Datasets:

anumafzal94

/

10k-pubmed-4096

like 0

there are studies to examine proliferation and apoptosis associated biomarkers expressions in parathyroid lesions to reveal specific features . in this study , we evaluated the expression of some growth factors and their receptors in parathyroid gland of patients with sh or primary hyperparathyroidism ( ph ) . parathyroid tissue samples were evaluated histopathologically and immunohistochemically using antibodies to human p53 , ki-67 , anti - human p21 , antitransforming growth factor ( tgf ) , cpp32 ( caspase 3 ) , and epidermal growth factor receptor ( egfr ) . adenoma was higher in ph compared with sh as 48/49 and 3/26 , respectively ( p = 0.000 ) . parathyroid hyperplasia was found in 23/26 patients with sh and 1/49 patient with ph . in parathyroid tissue there were no difference between ph and sh for p53 , ki-67 , caspase , egfr expressions ; while there were significantly difference for tgf ( p = 0.047 ) and borderline significant difference for p21 ( p = 0.06 ) expressions . . there were no differences between primary and sh or adenoma and hyperplasia for expressions of cycline - dependent kinase inhibitor p21 , p53 , egfr , ki67 , caspase ; while tgf expression was found to be different . secondary hyperparathyroidism ( sh ) is one of the major problems of chronic renal failure ( crf ) . phosphorus retention , disorders of metabolism and secretion of vitamin d , parathyroid hormone ( pth ) , fibroblast growth factor 23 ( fgf23 ) , mg , and other various factors play role in the pathogenesis of the sh . pathological findings of the parathyroid gland in sh are diffuse or nodular hyperplasia , and adenoma . there are a lot of studies to examine proliferation and apoptosis associated biomarkers expressions in the parathyroid lesions to reveal specific features . in parathyroid hyperplasia down regulation of vitamin d receptor ( vdr ) and calcium sensitive receptor ( casr ) were reported , whereas in highly proliferative parathyroid adenomas , vdr and casr were found markedly decreased . in severe renal disease , vdr and casr decrease on parathyroid cells . in asian indians , these authors also found that cyclin d1 expression was greatly increased and correlated with adenoma weight , implying a potential role for cd1 in adenoma growth and differential clinical expression of ph . in parathyroid hyperplasia expression of transforming growth factor- alpha ( tgf , ) and its epidermal growth factor receptor ( egfr ) were found increased . ki-67 plays role through all cell cycle ( g1 , s , and g2 ) except g0 . p21 and p27 labeling index were found diminished significantly in both nodular hyperplasia and adenoma compared with that of diffuse hyperplasia and normal . it was reported that p53 , bcl-2 , and bax spectrum were similar primary and secondary ( i.e. renal failure ) parathyroid alterations . in this study , we aimed to evaluate the expression of proliferation and apoptosis biomarkers such as p53 , ki67 , egfr , tgf , and p21 in parathyroid tissue in patients with primary and sh . parathyroid tissue samples obtained from patients undergoing parathyroid surgery because of primary or sh , were evaluated . clinical data [ age , sex , primary disease , disease period , dialysis period if there 's and laboratory results including hemoglobin ( hb ) , hematocrit ( hct ) , blood urea nitrogen ( bun ) , creatinine ( cr ) , sodium ( na ) , potassium ( k ) , calcium ( ca ) , phosphorus ( p ) , caxp product , pth , aspartate aminotransferase ( ast ) , alanine aminotransferase ( alt ) , alkaline phosphatase ( alp ) , total protein , and albumin ] were recorded . immunohistochemistry was performed on formalin - fixed , paraffin - embedded tissue sections of 5 m thick by using a manual strept avidin - biotin complex immunoperoxidase procedure . for the procedure monoclonal mouse antibodies against human p53 ( novocastra , ncl - l - p53-d07 ; diluted 1:80/60 min incubation ) , ki 67 ( dako , m7240 ; diluted 1:100/60 min incubation ) anti - human p21 ( dako , m7202 ; diluted 1:100/60 min incubation ) , antitgf ( biogenex mu 377-uc ; diluted 1:80/90 min incubation ) , cpp32 ( caspase-3 ) ( novocastra , ncl - cpp32 ; diluted 1:100/45 min incubation ) , egfr ( dako , m3563 ; diluted 1/150/90 min incubation ) were used . for all antibodies tested , antigen retrieval treatment 15 min in 1 mmol citrate buffer solution ( ph 6.0 ) , using a microwave oven was performed and immune complexes were then detected with the ( dako , k 0690 ) and visualized by aec . slides were counterstained with mayer 's hematoxyline and mounted . for p53 ; colorectal carcinoma , for ki 67 ; tonsil , for p21 ; skeletal muscle , for tgf ; breast carcinoma , for cpp32 ; tonsil , for egfr ; skin tissue was used as positive controls . immunohistochemical evaluation of all antibodies was performed by using a double evaluating system calculated by multiplying the intensity of staining ( 0 , negative ; 1 , weak ; 2 , moderate ; and 3 , strong ) with the percentage of stained cells in a low power field ( 1 , 1%10% ; 2 , 11%-50% ; 3 , 51%-75% ; and 4 , > 75% ) . the immunohistochemical staining score was recorded . statistically , spss - x14 program were used and p < 0.05 was accepted significant . a total of 3 of the 26 patients with sh were operated in 6 months , following renal transplantation . a total of 48 of the 49 ph patients had adenoma , 23 of the 26 sh patients had hyperplasia . there was no difference from the point of diabetes mellitus ( dm ) and hypertension ( ht ) between the both groups of the ph and sh patients . presence or absence of chronic glomerulonephritis , autosomal dominant polycystic renal disease , urinary system stone disease , dm , and ht were not found significant in adenoma and hyperplasia groups . the results of expression of p21 , p53 , ki67 , capes , tgf on parathyroid tissue samples according to primary or sh are presented on table 2 . the biochemical parameters of patients with primary and secondary hyperparathyroidism the immunohistochemical staining score for p21 , p53 , ki67 , caspas , tgf expression on parathyroid tissue samples according to primary or secondary hyperparathyroidism sh is a frequent complication of crf and is characterized with parathyroid hyperplasia , increase of the expression and secretion of pth . persistence of hypocalcemia , hyperphosphatemia , and deficiency of vitamin d stimulates pth secretion and parathyroid gland hyperplasia . high serum levels of pth causes bone lesions , systemic and cardiovascular complications which increase morbidity and mortality . in crf patients , active form of vitamin d ( calcitriol ) inhibits expression of pth gene and stops growth of gland . so , calcitriol is an alternative therapy for sh . by the progression of renal failure , resistance of vitamin d and parathyroid cell proliferation developed . turnover of normal parathyroid cell cycle is slow , but in crf parathyroid cell proliferation increases by mitogenic stimuli of hypocalcemia , calcitriol deficiency , and retention of phosphorus . it was reported that downregulation of vdr and casr causes parathyroid hyperplasia . in highly proliferative varshney et al . , reported that the expression of both vdr and casr were found reduced in symptomatic ph in asian indians . these authors also found that cyclin d1 expression was greatly increased and correlated with adenoma weight , implying a potential role for cd1 in adenoma growth , and differential clinical expression of ph . according to latus et al . , casr , vdr , and an impaired klotho - fgfr - axis seem to be the major players in the development of sh . differences in some other expression molecules have also been described in parathyroid hyperplasia . increased expression of tgf and its egfr are the most important ones . in our study , tgf showed no significant difference between ph and sh patients ( p = 0.077 ) , but it was significantly different between adenoma and hyperplasia groups ( p = 0.047 ) . , found strongly expression of tgf mrna and protein in parathyroid endocrine cells of all six cases with primary parathyroid adenoma and nearly all cases of secondary hyperplasia , in contrast to absence of expression in normal control parathyroid tissue . ki-67 is associated with proliferation and plays role through all cell cycle ( g1 , s , and g2 ) except g0 . cyclin - dependent kinase ( cdk ) family is a group of protein that acts with cyclin proteins during cell proliferation . this role of cdk family is inhibited by cdk inhibitors and prevents progression of the cell cycle . p21 and p27 are cdk inhibitors . in our study , there were no significant differences from the point of these three proteins between ph and sh or adenoma and hyperplasia . p21 and p27 labeling index was found diminished in nodular hyperplasia and adenoma compared with control group and diffuse hyperplasia . according to some authors ; the reduced expression of p21 and p27 , in a vdr - dependent manner , is a major pathogenetic factor for a nodular parathyroid gland growth . p53 is a tumor suppressor gene located on chromosome 17p13 and codes p53 protein , known as gatekeeper of the cell . phosphoprotein which plays role in cell proliferation , apoptosis and differentiation , and acts in arrest of cell cycle , gene transcription and dna repair . control of apoptosis gets lost and uncontrolled cell proliferation becomes as a result . in our study , there was no significant difference between ph and sh , or adenoma and hyperplasia . in another study , no significant differences in the p53 , bcl-2 and bax spectrum were found in primary and secondary parathyroid alterations . p53 immunoexpression was not found useful in differentiating between the histopathological parathyroid subgroups . in sh group , vdr density was found diminished in nodular hyperplastic parathyroid gland and this was associated with diminished expression of p21 and p27 . in our study , we could not evaluate vdr density . calcitriol decreases parathyroid cell proliferation on c - myc gene expression which modules transition from g1 to s phase . decrease in serum calcitriol levels or deficiency of effect on parathyroid cell is frequently seen in uremic patients . this causes loss of inhibition of c - myc expression , so cell cycle progresses . calcitriol activates p21 gene by vdr - dependent way and p53-independent way . on the other side , cozzolino et al . , have showed uremic rats that 1,25 vitamin d and its lesser calcemic analog 19-nor-1,25 vitamin d prevents hyperphosphatemia and parathyroid hyperplasia , this effect develops with decreased ki67 levels which causes increase of p21 expression . this condition makes to think that calcitriol plays role in parathyroid cell proliferation . in our study , there was no significant difference from the point of ki67 , p21 between sh patients who received vitamin d therapy and ph patients who did not receive vitamin d therapy . vitamin d therapy may affect p21 and ki67 expression in sh patients . in our study , adenoma was priority present in ph patients , hyperplasia was present in sh . our patients with sh were treated with vitamin d to which affects low vdr levels , but we did not give therapy for casr . p21 , p53 , ki67 , caspase , and egfr expression were similar in primary and secondary hpt patients .

background : secondary hyperparathyroidism ( sh ) is major problem in chronic renal failure . there are studies to examine proliferation and apoptosis associated biomarkers expressions in parathyroid lesions to reveal specific features . in this study , we evaluated the expression of some growth factors and their receptors in parathyroid gland of patients with sh or primary hyperparathyroidism ( ph).materials and methods : a total of 49 patients had been operated for ph and 26 for sh . parathyroid tissue samples were evaluated histopathologically and immunohistochemically using antibodies to human p53 , ki-67 , anti - human p21 , antitransforming growth factor ( tgf ) , cpp32 ( caspase 3 ) , and epidermal growth factor receptor ( egfr).results : adenoma was higher in ph compared with sh as 48/49 and 3/26 , respectively ( p = 0.000 ) . parathyroid hyperplasia was found in 23/26 patients with sh and 1/49 patient with ph . in parathyroid tissue there were no difference between ph and sh for p53 , ki-67 , caspase , egfr expressions ; while there were significantly difference for tgf ( p = 0.047 ) and borderline significant difference for p21 ( p = 0.06 ) expressions.conclusion:adenoma was priority present in ph patients , hyperplasia was present in sh . there were no differences between primary and sh or adenoma and hyperplasia for expressions of cycline - dependent kinase inhibitor p21 , p53 , egfr , ki67 , caspase ; while tgf expression was found to be different .

most cases of hepatoblastoma are found under age two , and occurrence in adults is extremely rare.12 there are only 45 reported cases of adult hepatoblastoma globally,345 and only 3 cases in korea.267 most of the cases are asymptomatic and might be diagnosed at late stages of the disease.28 complete surgical resection is essential in the treatment of hepatoblastoma and standardized chemotherapy which reduces tumor size increases resectabilities,9 but not so many experiences in adult hepatoblastoma makes it difficult to occur complete remission . survival time varies from 2 week to 38 months , with a median of 6 months and is shorter in adults than childhood.10 we report a case of adult hepatoblastoma with chronic hepatitis b ( chb ) which was misdiagnosed as a combined hepatocellular carcinoma and cholangiocarcinoma ( chcc - cc ) . a 36-year - old female presented at the emergency department with aggravating right upper abdominal pain for 2 hours . the patient was diagnosed hepatitis b virus ( hbv ) carrier for several years and non - alcoholics . initial blood pressure was 100/60 mmhg , pulse rate 70/min , respiration rate 20/min , body temperature 37.5. the laboratory findings were white blood cell 12,000/mm ( poly : 70% ) , hemoglobin 12.8 g / dl , platelet 198,000/mm , prothrombin time 14.3 seconds , international normalized ratio 1.11 , aspartate aminotransferase 22 iu / l , alanine aminotransferase 12 iu / l , total bilirubin 0.5 mg / dl , alkaline phosphatase 134 iu / l , lactate dehydrogenase 295 iu / l , gamma - glutamyl transpeptidase 26 iu / l , protein / albumin 6.4/4.0 g / dl , uric acid 5.0 mg / dl , blood urea nitrogen / creatinine 16.6/0.7 mg / dl . and serum viral markers were hbsag ( + ) , anti - hbs ( - ) , anti - hbc ( + ) , hbeag ( - ) , anti - hbe ( + ) , hbv - dna < 20 iu / ml , anti - hcv ( - ) and anti - hiv ( - ) . the patient 's serum -fetoprotein ( afp ) was 676.5 ng / ml and carbohydrate antigen 19 - 9 ( ca19 - 9 ) < 0.6 u / ml . she took an abdominal ct scan , which showed a 9 cm sized necrotic mass with internal hemorrhage at the right hepatic lobe and ruptured to peritoneum ( fig . the initial histological diagnosis was chcc - cc with spindle cell metaplasia of cholangiocarcinoma element ( fig . regarding as chcc - cc , postoperative adjuvant chemotherapy with tegafur / uracil ( uft ) was administrated for 3 months . 3 months later , follow - up abdominal ct scanning showed previously unseen a 5.5 cm sized left subphrenic mass with mild enhancement in delayed image ( fig . on histologic examination , mesenchymal elements consisted of a proliferation of primitive - appearing mesenchymal spindle - shaped cells , intimately admixed with the epithelial elements in a highly cellular pattern . cytoplasm was more abundant than that of mature fibroblasts , and the nucleus was elongated and plump . these cells blended progressively with areas of less intense cellular mesenchymal proliferation , and with relatively acellular , fibrous septa . osteoid was present either within the primitive mesenchyme , near the fibrous septa or pseudocapsule , or admixed within the epithelial elements . the immunohistochemistry stains showed expression of hepatocyte , -hcg , afp , vimentin , ck7 , ck19 , cd56 and -catenin and negativity for cea . metastatic hepatoblastoma was confirmed by histologic examination with immunohistochemistry stains , so immunohistochemistrically re - examination of previous surgical specimens was also confirmed as hepatoblastoma . follow - up abdominal ct scan performed 1 month after reoperation showed a newly onset 1.7 cm sized subtle enhancing soft tissue mass in splenic bed , and positron emission tomography ( pet ) showed multiple fdg uptake(max suv > 3.80 ) in left upper and lower quadrant area of abdomen , paralumbar area including right subphrenic area ( fig . 5a , b , c ) . follow - up afp was 162.69 ng / ml . systemic chemotherapy started with cisplatin ( 60 mg / m ) , 5-fluorourasil ( 5-fu ) ( 600 mg / m ) , vincristine ( 1.5 mg / m ) and total 3 cycles of chemotherapy were done every 4 week . after the 3rd chemotherapy cycle , follow - up abdominal ct and pet scan showed progression of multiple intraperitoneal metastasis with large amount of intraperitoneal fluid ( fig . 6a , b ) and follow - up afp was further increased to 254 ng / ml . so chemotherapy regimen was changed to carboplatin ( 350 mg / m ) with doxorubicin ( 30 mg / m ) every 3 weeks . the patient experienced neutropenia after the new regimen , but recovered shortly after treatment with granulocyte colony - stimulating factor ( g - csf ) . after second carboplatin with doxorubicin chemotherapy , follow - up afp was increased 1510.19 ng / ml , but abdominal ct scan showed that amount of ascites was decreased ( fig . 7 ) . after 4th chemotherapy , follow - up abdominal ct revealed progression of multiple intraperitoneal metastatic masses , newly developed hepatic metastasis and large amount of intraperitoneal fluid ( fig . 8) . a diagnostic paracentesis was performed and showed white blood cell 310/mm ( poly 20% , lymph 80% ) , protein 3.6 g / dl and albumin 2.3 g / dl on ascitic fluid analysis . the serum albumin was 3.1 g / dl and serum - ascites albumin gradient ( saag ) was 0.8 g / dl . regarded as peritoneal carcinomatosis , the patient underwent conservative treatments including the use of repeated therapeutic paracentesis for 1 month before death . hepatoblastoma is a highly malignant tumor occurring in infants , and reports of adult cases are extremely rare . initial symptoms are non - specific and the usual presentation is failure to thrive , loss of weight and a rapidly enlarging abdominal mass . it has been shown that chronic hepatitis or liver cirrhosis is often present in adult cases , whereas in children hepatoblastoma can occur in a normal liver.11 in our case , the patient was a hbv carrier . because of the rare incidence of hepatoblastoma in adult , the initial consideration was a primary chcc - cc rupture associated with chb . abdominal ct scan demonstrated a 10814 cm - sized huge low - density mass in the liver and selective celiac angiogram revealed faint tumor staining from hepatic artery and splenic artery . the mesenchymal cells were spindle in shape and proliferated over the whole tumor with focal osteosarcomatous differentiation . the epithelial components showed well - differentiated hepatocellular carcinoma - like areas , poorly differentiated acinar or tubular structures . the patient 's serum hbsag was positive and afp was 9,103 ng / ml . abdominal ct scan demonstrated a 67 cm - sized huge low - density mass with central necrosis in liver . after surgery , the mass was finally diagnosed as hepatoblastoma on h&e stain.6 lee et al . , also reported a case of hepatoblastoma diagnosed by h&e stain in a pregnant woman . the patient 's serum hbsag was negative and afp was 199 ng / ml . abdominal ct scan demonstrated a huge heterogeneous mass in the liver . after surgery , patient died in about 25 days.7 all of these cases were confirmed by h&e stain . but , the mass was confirmed as a hepatoblastoma by histologic re - examination with immunohistochemistry stain . according to the widely used classification of ishak and glunz,12 hepatoblastoma can be divided into mixed epithelial and mesenchymal type and epithelial type , and the latter can be divided into fetal type and embryonal type,13 but mixed type is more common.10 the pathogenesis of hepatoblastoma are not yet exactly discovered , but chromosome 1q , 2(or 2q ) , 4q , 8(or 8q ) and 20 are known cytogenetic and molecular genetic alteration.14 loss of heterozygosity imprinting at locus 11p 15.5 , nuclear p53 accumulation and p53 mutation are other suggested pathogenesis of the malignancy.15 high expression of polo - like kinase 1 may be related to poorer outcome , but need to get more research outcome.16 according to embryologic theory , hepatoblastoma is known to originate during intrauterine life , but this hypothesis seems difficult to apply in the adult . because several cases of hepatoblastoma were found in more than 70 years of age,31117 and underlying liver cirrhosis was frequently found in adult,34 but not in children . the mass size varies from 2.5 cm to 25 cm in diameter , more commonly presented as single mass in right lobe , so multifocal type was reported only 1 case.10 in this case , presented with single mass in right lobe , afp - producing mixed epithelial and mesenchymal type . an additional 5 patients had a history of viral hepatitis ( a , b or c ) , but no reported fibrosis . general presenting symptoms are body weight loss , fever , abdominal pain , abdominal lymphadenopathy and masses , but these are non - specific , so found in a more advanced state.11 imaging study plays an important role in the initial diagnosis . ultrasonography can be used for initial evaluation , and ct , magnetic resonance imaging and laboratory examination like serum afp , beta- human chorionic gonadotropin ( hcg ) , serum platelet count also can be helpful . afp is usually elevated,11 beta - hcg is rarely elevated but can be the cause of pediatric isosexual precocity.18 in the final diagnosis , histologic confirmation is essential to differentiate from hepatic sarcoma , carcinosarcoma , malignant mesenchymal tumor , hcc with sarcomatous change.11 even if microscopic examination , differential diagnosis was difficult.111920 especially , chcc - cc which are intimately admixed hcc and cc was more difficult to distinguish from hepatoblastoma by histologic morphology.12 actually , gonzalez - crussi et al . , reported that pathologists were unfamiliar with various epithelial hepatoblastoma , so they mistook hepatoblastoma for hepatocellular carcinoma in adult.21 because the lack of experience of hepatoblastomas in adult patients with chb , we mistook it for chcc - cc initially . the reactivity has been found for keratin , ema , vimentin , polyclonal cea , heppar-1 , afp , 1-antitrypsin , cd99 , cd56(n - cam ) , human chorionic gonadotropin , transferrin receptor , and delta - like protein.2223 there was also showed that aberrant nuclear immunostaining for -catenin is a highly characteristic feature.24 our case showed that positive immunohistochemical stains of vimentin , -hcg , afp , ck7 , ck19 , cd56 and -catenin . survival improvement in last 30 years has been due to not only the surgery itself , but standardized chemotherapy which reduces tumor size and increases resectabilities.9 in 1990~1994 , siopel-1 ( society of pediatric oncology liver tumor study group launched its first prospective trial ) revealed preoperative chemotherapy and delayed surgical resection increases tumor resectability.25 doxorubicin , cisplatin , vincristine , 5-fu , cyclophosphamide are known relatively well responding chemotherapeutic agents.26 radical resection and chemotherapy are known most appropriate approach for hepatoblastoma , but not so many experiences in adult hepatoblastoma makes it more urgent to establish determinant of prognosis in hepatoblastoma.27 suggested poor prognostic factors were multiple lobes involvement , embryonic type , decreased p27 gene expression , multifocal dissemination , afp level lower than 100 or higher than 100,000 ng / ml.2829 survival time varies from 2 weeks to 38 months , 6 months in median , shorter in adult than childhood.10 the 3 reported cases in korea , survival time of 2 cases were about 25 days and 2 months after surgery.27 the one case could not be identified.6 but , our case showed that survival time was extended 12 months after the cisplatin , 5-fu , vincristine of 3 cycles chemotherapy and carboplatin , doxofubicin of 4 cycles chemotherapy . in addition , our case was quite severe that the size of tumor was 9 cm and intraperitoneal metastasis from a ruptured hepatoblastoma compared to the previous three cases , however , aggressive chemotherapy improved survival time . in conclusion , hepatoblastoma in adults is rare , but must be a consideration . it shows no distinct histological findings , but the diagnosis requires a pathologic examination including immunohistochemical stain .

