while the urinanalysis has shown the presence of 2030 rbc per high - power field , which was considered in concordance with the renal colic pain . urine cytology showed a nonspecific cellular atypia , while chest x - rays were normal . an ultrasound exam was performed as a first diagnostic imaging approach , which found the presence of a 4.5-cm renal pelvic mass on the left kidney . a computed tomography ( ct ) exam was recommended to the patient and the result consisted of renal stones on both kidneys , and a soft tissue mass , mostly located inside the left renal pelvis , of 4.3 4 4.6 cm ( fig . the patient was subsequently subjected to ureteroscopy , which confirmed the presence of a large exophytic mass , which occupied a big part of the renal pelvis , with apparent characteristics of malignant tumor . a tumor biopsy specimen was taken for histologic examination , and the pathological report confirmed the presence of a renal pelvis tissue with a dysplastic urothelium . the subepithelial tissue immunohistologic examination [ panker( ) , s100( ) , cd34(+ ) and sma(+ ) ] was indicative of hyperplasia of smooth muscle , with no apparent evidence of malignancy . even though the pathological result was benign , the apparent malignant macroscopic characteristics of the tumor , in combination with a detailed consultation with the patient , pointed to the decision of an open left radical nephroureterectomy , which was performed 5 days after the ureteroscopy . the intervention took place uneventfully , the postoperative period was uncomplicated and the patient was discharged 4 days after the operation . the surgical pathology report described the presence of a myxomatoid tumor of 4.7 cm in diameter in the renal pelvis . histologically , the tumor had a compact structure showing an admixture of hypocellular myxoid and hypercellular collagenized zones , consisting mostly of delicate spindle - shaped cells ( fig . mitoses were rare . arcades of blood vessels were also seen , while giant areas of hyalinizing collagen were seen . the tumor was in contact with the renal pelvis urothelial wall through a thin fibrous capsule , without infiltrating the urothelium . the immunohistochemical results [ vimentin(+ ) , sma( ) , c - kit(focally weak positivity ) , desmin( ) , s-100( ) , ema( ) , bcl2( ) , cd31( ) , cd99( ) , cd34(+ ) and ki-67 = 1% ] , demonstrated the presence of a malignant mesenchymal tumor of the renal pelvis , strongly suggesting the diagnosis of lgfs . the patient was referred to an oncologist for a second opinion and a close follow - up was decided , without any adjuvant therapy . the patient is until now ( 7 months of follow - up ) free of local recurrence , or metastatic disease . renal sarcomas are quite rare tumors with less than 150 cases reported in the literature . silverman et al . reported the first lgfs of the renal capsule ( capsuloma ) . we believe our case is the first to report a lgfs of the renal pelvis . evans tumor , because the first 2 cases were reported by evans in 1987 , followed by a series of 33 cases in a recent report [ 6 , 7 ] . in these series lgfs occurred mostly in young adults with almost even sex distribution . tumor size ranged from 1.5 to 16 cm , while the operated tumors were estimated to be 1 month to 25 years old . local recurrences were noted at intervals varying from 0 to 15 years and metastases developed after intervals ranging from 0 to 45 years and were mostly located in the lungs , pleura and chest wall . although the estimated 5-year overall survival exceeds 90% , these findings underline the need for a long - term follow - up of the patients , and a more detailed evaluation of the tumor 's behavior . the primary treatment of choice is surgical removal of the tumor . although the tumor prognosis has been improved due to the early radical surgery , the disease - specific mortality is obscure , because of the tumor capability of distant metastasis , even 50 years after surgery . negative surgical margins and tumor size seem to be the most important accepted prognostic factors for better survival and local control of the tumor . lgfs of the kidney is a rare soft tissue neoplasm entity that can have a deceptively indolent histologic appearance but clearly malignant course . surgery is the treatment of choice and long - term follow - up is implicit due to late local and metastatic occurrences . radiotherapy and chemotherapy should be reserved for local recurrence and/or local metastasis treatment . to our knowledge

sarcomas of the genitourinary tract are quite rare , accounting for 2.1% of all soft tissue sarcomas and have a poor prognosis . kidney sarcomas are quite rare , representing 13% of malignant renal cases . low - grade fibromyxoid sarcoma ( lgfs ) of the kidney is an exceedingly uncommon , indolent but metastasizing soft tissue sarcoma with deceptively benign - appearing histological features . the estimated 5-year overall survival seems to be over 90% , but very late local relapses and distant metastasis may occur , which underlines the need for a long - term follow - up . we present a case of a 48-year - old male patient with a lgfs located on the renal pelvis . this is probably the first report of lgfs arising from the renal pelvis .