hepatoblastoma usually occurs in children under the age of 2 years , with very few cases reported in adults . we experienced a case of adult hepatoblastoma in a 36-year - old female with chronic hepatitis b. she had experienced sudden onset abdominal pain . her serum alpha - fetoprotein level was markedly elevated , and abdominal ct showed a 9-cm mass with internal hemorrhage in the right hepatic lobe with hemoperitoneum , so an emergency hepatic central bisectionectomy was performed . the initial histologic examination revealed that the mass mimicked combined hepatocellular carcinoma and cholangiocarcinoma with spindle - cell metaplasia of the cholangiocarcinoma element . follow - up abdominal ct performed 3 months later showed a 5.5-cm metastatic mass in the left subphrenic area . laparoscopic splenectomy with mass excision was performed , and hepatoblastoma was confirmed histologically . a histologic re - examination of previously obtained surgical specimens also confirmed the presence of hepatoblastoma . metastatic hepatoblastoma was found at multiple sites of the abdomen during follow - up , and so chemotherapy with cisplatin , 5-fluorouracil ( 5-fu ) , and vincristine was applied , followed by carboplatin and doxorubicin . despite surgery and postoperative chemotherapy , she died 12 months after symptom onset .

virus taxonomy has historically considered multiple contributing types of biological data and hence is referred to as a polythetic system of classification ( as opposed to monothetic).1 our understanding of virus evolution has itself changed in parallel with the multiple technological developments that have made this classification system possible , with the emphasis at any one time being on the technology in vogue in that era . the types of data used for the purposes of classification range from what might be considered absolute ( eg , structural or genome data ) to comparative ( eg , serological ) . following the recognition of mosquitoes and ticks as vectors for virus transmission and isolation and propagation of these arthropod - borne viruses ( arboviruses ) in newborn mice , classification was largely dependent on antigenic evidence , which was painstakingly obtained using hemagglutination and various serological techniques.2 the comparative nature of this analysis meant that it was entirely dependent on sequential viral isolations and the storage of archival serological specimens , both crucial for determining accurate taxonomic groupings and defining the etiology of disease and transmission . ongoing collections of reference arboviral isolates have indeed provided the backbone for phenotypic , genotypic , and evolutionary studies of these important viruses and enabled significant advances in vaccine and therapeutic agent development . equally important is the continued development of vector control mechanisms and early diagnosis to assist public health initiatives and mitigation of disease . thus , it is the intention of this commentary to demonstrate the indisputable importance of arbovirus reference collections and their significance in future research and disease control . the advent of the molecular biology era , with its emphasis on nucleic acids , has led to the suggestion that it might theoretically be possible to develop a mathematically based system of virus classification using only genome sequence data , but it has yet to be demonstrated . on the other hand , it has also been argued that such a system may be practically unfeasible.3 with increasing emphasis on the storage of genome sequence data rather than the viruses themselves , there is the perception that the value of reference collections has diminished . this is particularly so when the biosecurity risk of carrying such material is considered , particularly in the absence of a vaccine . between 1980 and 1991 , a review of 58 publications revealed that of the 119 reported laboratory - acquired viral infections , approximately 75% were caused by arboviruses or hantaviruses , and by 1991 , the american committee on arthropod - borne viruses had assigned 535 registered arboviruses to biosafety levels 14.4 in australia , the department of health has designated nonvaccine strains of yellow fever virus as tier 2 level security sensitive biological agents ( http://www.health.gov.au/ssba ) . fundamentally , the above considerations potentially apply to all infectious agents . for example , in the case of variola virus , it could be argued that historic stocks of the virus have contributed little to recent research and hence should be destroyed.5 however , rapid urbanization and greater mobility have increased the epidemic risk of both previously known and new viral pathogens . with the current proportion of emerging viruses such as ebola , chikungunya virus ( chikv ) , and zika virus ( zikv ) , it is clear that we are far from a complete understanding of their unpredictable nature and ability to evolve into new , highly transmissible agents of disease . it is only from methodical analysis of previous strains that we can fully assess the true pathogenic potential of viruses , and this must be continually revised as new and more advanced technological capabilities become available . therefore , more detailed study of stored viral strains may unlock vital information necessary for future diagnostics and infection control . a good example of this is the use of archival isolates for the development and testing of pan - genus conserved primer sets.68 the primary value of reference collections is their inherent comparative capacity such that when new material is collected , it can be directly assessed against agreed reference strains , enabling the classification of material collected worldwide . reference strains are often the first strain ( or prototype ) obtained , and their authenticity can only be verified in reference to the original archival specimens . for example , the strain sofjin was the first isolate of tick - borne encephalitis virus collected and has since become the de facto reference strain . recent genome sequencing of the sofjin tick - borne encephalitis virus strain from an original collection was used to determine that a strain that had been designated sofjin held at another site had most likely been contaminated.9 this example demonstrates the value of archival material in maintaining the authenticity of reference strains , enabling data in different laboratories to be consistent for the purposes of comparison . strain authenticity is also imperative in the development of antigens for vaccines and diagnostic platforms . in 1962 , it was discovered that a seed lot of the yellow fever virus 17d - attenuated vaccine was contaminated with avian leukosis virus , a potentially oncogenic agent . rigorous measures had to be undertaken to eliminate the contaminant , and since 1982 only cleared and archived seed stocks of the vaccine have been used.10 another issue that has arisen in recent years is the repeated sampling of isolates of a given species of arbovirus , and the assignation of multiple names to essentially the same virus . in particular , this has occurred when a virus has been isolated at sites separated by a large geographic area . for example , malakal virus and kimberley virus are ephemeroviruses ( family rhabdoviridae ) which are midge and mosquito - transmitted arboviruses of cattle . these two viruses were collected on separate continents : malakal virus in 1963 in africa and kimberley virus in 1973 in australia . intriguingly , they share 90.6% nucleotide identity.11 based on current species demarcation for the group , they can be assigned to the same species . another example is tibrogargan virus and bivens arm viruses , tibroviruses ( family rhabdoviridae ) isolated in 1976 in australia and 1981 in the united states , respectively . similarly , these viruses share 93% nucleotide sequence identity and also should be considered part of the same species.12 these examples show that it is only by sequencing archival specimens that conflicts regarding accurate species designations can be resolved . this issue of double naming has been exacerbated when repeated samplings have occurred decades apart . in these cases , one isolate may be characterized using one technology , while the later one is characterized using an entirely different technology . as a result , a connection is never made between the two isolates , and they are designated different names . this was exemplified recently by two orthobunyaviruses ( family bunyaviridae ) : gan gan virus and trubanaman virus , isolated in australia in 1970 and 1965 , respectively . they have both been re - isolated and re - named as either salt ash virus ( gan gan virus ) or murrumbidgee and buffalo creek virus ( trubanaman virus ) , respectively.1315 in these cases , the original isolate was characterized using serological techniques , whereas the recent isolations were only characterized by sequencing . only by sequencing the original isolate was it apparent that the older and newer isolates were in fact the same species . hence , this example demonstrates the value of maintaining archival material for the purposes of clarifying virus classification in future . this is particularly evident when new technologies emerge which open previously unexplored opportunities for virus characterization . new phenotypes can emerge , as was seen recently with the emergence of a mutated , highly transmissible chikv strain on runion island and in the indian ocean in 20052006 , resulting in 266,000 human cases.16,17 in 2013 , chikv was introduced into the americas following an initial outbreak on the caribbean island , saint martin.18 surprisingly , phylogenetic analysis demonstrated that the indian ocean chikv lineage belonging to the east , central , south african genotype was not responsible for the later epidemics in the americas , which was caused by a strain belonging to the asian lineage . in both instances , it was crucial that contemporary circulating chikv strains could be compared both genotypically and phenotypically with older african and asian strains . similarly , with the advent of zikv emergence in the pacific in 2007 and the americas in 2015 , archival zikv strains were essential for comparative analyses . in particular , when infection of pregnant mothers with the 2015 brazilian strain of zikv was associated with cases of congenital malformation in newborns,19 a rapid cascade of research initiatives were undertaken . codon usage adaptation has been observed in the zikv asian lineage from which the brazilian strain was derived.20 an in vitro study comparing the 1947 african strain with the brazilian strain showed that the latter had significantly different growth properties in human cortical progenitor cells and organoids and induced cell death.21 it was only by comparing the brazilian strain with the archival strain that an emerging pathogenic phenotype could be demonstrated . the rapid change of the rna viruses , including arboviruses , has resulted in great diversity and adaptability . this does not always translate into viability , as various lineages go to extinction , to eventually be replaced by others . hence , archival specimens are essential to get an appreciation of the historical diversity of arboviruses . for example , japanese encephalitis virus ( jev ) isolates collected in indonesia before 1980 were predominantly genotype ii ( gii ) , while after that they were replaced with predominantly giv strains.22 in northern vietnam , prior to 1990 , the isolates collected were predominantly giii , while after that date they were replaced with strains of gi.23 similarly , in 1995 , an incursion of jev occurred for the first time in the australasian region in the torres strait.24 the arbovirus reference collection at queensland health provides key antigenic material that allowed the first cases to be diagnosed and provided subsequent material for further research . in 2000 , a second jev incursion into the region was identified , and it was discovered that the previously circulating gii virus was replaced in the torres strait with a gi virus.25 likewise with dengue virus serotype i , an isolate of gii has not been collected since the 1960s , and a subclade of gi has not been collected since the 1940s.26 it is only the historical collection of these isolates , and the subsequent sequencing when the technology becomes commonplace , which has made these evolutionary studies possible . these examples illustrate the importance of archival specimens to understanding the historical diversity of arboviruses and their evolution . there are a number of other examples of where archival isolates can shed light on viral evolution . by comparing the archival specimen with newer strains , they can provide direct evidence of genetic restructuring such as recombination or reassortment . for example , reassortment has been documented many times in the family bunyaviridae.27 the sequencing of the genome segments of archival specimens of this family will enable the origin of the various reassortant segments to be determined . importantly however , it is only the archival specimens themselves that present an opportunity to compare viral phenotypes at some future time and hence enable the evolution of such traits as virulence to be studied . finally , by their inclusion in long - term datasets , they can provide the basis for the accurate calculation of the rates of rna virus evolution . given the importance of arbovirus reference collections , a concerted effort should be made to address any biosecurity concerns rather than using this aspect as a means to eliminate them permanently . archival arbovirus isolates and specimens are an invaluable source of genetic information , enabling researchers to explore a number of important questions on virus evolution and pathogenesis , track the history of disease and assist identification of hosts and reservoirs . such collections should be adequately maintained to ensure the authenticity of reference material , establish taxonomic relationships , test improvements in diagnostics , and to answer fundamental questions as new technologies emerge .

historically , classifications of arboviruses were based on serological techniques . hence , collections of arbovirus isolates have been central to this process by providing the antigenic reagents for these methods . however , with increasing concern about biosafety and security , the introduction of molecular biology techniques has led to greater emphasis on the storage of nucleic acid sequence data over the maintenance of archival material . in this commentary , we provide examples of where archival collections provide an important source of genetic material to assist in confirming the authenticity of reference strains and vaccine stocks , to clarify taxonomic relationships particularly when isolates of the same virus species have been collected across a wide expanse of time and space , for future phenotypic analysis , to determine the historical diversity of strains , and to understand the mechanisms leading to changes in genome structure and virus evolution .

in 2009 , a novel influenza a(h1n1 ) virus caused the first influenza pandemic of the 21st century . , in the netherlands , the first case of infection with the pandemic virus strain was reported on 30 april , and 1622 cases were registered until 15 august 2009 . on this date , little is known about the clinical dynamics of symptoms during an influenza infection , despite this information being of potential use for control efforts , policy and communication . we investigated the dynamics of symptoms of pandemic influenza a(h1n1)pdm09 infections in community cases in the netherlands , and studied possible relationships between symptoms and viral load . a core research protocol was designed to enable collection of relevant data in case of an epidemic of an unusual human influenza virus . this protocol and the adapted 2009 version were approved by the medical ethical review committee of the university medical centre , utrecht . laboratoryconfirmed cases were recruited via municipal health services , general practitioners and academic hospitals . between 30 april and 14 august 2009 , as from 15 august , recruitment was continued in collaboration with the sentinel general practice network of nivel , the netherlands institute for health services research . twelve of the 42 gp practices were willing to participate requiring the gp to collect a nose and throat swab and finger prick sample at time of consultation . these samples had to be taken within 4 days of onset of illness . in november and december 2009 , patients with a laboratoryconfirmed infection hospitalized in one of three university hospitals were also approached . consenting patients agreed to sequential sampling of nosethroat swabs and blood specimens ( table 1 ) . furthermore , cases completed a questionnaire about demographics , medical history , vaccinations , symptoms and the use of antivirals . the cases were also asked to keep a daily diary recording symptoms and the use of antivirals each day for a maximum of 14 days . the cases rated severity of each symptom on a scale ranging from 0 ( none experienced ) to 10 ( symptom was present throughout the day ) by the case . research scheme of sampling and questionnaires per house visit * for cases recruited through the gp , visit 1 and 2 were combined . realtime rtpcr for detection of a(h1n1)pdm09 virus in combined nose and throat swabs and in rectal swabs was performed as described previously . to determine of the exact viral load in virus particles per ml , an electron microscopy ( em)counted standard of human influenza virus a / puertorico/8/1934 ( h1n1 ) was used ( provided by m. schutten , erasmus mc , rotterdam , nl ) . all clinical specimens and a dilution series of the emcounted control were retrospectively subjected batchwise to rna isolation and onestep matrix genebased realtime rtpcr , and the viral loads of the clinical specimens were estimated based on the batch calibration curve . the evolution of symptoms was examined by calculating the percentage of cases experiencing each symptom per day , together with the median severity score per symptom per day . the diary could be completed for a maximum of 14 days , which led to a censoring of duration of illness for cases who had symptoms for a longer period . associations between the highest estimated viral load in the first 5 days of illness and age , gender , underlying disease , duration of illness , and reported symptoms on the day of sampling were examined using the kruskal secondly , associations between all estimated viral loads and severity scores per symptom on the day of sampling were calculated using spearman correlations . all analyses were carried out for all cases , stratifying by the use of antivirals . a total of 120 laboratoryconfirmed cases were approached ; 76 ( 63% ) were willing to participate of whom 61 ( 51% ) cases reported their symptoms either in the questionnaire ( 46 cases ) and/or in the diary ( 38 cases ) . thirtyfour cases were treated with oseltamivir , and about twothirds started treatment within 3 days of the first symptoms occurring ( range 17 days ) . the cases reported an overall median duration of illness of 75 days ( range 221 days ) . the admitted cases were hospitalized for 39 days , and had a median duration of illness of 10 days ( range 713 days ) . characteristics of cases with a laboratoryconfirmed influenza a(h1n1 ) 2009 virus infection ( n = 61 ) cases with fever reported a maximum of 6 days of fever with a median of 2 days ( figure 1 ) . complaints of coughing were still present in more than 10% of the cases at day 14 . men appeared to have fever for a longer period ( 4 days ; 16 days ) than women [ 15 days ; 15 days ( p = 009 ) ] . all cases coughed in the first few days of illness and these complaints persisted ( figure 2 ) . diarrhoea was reported most frequently between day 4 and 6 ( almost half of the cases ) . nausea was reported by onethird of the cases on day 1 , and then declined . the severity of complaints was highest in the first 4 days for all symptoms ( figure 3 ) . a notable result is the unexplained rise in score for sputum production after day 9 . median severity score ( 110 ) per day per symptom as reported by the cases ( when reported by at least six cases per day ) . ninetytwo per cent of the nosethroat swabs taken within 1 week after onset of illness were positive ( 46/50 ) compared to 24% ( 9/37 ) in the second and 18% ( 4/22 ) in the third week . five of the six positive samples taken more than 14 days after day of onset were from three hospitalized cases . four cases , with a period of illness of 312 days , had a positive swab ( < 3000 viral particles / ml ) at 13 days after clinical recovery . median load was 8130 viral particles / ml ( range : 20117 000 000 ) . no difference in load was seen between samples taken at day 12 versus day 35 post onset of illness or use of antivirals . no difference in prescription of antivirals was seen between cases with and without underlying disease . a negative correlation was found between number of days with diarrhoea and highest available viral load [ 039 ( p = 002 ) ] , but no association between viral load and severity score for diarrhoea on the day of sampling was seen . a rectal swab , taken between day 4 and day 13 , was available for 31 cases . four specimens were positive , two cases had diarrhoea somewhere during their episode of influenza , but none on the day of sampling . of the 27 cases with a negative rectal sample , cases with comorbidities had on average a higher viral load than cases without , but without difference in the duration of illness . the opposite has been reported for seasonal influenza , but no association was found for a(h1n1)pdm09 influenza . previous comparisons of cases of varying severity did not reveal differences in initial viral loads , but patients with more severe disease or with comorbidities cleared the virus more slowly . , a negative association was only found between viral load and diarrhoea in the present study , whereas li et al found higher viral loads in patients with fever and in patients who developed pneumonia . faecal excretion of a(h1n1)pdm09 influenza virus could not be linked to diarrhoea in the current study , which has also been reported elsewhere . initially , the course of the 2009 pandemic resulted in staff resource challenges , which made it difficult to include more cases . subsequently , the mandatory notification in the netherlands was restricted , and a new route for inclusions had to be found . seventy per cent of the participants reported underlying diseases , mainly lung diseases ( 39% ) , compared to 168% of all notified laboratoryconfirmed cases in the netherlands ( 91% lung diseases ) , indicating that selection bias is likely to have occurred . furthermore , people with comorbidities will visit their gp faster in the case of influenzalike illness ( ili ) than healthy persons experiencing ili , and thus have a higher chance to be included . however , no indications were found for a different course of the disease in the cases with comorbidities . in conclusion , the pandemic offered a unique opportunity to investigate the clinical dynamics of influenza , complementing the information obtained through traditional public health surveillance . systemic symptoms dominated during the first 4 days , whereas respiratory symptoms peaked in the first few days and resolved slowly . the severity of each symptom was rated highest in the first few days and then declined . diarrhoea appeared to be negatively associated with viral load , but not with faecal excretion of influenza virus . patients with underlying disease seemed to have higher viral loads , suggesting a less effective immune response , although they were not significantly more severely ill . if participated in the design and coordination of the study , performed the statistical analyses and drafted the manuscript . am participated in the design and coordination of the study , drafting the manuscript and was responsible for the virological assays . avg participated in the design and coordination of the study , in performing the statistical analyses and drafting the manuscript . mvdl participated in the design and coordination of the study , and was responsible for the virological assays . jvb participated in the design and coordination of the study , and processing the laboratory results . gd participated in the coordination of the study , and headed the network of general practices . jp and mdj participated in the design and coordination of the study with respect to the academic centres . mk participated in the design and coordination of the study as project leader of the dutch zonmw influenza a(h1n1 ) 2009 consortium . mvds participated in the design and coordination of the study in performing the statistical analyses and drafting the manuscript . rivm , bilthoven : l van asten , d baas , d beaujean , j van beek , r van binnendijk , m van boven , r coutinho , f dijkstra , t donker , ihm friesema , ab van gageldonklafeber , f heijningen , w van der hoek , l isken , f van der klis , t van t klooster , m koopmans , m kretzschmar , i m van der lubben , m mak , a meijer , j reimerink , r riesmeijer , mab van der sande , j van steenbergen , a steens , p teunis , a timen , l vinck , j wallinga , a westerhof , l wielders , cc van den wijngaard ; nivel , utrecht : ga donker , m hooiveld , j ijzermans , f schellevis , r verheij ; erasmus medical centre , rotterdam : c boucher , r fouchier , p de fraaij , a osterhaus , g rimmelzwaan , m schutten ; academical medical centre university amsterdam : m de jong , j prins ; utrecht university medical centre , utrecht : c kesmir , jj van oosterheert ; radboud university nijmegen medical centre , nijmegen : jc braspenning , m bults , r grol , m hulscher , j van der meer , majb tacken ; leiden university medical centre , leiden : j van dissel ; public health service of amsterdam and loi , amsterdam : a van den hoek ; rotterdamrijnmond public health service , rotterdam : o de zwart ; iresearch , berg en dal : m van der velden .

please cite this paper as : friesema et al . ( 2012 ) . course of pandemic influenza a(h1n1 ) 2009 virus infection in dutch patients . influenza and other respiratory viruses 6(3 ) , e16e20.the clinical dynamics of influenza a(h1n1 ) 2009 infections in 61 laboratoryconfirmed dutch cases were examined . an episode lasted a median of 75 days of which 2 days included fever . respiratory symptoms resolved slowly , while systemic symptoms peaked early in the episode and disappeared quickly . severity of each symptom was rated highest in the first few days . furthermore , diarrhoea was negatively associated with viral load , but not with faecal excretion of influenza virus . cases with comorbidities appeared to have higher viral loads than the cases without , suggesting a less effective immune response . these results complement information obtained through traditional surveillance .

cysts in the lungs are airspaces lined by epithelia and may arise due to a number of causes . cysts arising as a complication of pulmonary tuberculosis have been very rarely reported and are amongst the rarest presentation of this common disease . in tuberculosis cysts may evolve with varied outcome and severity during the course of the disease and may persist following treatment of tuberculosis . here , we report a case of lung cysts in a young patient with pulmonary tuberculosis . a13-year - old female patient presented with the complaints of fever for 1 month duration and shortness of breath for 10 days . she also complained of decreased appetite and significant loss of weight for the same duration . on examination , patient 's pulse rate was 130 beats / min , blood pressure was 100/70 mmhg , respiratory rate was 48/min . a contrast enhanced computed tomography thorax [ figures 1 and 2 ] showed multiple thin walled cysts seen in both the lungs ( left > right ; upper lobe > lower lobe ) ; diffuse ground glass opacities and centrilobular nodules in both lung fields . transverse section of computed tomography thorax showing nodular opacities and cysts in both lungs at the time of presentation coronal section of computed tomography thorax showing the widespread lung cysts at the time of presentation patient was intubated and ventilated in view of respiratory failure and impending respiratory arrest in the intensive care unit bronchoscopy was performed through the endotracheal tube and washings taken . transbronchial lung biopsy was performed and sent for histopathological examination , which showed granulomatous inflammation consistent with tuberculosis . patient was treated with antitubercular regimen ( isoniazid , rifampicin , pyrazinamide and ethambutol ) with steroids ( 1 mg / kg ) . the fever subsided and the patient could be weaned off the ventilator within 10 days of starting the above treatment . patient was discharged after 1 week . at the time of discharge abg showed pao2:73 mmhg , paco2:28.5 mmhg , ph:7.446 . steroids were continued for 1 month after which it was tapered gradually over 1 month . anti - tubercular drugs were continued for 6 months . at the end of treatment , abg showed pao2:95 mmhg , paco2:39 mmhg , ph:7.39 . repeat high resolution computed tomography thorax [ figures 3 amd 4 ] showed a reduction in the number and size of cysts in both the lung fields with decrease in diffuse lung opacities and nodular lesions . coronal section of computed tomography thorax repeated after completion of 6 months of treatment showing reduced number and size of cysts in the lung transverse section of computed tomography thorax repeated after completion of 6 months of treatment showing reduced number and size of cysts in the lung a lung cyst is defined as a well - circumscribed air - filled structure that is localized with in the lung parenchyma , is > 1 cm in diameter and has a definable epithelial or fibrous wall that is usually < 1 mm thick , but that may be upto 2 or 3 mm thick . a variety of lung diseases can cause or mimic thin - walled air - containing cysts in the lung . the more common congenital causes for cysts in lung diseases include central and peripheral bronchogenic cysts , intralobar pulmonary sequestrations , congenital cystic bronchiectasis , cystic adenomatoid malformation of lung and tracheobronchial papillomatosis . cystic lung disease may be acquired in conditions such as histiocytosis - x , bullous emphysema , pneumatocoeles and post - infectious states . tuberculosis may present with atypical manifestations in one - third of the cases and multiple thin - walled cysts are one such rare manifestations of tuberculosis . some of the possible causes attributed to the development of cystic lesions in lung due to tuberculosis are : ( 1 ) caseating necrosis of the bronchial walls , leading to cystic bronchiectasis as a distal extension of fulminant tubercular bronchitis . ( 2 ) granulomatous involvement of the bronchioles may lead to a check - valve mechanism leading to cyst formation . ( 3 ) scarring of larger bronchi due to tuberculosis may lead to stenosis proximally , with dilatation of the distal end with retained secretions due to secondary bacterial infections causing inflammatory destruction of the bronchial wall leading to cyst formation . ( 4 ) some healed tubercular cavities may be partly re - lined by ciliated epithelia and form cyst like structures . ( 6 ) intermittent obstruction of the bronchioles by caseous material originating from parenchymal lesions . most of patients developing lung cysts with tuberculosis have an extensive bilateral infiltrative and an exudative kind of disease as a part of pneumonitic process . while in some cases , the cysts are reversible , in others , the cysts remain static without progression and may persist following tuberculosis . it should be remembered that development of cysts is seen in tuberculosis often with varying severity , extent and unpredictable outcome . thus , pulmonary tuberculosis may present as cystic lung disease in rare instances and should be kept as a possible cause of acquired cystic lung disease in appropriate clinical settings .

cysts in the lung can arise due to large number of causes out of which tuberculosis is very rare , we report a case of tuberculosis in a young female presenting as a febrile illness and respiratory failure with radiological features of cystic lung disease . with treatment , fever and respiratory distress subsided and cysts in the lungs showed partial regression . we highlight the need to consider tuberculosis in the differential diagnoses of cystic lung disease under appropriate circumstances .

cost - effectiveness in health care can be defined as that intervention indicated relative to the resources consumed ( atherly et al . , 2000 ) . in orthodontics , this is of importance to the patient , the practitioner , and the health care provider . in the case of publicly funded or insurance - based services , cost - effectiveness is of interest to the health care providers , be they a department of health or an insurance company . where finite resources exist , failure to apply the principles of cost - effectiveness may bring an opportunity cost ( tickle , 1997 ) manifesting as an unsustainable financial overspend or reduced health care services in other areas . when orthodontic provision is paid for solely by the patient , cost - effectiveness is of interest to both patient and practitioner , as improved cost - effectiveness results in lower patient costs and/or increased practitioner profit . orthodontic treatment has been reported to have no effect on quality of life ( shaw et al . , 2007 ) , so a cost - effectiveness analysis ( cea ) may be more appropriate than a cost - utility analysis . in order to carry out a cea , a well - defined treatment outcome is required . orthodontic indices provide a valid and reliable method of measuring treatment outcomes ( shaw et al . , 1991 ) . the index of complexity , outcome and need ( icon ) with its internationally agreed values ( daniels and richmond , 2000 ) allows quality assurance assessments to be carried out and compared between different operators . incremental cost - effectiveness ratios ( icers ) have previously been used to study cost - effectiveness in orthodontics ( richmond et al . , 2005 ) . such ratios are accepted as the gold standard in the health economics community ( karlsson and johannesson , 1996 ) and permit the construction of cost - effectiveness league tables to rank practitioners . in order to allow significance testing to be applied to these leagues tables , complex statistical inference techniques such as non - parametric bootstrapping ( efron and tibrishani , 1993 ) are required . although cost per icon point reduction is only an average cost - effectiveness ratio , it is a simple means of comparing the cost - effectiveness of practitioners without the need for complex statistical advice or software . health tourism is a commonly used term in the medical and lay press describing the situation whereby patients seek treatment in countries in which they are not normally resident . this situation occurs across the european union ( eu ) and has implications for health care planners and providers . notably , the patient 's right to claim remuneration for cross - border orthodontic care without pre - authorization has already been ratified by the european court ( hermans , 2000 ) . the future is likely to see a rise in health tourism with the possibility also of a trans - european health care provider . the choice of location to receive care will have many factors but the quality and cost of treatment will always be considered . health care providers and patients may increasingly demand cross - border analysis of both factors . this study aims to demonstrate a simple method of comparing cost - effectiveness of orthodontic practitioners from different countries within the eu . ten specialist orthodontic practitioners were visited in seven european countries [ two in the czech republic ( a and b ) , two in germany ( a and b ) , italy , latvia , lithuania , and netherlands , and two in slovenia ( a and b ) ] during the summer of 2005 cases that had insufficient or inadequate records were excluded , as well as those that involved orthognathic surgery . the costs of surgery for orthognathic patients are complicated to assess and have been shown to be proportionately larger than the associated costs of orthodontic treatment ( kumar et al . , 2006 ) . icon considers dental aesthetics , crossbites , anterior vertical relationship , upper anterior crowding , and buccal segment relationships . icon uses the standardized continuum of aesthetic need ( evans and shaw , 1987 ) used in the aesthetic component of the index of orthodontic treatment need . each component is adjusted by its pre - determined weighting and then totalled to give an icon score . one author ( jd ) was formally calibrated in the use of icon and scores were calculated for pre- and post - treatment study models . intra - operator reliability testing was carried out by randomly repeating icon scoring for 10 per cent of the cases at the end of each day of data collection . these costs were converted into euros ( ) using current exchange rates and then adjusted to reflect real exchange rates as described by schreyer and koechlin ( 2002 ) using purchasing power parity ( ppp ) indicators published by the union bank of switzerland ( 2005 ) . ppp indicators are calculated by comparing the cost of living , domestic goods and services in cities across the world . the costs in this study were adjusted according to equivalent united kingdom ppp score of 99 ( table 1 ) . cost - effectiveness was calculated as the cost per icon point reduction for each of the practitioners . a root mean square error of less than nine for reliability scoring using icon has been recommended ( richmond et al . , 2005 ) . a one - way analysis of variance ( anova ) was used to test normally distributed data with tukey post hoc tests where applicable . where possible , skewed data were transformed to its natural log to allow an anova to be carried out . a total of 429 cases were included in the study , 172 male ( 40.1 per cent ) and 257 female ( 59.9 per cent ) . the median age of the patients at the start of treatment was 13.0 years , with a minimum of 7.3 years and a maximum of 50.3 years . the patients had a range of malocclusions and the majority ( 97 per cent ) were treated with upper and lower fixed appliances . altman plots were constructed to provide a visual appreciation of intra - operator reliability testing . they showed that 87 per cent of pre - treatment and 69 per cent of post - treatment icon scores lay within 1 standard deviation ( sd ) of the mean . the 1 sd for pre - treatment scores was 6.5 and for post - treatment scores 2.3 icon points . the root mean square error was calculated which for pre - treatment icon scores was 7.83 and for post - treatment icon scores 2.12 . the median adjusted cost of treatment was calculated for each of the practitioners ( table 2 ) and ranged from 1119.67 ( lithuania ) to 5811.89 ( slovenia a ) . there were significant differences in the cost of treatment between practitioners ( kruskal wallis p < 0.001 ) . the effectiveness of the practitioners was measured in icon point reduction and acceptability ( table 3 ) . a successful case was one with an icon score of less than 31 at the end of treatment . the mean icon point reduction ranged from 39.04 ( czech republic b ) to 57.67 ( lithuania ) . anova demonstrated significant differences in the mean icon reduction between practitioners ( p < 0.001 ) . effectiveness of treatment for orthodontic practitioners measured by the index of complexity , outcome and need ( icon ) point reduction and percentage of cases achieving an acceptable icon score ( < 31 ) . the cost - effectiveness was calculated as the cost per icon point reduction using costs adjusted for ppp indicators . the median cost per icon point reduction for all the cases in this study was 57.70 . there was great variation in the median cost per icon point reduction for the practitioners ( table 4 and figure 1 ) . these ranged from 21.70 ( lithuania ) to 116.62 ( slovenia a ) and the differences between practitioners for cost per icon point reduction were significant ( kruskal cost - effectiveness of orthodontic provision for practitioners measured as cost ( in euros ) per point reduction of the index of complexity , outcome and need ( icon ) . box plot of data for cost per index of complexity , outcome and need ( icon ) change for practitioners in this study . the heavily skewed data for cost per icon point reduction were converted to its natural log to allow an anova to be carried out . this showed a statistically significant difference in cost per icon point reduction between orthodontic practitioners ( p < 0.001 ) . subsequent tukey post hoc tests showed the individual association between practitioners ( table 5 ) . statistically significant differences in cost - effectiveness between practitioners for the mean of the natural log of cost per index of complexity , outcome and need point reduction . this cross - sectional study demonstrates a simple and robust method of comparing the cost - effectiveness of orthodontic practitioners within the eu , which has the potential to be routinely used by the practitioners themselves . the icon was found to be a reliable index , its international validation permits its use across europe to assess treatment need , complexity and outcome . this may lead to a possibility of some orthodontists selecting their best cases to be scored . all the practitioners were shown to be effective in their provision of orthodontic care . the percentage of cases achieving an acceptable post - treatment icon score ranged from 70 to 100 . this compares favourably with two previous icon studies that found 71 and 59 per cent of cases achieved an acceptable outcome ( richmond et al . , 2001 , 2005 ) . as the 2005 study was carried out prospectively and the practitioners selected randomly , those findings may be a more accurate representation of orthodontic treatment outcome . other studies investigating the effectiveness of orthodontic provision that have used the peer assessment rating index have shown great variation in outcomes . the lower outcomes ( kerr et al . , 1993 , turbill et al . , 1999 , teh et al . , 2000 ) can be partially explained by the high percentage of cases treated with removable appliances or fixed appliances limited to one arch only . higher outcomes , such as those found in norway ( richmond and andrews , 1993 ) could be explained by the retrospective nature of the study and the voluntary basis of practitioner recruitment . the findings in the present investigation suggest that there may be significant differences in the cost - effectiveness of orthodontic care when viewed from a pan - european perspective , but this is largely explained by the differences in costs . the prescribing habits of the orthodontists in this study were not sufficiently different to be a significant factor in cost - effectiveness . a larger study is required to confirm that this is the case for all eu practitioners . the true value of a cost - effectiveness study occurs when differences in cost - effectiveness can not be explained by costs alone . in such a situation , practicing habits should be analysed to identify procedures or appliances that are more cost - effective . cost per icon point reduction offers a simple and robust method for practitioners to calculate the cost - effectiveness of their treatments and to compare their performance with colleagues . the results of the research are compromised by the small number of orthodontists who took part . the standard of orthodontic treatment provided by the participants in this study may not be representative of orthodontists working in that country . this study was exploratory in nature and to investigate differences in orthodontic provision in detail , a large prospective investigation will be necessary . the orthodontists from the accession states of the czech republic , latvia , and lithuania all performed well in terms of cost - effectiveness mainly as a result of the lower costs of care associated with these growing economies . however , unlike other one - off health care interventions , the multiple visit nature of orthodontic care imposes travel and subsistence costs for the health tourist . as a result , cross - border care of this nature is likely to be localized to short car journeys unless the cost differential is significantly great to justify treatments further a field . cost - effectiveness league tables are a useful tool for health care planners to allocate finite resources to best treat a population or society as a whole . the accurate construction of these league tables ( karlsson and johannesson , 1996 ) involves the exclusion of dominated ( the cost effectiveness ratios are usually ranked this means theoretically dismissing the treatment option of using a particular practitioner . unlike a drug or treatment modality , excluding highly trained practitioners from treating patients on the grounds of cost - effectiveness performance alone is unlikely to be cost - effective . using cost - effectiveness analyses to identify procedures and appliances that make better use of resources and help implement efficient working practices will enable orthodontists and third - party payment agencies achieve value for money. previously , only one publication has considered cost - effectiveness in orthodontics ( richmond et al . , 2005 ) . this study used icon to calculate icers and subsequently construct league tables ( fox - rushby et al . , 2001 ) . when constructing league tables , it is important to stress that the order of ranking should be dependent on the statistically significant differences between orthodontists . when orthodontists show similar cost - effectiveness , they should be grouped together rather than ranked . the use of league tables for the identification of low cost and highly effective orthodontists will be of benefit to the patient , the orthodontist , and third - party payment agencies . the cost per icon point reduction offers a simple measure that can be used by all parties to evaluate cost - effectiveness . icon is a reliable orthodontic index that can be used in cost - effectiveness studies . cost per icon point reduction is a simple and effective method of comparing cost - effectiveness between practitioners . by calculating real exchange rates using ppp indicators , treatment costs can be compared between practitioners in different countries .

this study investigated the orthodontic treatment of 429 consecutive patients [ 172 male ( 40.1 per cent ) and 257 female ( 59.9 per cent ) ] carried out by 10 orthodontic specialist practitioners in seven european countries [ two in the czech republic ( a and b ) , two in germany ( a and b ) , italy , latvia , lithuania , and netherlands , and two in slovenia ( a and b ) ] . the median age of the patients at the start of treatment was 13.0 years ( minimum 7.3 years maximum 50.3 years ) . the patients had a range of malocclusions and the majority ( 97 per cent ) were treated with upper and lower fixed appliances.real exchange rates were calculated using purchasing power parity ( ppp ) indicators to allow cross - border comparisons of costs . the index of complexity , outcome and need ( icon ) was used to measure the effectiveness of treatment and cost per icon point reduction to compare cost - effectiveness of orthodontic treatment between practitioners in different european countries.the median cost per icon point reduction for all the cases treated was 57.69 . the median cost per icon point reduction varied greatly between practitioners from 21.70 ( lithuania ) to 116.62 ( slovenia a ) . analysis of variance and tukey post hoc tests showed the differences in cost - effectiveness between the practitioners to be statistically significant ( p < 0.001).the cost per icon point reduction is a simple and effective method of comparing cost - effectiveness between orthodontic practitioners in different countries .

ectoparasites are important cause of pruritic and non - pruritic skin disorders in dogs and can cause hypersensitivity or death depending on the host nutritional and immunological condition and intensity of parasitic infestation . ectoparasites play an important role not only as pests but also as vectors of various infectious diseases of humans , livestock , pets and wild animals . they can transmit different pathogens like viruses , bacteria , protozoa or act as intermediate hosts for filarids and cestodes ( fuehrer et al . ticks , after mosquitoes , are the second most important arthropods that may transmit pathogens to animals and human beings . moreover , fleas can transmit pathogens , such as the agent of flea - born rickettsioses , murine typhus and bubonic plague . they can also serve as intermediate hosts for some species of cestodes ( xhaxhiu et al . chewing lice are active arthropods that can produce intense irritation with secondary bacterial infections ( wall et al . trichodectes canis are highly host specific , but they can act as an intermediate host for dipylidium caninum that may affect humans , especially children ( scott et al . some studies regarding etoparasites on dogs have been done in iran ( shoorijeh et al . 2008 , mosallanejad et al . 2011 , jamshidi et al . 2012 , bahrami et al . 2012 ) but information about ectoparasites on stray dogs is still lacking . the aim of this study was to determine the prevalence of ectoparasite infestations in stray dogs in mazandaran , gilan and qazvin provinces , iran . seventy stray dogs were inspected from december to march 2013 , for the presence of ectoparasites in mazandaran , gilan and qazvin provinces , iran . their sex and age were recorded . the studied animals were divided into three groups based on the age ( <3 , 35 and > 5 years old ) . the body of the dogs was completely examined and the ectoparasites were removed by using forceps , combing or brushing from the animals and stored in 70% ethanol . areas of the skin with dermatologic lesions were scraped deeply with an oily scalpel blade until capillary bleeding was visible . skin scrapings and ears swabs were placed in 10% potassium hydroxide and gently heated for 30 min . then , the material was centrifuged , and the sediment was microscopically examined for mites . the ectoparasite species were identified under a stereomicroscope , according to the identification keys ( hopkins and rothschild 1953 , smit . a chi - square test was used to determine any significant associations between rate of infestation and age and sex . analyses were conducted using spss software version 16 ( chicago , il , usa ) with a probability ( p ) value of < 0.05 as statistically significant . a chi - square test was used to determine any significant associations between rate of infestation and age and sex . analyses were conducted using spss software version 16 ( chicago , il , usa ) with a probability ( p ) value of < 0.05 as statistically significant . fifty - eight out of 70 examined dogs ( 82.8% ) were positive for ectoparasites . the rate of infestation in qazvin , gilan and mazandaran provinces were 100% , 68.5% and 93.3% respectively . the isolated arthropods were fleas in 45 ( 77.5% ) , lice in 29 ( 50% ) , ticks in 5 ( 8.6% ) , flies in 4 ( 6.8% ) and mites in 3 ( 5.1% ) infested dogs ( table 1 ) . in this survey , 4 species of flea consist of ctenocephalides canis ( 29.8% ) , c. felis ( 19.9% ) , pulex iritans ( 2.9% ) and xenopsiella cheopis ( 0.7% ) , one species of louse , tick , fly and mite including : trichodectes canis ( 41.3% ) , rhipicephalus sanguinus ( 0.7% ) , hippobosca sp . ( 1.1% ) and sarcoptes scabei ( 3.6% ) were found , respectively ( table 2 ) . the number of stray dogs infested by different ectoparasites based on each studied areas number and percent of ectoparasite species on infested dogs in the studied areas triple infestation was observed in 8.6% of the infested dogs ( 40% of these with flea+lice+tick , 40% with flea+lice+fly and 20% with tick+lice+mite ) . 39.6% of dogs exhibited double infestation ( 73.9% of these with lice+fleas , 8.7% with ticks+lice , 8.7% with fleas+flies and 8.7% with fleas+mites ) . the analysis of different infestation types showed that the most of these hosts had single infestation , followed by double and triple infestation . the mean number of fleas , lice , ticks , flies and mites on each infested dogs was 9.9 , 11.9 , 1.2 , 2.5 and 10 , respectively . according to the host age , the highest prevalence of infestation was observed in <3 years old ( 88% ) followed by 35 ( 77.7% ) and > 5 years old ( 70.5% ) , however no significant differences were observed between infestation rate and age groups of dogs ( p= 0.267 ) . ectoparasitic infestations were recorded on 33 male dogs ( 89.1% ) and 25 female dogs ( 75.7% ) . no statistically significant difference was observed between ectoparasite infestation and host gender ( p= 0.137 ) ( table 2 ) . ectoparasites distribution of the studied dogs was 36% around the neck , 20% on backside portion , 25% on abdomen and 19% on other body sites . ( 2011 ) have recorded a prevalence of 88.6% in dogs in ethiopia and identified 8 species of ectoparasites in their study . different studies have been done to detect ectoparasites on dogs in various parts of the world . ( 2009 ) determined nine species of arthropods with a prevalence of 79% in dogs in albania . kumsa and mekonnen ( 2011 ) identified six species of ectoparasites with a prevalence of 99.5% in dogs in ethiopia . ( 2012 ) have reported seven species of ectoparasites in 44.26% of the dogs from ilam province . ( 2011 ) found eight species of ectoparasites in companion dogs in ahvaz district , 36 out of 126 dogs ( 28.57% ) were positive for ectoparasites . nine and seven species of arthropods have been reported in pet dogs in tehran and shiraz province , with a prevalence of 36.4% and almost 25% , respectively ( shoorijeh et al . 2008 , jamshidi et al . 2012 ) . fleas were the most common ectoparasites in this survey and c. canis was the most common flea , followed by c. felis , p. irritans and x. cheopis . they identified three species of fleas consist of c. canis , c. felis and p. irritans . in addition , c. canis was more predominant than c. felis and p. irritans . examination of dogs in greece revealed the presences of four species of fleas consisting of c. canis , c. felis , p. irritans and x. cheopis , the first species was the most frequent that was found on the dogs ( koutinas et al . 1995 ) . c. canis was the only species found on dogs in rural areas ( gonzlez et al . in other studies c. canis was not observed on dogs ( alberto cnn - franco et al . beresford - jones ( 1981 ) , dryden and rust ( 1994 , usa ) and alcno et al . ( 2002 ) noted that within flea species , c. canis is the most predominant species on dogs in rural areas , whereas c. felis is the most common in urban areas . since our study was done on stray dogs in rural and urban areas , this could explain the presence of both these two flea species . in our study , female fleas were more abundant than males , which is in agreement with other findings . one reason of this matter could be related to greater ability of females to evade capture during host grooming ( durden et al . 2005 , gracia et al . ( 2011 ) determined only one louse species , heterodoxus spinigera and that was the most common ectoparasites on dogs in their study in ahvaz province . in the present study , only one louse species was observed , including trichodectes canis . ( 2008 ) in shiraz province iran . in the study carried out by jamshidi et al . ( 2012 ) 5.6% and 4% of ectoparasites were t. canis and linognathus setosus respectively . ( 2012 ) observed lice species including heterodoxus spinigera and l. setosus on dogs from ilam province . ( 2012 ) identified ticks as the main species of ectoparasites in dogs , with a prevalence of 47% and rh . the mean number of ticks was very low , almost one tick on each infested dogs . the reason can be related to sampling season , ticks are abundant in the warm and humid weather ( adamu et al . 2012 ) . rhipicephalus sanguineus can transmit the etiological agents of canine babesiosis and canine monocytic ehrlichiosis ( dantas - torres 2008 , rene et al . one species of fly ( hippobosca ) and mites ( sarcoptes scabiei ) were detected . ectoparasites from dogs belonging to people in resource - poor communities in south africa has studied that harbored hard ticks belonging to 6 species ( haemaphysalis leachi , rh . simus ) , fleas ( c. felis , echidnophaga gallinacea ) and lice ( h. spiniger ) and myiasis , caused by the larvae of cordylobia anthropophaga ( brysona et al . high infestation with different arthropods were observed on stray dogs in center and north of iran . ectoparasites play an important role not only as pests but also as vectors of various infectious diseases of humans , livestock , pets , and wild animals , then regular monitoring of them is an important concern to control the arthropods and arthropods - borne diseases .