a total of 50 rectal swabs were collected from 40 alpacas and 10 llamas in different farms of putre ( parinacota ) . samples were collected during 2 different days , maintained at room temperature using copan transystem swabs ( copan , brescia , italy ) , and transported to the antofagasta university . samples were pre - enriched on brain heart infusion broth at 37c for 18 h , and then seeded on m - enterococcus and incubated at 37c for 48 h. all media were purchased from difco ( detroit , mi ) . from each plate , at least five different colonies were reseeded and identified to the species level by maldi - tof mass spectrometry ( ms ) . complementary phenotypic analysis as well as antibiotic susceptibility were performed by the wider semiautomatic system ( fco . clinical and laboratory standards institute ( clsi ) criteria for antibiotic susceptibility breakpoints were applied ( 13 ) . whole dna of all enterococci strains was obtained by resuspending one colony in 200 l of distilled water , heating at 95c for 10 min , centrifuging for 5 min at 13,000 rpm , and collecting the supernatant . five l of the supernatant were used as a template in the polymerase chain reaction ( pcr ) . enterococcal species were assigned after pcr amplification of 16s rrna , rpob , rpoa , aac(6)-i , and phes genes ; subsequent nucleotide sequencing in a abi prism 3130 genetic analyzer ( applied biosystems , san mateo , ca ) ; and comparison with the blast database tool ( http://blast.ncbi.nlm.nih.gov/blast.cgi ) . primers and conditions used in this study the presence of efaa , agg , gele , esp , cyla , and ace genes was investigated by pcr using specific primers and conditions previously described ( table 1 ) . pulsed field gel electrophoresis ( pfge ) genomic dna was prepared in agarose plugs , digested with smai ( new england biolabs , beverly , ma ) , and run on a chef - dr iii ( bio - rad laboratories , hercules , ca ) , as described previously ( 18 ) . band pattern analysis was performed constructing an upgma ( unweighted pair group method with arithmetic mean ) dendrogram based on dice 's coefficient by the phoretrix 5.0 software ( totallab , newcastle upon tyne , uk ) . a total of 50 rectal swabs were collected from 40 alpacas and 10 llamas in different farms of putre ( parinacota ) . samples were collected during 2 different days , maintained at room temperature using copan transystem swabs ( copan , brescia , italy ) , and transported to the antofagasta university . samples were pre - enriched on brain heart infusion broth at 37c for 18 h , and then seeded on m - enterococcus and incubated at 37c for 48 h. all from each plate , at least five different colonies were reseeded and identified to the species level by maldi - tof mass spectrometry ( ms ) . complementary phenotypic analysis as well as antibiotic susceptibility were performed by the wider semiautomatic system ( fco . clinical and laboratory standards institute ( clsi ) criteria for antibiotic susceptibility breakpoints were applied ( 13 ) . whole dna of all enterococci strains was obtained by resuspending one colony in 200 l of distilled water , heating at 95c for 10 min , centrifuging for 5 min at 13,000 rpm , and collecting the supernatant . five l of the supernatant were used as a template in the polymerase chain reaction ( pcr ) . enterococcal species were assigned after pcr amplification of 16s rrna , rpob , rpoa , aac(6)-i , and phes genes ; subsequent nucleotide sequencing in a abi prism 3130 genetic analyzer ( applied biosystems , san mateo , ca ) ; and comparison with the blast database tool ( http://blast.ncbi.nlm.nih.gov/blast.cgi ) . the presence of efaa , agg , gele , esp , cyla , and ace genes was investigated by pcr using specific primers and conditions previously described ( table 1 ) . pulsed field gel electrophoresis ( pfge ) genomic dna was prepared in agarose plugs , digested with smai ( new england biolabs , beverly , ma ) , and run on a chef - dr iii ( bio - rad laboratories , hercules , ca ) , as described previously ( 18 ) . band pattern analysis was performed constructing an upgma ( unweighted pair group method with arithmetic mean ) dendrogram based on dice 's coefficient by the phoretrix 5.0 software ( totallab , newcastle upon tyne , uk ) . after selective culture of the 50 rectal swabs from 40 llamas and 10 alpacas , a total of 57 unrelated colonies presenting compatible morphology with enterococcus were finally selected . initially , up to five morphologically different colonies were analyzed from each sample , but finally only one colony by species and pulsotype was further selected . the most frequently human - related species , enterococcus faecalis and enterococcus faecium , were not found , and some discrepancies were detected in their identification ( table 2 ) . bacterial identification obtained by the