background : the aim of the present study was to determine the prevalence of ectoparasite infestations in stray dogs in mazandaran , gilan and qazvin provinces in fall and winter in 2013(december to march).methods : seventy dogs in 2013 , from these provinces were examined for ectoparasite infestation and diagnosis of them based on parasitological methods and identification keys was done.results:the rate of infestation in these areas was 100% , 68.5% and 93.3% respectively . fleas were the most common ectoparasites on dogs in this study followed by lice , ticks , flies and mites respectively . the isolated arthropods were fleas in 77.5% , lice in 50% , ticks in 8.6% , flies in 6.8% and mites in 5.1% of infested dogs . the ectoparasite of the dogs included 4 flea species : ctenocephalides canis ( 29.8% ) , c. felis ( 19.9% ) , pulex iritans ( 2.9% ) and xenopsiella cheopis ( 0.7% ) , 1 louse species : trichodectes canis ( 41.3% ) , 1 tick species : rhipicephalus sanguinus ( 0.7% ) , 1 fly species : hippobosca sp . ( 1.1% ) and 1 mite species : sarcoptes scabiei ( 3.6%).conclusion : fleas and lice were the most common ectoparasites in stray dogs of the studied area . some ectoparasites transmit important human disease , therefore regular monitoring of them is a major concern to control the arthropods and arthropods - borne diseases .

the calculation of free energy using molecular dynamics simulations is complicated by the dependence on the amount of the relevant phase space sampled . the complication is more pronounced when two alchemical free energy end points differ by more than a few trivial moieties . the use of restraints to restrict the phase space has proven useful in the convergence of thermodynamic integration , umbrella sampling , and the bennett acceptance ratio techniques . another approach is to enhance phase space sampling instead of restricting the phase space and often relies on the modification of the original hamiltonian during molecular dynamics simulations . accelerated molecular dynamics ( amd ) , which conventionally modifies the energy landscape by adding a bias to states below an energy threshold , ecut ( eq 1 ) , is an example of the hamiltonian modification approach and has proven capable of efficiently generating canonical ensembles consistent with experiments on the millisecond time scale . a potential problem with modifying the hamiltonian occurs when reweighting an observable o * from the accelerated simulation to find o on the original potential ( eq 2 for amd ) . if the simulation is highly accelerated and involves a large range of boost factors v , the reweighted average will be dominated by the relatively few points / structures with large values of v in the limit of finite sampling . this statistical problem has recently been quantified as a reduction in the effective number of data points in the simulation.(8 ) thus there is a tradeoff between the degree of acceleration and the statistical precision in amd simulations . the calculation of free energies using thermodynamic integration computes dv / d over the course of a simulation , and the calculation of free energy is very sensitive to the statistical accuracy of the computed averages . in order to take advantage of the sampling efficiency of the amd method as well as maintain the statistical relevance of every data point , we propose using a replica - exchange framework to couple varying degrees of acceleration . the low degrees of acceleration will not be prone to the reweighting problem and can still take advantage of the high acceleration through replica exchanges . this replica - exchange accelerated molecular dynamics ( rexamd ) is a member of the hamiltonian replica - exchange ( hrem ) class of simulations , varying from other hrem techniques in the specific hamiltonian modification scheme . a similar rexamd approach has recently been applied to studying the effects of neighboring side chains on peptide backbone conformations in short peptides.(9 ) we demonstrate the rexamd approach by increasing the convergence rate of thermodynamic integration ( ti ) for two simple gas - phase model systems , although the method could utilize other free energy calculation methods instead of ti . state is used to denote a specific level in the replica - exchange scheme . for example , in temperature replica - exchange each state corresponds to a specific temperature , and in rexamd each state is a modified hamiltonian described by a set of boost parameters . the term replica is used to denote the individual structures that are exchanged between the various rexamd states . the term simulation refers to a specific setup of rexamd , and the term run refers to an instance of a simulation . simulation is also used to identify the average and standard error computed from multiple runs . the current replica - exchange framework is a python program that launches a modified amber8 accelerated molecular dynamics simulation(6 ) for each replica in between metropolis monte carlo exchanges ( eq ) . the monte carlo ( mc ) exchanges occur every 1000 molecular dynamics ( md ) steps , and the pairs that attempt exchanges alternate every other mc period . for example , in a simulation with four states ( labeled s0-s3 ) the simulation would execute 1000 md steps , attempt mc exchanges between the s0-s1 states and the s2-s3 states , execute 1000 md steps , attempt a mc exchange between the s1-s2 states , and repeat . the molecular dynamics simulations used a 1 fs time step and were coupled to a 300 k langevin thermostat with a collision frequency of 10.0 ps . the python program reset the seed number for the amber random number generator after every mc exchange . the boosting scheme is identified as a suffix added to the rexamd acronym as follows : rexamdt denotes a boost only to the torsional potential , and rexamdtt denotes a dual boost scheme applied to the torsional and total potentials.(10 ) the -rw suffix indicates the reported results are from the reweighting of the most accelerated state in a specific simulation . -rw suffix is not present , the result is coming from the least accelerated state , which in this paper is always no acceleration . in order to separate the effect of acceleration from the effect of using m replicas , note that this makes the acceptance probability of mc exchange in eq identically equal to one . the rexreg simulations are analogous to m independent runs from the same starting point with different initial velocities and taking an average result from the m runs . the first criterion is the average acceptance ratio of the replica - exchanges over the course of a run and gives a rough idea of how capable the given replica - exchange scheme is at mixing replicas . the second criterion is the observed relative frequency rmsd metric.(11 ) this metric compares the observed population frequency of the replicas against the idealized case where each of m replicas spends 1/m of the total time in any given state of the system . the rmsd metric varies from zero for the ideal mixing to for no mixing . the observed relative frequency metric is more detailed than the average acceptance ratio in monitoring the mixing efficiency of the replica - exchange simulation . the thermodynamic integration of the model systems was computed using a linear scaling of an all - atom potential ( eq 4 ) . gaussian quadrature integration was used to evaluate the thermodynamic integral from a finite number of dv / d calculated at specific values ( eq 5 ) . the gaussian quadrature points and weights were taken from the amber8 manual.(12 ) two strategies were used to calculate dv / d at each . the first strategy , reweighted periods , calculated the reweighted average of each block of 1000 md steps in between mc exchanges . / d for a specific . the assumption behind this approach is that the dv / d values sampled during 1 ps give rise to dv / d for a local region of the conformational space . this strategy becomes exact when the period is longer than the potential energy correlation time of the system . the second strategy , reweighted run , takes an instantaneous dv / d and its corresponding v from the md step immediately prior to a mc exchange . these values are then used to compute a reweighted dv / d for the entire simulation . this approach virtually guarantees uncorrelated dv / d values at the expense of the number of points being considered in the average . in both strategies each was simulated ten times with different random seeds and velocities . an average and standard error for each dv / d the average g is only reported to the first significant digit of the standard error . both model systems are symmetric alchemical mutations where the product has an identical structure to the reactant , and thus the g is zero and independent of the force field . model system a ( msa ) is a gas - phase alchemical mutation from ethane - to - ethane ( figure 1a ) . this system will serve as a positive control to show that rexamd can reproduce the results of an ergodic regular molecular dynamics simulation . the relative simplicity of the system and the low transition barriers guarantees that the regular molecular dynamics ( rexreg ) is able to sample the entire conformational space in a short time scale . the msa rexamdt simulations used only two replicas : an unmodified potential and an accelerated potential with a torsional boost ( ecut of 5.0 kcal mol , of 2.0 kcal mol ) . each run was simulated for 8 million md steps or the equivalent of 8 ns for an unmodified potential . model system b ( msb ) is a highly halogenated butane ( figure 1b ) . the initial conformation of the system is in a different rotameric state for the two end points , as seen in the newman projections in figure 1b , and thus requires proper conformational sampling to yield the correct g . the chlorine atoms attached to c2 and c3 were added to make the rotameric sampling more difficult , requiring acceleration to achieve the correct answer within the current time scale of 20 ns . the dual boosting scheme was used for this model system in order to accelerate the large van der waals interactions experienced in this system . in order to increase the difficulty of converging to the correct result the boost parameters for the eight replicas in the msb rexamdtt simulations are shown in table s - i ( supporting information ) and are labeled from s0 to s7 in terms of increasing boost . in msa both the rexreg and rexamdt simulations were able to efficiently and exhaustively explore the conformational space ( data not shown ) , and the replica mixing was quite efficient ( table 1 ) within the 8 ns runs . the exhaustive sampling resulted in converged g values within the first ns of the rexreg and rexamdt simulations ( figure 2 ) . msa rexamdt refers to results taken from the nonaccelerated state and msa rexamdt - rw refers to the reweighted results of the accelerated state . the average and standard deviation of the acceptance ratios are from the ten runs and the m states . the average and standard deviation of the rmsd of the relative occupancy of the m replicas over the m states , as defined by abraham et al.,(11 ) are reported . the symbols show the average value of each simulation type , and the shaded region shows the standard error from the ten duplicate runs . the statistical precision can be monitored in terms of the number of values that were used in computing dv / d. for example , applying the reweighted run strategy to the rexamdt simulation yields a total of 80,000 data points for each dv / d ( ten 8 ns trajectories ) . this strategy resulted in a g of 0.02 0.02 kcal mol . in order to produce the same number of points when using the reweighted periods strategy we consider only the first 8 ps of the ten duplicate runs for each , which yields a g of 0.02 0.03 kcal mol . note the similarity in both the accuracy and precision of these two results , indicating that exhaustive sampling occurs below the picosecond time scale . the slower g convergence of the reweighted run strategy versus the reweighted periods strategy is due to the slower rate of data collection for the reweighted run strategy . the rexamdt - rw simulations also exhibit high accuracy and precision ( figure 2 and table 2 ) . the average boost applied over the msa rexamdt simulations from all of the values was 2.0 0.9 kcal mol . the small range of boosts ( standard deviation of 0.9 kcal mol ) is predicted to have a relatively small effect on the reweighted precision as predicted by shen and hamelberg.(8 ) the reweighted periods strategy reduces the effective number of instantaneous dv / d values from 80 million to 16 million for each dv / d , and the rexamdt - rw simulations exhibit marginally worse precision than the rexamdt ( table 2 ) . a similar effect is observed in the reweighted runs strategy ( a reduction from 80,000 to approximately 15,000 ) . the 20 ns msb rexamdtt simulations are well mixed ( table 1 , figures s - i and s - ii ( supporting information ) ) . the regular molecular dynamics ( rexreg ) was unable to efficiently sample the conformational space ( figure s - iii in the supporting information ) and still shows a substantially nonzero g after the 20 ns for both the reweighted periods and reweighted runs strategies ( table 3 ) . the slow convergence of the rexreg result can also be seen in the block averaging of g in figure 3 . in contrast , the rexamdtt simulations were able to efficiently sample the conformational space figure s - iv in the supporting information . the g was consistently within 0.1 kcal mol of zero after 2.9 and 5.5 ns for the reweighted periods strategy and the reweighted runs strategy , respectively . the symbols show the average value of each simulation type , and the shaded region shows the standard error for each simulation type . the reweighting procedure was applied to the state with the highest degree of acceleration , s7 , because this state is the most independent of the other states in terms of convergence . the most accelerated state is also expected to have the highest range of v boost factors and therefore exhibit the largest reweighting problem.(8 ) this prediction can be seen in the poor accuracy and precision of the g of reweighted runs for rexamdtt - rw ( table 3 , figure 4 ) . the effective numbers of data points for the s7 states are shown in table s - i ( supporting information ) and demonstrate the source of the poor statistics . for example , the of 0.5 simulations had a standard deviation of boost values of 13 kcal / mol , and only 30 of the 200,000 data points from the ten duplicate runs contributed to dv / d=0.5 . block average of the msb thermodynamic integration results from the reweighted runs strategy shown on two different scales . the symbols show the average value of each simulation type , and the shaded region shows the standard error for each simulation type . the top plot shows the rexamdtt - rw results on scale and shows how poor the statistics are after reweighting . the bottom plot shows the rexamdtt results on scale and shows how quickly the rexamd technique converges to within statistical accuracy . the reweighted periods strategy for rexamdtt - rw has at least one effective point in each 1 ps period and therefore at least 200,000 data points for each dv / d when the ten duplicate runs are considered . compared to the reweighted runs strategy , the increase of the effective number of points results in the increase of the accuracy and precision of the computed g by 2 orders of magnitude ( table 3 ) . the effective number of points is still less than that of rexamdtt , which has 200 million data points , and the accuracy and precision of rexamdtt are still better than those of rexamdtt - rw when using the same averaging strategy ( table 3 , figure 3 ) . the rexamd method has been shown to efficiently accelerate conformational sampling while avoiding the statistical reweighting problem inherent in amd . the rexamd method was validated on the simple model system a. in the more complex model system b the dual boost rexamd scheme showed marked improvement over the regular molecular dynamics approach as well as better statistical accuracy and precision in comparison to the reweighted results of the accelerated replicas .

accelerated molecular dynamics ( amd ) is an efficient strategy for accelerating the sampling of molecular dynamics simulations , and observable quantities such as free energies derived on the biased amd potential can be reweighted to yield results consistent with the original , unmodified potential . in conventional amd the reweighting procedure has an inherent statistical problem in systems with large acceleration , where the points with the largest biases will dominate the reweighted result and reduce the effective number of data points . we propose a replica exchange of various degrees of acceleration ( rexamd ) to retain good statistics while achieving enhanced sampling . the rexamd method is validated and benchmarked on two simple gas - phase model systems , and two different strategies for computing reweighted averages over a simulation are compared .

organophosphorus ( op ) insecticides are applied in agricultural situations for insect control and have served as the active ingredients in many household insecticides . although their use has been restricted in many countries , they are still heavily used in many developing nations of the world . in these areas , there is significant potential for the unlabelled use of agricultural grade insecticides for pest control in homes and barns with concomitant risk to companion and farm animals . these op insecticides exert their neurotoxic action in pests through the inhibition of acetylcholinesterase ( che : acetylcholine hydrolase , ec 3.1.1.7 ) , a serine esterase that degrades the widely distributed neurotransmitter acetylcholine ( ach ) . significant inhibition of che activity can lead to the accumulation of ach causing hyperexcitation in the central nervous system and at neuromuscular junctions . . however , many of the op insecticides are phosphorothionates which are not very potent inhibitors of che . in order to be toxic , the phosphorothionates must be converted to their active metabolites or oxons through the action of cytochrome p450 . in addition to inhibiting che and other enzymes , the oxons are a nonphysiological substrate for paraoxonase 1 ( pon1 ; ec 3.1.8.1 ) , an esterase classified by its ability to hydrolyze paraoxon , the active metabolite of the insecticide parathion [ 2 , 3 ] . using diethyl p - nitrophenyl diethyl phosphate ( paraoxon or e600 ) as a substrate , aldridge [ 2 , 3 ] first reported that distinct differences in terms of pon activity exist in the sera of various species . others verified these species differences using paraoxon [ 47 ] and also diisopropyl phosphorofluoridate ( dfp ) . within the op insecticide class previous work in rats [ 8 , 9 ] and humans indicates that activity differences exist for different oxons . the present study compared the activity of pon1 from the sera of several mammalian species towards the oxons of three structurally different organophosphorus insecticides , chlorpyrifos , parathion , and methyl parathion . rabbit , pig , goat , cow , sheep , and horse sera were purchased from sigma chemical company ( st . three differing batches of sera were purchased with each assay conducted on a different batch of sera . male and female rat sera were collected from an association for assessment and accreditation of laboratory animal care - accredited sprague - dawley - derived rat colony housed at the college of veterinary medicine , mississippi state university . labdiet rodent chow and tap water were freely available in this temperature - controlled environment ( 22 2c ) with a 12 h dark - light cycle with lights on between 0700 and 1900 h. the mississippi state university animal care and use committee approved all procedures . analytical grade paraoxon , methyl paraoxon , and chlorpyrifos - oxon ( > 99% ) were synthesized as previously described . the incubation mixture ( 1 ml ) consisted of serum ( 5 l / ml for chlorpyrifos - oxon hydrolysis and 20 l / ml for paraoxon and methyl paraoxon ) , 0.05 m tris - hcl buffer ( ph 7.4 ) , and either 1 mm cacl2 ( to stimulate the pon1 activity ) or 1 mm edta ( to chelate calcium , thereby preventing pon1 activity ) . the reaction was initiated by the addition of substrate ( 320 m chlorpyrifos - oxon , 5 mm paraoxon , or 5 mm methyl paraoxon in ethanol , final concentrations ) and incubated for 15 min with shaking at 37c . for chlorpyrifos - oxon hydrolysis , the reaction was terminated by the addition of 250 l of 2% sodium dodecyl sulfate and absorbance was read at 315 nm . for paraoxon and methyl paraoxon hydrolysis , the reactions were terminated by the addition of 250 l of a mixture of 2% sodium dodecyl sulfate and 2% tris - base and absorbance was read at 400 nm . differences between the cacl2 fortified and the edta samples were used to correct for non - pon1 hydrolysis . for each substrate , the shapiro - wilk test was used to check the normality of the residuals and the homoscedasticity of the data . nonnormal distribution of pon1 activity was indicated ( p 0.05 ) and data were log - transformed prior to further analysis using the sas statistical package . the model identified significant differences between species , op , and species op interactions . mean separation was performed by the least significant difference . the criterion for significance was set at p 0.05 . overall , there was a significant effect of species ( f7,48 = 404.15 , p 0.0001 ) and op ( f2,48 = 5245.39 , p 0.0001 ) . there was also a significant species op interaction ( f14,48 = 42.44 , p 0.0001 ) . thus , means were separated based on the species op interaction . when paraoxon was used as the substrate , rabbit serum exhibited the highest activity of all species ( table 1 ) . female rat serum had significantly higher activity than male rat serum which was similar to that of goat serum . the activity in sheep serum was significantly lower than goat but significantly higher than cow , horse , and pig serum which were all statistically similar . when chlorpyrifos - oxon was used as the substrate , rabbit serum again exhibited the highest activity of all the species ( table 1 ) . while being significantly lower than that of rabbit , the activity in sera of female and male rats , goat , and sheep was all statistically similar . lower activities were observed in pig , cow , and horse in decreasing order and these were statistically different from one another . when methyl paraoxon was used as a substrate female rat serum had significantly higher activity than male rat serum which was similar to that of goat serum . the activity in goat serum was similar to that of sheep which was similar to that of horse and cow . pig had the lowest activity towards methyl paraoxon but was statistically similar to horse and cow . with respect to substrate affinity as measured based on activities , chlorpyrifos - oxon was a much better substrate than paraoxon and methyl paraoxon in all species ( table 1 ) . paraoxon was a significantly better substrate than methyl paraoxon in all species except horse , cow , and pig whose activity levels were statistically similar for paraoxon and methyl paraoxon . regardless of the oxon used as substrate , rabbit serum contained higher op hydrolysis activity . this greater ability of rabbit serum to hydrolyze ops relative to other species was expected as it has been frequently reported in the literature [ 37 ] . while there is a lack of information about most species , rabbit serum pon1 has been reported to bind calcium more tightly and with more stability than human serum pon1 . these two characteristics have been suggested to be partially responsible for the greater activity of rabbit serum in combination with potential quantitative ( numbers of enzyme molecules per volume serum ) and qualitative ( catalytic turnover ) differences . it has been demonstrated in humans that serum pon1 quantitative and qualitative differences are affected by single nucleotide polymorphisms in the gene 's coding [ 12 , 18 ] and promoter regions . reported that the rabbit pon1 has a lysine ( k ) at amino acid position 192 which is similar in size and shape to the arginine ( r ) found in the human pon1 allozyme which has been associated with faster hydrolysis of paraoxon . it is possible that a portion of the species differences may be due to similar variations , but many species do not possess polymorphisms . using paraoxon and methyl paraoxon as substrates , female rat serum possesses greater hydrolytic activity than does male rat serum . this sex difference in activity has been reported for both mice [ 22 , 23 ] and rats [ 24 , 25 ] . serum pon1 is synthesized in the liver and both female mice and rats have higher levels of pon1 mrna in their liver as compared to their male counterparts [ 26 , 27 ] , suggesting that the higher activity is merely a result of higher enzyme levels . in addition , the majority of serum pon1 is associated with high density lipoprotein ( hdl ) that contains apolipoprotein a - i ( apoa - i ) and the association of pon1 with apoa - i functions to stabilize enzyme activity . female rats possess higher levels of serum apoa - i and it has been proposed that this is an additional factor in the higher serum pon1 activity observed in females . this sex difference in pon1 activity has been reported in a few other species including humans [ 29 , 30 ] and baboons and , in most cases , paraoxon was utilized as a substrate . however , when chlorpyrifos - oxon was used as the substrate , the sex difference in activity was no longer present . while this was unexpected , the absence of sex differences using chlorpyrifos - oxon as a substrate has been previously reported in mice the basis for this lack of sex differences with respect to substrate utilized is unclear . in a human study , [ 33 , 34 ] reported that genes other than pon1 can contribute to the sex - related variation in pon1 activity in humans . in the population studied , there were genetic sex differences located on chromosome 17 associated with sex differences in pon1 activity in the absence of any differences in the catalytic structure of pon1 . it is possible that a similar situation exists in rodents , but this is unknown . cheng and klaassen showed that androgens and male - pattern growth hormone decreased pon1 expression in male mouse livers , most probably by the activation of stat5b which may have a response element within the mouse pon1 promoter region . in addition , hormonal supplementation ( progesterone and estradiol ) of female mice for 21 days increased the levels of serum pon1 activity suggesting a role of estrogen in the higher activity of females . in an in vivo system , addition of estradiol to a cell - based assay designed to measure cell - associated pon1 activity resulted in an increase in pon1 activity but no change in the levels of pon1 mrna or protein , suggesting that the estrogen was enhancing the activity by stabilizing the catalytic conformation of pon1 either by inducing posttranslational modification of the protein or through inducing a factor that associates with pon1 . the latter situation could explain sex differences in the activity of pon1 and partially explain the substrate - specific sex differences . if sex differences in posttranslational modification of pon1 could slightly influence the conformation of the catalytic site paraoxon and chlorpyrifos - oxon differ in structure only in their leaving group moieties with paraoxon having paranitrophenol and chlorpyrifos - oxon having trichloropyridinol . previous cholinesterase inhibition studies with these two compounds demonstrated that the difference in the attraction of the leaving group is the basis for the different rates of binding to the enzyme . it has been demonstrated that slight changes in the leaving group can drastically change the kcat ( the catalytic constant for the conversion of substrate to product ) for pon1 . thus , how well the leaving group is attracted to the enzyme can control its orientation into the active site and hence its catalysis . in this situation , slight differences in changes in structure in the area that attracts the leaving group can alter the rate catalysis . it may be that this difference is not detectable with very good substrates , such as chlorpyrifos - oxon whose structure has an excellent fit between enzyme and leaving group . in contrast , the differences in pon1 between sexes only become evident when a substrate has a better fit for pon1 of one sex than the other . in conclusion , species differences exist in pon1 activity , but these differences are not merely due to greater levels of pon1 . if the level of enzyme in each species was the determining factor , the pattern of activity with respect to species would be similar across substrates . however , species that differ significantly in activity with the substrates paraoxon and methyl paraoxon become similar when chlorpyrifos - oxon is used as a substrate . there are also many studies that provide solid evidence for sex - specific effects on pon1 activity in rodents [ 22 , 2427 ] . in contrast , our findings , observing that these sex - specific differences are detectable with some substrates but not detectable with others , lead us to hypothesize that the differences are possibly due to sex - specific effects on either posttranslational modification of the catalytic structure of pon1 or the induction of other factors that play roles in the activity of pon1 .

paraoxonase ( pon1 ) is a calcium dependent enzyme that is capable of hydrolyzing organophosphate anticholinesterases . pon1 activity is present in most mammals and previous research established that pon1 activity differs depending on the species . these studies mainly used the organophosphate substrate paraoxon , the active metabolite of the insecticide parathion . using serum pon1 from different mammalian species , we compared the hydrolysis of paraoxon with the hydrolysis of the active metabolites ( oxons ) of two additional organophosphorus insecticides , methyl parathion and chlorpyrifos . paraoxon hydrolysis was greater than that of methyl paraoxon , but the level of activity between species displayed a similar pattern . regardless of the species tested , the hydrolysis of chlorpyrifos - oxon was significantly greater than that of paraoxon or methyl paraoxon . these data indicate that chlorpyrifos - oxon is a better substrate for pon1 regardless of the species . the pattern of species differences in pon1 activity varied with the change in substrate to chlorpyrifos - oxon from paraoxon or methyl paraoxon . for example , the sex difference observed here and reported elsewhere in the literature for rat pon1 hydrolysis of paraoxon was not present when chlorpyrifos - oxon was the substrate .

the cervicobrachialgia is defined as the presence of pain ( algia ) in the cervical region with irradiation to the arm , due to compression of the nerve root of the brachial plexus . this problem can be related to brusque movements , and long periods standing in uncomfortable positions which cause frequent muscular spasms and trigger points ( tps ) resulting from the opening of the sarcoplasmatic reticulum . this causes the release of calcium which is combined with adenosine triphosphate ( atp ) , activates the local mechanisms of contraction , generating landslide and interaction of actin and myosin which shortens the affected muscular beam . in this experiment with the superior portion of the muscle trapeze when the bilateral contraction of the trapezes is symmetrical , it promotes the extension of the cervical column and of the head with accentuation of cervical lordosis . when the contraction of the trapeze is unilateral or anti - symmetrical , it promotes the extension of the head and the cervical column with hyper - lordosis , with inclination to the same side of the contraction and rotation of the head for the opposing side . positional release therapy ( prt ) , a method for assessing the whole body . it is also a treatment that uses sensitive points and a position of comfort to solve the associated dysfunction . prt is a passive and indirect therapy for tissue resistance ( application of the technique in the direction of ease ) , using the positioning of the body and sensitivity to identify and monitor the injury . by doing so , it improves the function , relieves the tension and eases the musculoskeletal pain[36 ] . the fundamental principle of the prt technique is to determine the ( ideal ) position of maximum comfort of articulation , lowering the sensitivity of the painful point . this treatment is done by placing the tissue involved in the position of comfort , which in the case of this experiment was evaluated through surface electromyography . the surface electromyography has been a widely used method in biomechanics , along with other measurement procedures , to obtain data on the components of neuromuscular movement control . the objective of the study was to emonstrate throuth electromyography the reduction of tension in the upper portion trapezius in patients with cervicobrachialgia after application of the positional release therapy ( prt ) . six volunteers with average age 55.3 , male and female , with cervicobrachialgia and tension in the trapezius muscle ( upper ) . the criteria of inclusion were : age , tension in trapezius upper portion and base disturbances , and not be undergoing any other treatment that might interfere in the study . the subjects received treatment , and electromyography analysis was conducted at initial rest with the application of the prt technique in bilateral the upper trapezius and at rest after the application . the points of palpable tension in the upper trapezius were demarcated and the mcgill pain questionnaire was applied before the initial assessment . the treatment was conducted with the application of the prt technique in point(s ) of tension in the upper trapezius by palpation . the muscle was placed in a position of comfort , and maintained by reduction or abolition of tension and monitored by a gentle touch on these points . before and after application of the prt of each session , patients were questioned about the intensity of pain , which could range from 0 ( no pain ) to 10 ( unbearable pain ) . ten thirty minute sessions were held , twice a week in the school hospital wladimir arruda ( hewa ) . the electromyographyc measurements were conducted in the laboratory of human biodynamics of the faculty of physical education of the university of santo amaro , where the data were taken on the first and tenth days of treatment . the electrodes were placed in the upper trapezius of both sides , according to the delagi protocol ( figure 1 ) . the subjects were placed on an isometric test table in dorsal decubitus position with the head on the table ( resting position ) , keeping this position for 90 seconds to collect emg signs ( figure 2 ) . in the second collection , the physiotherapist held the head both in rotation and passive tilt , with the passive lifting of the homolateral shoulder ( zone of comfort ) to the trapezius muscle ( figure 3 ) . a third collection was performed with the contralateral side ( figure 4 ) , in the same position and duration previously cited . the command to start to capture the electromyography records was previously arranged with the therapist , so as not to activate unconscious isometric upper trapezius contractions of the patient . biological signals were obtained using a 16 channel module ( emg system do brasil ltda ) , consisting of a signal conditioner with a band pass filter with cut - off frequencies at 201000 hz , an amplifier gain of 1000 and a common mode rejection ratio higher than 120 db . the data were processed using specific software for acquisition and analysis ( emg analysis v1.01 ) , a converting plate for a / d 16 bits signal to convert analog into digital signals with a sampling frequency of anti - aliasing 2.0 khz for each channel and an input range of 5 mv . active bipolar superficial electrodes consist of two rectangular parallel bars of ag / agcl ( 1 cm in length , 0.2 cm in width and 1 cm apart ) . these bars are coupled to a rectangular acrylic resin capsule 2.2 cm in length , 1.9 cm in width and 0.6 cm high with an internal amplifier in order to reduce the effects of electromagnetic interferences and other noises . electrodes were fastened to the skin , which was previously cleaned with alcohol , guided by bone prominences and the route of the muscle fibers . the electrodes were then coated with a thin film of conductive gel and fixed with micropore adhesive tape at the midline of the muscle belly with their detection surface perpendicular to the muscle fibers . in all procedures the capture and analysis of emg signals were carried out as recommend by the international society electrophysiology kinesiology ( isek ) . the records were standard in the time through the origin software and subjected to an analysis of the variability at the number of repetitions and at volunteers among themselves , using the calculation of the variability coefficient . the image acquisition was made aiming to demonstrate the maintenance of the initial positions of volunteers during the position of relaxation of the upper trapezius , before and after the application of the technique in rest , and in the position of greater relaxation of trapezius , during the implementation of technique . the results showed that all patients had a gradual decrease in pain after each session . the numerical scale of pain ( figure 5 ) shows that , four patients had 100% of pain reduction , one presented 87.5% and the other 84% . the values were measured according to the mcgill pain questionnaire which examines the pain by the numbers of descriptors and rates of pain , showing a reduction of these values . the number of descriptors decreases 64.34% on average , ranging from 25% to 100% ( figure 5 ) and the pain index decreases 67.65% in average , ranging from 24.32% to 100% ( figure 6 ) . average of numbers of descriptors and pain scale , according to the mcgill pain questionnaire , respectively . the state of tension of the upper fibers of the trapezius muscle of the patients decreases in average , 31.86% on the right side and 43.38% on the left side ( figure 8) after the treatment . the electromyography data show a decrease during the application of the prt technique in the upper trapezius , on the right side at 51.87% and on the left side in 50.81% ( figure 9 ) , but they did not show significant values in accordance to the coefficient of variability . rms values to the average of muscle tension of upper trapezius at rest before , during and after the prt session . there are some difficulties in researches that include manual therapy as an object of study . this happens mainly because of disagreements among the various authors about the origin of skeletal muscle pain and of the influence of the interaction between patient and therapist . therefore , it is important to note that the relationship developed with the patients is a significant factor for the confidence deposited by them from the outset , because in the technique of prt relaxation of the patient is essential to achieve the ideal position of comfort . the treatment position of the upper trapezius described in the literature is : patient placed in dorsal position with the therapist positioned on the side of the sensitive point . the therapist secures the patient 's forearm and abducts the shoulder to almost 90 , and for the adjustment of the position , holds a flexion or a discreet extension . this position is not always ideal for the patient , because the area of comfort varies from person to person . the literature also reports that the ideal position of comfort is the final goal of treatment and requires a greater degree of clinical refinement , to be specific and different for each position of treatment . this encouraged adapting a position , considering the biomechanics of the upper fibers of the trapezius muscle , which has been effective in the course of treatment through the release of the points of tension . the present study demonstrated that a ) the application of the prt promotes a decrease in pain and muscle tension in the upper trapezius , confirming the assumptions that the prt seems to relieve the muscle spasm and restore the appropriate painless movement and the tissular flexibility ; b ) the relaxation of tensioned muscle fiber promotes normalization of local vascularization and decreased pain , caused by ischemia ; and c ) the action of prt on the nociceptive system can be exercised through the relaxation of the surrounding tissues and the consequent improvement in the vascular and interstitial movement . this can have an indirect effect on the removal of chemical mediators of inflammation , the subsequent resolution of protective reflexes of the myofascial structures can also contribute to a reduction of the release of more nociceptive substances . the prt also can act on the traumatic cycle and assist in the resolution of facilitated segments of the central nervous system . as demonstrated by the results , the pain was gradually decreased during the ten sessions of treatment , agreeing with the statement : the manual therapy induces immediate analgesia , cumulative with repetition of the treatment . with the reduction of pain , from the first session , the treatment allowed the patients to move in an appropriate way in their daily life activities ( dla ) , also promoting the improvement of self - esteem . treatment should be focused on the correction of joint , muscle and postural shortcomings , and the adequacy of dla . some factors may have influenced the statistical analysis , by calculating the coefficient of variability for example , the small number of patients with cervicobrachialgia , which showed tension in the upper fibers of the trapezius muscle , and the difficulty in finding the ideal position of comfort ( the sensitive points were very near or below the electrodes of electromyography , which made palpation difficult ) . the completion of treatment with a larger number of patients is suggested , with monitoring at the end of the sessions for verification of recurrence of the clinical state . development of a method to monitor the sensitive points by palpation during electromyography without generating interference is also indicated . the analysis of data collected and the electromyography data showed that the positional release therapy ( prt ) for the treatment of patients with cervicobrachialgia has proved effective because it reduced the muscle tension in the upper trapezius and decreased the musculoskeletal pain , with consequent improvement of posture and daily life activities . the technique is very simple , safe and easy to learn , and it can serve as an introduction to the musculoskeletal techniques for the less experienced and also as a technical assistant to the most qualified professional . moreover , it is efficient and easy to implement and can be used by any professional in the health area with technical training and knowledge in physiology .

background : this quantification process is made through electromyography analysis . this technique of analysis is able to provide a general view of the tension decrease in the superior muscle fibers of the trapezius after therapy.aims:the focus of the present work is to evaluate the treatment of the cervicobrachialgia by positional release therapy ( prt).material and methods : the present work studies six patients , with ages 44 to 63 ( 1 male and 5 female ) who present tension in the trapezius upper portion fibers . all patients were submitted to 10 session of 30 minutes each . the electromyography was collected on the first and tenth day of treatment.results:the results demonstrated a progressive decrease of pain in each session . the tension was evaluated by the electromyography analysis , which showed the relations between time of treatment and less pain.conclusion:with these results , it was possible to verify quantitatively the efficiency of the prt in the improvement of life quality .

the incidence of perioperative complications is low and the number of life - threatening complications with this surgery is even lower . avascular necrosis of the maxilla after le fort i osteotomy is a rare complication that has been reported to occur in < 1% of cases . during down fracture of the maxilla , the blood supply is by the ascending pharyngeal artery , the ascending palatine branch of the facial artery and the rich mucosal alveolar network overlying the maxilla . table 1 outlines the factors that may result in impaired blood supply to the maxillary segments and increase the risk of ischaemia . when the descending palatine artery is sacrificed , the main blood supply of the maxilla will now be the soft tissue pedicle , which incorporates the anterior faucial pillar and the palatal mucosa ( see fig . ( a ) nasopalatine artery , ( b ) descending palatine artery , ( c ) greater palatine artery , ( d ) lesser palatine artery , ( e ) maxillary artery , ( f ) ascending pharyngeal artery , ( g ) ascending palatine artery , ( h ) facial artery , ( i ) external carotid artery , ( j ) le fort i downfracture . table 1factors increasing the risk of avascular necrosis of the maxillalocalsystemicradiation treatmentcigarette smokinginfectionpregnancytraumachemotherapysurgery relatedhaematological conditions sacrifice of descending palatine artery sickle cell disease perforation / stripping palatal mucosa leukaemia adrenaline injected into mucosa gaucher 's disease perioperative vascular thrombosis thalassaemia segmental osteotomiescaisson disease extensive advancementsystemic lupus erythematosisanatomy relateddiabetes mellitus craniofacial dysplasiasvasculitis orofacial cleftsinflammatory bowel disease vascular anomaliesdrugsprevious surgery vasoconstrictors cleft palate repair high dose steroid surgically assisted rapid palatal expansion blood supply of the maxilla . ( a ) nasopalatine artery , ( b ) descending palatine artery , ( c ) greater palatine artery , ( d ) lesser palatine artery , ( e ) maxillary artery , ( f ) ascending pharyngeal artery , ( g ) ascending palatine artery , ( h ) facial artery , ( i ) external carotid artery , ( j ) le fort i downfracture . we report a case of a 45-year - old afro - caribbean female who underwent orthognathic surgery to correct her malocclusion . she was previously investigated for a fibro - osseous lesion , which presented as a hyperplastic right maxillary tuberosity ( see fig . the patient had lost her lower posterior teeth and there was downward displacement of the upper right posterior segment into the edentulous area of the lower posterior jaw . the operation planned was a le fort i osteotomy with a right posterior segment osteotomy , which would set back the upper incisors by 6 mm , impact the upper left second molar by 4 mm and impact the posterior segment from the upper right first premolar ( by 5 mm ) to the upper right first molar ( by 12 mm ) . the segmental osteotomy was performed following down fracture of the maxilla and the final occlusion was aligned to a full coverage occlusal splint . the patient presented with wound infection and avascularity of the maxilla 1 week after the procedure . a course of hyperbaric oxygen treatment was organized at 14 and 18 days post - operatively . she was started on therapeutic doses of pentoxyfylline and vitamin e to improve capillary blood flow . most of the maxilla was affected , the right side to a greater degree . despite treatment , over time an oro - antral fistula developed in the upper right quadrant , as seen in fig . blood flow to the maxilla is reduced by 50% in the first post - operative day after sacrifice of the descending palatine arteries . however , there is excellent collateral blood supply particularly if only one artery is sacrificed , as in this case . experimental studies have shown that loss of the descending palatine arteries results in a transient ischaemic period that is compensated for by a vascular proliferation that allows tissue healing . the collateral microvasculature from other vessels including the ascending pharyngeal and facial arteries ( fig . the pedicle can withstand stretching greater than 10 mm of anterior repositioning of the maxilla . the haemogloblinopathy screen confirmed hb a ( adult haemoglobin ) and hb s ( sickle haemoglobin ) . the hb f ( foetal haemoglobin ) level was < 0.5% and the hb s level was 39.4% . these parameters are typical for sickle cell trait . however , for patients in sickle cell crisis or those expected to be exposed to severe hypoxia , hb s level < 30% is advised . craniofacial dysplasias may represent areas of anatomical variation where the blood supply may be susceptible to disruption . although the patient had a biopsy showing normal bone , the maxillary tuberosity was expanded and hyperplastic clinically . this in itself would not however have accounted for the degree of avascularity seen in this case . literature suggests that segmental osteotomy is at a higher risk of ischaemic complications [ 5 , 6 ] . necrosis of the maxilla can be minimized in the following ways : divide into as few segments as possible and avoid small segments anteriorly. maintain the integrity of the palatal mucosa. perform sagittal segmentation in paramedian sites as the mucosa is thicker and the bone thinner than the midline.although hypotensive anaesthesia was not purposely utilized for the procedure , it is a technique commonly used to help maintain a bloodless surgical field . a mean arterial blood pressure ( map ) 30% below a patient 's usual map , with a minimum map of 50 mm hg in american society of anesthesiologists class i patients and a map not < 80 mm hg in the elderly , is suggested to be clinically acceptable . it is recommended that with respect to hypotensive anaesthesia: it should be adjusted in relation to the patient 's preoperative blood pressure rather than to a specific target pressure. it should be limited to that level necessary to reduce bleeding in the surgical field. it should be confined to that part of the surgical procedure deemed to benefit by it. there is little need for blood transfusion perioperatively . perform sagittal segmentation in paramedian sites as the mucosa is thicker and the bone thinner than the midline . although hypotensive anaesthesia was not purposely utilized for the procedure , it is a technique commonly used to help maintain a bloodless surgical field . a mean arterial blood pressure ( map ) 30% below a patient 's usual map , with a minimum map of 50 mm hg in american society of anesthesiologists class i patients and a map not < 80 mm hg in the elderly , is suggested to be clinically acceptable . it is recommended that with respect to hypotensive anaesthesia : it should be adjusted in relation to the patient 's preoperative blood pressure rather than to a specific target pressure . it should be limited to that level necessary to reduce bleeding in the surgical field . it should be confined to that part of the surgical procedure deemed to benefit by it . the anaesthetic concerns include the management of perioperative hypoxia , acidosis , hypovolaemia and hypothermia . points to consider with this case are : hypoxia never occurred and is usually avoided as anaesthetised patients are always maintained with an fio2 > 0.35.acidosis may trigger a vaso - occlusive crisis and would affect all micro - circulation ; it is easily prevented by proper perfusion and maintaining circulating blood volume.hypothermia was prevented by patient warming.hypovolaemia could be contentious , especially with hypotension . hypoxia never occurred and is usually avoided as anaesthetised patients are always maintained with an fio2 > 0.35 . acidosis may trigger a vaso - occlusive crisis and would affect all micro - circulation ; it is easily prevented by proper perfusion and maintaining circulating blood volume . hypovolaemia could be contentious , especially with hypotension . with this patient , the mechanism of avascular necrosis could not clearly be explained . in the analysis of patient , surgical and anaesthetic factors

we present a patient with sickle cell trait who suffered avascular necrosis of the maxilla as a complication of maxillary osteotomy . understanding the blood supply of the maxilla and how possible patient related , anaesthetic and operative factors affect it , is important in understanding how the vascularity of the maxilla can become compromised in a surgical procedure . the perioperative parameters were analysed to identify any prognostic elements . avascular necrosis of the maxilla is a rare complication of orthognathic surgery with few cases reported in the literature . there are identifiable risk factors that can influence the blood supply of the maxilla . careful preoperative assessment is required to exclude patient factors that have the potential to affect tissue vascularity . this in conjunction with sound anaesthetic and surgical technique should all minimize the risk of avascular necrosis . even so it is still possible for this rare complication to occur .