different systems used in the 57 isolates according to material previously described ( 14 ) , the species was finally assigned by the 16s rrna , rpob , phes , and aac(6)-i genes , which were concordant in all of them . the worst result was obtained with the semiautomated wider system , based on phenotypical and biochemical tests . maldi - tof technology misidentified only the enterococcus hirae isolates , which were assigned to enterococcus mundtii . nevertheless , maldi - tof could be actually considered as a reliable method for enterococcal identification ( 1922 ) . e. hirae was the most frequent species detected ( 82.5% ) , followed by e. mundtii ( 10.5% ) , enterococcus casseliflavus ( 5.2% ) , and , finally , enterococcus gallinarum ( 1.7% ) . previous reports of gut microbiota from wild animals , including geese , free - living raptors , and other animals , confirmed the presence of these species ( 2325 ) . antibiotic resistance for penicillin , ampicillin , amoxicillin / clavulanate , daptomycin , levofloxacin , erythromycin , linezolid , minocycline , and nitrofurantoin was not detected in any enterococcal isolate , and glycopeptide resistance was confirmed in three e. casseliflavus isolates ( cmi=8 g / ml for vancomycin and susceptibility to teicoplanin ) . five e. hirae isolates and one e. casseliflavus isolate exhibited resistance to quinupristin / dalfopristin . dissemination of antibiotic resistance mechanisms and virulence genes has been demonstrated in enterococcal isolates from wild animals ( 2528 ) , although in our case , the altiplano remains a remote region with scarce antibiotic exposition . as to the genetic variability of these isolates by the pfge analysis , eight unrelated band patterns for the e. hirae isolates and three for the e. mundtii isolates were identified ( fig . pulsotype f was the most frequent , representing 57% of all e. hirae isolates , suggesting a common source of this clone or animal - to - animal transmission . although the animals belonged to different farms and are separated at night , during the day they roam freely and can have contact . dendrogram of the genetic relationship of the most frequent e. hirae and e. mundtii pulsotypes . in conclusion , enterococcus spp . from the chilean camelids gut microbiota were different from those adapted to humans ( e. faecalis and e. faecium ) , and remained free of antibiotic resistance mechanisms as well as virulence factors . genetic studies demonstrated the existence of several lineages in each species , suggesting a non - clonal situation . although enterococcus might be a major cause of bacteremia in newborn animals ( 11 , 12 ) , our results pointed out that potentially pathogenic isolates are not present in the gut of these animals . the authors have not received any funding or benefits from industry or elsewhere to conduct this study . part of this work has been finnanced by the european commission project evotar-282004 and the proyecto codei n5393 , dinv , universidad de antofagasta .

background enterococcus is one of the major human pathogens able to acquire multiple antibiotic - resistant markers as well as virulence factors which also colonize remote ecosystems , including wild animals . in this work , we characterized the enterococcus population colonizing the gut of chilean altiplano camelids without foreign human contact.material and methodsrectal swabs from 40 llamas and 10 alpacas were seeded in m - enterococcus agar , and we selected a total of 57 isolates . species identification was performed by biochemical classical tests , semi - automated wider system , mass spectrometry analysis by maldi - tof ( matrix - assisted laser desorption / ionization with a time - of - flight mass spectrometer ) , and , finally , nucleotide sequence of internal fragments of the 16s rrna , rpob , phes , and aac(6)-i genes . genetic diversity was measured by pulsed field gel electrophoresis ( pfge)-smai , whereas the antibiotic susceptibility was determined by the wider system . carriage of virulence factors was explored by polymerase chain reaction ( pcr).resultsour results demonstrated that the most prevalent specie was enterococcus hirae ( 82% ) , followed by other non enterococcus faecalis and non enterococcus faecium species . some discrepancies were detected among the identification methods used , and the most reliable were the rpob , phes , and aac(6)-i nucleotide sequencing . selected isolates exhibited susceptibility to almost all studied antibiotics , and virulence factors were not detected by pcr . finally , some predominant clones were characterized by pfge into a diverse genetic background.conclusion enterococcus species from the chilean camelids gut microbiota were different from those adapted to humans , and they remained free of antibiotic resistance mechanisms as well as virulence factors .