optical approaches to compensate for presbyopia include reading glasses , monovision , multifocal contact lenses , multifocal intraocular lenses ( miols ) , and accommodating iols . none of these can restore accommodation , but all are compromises that establish a fair quality of near vision at the expense of good far vision . even a small amount of astigmatism provides some pseudoaccommodation in pseudophakic patients.1 several methods to restore accommodation with scleral expansion near the ciliary body were designed ; however , none has proven to be effective.24 corneal procedures for the compensation of presbyopia include presbyopic laser in situ keratomileusis ( presby - lasik ) , conductive keratoplasty , intracorneal implants ( or inlays ) , and the intracor and supracor ( technolas perfect vision gmbh , munchen , germany ) procedures . we describe a case series of patients with a history of prior phakic iol implantation surgery in whom an intracorneal inlay ( kamra ) ( model aci 7000pdt , acufocus inc , irvine , ca , usa ) was implanted in the nondominant eye after creating a femtosecond laser corneal pocket . the kamra small - aperture intracorneal inlay is designed to increase the depth of focus in the implanted eye , based on the principle of small - aperture optics.5 the inlay restores near and intermediate visual acuity without a significant impact on distance vision.68 this study conforms to the ethics codes established by the ethical board committee of japan . all patients read and signed informed consent forms , which explained the surgical procedure , possible risks , and patients rights . this case study includes three eyes with a history of prior phakic iol implantation surgery . the aim of the present study was to show the efficacy of the kamra small - aperture intracorneal inlay in presbyopic patients with prior refractive surgeries , which was one of the exclusion factors in previous reports.5,810 the preoperative and postoperative assessment of patients and surgical techniques is already described in our previous study.9 patient satisfaction after surgery was estimated from the patients satisfaction questionnaires , as was done previously.9 a 55-year - old woman had presbyopia correction with inlay implantation in her left eye . her preoperative visual acuity was evaluated using a snellen chart for distance and log - mar for near vision ( which was converted to a jaeger chart thereafter ) . preoperative spherical equivalent ( se ) was 0.25 diopter ( d ) ; uncorrected distance visual acuity ( udva ) and corrected distance visual acuity ( cdva ) were 20/20 and 20/16 , respectively ; and uncorrected near visual acuity ( unva ) and corrected near visual acuity ( cnva ) were j4 and j1 , respectively . the patient underwent a comprehensive preoperative examination.9 during surgery , the corneal pocket creation was done for the kamra inlay implantation with a crystal line femto ldv ( ziemer ophthalmic systems ag , port , switzerland ) . the kamra inlay implantation was done with a 230 m pocket depth , not 200 m as is usual , due to the presence of 603 m central corneal thickness . the inlay was carefully placed in the pocket over the estimated line of sight based on the midpoint of the first purkinje image and the pupil center with coaxial patient fixation.9 three - month results showed an improvement in unva to j2 , with even better outcomes for udva , which improved to 20/16 ( table 1 ) . se was 1.0 d. cdva and cnva remained stable during the follow - up period . the patient did not report needing reading glasses in any light conditions . a 54-year - old woman with a history of a lasik procedure that was done soon after her the patient underwent a rigorous ophthalmic examination.9 udva and cdva were both 20/16 ; unva and cnva were j6 and j1 , respectively . the corneal pocket formation was done for her kamra inlay implantation with a crystal line femto ldv ( ziemer ophthalmic systems ag ) . the inlay was placed in the pocket the same way as has already been described.9 three - month results showed an improvement in unva to j4 with minimal change in udva , which was 20/20 . se was 0.38 d. cdva and cnva remained stable during the follow - up period . regarding patient satisfaction , the patient complained of a slight worsening of her near vision at night . a 51-year - old woman was a candidate for presbyopia treatment by kamra inlay implantation surgery . one month before inlay surgery , the patient underwent a lasik procedure in order to correct the refractive error after her first phakic iol implantation procedure . se just before inlay implantation surgery was 0.00 d. udva and cdva were both 20/16 . the kamra inlay was implanted the same way as with the case 2 patient at a depth of 200 m . there was an improvement in unva at the 3-month follow up , from j10 to j5 . a minimal change in udva se was 0.5 d. cdva and cnva remained stable . at the 3-month follow - up a 55-year - old woman had presbyopia correction with inlay implantation in her left eye . her preoperative visual acuity was evaluated using a snellen chart for distance and log - mar for near vision ( which was converted to a jaeger chart thereafter ) . preoperative spherical equivalent ( se ) was 0.25 diopter ( d ) ; uncorrected distance visual acuity ( udva ) and corrected distance visual acuity ( cdva ) were 20/20 and 20/16 , respectively ; and uncorrected near visual acuity ( unva ) and corrected near visual acuity ( cnva ) were j4 and j1 , respectively . the patient underwent a comprehensive preoperative examination.9 during surgery , the corneal pocket creation was done for the kamra inlay implantation with a crystal line femto ldv ( ziemer ophthalmic systems ag , port , switzerland ) . the kamra inlay implantation was done with a 230 m pocket depth , not 200 m as is usual , due to the presence of 603 m central corneal thickness . the inlay was carefully placed in the pocket over the estimated line of sight based on the midpoint of the first purkinje image and the pupil center with coaxial patient fixation.9 three - month results showed an improvement in unva to j2 , with even better outcomes for udva , which improved to 20/16 ( table 1 ) . se was 1.0 d. cdva and cnva remained stable during the follow - up period . a 54-year - old woman with a history of a lasik procedure that was done soon after her prior phakic iol implantation surgery complained about her near vision . the patient underwent a rigorous ophthalmic examination.9 udva and cdva were both 20/16 ; unva and cnva were j6 and j1 , respectively . the corneal pocket formation was done for her kamra inlay implantation with a crystal line femto ldv ( ziemer ophthalmic systems ag ) . the inlay was placed in the pocket the same way as has already been described.9 three - month results showed an improvement in unva to j4 with minimal change in udva , which was 20/20 . se was 0.38 d. cdva and cnva remained stable during the follow - up period . regarding patient satisfaction , the patient complained of a slight worsening of her near vision at night . a 51-year - old woman was a candidate for presbyopia treatment by kamra inlay implantation surgery . one month before inlay surgery , the patient underwent a lasik procedure in order to correct the refractive error after her first phakic iol implantation procedure . se just before inlay implantation surgery was 0.00 d. udva and cdva were both 20/16 . the kamra inlay was implanted the same way as with the case 2 patient at a depth of 200 m . there was an improvement in unva at the 3-month follow up , from j10 to j5 . a minimal change in udva se was 0.5 d. cdva and cnva remained stable . at the 3-month follow - up the inlay s polyvinylidene difluoride material incorporates nanoparticles of carbon to make it opaque.5 this permeable material has a light transmission rate of 5% . the inlay has a pseudorandom microperforation pattern consisting of 8,400 holes ranging in size from 5 m to 11 m in diameter , to allow water and nutrition flow . the inlay is 5 m thin and has a 3.8 mm total diameter and a 1.6 mm diameter central aperture . there is no refractive power in the central aperture.9 the kamra inlay can be implanted under a flap or into an intrastromal pocket , both created by a femtosecond laser . all three patients of our study had corneal pocket formation during the inlay implantation . in the postphakic eye of case 1 , the main point to mention is that the kamra inlay implantation was with a 230 m depth pocket due to 603 m central corneal thickness appearing . the unva improved by two lines at 3 months postoperatively in this patient . no need for reading glasses was reported from this patient . in all presented cases , the corneal inlay was implanted as per the normal post - lasik procedure using a pocket . we saw near vision improvement in all patients with postphakic eyes . only one patient ( case 2 ) reported some worsening of her near vision at night . the reason for this may be the decreasing of the depth of focus with a larger pupil diameter . figure 2 presents the unva change during the entire follow - up period for all three cases . thus , based on our results , with improved near visual acuity , minimum impact on udva , and the appearance of clear corneas , with no opacities or changes in epitheliums , we may consider that kamra inlay surgery in postphakic iol patients appears to be safe . additionally , it should be noted that there are other options for presbyopia corrections , such as intrastromal femtosecond laser correction and miol . but we consider , based on the reported study,11 that intrastromal femtosecond laser correction has more impact on udva than does kamra inlay . miol implantation might be another option for these patients , but as the patients of our study did not have any cataract formation , and knowing that cataract surgeries are not as safely reversible as kamra inlay surgeries , the patients of our study were not good candidates for miol surgery . in summary , our case report study results suggest that the implantation of a kamra corneal inlay may improve monocular near visual acuity in presbyopic patients with a history of a prior phakic iol implantation surgery , based on our short - term follow - up .

we report a series of three case reports of kamra inlay implantation procedures in presbyopic patients with a history of prior phakic intraocular lens implantation surgery . three - month results showed a two to five - line improvement for uncorrected near visual acuity . the absolute uncorrected near visual acuity change for case 1 was from j4 to j2 , for case 2 was from j6 to j4 , and for case 3 was from j10 to j5 . no significant change of uncorrected distance visual acuity was observed in all three cases .

although it accounts for 2030% of all acute mesenteric ischemia , it has more than 70% mortality . it commonly occurs in an elderly person having cardiovascular disease with low - cardiac output . however , our case report describes nomi in a 21-year - old student , in all probability due to demand - supply imbalance in splanchnic circulation under vasopressor support during septic shock . a 21-year - old college student presented to a tertiary care hospital with history of on and off low - grade fever for 3 months and abdominal pain for 1 week . both tuberculosis and vasculitis like systemic lupus erythematosus ( anti - dsdna , anti - sm - rna ) were ruled out in view of low - grade fever with abdominal pain . erect x - ray and abdomen ultrasonography were normal . on the third day of hospital admission , she developed septic shock ( mean blood pressure < 65 mmhg ) with altered sensorium for which she was intubated and transferred to the intensive care unit ( icu ) . she had leukocytosis ( 21,000/cmm ) , anemia ( 5 gm / dl ) , thrombocytopenia ( 20,000/cmm ) and deranged liver function tests ( prothrombin time 6 s prolonged ) . she was managed conservatively with fluids , sedation , noradrenaline ( 0.53 g / kg / min ) , vasopressin ( 0.01 u / min ) infusion , broad - spectrum antibiotics and platelet and packed cell transfusion . several blood and endotracheal tube aspirate cultures were sterile . on the fifth day , repeat ultrasonography of the abdomen revealed thickened and dilated nonobstructed bowel loops with coarse hepatic echo - texture . since icu admission , she had high nasogastric aspirates with feed intolerance despite the use of prokinetics ; however , she started accepting nasogastric feeds on day 6 . but , after a few hours of enteral feed , she developed rapidly rising intraabdominal pressure ( > 18 mmhg ) with sudden deterioration in hemodynamics and increasing metabolic academia and hyponatremia ( serum sodium 124 she passed large amounts of fresh blood - mixed loose stools , which was later found to be negative for clostridium dificile . urgent computed tomography ( ct ) scan abdomen revealed pneumatosis intestinalis of the small bowel with dilated bowel loops [ figure 1 ] and gas in portal venous system [ figure 2 ] . in a setting of prolonged septic shock , vasopressor support and metabolic acidosis , the clinical and radiological picture was that of mesenteric ischemia . exploratory laparotomy , done immediately , showed multiple areas of gangrenous patches and dusky discoloration of the jejunum with air bubbles in the subserosa . the major mesenteric vessels were pulsating and there was no evidence of thrombus , atherosclerosis or visible occlusion . the surgical team released the intrabowel pressure by surgical incisions in the wall of the jejunum so as to reduce the increasing distension . compter tomography scan of the abdomen showing pneumatosis intestinalis ( arrowed ) compter tomography scan of the abdomen showing hepatic portal venous gas ( arrowed ) she succumbed within 4 h of operation . in nomi , mesenteric blood flow ceases for a while due to an acute splanchnic vasospasm . it tends to occur mostly in the elderly patients who have low - cardiac output . myocardial infarction , ventricular dysfunction or arrhythmias , circulatory or cardiogenic shock , vasoactive drugs and heart failure are the various risk factors . nor - epinephrine and vasopressin can both lead to profound vasoconstriction of the splanchnic circulation . we believe that nomi in our case could be secondary to excessive circulatory vasopressin as a consequence of altered metabolism with deranged liver function . initiation of an enteral feed alters the intestinal supply - demand ratio , leading to reperfusion injury mediated by oxygen free radicals and neutrophil adhesion to the endothelium of mesenteric venules , which can result in nomi . the temporal relationship of enteral feeding and the episode suggests that enteral feeding - related supply - demand mismatch is the likely precipitating event . it is a known fact that diagnosis of nomi requires a high index of suspicion , especially in elderly patients with risk factors . however , the index of suspicion must also be high for young patients with prolonged shock requiring vasopressor support . early diagnosis of altered splanchnic blood flow in the backdrop of prolonged shock and vasopressor support could have averted the fatal outcome of a young patient . our report shows that findings like increasing gastric aspirates , bowel wall thickening and dilated bowel loops should be investigated with increased vigor and managed accordingly . gut - based organ failure scoring may help in early diagnosis as well as in monitoring therapy . routine intraabdominal pressure measurement in septic shock may also help in the early detection of this fatal condition . definitive diagnosis of nomi however requires an arteriographic study , which is costly and not widely available . gastric mucosal tonometry is the only technique available at the bedside to measure splanchnic blood flow , but this technique certainly has limitations . pneumatosis intestinalis and hepatic portal venous gas are late radiological features of bowel ischemia , and the presence of hepatic portal venous gas in bowel ischemia signifies mortality as high as 83% . through this case report , we wish to emphasize the probability of occurrence of nomi even in young age , especially in patients with prolonged septic shock on vasopressor support . the importance of early enteral feeding even in septic shock is proved , but hindrance in early enteral feeding needs to be timely appreciated and appropriately managed .

nonocclusive mesenteric ischemia is a type of acute mesenteric ischemia with high mortality seen mostly in elderly cardiac patients . we present a 21-year - old healthy student with nonocclusive mesenteric ischemia along with radiological evidence of hepatic portal venous gas and pneumatosis intestinalis , with subsequent fatality . its significance and its possible etiology are discussed .

the ewing 's sarcoma / primitive neuroectodermal tumour ( es / pnet ) family of tumours is part of a rare group of malignant neoplasms with small round - cell morphology . es / pnet is an uncommon primary malignancy of the bone primarily affecting children and young adults with more than 80% of patients being younger than 20 years of age at the time of presentation . less frequently , es / pnet arises from soft tissues and then the neoplasm is classified as extraskeletal es / pnet . involvement of the mediastinum as the primary site of origin is extremely uncommon in the literature , only four cases were reported in a span of 20 years in a large case series from a tertiary care centre in india . a rare case of primary pnet tumour of the anterior mediastinum mimicking massive pleural effusion in a young male is reported here . a 30-year - old male , carpenter by profession , presented with dry cough and progressive shortness of breath for two months , right - sided severe chest pain for one and half month and low - grade fever for one month . the patient was a non - smoker , non - alcoholic and non - diabetic . clubbing was absent and there was no peripheral lymphadenopathy . on examination of the respiratory system features of right hemithoracic volume enlargement were present . percussion note was dull all over the right hemithorax with presence of tenderness on superficial percussion . on auscultation , a tubular breath sound was heard near the right infraclavicular area parasternally , in all other areas on the right side vesicular breath sound was markedly diminished . examination of other systems including the lymphoreticular system and testicular examination were all within normal limits . chest x - ray postero - anterior view revealed right - sided homogenous opacity involving all three zones with loss of costophrenic and cardiophrenic angles along with contralaterally shifted mediastinum [ figure 1 ] , suggesting right - sided massive pleural effusion ; but on thoracentesis , only 50 ml hemorrhagic fluid could be aspirated from the right infrascapular area after repeated attempts . pleural fluid study yielded reddish - coloured , predominantly lymphocytic , exudative fluid with high adenosine de - aminase ( ada ) [ total cell count 170/cmm , lymphocyte- 80% , neutrophil-15% , ada-122 iu , protein-3.7g / dl , sugar- 86 mg / dl ] and pleural fluid for pap stain was negative . subsequently contrast - enhanced ct ( cect ) scan of the thorax was done and showed a huge non - homogenous mass of heterogeneous density with multiple foci of necrosis occupying the entire right hemithorax , possibly arising from the anterior mediastinum , causing shifting of the mediastinum to the left and compression of the superior venacava ( svc ) , there was minimal pleural effusion [ figure 2 ] . chest x - ray pa view showing homogenous opacity on the right side involving all zones with obliteration of the costophrenic angle and contralateral mediastinal shift ct scan of the thorax ( cect ) showing a large mass of heterogeneous density with foci of necrosis occupying the entire right hemithorax ct - guided fine needle aspiration cytology ( fnac ) was performed and the pathologist opined it as small round - cell tumour , possibilities : non - hodgkin 's lymphoma or small - cell carcinoma of lung [ figure 3 ] . ct - guided tru - cut biopsy of the lesion was performed next and it revealed a tumour composed of round , oval or fusiform cells with hyperchromatic nuclei and scanty cytoplasm , mitotic figures were present [ figure 4 ] and it was reported again as small round - cell tumour , possibly small - cell carcinoma of the lung . subsequently , fibreoptic bronchoscopy was done and it showed narrowing of the right bronchial tree possibly due to external compression but no intraluminal growth was noted . on immunohistochemistry of the histology block of tru - cut biopsy , tumour cells expressed mic-2 and were immunonegative for cytokeratin , synaptophysin , chromoganin a , cd 20 , cd 3 , tdt , and the findings were consistent with primitive neuroectodermal tumours ( pnets ) . cytology of ct - guided fnac slide under high - power field showing highly cellular smear with small round cells with hyperchromatic nuclei and scanty cytoplasm ( hematoxylin - eosin , 400 ) histopathology of ct - guided tru - cut biopsy slide under high - power field showing sheets of small round or oval cells with hyperchromatic nuclei and variable amount of cytoplasm , tumour cells showing rosette formation at places ( hematoxylin - eosin , 400 ) finally , a diagnosis of pnet of the mediastinum was made . so it was an extremely rare case of peripheral pnet arising from the anterior mediastinum . in 1973 , hart and earle first coined the term primitive neuroectodermal tumour ( pnet ) , which drew attention to the primitive nature of the tumour rather than histogenesis . this entity is primarily a disease of childhood and young adults with a median age at diagnosis being nine years , and 80% of the cases are under 20 years of age . pnets are highly malignant , undifferentiated neoplasms of the es / pnet family , arising from the germinal matrix cells of the primitive neural tube . pnets are a variety of small round blue cell tumors ( srbct ) and may involve more than one site at presentation . when located in extraosseous sites , supratentorial brain , spinal canal , and soft tissues of the thigh are the usual sites ; primary involvement of extracranial sites like the mediastinum , chest wall , kidney is very rare . in a study of extraskeletal es by ahmad et al . primary mediastinal pnets are mostly located in the posterior mediastinum like other neurogenic tumours , primary involvement of the anterior mediastinum is extremely uncommon . these neoplasms are usually seen in young males who predominantly present with chest pain as in our case . radiologically , it is very difficult to differentiate these neoplasms from other common anterior mediastinal tumours , ct scan of the thorax reveals an ill - defined , heterogeneous mass with necrotic foci within , calcification is usually absent . smears are generally highly cellular and are composed of both single cells and groups of loosely cohesive cells with a high nuclear / cytoplasmic ratio , hyperchromatic nuclei without prominent nucleoli , distinctively smooth nuclear membrane contour , finely granular chromatin , one or two small nucleoli and scanty but almost always present perinuclear clear cytoplasm suggesting epithelial differentiation . in atypical es and pnet the cellular and nuclear atypia is more marked than in conventional es , rosette- like structures are more common , the distinction between large light and small dark cells less obvious and cells with thin cytoplasmic processes are present . in atypical cases diagnosis on fnac is quite challenging and the extraskeletal variant of es / pnet is more often difficult to diagnose on cytopathology , and a histology with immunohistochemistry can only clinch the diagnosis in these cases.the classic histological pattern of es / pnet consists of solid sheets of small uniform primitive cells with round nuclei and scanty cytoplasm that lack significant differentiation . in more differentiated es / pnet , homer - wright rosettes may be identified . due to the lack of characteristic morphologic features , es / pnet is difficult to distinguish from histologically similar small round - cell tumours including rhabdomyosarcoma , desmoplastic small round - cell tumour , poorly differentiated synovial sarcoma , mesenchymal chondrosarcoma , neuroblastoma and lymphoma . immunohistochemical expression of the mic2 gene product ( cd99 ) in es / pnet is helpful in separating this entity from other small round - cell tumours . however , cd99 expression is not specific for es / pnet , as it can be expressed by other sarcomas , including poorly differentiated synovial sarcoma and mesenchymal chondrosarcoma . other ancillary techniques , including cytogenetic analysis , reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization may provide further aid in confirming the diagnosis of es / pnet . demonstration of the t(11;22)(q24;q12 ) chromosomal translocation ( ews - fli1 gene rearrangement ) is highly specific for es / pnet as it is encountered in more than 90% of the neoplasms . management is usually multimodal : surgery followed by ifosfamide or doxorubicin - based chemotherapy and radiotherapy . overall , pnets are aggressive neoplasms that have less than 20% five - year survival , but the overall prognosis of extraskeletal es / pnet seems to be better . a retrospective study of 24 patients with extraskeletal es showed an overall five - year survival rate of 61% . wide tumor - free resection margins in conjunction with multi - agent chemotherapy are necessary for good clinical outcomes . although , a rare entity , extraskeletal es / pnet should be considered in the differential diagnosis of primary mediastinal neoplasms , especially in children or young adults and if a primitive small round - cell tumour is encountered in cytology or histology . histopathology with immunohistochemistry , cytogenetic analysis and other molecular tests to identify chromosomal translocations , are invaluable to establish specific diagnosis .

a 30-year - old male , carpenter by profession , presented with a history of dry cough and progressive shortness of breath for two months along with right - sided chest pain for one and a half months . the clinico - radiological picture was suggestive of right - sided massive pleural effusion . computed tomography ( ct ) scan of the thorax showed a huge mediastinal mass occupying the entire right hemithorax with very small amount of pleural effusion . ct - guided fine needle aspiration cytology and tru - cut biopsy from the mass both revealed small round - cell tumour , possibly small cell carcinoma of the lung . however , on immunohistochemistry tumour cells expressed mic-2 and it was consistent with a diagnosis of primitive neuroectodermal tumour .

we obtained the number of respiratory swabs tested throughout each year and the number that were positive for influenza virus from the global influenza surveillance and response system ( 5 ) . data from canada , mexico , and the united states ( population 458 million ) collected during 20022013 were aggregated to represent north america ; data from belize , costa rica , el salvador , guatemala , honduras , nicaragua , and panama ( population 42 million ) to represent central america ; and data from argentina , brazil , chile , paraguay , and uruguay ( population 262 million ) to represent south america ( 6 ) . we obtained antigenic characterization data from the centers for disease control and prevention ( atlanta , ga , usa ) . we determined the proportion of respiratory specimens that tested positive for influenza virus each month in north , central , and south america and then determined the annual median for each subregion ; months in which the proportion exceeded the annual median were considered epidemic ( 7 ) . the timing and length of epidemics in each subregion were also explored , and the proportion of samples testing positive for influenza virus was used as a proxy for epidemic severity . antigenic virus strains were defined as predominant if they made up the largest proportion of positive samples by type or subtype during an influenza season . we assessed whether predominant virus strains identified in south america were subsequently identified in central and north america and whether strains identified in north america were subsequently identified in central and south america . we also investigated whether predominant strains were represented by components of available southern or northern hemisphere vaccine formulations . during 20022013 , south america reported 877,770 influenza - positive respiratory samples ( 2.8/10,000 persons / y ) and north america 4,535,508 results ( 9.0/10,000 persons / y ) to the global influenza surveillance and response system ( 5 ) . during 20062013 , central america reported 82,163 results ( 2.4/10,000 persons / y ) . in each subregion , during 20062013 , the centers for disease control and prevention analyzed 2,971 samples from south america , 1,279 from central america , and 215,127 from north america for antigenic characterization . in south america , influenza epidemics started in april , in central america in june , and in north america in december . with the exception of 2 ( 25% ) of 8 years in central america and 2 ( 17% ) of 12 years in south america , when there was 1 southern temperate winter epidemic and a smaller northern temperate winter epidemic , all subregions had 1 annual influenza epidemic that lasted 5 months . the predominant influenza a(h1n1 ) virus strains in south america predominated in 9 of 9 subsequent seasons in central america and 12 ( 92% , 95% ci 78%107% ) of 13 subsequent seasons in north america ( table 1 ; technical appendix ) . similarly , a(h3n2 ) virus strains in south america predominated in 11 ( 92% , 95% ci 76%107% ) of 12 subsequent seasons in central america and 10 ( 71% , 95% ci 48%95% ) of 11 subsequent seasons in north america . predominant influenza b virus strains in south america only predominated in 8 ( 67% , 95% ci 40%93% ) of 12 subsequent seasons in central america and 8 ( 57% , 95% ci 31%83% ) of 14 subsequent seasons in north america . the proportion of influenza b virus strains in south america that predominated in subsequent seasons in north america , however , increased from 55% to 73% when we accounted for all identified virus strains and not just those that predominated in south america . virus strains in south america during 1 season typically did not predominate in subsequent seasons in south america ( 54% , 95% ci 38%70% ) . * data from canada , mexico , and the united states were aggregated to represent north america ; data from belize , costa rica , el salvador , guatemala , honduras , nicaragua , and panama to represent central america ; and data from argentina , brazil , chile , paraguay , and uruguay to represent south america . for influenza a(h1n1 ) virus , a , a / new caledonia/20/99(h1n1 ) ; b , a / solomon islands/03/2006(h1n1 ) ; c , a / brisbane/59/2007(h1n1 ) ; d , a / california/07/2009-(h1n1)pdm09 . for influenza a(h3n2 ) virus , a , a / panama/2007/99(h3n2 ) ; b , a / fujian/411/2002(h3 ) ; c , a / california/07/2004(h3n2 ) ; d , a / wisconsin/67/2005(h3n2 ) ; e , a / brisbane/10/2007(h3n2 ) ; f , a / perth/16/2009(h3n2 ) ; g , a / victoria/361/2011(h3n2 ) ; h , a / texas/50/2012(h3n2 ) . for influenza b virus , a , b / sichuan/379/99(yam ) ; b , b / shandong/7/97(vic ) ; c , b / shanghai/361/2002(yam ) ; d , b / malaysia/2505/2005(vic ) ; e , b / florida/07/2004(yam ) ; f , b / florida/04/2006(yam ) ; g , b / brisbane/60/2008(vic ) ; h , b / wisconsin/01/2010(yam ) i , b / massachusetts/02/2012(yam ) . newly identified strain ( 8 in south america , 2 in central america , and 8 in north america ) . the predominant a(h1n1 ) virus strains in north america predominated in 7 ( 78% , 95% ci 51%105% ) of 9 subsequent seasons in central america and 10 ( 83% , 95% ci 62%104% ) of 12 subsequent seasons in south america . a(h3n2 ) virus strains in north america predominated in 8 ( 67% , 95% ci 40%93% ) of 12 subsequent seasons in central america and 10 ( 77% , 95% ci 54%100% ) of 13 subsequent seasons in south america . influenza b virus strains in north america predominated in 9 ( 75% , 95% ci 51%100% ) of 12 subsequent seasons in central america and 7 ( 54% , 95% ci 27%81% ) of 13 subsequent seasons in south america . virus strains that predominated in north america during 1 season were less likely to predominate in the subsequent season in north america ( 62% , 95% ci 46%77% ) . at least 1 component of the southern hemisphere vaccine composition recommendations matched a predominant antigenic characterization in south america in 13 ( 93% , 95% ci 79%106% of 14 influenza seasons that occurred during 20012014 , and at least 1 component of the northern hemisphere vaccine composition recommendations matched a predominant antigenic characterization in north america in all 14 influenza seasons that occurred during 20012014 . of 33 predominant antigenic virus strains identified in central america during 20022014 , 21 ( 64% , 95% ci 47%80% ) matched the southern hemisphere recommendations and 24 ( 73% , 95% ci 58%88% ) matched the northern hemisphere recommendations ( table 2 ) . * values are proportions of occurrences when predominant strains are represented in each vaccine formulation . + , match ; , no match ; na , influenza type not among predominant circulating strains ; solomon is , solomon islands . our findings suggest that virus strains identified during influenza epidemics in south america typically became predominant in subsequent epidemics in central and north america . almost as frequently , virus strains identified during epidemics in north america became predominant in the subsequent central and south america epidemics . although strain selection for 1 hemisphere s vaccine formulation typically occurs before influenza activity is widespread in the opposite hemisphere , health officials have an opportunity to anticipate which influenza virus strains may predominate by observing activity in other subregions . for example , influenza a(h1n1)pdm09 virus predominated in brazil during 2013 ( 8) and became predominant in north america during 20132014 . health officials identifying influenza b virus strains in 1 hemisphere would have correctly predicted the predominant influenza b virus strains in the opposite hemisphere only half of the time unless they had also examined other co - circulating influenza b virus strains . nevertheless , such findings underscore the importance of year - round surveillance , viral characterization , data sharing , and annual influenza vaccination . our analyses are based on a convenience sample of respiratory specimens obtained from heterogeneous surveillance systems using different diagnostic assays ( e.g. , pcr and immunofluorescence ) and then aggregated by subregion . additional data will be needed to determine whether the characteristics of 1 subregion reliably predict influenza epidemics in another . new viral strains that appear might be introduced from outside the americas ( 3 ) . in summary , health officials in north and central america may find clues about which influenza a virus strains are likely to predominate during an upcoming season by observing which were predominant in south america and vice versa . our findings underscore the need to share timely and representative specimens with world health organization collaborating centres . in the future , shorter vaccine production times using novel technology might facilitate matching vaccine composition more closely to circulating virus strains .

during 20012014 , predominant influenza a(h1n1 ) and a(h3n2 ) strains in south america predominated in all or most subsequent influenza seasons in central and north america . predominant a(h1n1 ) and a(h3n2 ) strains in north america predominated in most subsequent seasons in central and south america . sharing data between these subregions may improve influenza season preparedness .

adrenocortical carcinoma ( acc ) is a highly malignant and rare tumor with a median of 35.2 months overall survival time . surgical resection is still the mainstay treatment for resectable accs and even some metastatic cases . mitotane , as an adrenotoxic agent that blocks cortisol synthesis , was suggested to be efficient for reducing recurrence risk , but validation trial is still needed . moreover , whether adjuvant mitotane after surgery would improve overall survival is not consistent . recently , radiotherapy has demonstrated benefits through reducing recurrence risk . however , the effect of radiation therapy is still controversial . we intended to investigate the effect of radiotherapy using a national population - based database with a large sample size . we queried the surveillance , epidemiology , and end results ( seer ) database ( 19732013 ) for cases diagnosed with acc . cases were identified from the seerstat client using the international classification of diseases for oncology , 3rd edition ( icd - o-3 ) . the initial condition was set as site recode b icd - o-3/who 2008 : adrenal gland . in all , 5321 cases with an adrenal malignant tumor were identified . the screening conditions were acc , being an adult , first tumor , and unilateral acc . ethical approval was not needed because the study was exempt from institutional review board review . variables included age , race , gender , marital status , tumor laterality , surgery , regional lymph node dissection ( rlnd ) , tumor size , and tumor stage . for tumor stage , we used the european network for the study of adrenal tumors ( ensat ) staging system to evaluate the acc stage according to the codes of the collaborative stage ( http://cancerstaging.org/cstage/about/pages/default.aspx ) . continuous variables were described with medians and interquartile range ( iqr ) , and mann whitney u tests were used to compare the differences between the groups . for categorical variables the follow - up cutoff date was december 31 , 2013 . a hazard ratio ( hr ) and its 95% confidence interval ( 95% ci ) were used to estimate the risk of mortality from multivariate cox regression analysis . compared with traditional multivariate analysis incorporating numerous independent variables , we also performed propensity score analysis , including propensity score adjustment ( psa ) , inverse probability treatment weighting ( iptw ) , standardized mortality ratio weighting ( smrw ) , and propensity score matching ( psm ) . psm was performed using the 1:1 nearest - neighbor method . for the propensity score matching cohort , all statistical analyses were performed using stata 14.2 ( stata corp , college station , tx ) . we queried the surveillance , epidemiology , and end results ( seer ) database ( 19732013 ) for cases diagnosed with acc . cases were identified from the seerstat client using the international classification of diseases for oncology , 3rd edition ( icd - o-3 ) . the initial condition was set as site recode b icd - o-3/who 2008 : adrenal gland . in all , 5321 cases with an adrenal malignant tumor were identified . the screening conditions were acc , being an adult , first tumor , and unilateral acc . ethical approval was not needed because the study was exempt from institutional review board review . variables included age , race , gender , marital status , tumor laterality , surgery , regional lymph node dissection ( rlnd ) , tumor size , and tumor stage . for tumor stage , we used the european network for the study of adrenal tumors ( ensat ) staging system to evaluate the acc stage according to the codes of the collaborative stage ( http://cancerstaging.org/cstage/about/pages/default.aspx ) . continuous variables were described with medians and interquartile range ( iqr ) , and mann whitney u tests were used to compare the differences between the groups . for categorical variables a hazard ratio ( hr ) and its 95% confidence interval ( 95% ci ) were used to estimate the risk of mortality from multivariate cox regression analysis . compared with traditional multivariate analysis incorporating numerous independent variables , we also performed propensity score analysis , including propensity score adjustment ( psa ) , inverse probability treatment weighting ( iptw ) , standardized mortality ratio weighting ( smrw ) , and propensity score matching ( psm ) . psm was performed using the 1:1 nearest - neighbor method . for the propensity score matching cohort , all statistical analyses were performed using stata 14.2 ( stata corp , college station , tx ) . all cases were diagnosed from 2004 to 2013 ( relatively modern samples due to consideration of radiation technique development ) . among them , 74 patients received radiation therapy . the distribution of tumor stage was significantly different between the radiotherapy and no radiotherapy groups ( p = .002 ) . no differences between the 2 groups were observed on age , gender , race , marital status , tumor laterality , surgery , tumor size , or rlnd status ( table 1 ) . table 2 presents the traditional multivariate survival analysis of overall and cancer - specific survival . radiotherapy did not increase the overall survival ( hr 0.794 , 95% ci 0.5501.146 , p = .218 ) or cancer - specific survival ( hr 0.842 , 95% ci 0.5741.236 , p = .388 ) . the results consistently presented no survival benefits regardless of the use of psa , iptw , smrw , and psm . after propensity score matching , the p values of the log - rank tests were .7223 and .8051 for overall survival and cancer - specific survival , respectively . considering the survival difference , we performed a subgroup survival analysis stratified by tumor stage . group 1 was stage i / ii and stage iii , group 2 was stage iv . overall mortality risk for radiation was similar to nonradiation patient in group 1 ( hr 1.026 , 95% ci 0.5991.757 , p = .926 ) and group 2 ( hr 0.807 , 95% ci 0.4841.344 , p = .410 ) , respectively . propensity score analysis for the efficacy of radiotherapy on overall survival and cancer - specific survival . both results showed no significant survival difference in overall survival ( log - rank p = .722 ) or cancer - specific survival ( log - rank p = .805 ) between radiotherapy subgroups . in this study , we used a relatively large cohort to demonstrate the efficacy of radiotherapy on acc . all results consistently showed that no oncologic survival improvement from radiotherapy was observed for acc patients . the results were stable on the basis of traditional multivariate analysis and propensity score analysis . an incisive criticism of the aforementioned studies is that all previous outcomes were based on a limited sample size that may have had low statistical power to demonstrate significance . the outcomes were similar to previous studies . because the acc was highly malignant , the majority of causes of death were acc - related causes . acc was deemed to be radiation - resistant , and only a very small portion of patients received radiotherapy , mainly as palliative treatment . it was reported that radiotherapy could reduce the risk of local recurrence but would not change the overall survival . moreover , radiotherapy did not reduce the risk of metastasis . in the study by else et al , it was mitotane , not radiation , that improved recurrence - free survival in the multivariate analysis . the results of this study also indicated the synergism of mitotane combined with radiation . despite no overall survival improvement thus , radiotherapy for acc could damage adjacent organs and tissues such as the kidney , vascular vessels , spinal cord , diaphragm , and stomach . however , the literature reported that adverse effects of radiotherapy in acc were mild to moderate . newly developed radiation techniques such as stereotactic body radiation therapy ( sbrt ) have been reported to be effective for controlling metastatic lesions . in summary , radiotherapy could not improve overall survival but may ameliorate tumor - related symptoms and achieve local control of accs . as the development of radiation technique , different radiation modalities used by different medical teams could lead to variations in outcomes . in addition , the number of patients who received radiotherapy was relatively small ( 74 patients ) and accounted for almost 14% of the total included population . resection margin played a critical role in cancer survival . for future clinical studies , multiple center

abstractadrenocortical carcinoma ( acc ) is a rare and malignant tumor . the main treatment is primary surgical resection with or without mitotane therapy . the role of radiation therapy is still controversial . we aim to investigate the survival efficacy of radiotherapy in a large population - based cohort.we queried the surveillance , epidemiology , and end results ( seer ) database ( 19732013 ) to identify cases with acc . traditional multivariate cox regression and propensity score analysis were used to evaluate the effect of radiotherapy on cancer survival . the survival outcomes included overall survival and cancer - specific survival . the treatment effect was evaluated using a hazard ratio ( hr ) and its 95% confidence interval ( 95% ci).five hundred thirty patients diagnosed with acc were identified . among them , 74 patients received radiotherapy . in the multivariate cox regression , radiotherapy did not increase the overall survival ( hr 0.794 , 95% ci 0.5501.146 , p = .218 ) or cancer - specific survival ( hr 0.842 , 95% ci 0.5741.236 , p = .388 ) . in the propensity score analysis , the results consistently showed no survival benefit of radiotherapy regardless of the different propensity score analysis methods.radiotherapy did not improve overall or cancer - specific survival in acc patients . further confirmation is needed from multi - institutional prospective studies in the future .

altered behavior is a common occurrence in critically ill patients , and has diverse etiologies . the situations are further complicated in elderly , those with underlying co - morbidities and in individuals on mechanical ventilation . we describe an elderly woman , who developed sepsis and respiratory failure , required mechanical ventilation , and had an unrecognized behavioral state that delayed her weaning . a 68-year - old woman with previous hypothyroidism and bipolar disorder was on multiple medications ( sodium valproate , clozapine , risperidone , and trihexyphenidyl ) for two decades . she was hypothermic , had pulse of 50/min , blood pressure of 90/60 mmhg , respiratory rates of 24/min , and her bilateral plantars were mute . she had crepitations over right lower lung fields . on laboratory evaluation , she had pancytopenia and normal renal and liver function tests . she was started on crystalloids , antibiotics , and hydrocortisone for sepsis due to right lower zone pneumonia . her previous drugs were withheld given the possibility of drug - induced pancytopenia due to either clozapine or valproate . she was intubated and initiated on mechanical ventilation , and vasopressors were started . by day 7 , sedatives were tapered , her infection was brought under control , and vasopressors were stopped . however , she remained lethargic , and had poor respiratory efforts , for which percutaneous tracheostomy was performed on d10 . magnetic resonance imaging brain , cerebrospinal fluid examination , total creatine kinase levels , and electroencephalography were normal . she persisted to be lethargic , with a fixed gaze , limited blinking , fixed flexor posturing , and muscle tone was increased in all limbs . she was initiated on intravenous ( iv ) lorazepam , i.e. 2 mg iv q8h . over next 5 days , she became fully conscious . by day 24 the patient was discharged after 35 days of hospital stay , and is doing well 6 months later . clinically , catatonia is characterized by excited or withdrawn features , though patients manifest some of both types during the course of their illness . its exact prevalence within the intensive care unit ( icu ) is unknown , with one report on a small number of patients suggesting it may affect up to 4% of critically ill patients . in our case , there were various risk factors for catatonia such as old age , affective disorder , withdrawal of antipsychotics , and chronic medical illness . other likely differentials in this case with altered sensorium can be metabolic disorders , i.e. , myxedema coma , hepatic encephalopathy due to valproate , central nervous system infections , neurodegenerative disorders , persistent vegetative states , serotonin syndrome , autoimmune encephalopathy , septic encephalopathy , or seizures . negative tests and positive response to benzodiazepine makes catatonia most likely etiology in this case . it has been proposed that basal ganglia thalamo - cortical circuit dysregulation with resulting changes in neurotransmitter function is a potential precipitant factor . have lower gamma - aminobutyric acid a ( gaba a ) activity in the orbito - frontal cortex than do healthy and psychiatric control patients . benzodiazepines , which are gaba a agonists , are first - line therapy for catatonia . the modified bush - francis catatonia rating scale ( bfcrs ) is a 23-item rating scale that provides a standardized schema for clinical examination . we used an algorithmic approach to the diagnosis and management of catatonia in the icu as proposed by saddawi - konefka . a trial of 12 mg of iv lorazepam can produce immediate , impressive reversal of catatonic features . this is known as the lorazepam test and is associated with reduced catatonia scores on the bfcrs by 60% within 10 min and response rates of 6080% within hours or days . despite the lack of prospective randomized evidence , benzodiazepines are the gold standard in the treatment of catatonia . iv lorazepam is commonly used , starting with doses of 2 mg daily , and titrating occasionally to total doses of 2030 mg daily . electroconvulsive therapy , the most successful treatment for catatonia , is usually reserved for patients with benzodiazepine - resistant catatonia . timely recognition and treatment of catatonia in the critically ill patients with altered mental status is essential , given the substantial morbidity and mortality associated with the condition .

the cause of altered sensorium in critical care settings includes metabolic derangements , drug and toxin overdose , central nervous system infections , neurodegenerative disorders , vascular events , hypo - perfusion states , and septic encephalopathy . here , we present a case of an elderly woman who presented to us with altered sensorium with respiratory failure requiring mechanical ventilation . her metabolic parameters , imaging , and cerebrospinal fluid study were all normal despite that she continued to remain in altered sensorium and had an unrecognized behavioral state that delayed her weaning .

a 41-year - old male patient presented with a complaint of deteriorating dyspnea for two months . at room air circumstances , arterial blood gas analysis was ph 7.39 , paco2 35.7 mmhg , pao2 64.2 mmhg , hco3 -21.2 mmol / l , and sao2 92.5% . chest x - ray showed a circumscribed mass shadow in the left lower lobe area and computed tomography ( ct ) scan revealed a large nodular lesion suggestive of pulmonary arteriovenous malformation ( pavm ) between left pulmonary artery to left pulmonary vein in the left lower lobe ( fig . 1 ) . because use of coil embolic device in the existing pavm had a high likehood of complications including device migration , we decided to perform transcatheter embolization using the amplatzer vascular plug ( avp ) ii as a new self - expanding device . under local anesthesia after systemic heparinization ( 3,000 iu intravenous ) , a 6f introducer sheath was placed through right femoral vein puncture . the feeding artery was selected by using a 6f guiding catheter and a selective angiogram was taken showing an arteriovenous malformation as an aneurismal dilatation with no thrombus and a drainage vein to a pulmonary vein and the left atrium . a 10 mm avp ii ( aga medical , golden valley , mn , usa ) was delivered through the catheter . the guiding catheter was pulled back a few centimeters to give the device space at the occlusion site to expand . after the proper position was reached , the plug was released by turning the release cable counterclockwise . an angiogram five minutes later confirmed incomplete occlusion of the fistula , we then added an additional 12 mm avp ii ( fig . 2 ) . there were no procedure related complications and there was marked improvement of patient 's symptoms . chest ct scan at three years - follow - up showed nearly complete regression of pulmonary arteriovenous malformation and complete occlusion of the fistula ( fig . acquired pavm is related to injury , mitral stenosis , or actinomycosis caused by chest trauma or chest surgery [ 1 - 3 ] . among congenital cases , about 50% to 80% are associated with osler - weber - render syndrome or hereditary hemorrhagic telangiectasia . our case was assumed to be congenital pavm without any apparent acquired origin , although there were no abnormalities in skin , oral , and nasal mucosa . about 13% to 15% of pavm show symptoms such as dyspnea , hemoptysis , or hemothorax related to the intrapulmonary arteriovenous shunt . in cases with severe symptomatologies , hemorrhage from a ruptured pavm and various neurological complications such as cerebrovascular accidents from brain abscess and paradoxical embolism may occur . in the past , surgical removal through ligation , segmentectomy , lobectomy , and pneumonectomy , among others , was the first approach used . however , because of high surgery - related morbidity and mortality , endovascular embolization with coil or balloon is currently preferred . in this case study , the diameter of the feeding artery was about 7 mm and sac diameter was 30 mm which would be associated with high risk of incomplete occlusion , recanalization and embolization of coil . although coil embolization has the advantage of precise placement and detachment , on occasions unstable positioning and anchoring might occur , causing distal coil migration ; also , use of multiple coils can be time - consuming and expensive . on the other hand , detachable balloon embolization is a single step device and has the merit of sealing the vessel lumen , but its lack of anchoring can lead to flow - induced migration . therefore avp ii was used for embolization in this case . the second generation avp ii utilizes the shape memory of nitinol , providing the practitioner the ability to deploy , recapture and redeploy thereby ensuring precise placement . once expanded , the 360 of vessel wall apposition creates a secure fit in the target vessel . the avp ii 's unique multi - segmented , multi - layered design significantly reduces time - to - occlusion for transcatheter embolization procedures while maintaining complete control during positioning and delivery of the occluder . currently , avp ii has been adapted for the treatment of high - flow lesions and parent artery occlusions . the mean reported time to flow cessation of avp ii in the treatment of pavm has been 4.8 minutes ( range , 3.0 to 11.2 minutes ) . therefore , delayed occlusion time during parent artery occlusion has potential risk of thromboembolic complications , making it important to perform complete occlusion of the primary artery in single step . minimum size of the guiding catheter is 5f and detachment can be done with a counterclockwise rotation of the pusher wire after deployment . in oversizing of the device , the company recommends a 20% larger diameter than that of the target vessel , but as seen in this case study , that also depends on the patient 's target vessel and anatomy vessel such as a pulmonary feeding artery . from our case , we suggest that transcatheter embolization with avp ii might be a reasonable alternative in the treatment of pavm because of its effectiveness and ease of device management .

pulmonary arteriovenous malformation ( pavm ) is a rare anomalous direct communication between the pulmonary artery and vein with a considerable risk of serious complications such as cerebral thromboembolism or abscess and pulmonary hemorrhage . although the past , surgical resection such as lobectomy was mostly used to treat pavm , the recent development of endovascular treatment has made it a primary consideration to perform transcatheter embolization using coils or detachable balloons . we report a case of successful transcatheter embolization of giant pavm with the second generation amplatzer vascular plug ii as a new self - expanding device .

leukemic retinopathy refers to numerous , abnormal fundoscopic findings that stem from complications of leukemia , such as anemia , thrombocytopenia , and hyperviscosity.1,2 the most prevalent of such findings include intraretinal hemorrhages , cotton - wool spots , and white - centered hemorrhages . these hemorrhages are typically found in the posterior pole and particularly in the inner layers with focal destruction.1 while ocular involvement can range from 39% to 53% of cases in patients with acute leukemia,1 only a small portion of these findings are a result of direct leukemic infiltration . in this case report , we present a rare scenario of bilateral , foveal leukemic infiltration , and vision loss in a patient with atypical chronic myelogenous leukemia who eventually had regression of these foveal lesions and recovered vision after chemotherapy . the clinical response was documented on serial spectral domain optical coherence tomography ( oct ) imaging , with image registration . a 59-year - old man with a history of asthma , hypertension , and newly diagnosed atypical chronic myelogenous leukemia , which was bcr - abl receptor - negative , presented to the eye clinic with a several - week history of decreased vision , floaters and photopsia , and central scotomas . his best corrected visual acuity was 20/80 oculus uterque ( ou ) , and intraocular pressures were 13 and 14 mmhg , respectively . his pupils were symmetric and reacted briskly to light without a relative afferent pupillary defect . his dilated fundus exam revealed a posterior vitreous detachment in his right eye without vitreous hemorrhage . his cup - to - disk ratio was 0.85 with healthy rims and bilateral peripapillary atrophy . focal areas of leukemic infiltration were present in the fovea ou ( figure 1 ) with larger leukemic lesions temporally in right eye and inferotemporally in the left eye . oct scans of the macula revealed hyperreflective lesions in the inner retina as well as a separate outer retinal lesion in the right eye ( figure 2 ) . the left eye demonstrated a larger inner retinal lesion with smaller adjacent lesions , without an outer retinal component . the patient was diagnosed with chronic phase chronic myelogenous leukemia ( bcr - abl - negative ) by bone marrow aspiration and biopsy with an overall cellularity of 95% . cytogenetic studies showed 47 , xxy . unlike acute lymphoblastic leukemia , central nervous system involvement in chronic myelogenous leukemia is rare,3 and in the absence of headaches or other focal neurological findings , he did not undergo further analysis of his cerebrospinal fluid . the patient s white blood cell count was noted to be 265.710/l ( reference range 4,50010,00010/l ) with a hemoglobin of 7.8 g / dl ( reference range 13.317.2 g / dl ) and platelets of 19910/l ( reference range 17910/l37310/l ) . differential revealed 31% neutrophils , 5% bands , 48% myelocytes , 2% metamyelocytes , 1% basophils , 1% eosinophils , 2% monocytes , 4% promyelocytes , and 5% blasts . one month into his induction therapy with imatinib ( gleevec ; novartis international ag . , basel , switzerland ) 400 mg daily , he developed lower extremity edema and failed to show response to therapy ; his white blood cell count remained elevated at 395.310/l . as his white blood cell decreased , he was noted to have improved vision at subsequent ophthalmologic visits . his dilated fundus examinations demonstrated a gradual regression of his leukemic lesions at his 2 and 3 month follow up visits ( figure 1b and figure 1c respectively ) . at 12 months from his initial presentation , there was complete resolution of his bilateral foveal infiltration , cotton - wool spots , and retinal hemorrhages ( figure 1d ) . oct scans revealed restored foveal contour with focal defects at the photoreceptor outer segments ( figure 2c ) . by this point , the patient had successfully completed his induction therapy and was undergoing maintenance therapy . his best corrected visual acuity was 20/30 ou . the virginia commonwealth university ( vcu ) institutional review board ( irb ) does not require approval for this case report as it does not constitute a human research subject that involves an investigational article . written patient consent was obtained in compliance with vcu health system , to use ophthalmic imaging and data in the publication of this case report . regardless of the type of leukemia , ocular manifestations can be found in up to half of the cases.1 most of these manifestations , such as retinal hemorrhages , represent conditions associated with leukemia as opposed to direct leukemic infiltration . a prior report has demonstrated the time domain oct findings of leukemic infiltration of the choroid with overlying serous detachment of the neurosensory retina , which resolved following successful treatment.4 further in another report , spectral domain oct revealed the presence of choroidal thickening in addition to associated serous retinal detachment in a patient with recurrent leukemia.5 our case is the first to demonstrate leukemic infiltration of the retina using oct . it describes not only resolution of retinal hemorrhages associated with leukemia but also resolution of leukemic infiltration of the macula as well , following successful systemic treatment . leukemic infiltration , as demonstrated in our scans , represents lesions of uniform reflectivity and can involve all layers of the retina . at month 3 , there are persistent hemorrhages present in the foveal regions in both eyes ( figure 1c ) , with complete resolution of the infiltrates and the corresponding hyperreflective lesions on oct on the right ( figure 2c ) . finally , there was no consecutive atrophy of the inner retinal layers upon resolution , but there were focal disruptions of the photoreceptor outer segments where there was initial leukemic involvement . this was supported by fluorescein angiography , which was performed at 3 months from presentation , where there was preservation of the perifoveal capillary bed ( figure 3 ) . this report demonstrates a rare case of leukemic infiltration of the macula , documented with serial octs . infiltration of the retina can be identified and monitored using oct and should be employed in cases of suspected leukemic retinopathy .

we report a case of a 59-year - old man with a history of atypical chronic myelogenous leukemia who presented with a several - week history of decreased vision in both eyes . his clinical examination revealed bilateral foveal infiltration , which was also demonstrated on optical coherence tomography . after a failed induction with imatinib ( gleevec ) , he was treated with omacetaxine ( synribo ) with an appropriate hematologic response . as his leukemia improved with chemotherapy , his retinal lesions regressed as demonstrated by serial optical coherence tomography and fundus photographs , with near complete restoration of foveal architecture .

more than 365 million people are estimated to have t2 dm , and almost 300 million people have major depression . both these disorders are projected to be among the five leading causes of disease burden by 2030 . depression can be viewed as a modifiable independent risk factor for the development of t2 dm and for progression of complications from either type 1 or type 2 diabetes . the recognition and addressal of this association can have profound implications for prevention and treatment of these disorders . eighty percent of people with t2 dm reside in low- and middle - income countries ( lmics ) . yet much of the research around depression among people with diabetes has been conducted in high - income countries ( hics ) . this study adds to the limited data available on the prevalence of depression in diabetes from india . it has special relevance for india ( middle - income country ) , having high prevalence of both these disorders . this prospective case study was carried out in september 2014 at the government medical college and hospital , chandigarh ( india ) . the patients with a diagnosis of type 2 diabetes above age 30 years were recruited on voluntarily basis for this study . the patient health questionnaire-9 ( phq-9 ) was used for evaluation of depression , and relevant clinical details were obtained . no intervention was part of the study and the investigations that were available with the patient were used for analysis purpose . the cases were not receiving any psychiatric treatment which could have an effect on the result . depression was assessed by administering the nine - item phq-9 , a self - report version of primary care evaluation of mental disorders that assesses the presence of major depressive disorder using modified diagnostic and statistical manual , fourth edition criteria . there is good agreement reported between the phq diagnosis and those of independent psychiatry health professionals ( for the diagnosis of any one or more phq disorder , = 0.65 ; overall accuracy , 85% ; sensitivity , 75% ; specificity , 90% ) . it assesses the symptoms experienced by participants during the 2-week period before they take the survey . on the basis of participant response to the frequency of any particular symptom ( 0 = not at all , 1 = several days , 2 = more than of the days , 3 = nearly every day ) , a total score ranging from 0 to 27 was obtained , with higher scores indicating patients increased self - report of depression severity . the arbitrary division of phq-9 scores into ratings of minimal ( 04 ) , mild ( 59 ) , and moderate to severe depression ( 10 ) suggested by reddy et al . was used in this study . those who had moderate to severe depression based on cut - off points in phq 9 10 were referred to psychiatry department for further management . the variables included in the study were socio - demographic factors , the presence of hypertension , microvascular complications were also assessed . since most of the patients were recruited as first - timers attending the endocrine clinic of the hospital , glycated hemoglobin ( hba1c ) was not available for all patients . the analysis is , therefore , with recent fasting blood glucose ( fbg ) value ( within the last 7 days ) , which was available for all patients . moreover , the value of fbg is more easily understood by the patient , rather than interpretation of hba1c . differences in characteristics between participants were tested with unpaired t - test for normally distributed variables , with the wilcoxon rank sum test for skewed variables , and with the chi - square test or fisher exact test for categorical variables . all statistical analyses were carried out using statistical package for social sciences ( version 20.0 , chicago , il , usa ) . depression was assessed by administering the nine - item phq-9 , a self - report version of primary care evaluation of mental disorders that assesses the presence of major depressive disorder using modified diagnostic and statistical manual , fourth edition criteria . there is good agreement reported between the phq diagnosis and those of independent psychiatry health professionals ( for the diagnosis of any one or more phq disorder , = 0.65 ; overall accuracy , 85% ; sensitivity , 75% ; specificity , 90% ) . it assesses the symptoms experienced by participants during the 2-week period before they take the survey . on the basis of participant response to the frequency of any particular symptom ( 0 = not at all , 1 = several days , 2 = more than of the days , 3 = nearly every day ) , a total score ranging from 0 to 27 was obtained , with higher scores indicating patients increased self - report of depression severity . the arbitrary division of phq-9 scores into ratings of minimal ( 04 ) , mild ( 59 ) , and moderate to severe depression ( 10 ) suggested by reddy et al . was used in this study . those who had moderate to severe depression based on cut - off points in phq 9 10 were referred to psychiatry department for further management . the variables included in the study were socio - demographic factors , the presence of hypertension , microvascular complications were also assessed . since most of the patients were recruited as first - timers attending the endocrine clinic of the hospital , glycated hemoglobin ( hba1c ) was not available for all patients . the analysis is , therefore , with recent fasting blood glucose ( fbg ) value ( within the last 7 days ) , which was available for all patients . moreover , the value of fbg is more easily understood by the patient , rather than interpretation of hba1c . differences in characteristics between participants were tested with unpaired t - test for normally distributed variables , with the wilcoxon rank sum test for skewed variables , and with the chi - square test or fisher exact test for categorical variables . all statistical analyses were carried out using statistical package for social sciences ( version 20.0 , chicago , il , usa ) . about 45% had at least one microvascular ( retinopathy , nephropathy , and neuropathy ) complication . nearly 50% of the subjects had moderate to severe hyperglycemia as indicated by fasting plasma glucose values > 150 mg% . severe depression ( phq score 15 ) was present in 3 ( 4% ) subjects , moderate depression ( phq score 10 ) was present in 7 ( 10% ) subjects , and mild depression was present in 20 ( 27% ) of subjects . depression was significantly more prevalent in rural subjects ( 57% ) as compared to urban ones ( 31% , p = 0.049 ) . the prevalence of depression increased with age and duration of diabetes though the difference was not significant . men , subjects with hypertension , microvascular complications , and subjects with moderate to severe hyperglycemia had more depression [ table 1 ] . baseline characteristics of study population correlation of phq score with continuous variables in bivariate risk factor analysis [ table 3 ] , rural subject was nearly three times more likely to have depression ( p = 0.03 ) as compared to urban . absence of microvascular complication was associated with 18% less chances of having depression , and fasting plasma glucose 150 mg% was associated with 26% lesser risk for depression . about 45% had at least one microvascular ( retinopathy , nephropathy , and neuropathy ) complication . nearly 50% of the subjects had moderate to severe hyperglycemia as indicated by fasting plasma glucose values > 150 mg% . severe depression ( phq score 15 ) was present in 3 ( 4% ) subjects , moderate depression ( phq score 10 ) was present in 7 ( 10% ) subjects , and mild depression was present in 20 ( 27% ) of subjects . depression was significantly more prevalent in rural subjects ( 57% ) as compared to urban ones ( 31% , p = 0.049 ) . the prevalence of depression increased with age and duration of diabetes though the difference was not significant . men , subjects with hypertension , microvascular complications , and subjects with moderate to severe hyperglycemia had more depression [ table 1 ] . in bivariate risk factor analysis [ table 3 ] , rural subject was nearly three times more likely to have depression ( p = 0.03 ) as compared to urban . presence of hypertension was associated with 60% more risk of having depression . absence of microvascular complication was associated with 18% less chances of having depression , and fasting plasma glucose 150 mg% was associated with 26% lesser risk for depression . the eight studies in india from both urban and rural populations were recently summarized in a systematic review . of the six urban clinic - based studies , between and of the participants with diabetes were depressed ; however , these studies demonstrated great variability ( highest was 84% , and lowest was 16.9% ) . we additionally found three more clinic - based studies from india . in total , four studies used ( phq-9 ) questionnaire for the assessment of depression among diabetics in india . the prevalence of depression in t2 dm patients in our study ( 41% ) was nearly similar to other studies ( 3550% ) . the interesting finding being higher prevalence of depression in a rural population , when compared to urban ones , and the difference was statistically significant . it may be related to socioeconomic status . the individuals with low earning power face the twin burdens of paying for health care , which is largely out - of - pocket expenditure in india and meeting the needs of their family . the diagnosis of t2 dm and its poor understanding in rural areas may be an additional stress causing depression in these people . we found no statistically significant association between depression and duration of diabetes , glycemic control and microvascular complications , the findings , also reported by siddiqui et al . these findings implicate that the depression should be assessed in all patients with diabetes , irrespective of gender , duration of diabetes , glycemic control or presence / absence of microvascular complications . american diabetes association also recommends screening and assessment of depression in patients with diabetes . a meta - analysis ( 16 studies ) , concluded that depression increases all - cause mortality , with the relative risk of dying being 2.5 times higher in depressed compared to nondepressed people . the mortality risk remained high even after additional adjustment for diabetes complications ( hazard ratio = 1.76 ) . the information presented , thus far , underscores the extensive adverse effects of untreated depression , including decreased capacity and functioning , increased risk of suicide , and increased medical morbidity and mortality from all causes . however , much of the evidence for depression and type 2 diabetes , came from hics , and few studies have systematically evaluated depression in diabetes in lmics , which includes india . therefore , more understanding on this relationship is essential , and the present study will add to the limited literature available in india on relationship between diabetes and depression . this study was cross - sectional , so inference about causality between depression and diabetes can not be made . the study was conducted in tertiary care hospital , so a possible selection bias can not be excluded , as more depressed / complicated patients might be seeking specialized diabetes care . to summarize , the present study found a high prevalence of depression among patients with diabetes . age , sex , duration of diabetes , microvascular complications , hypertension , were not significantly associated with depression . future studies from india , should evaluate the effect of treatment of depression on glycemic control , and also the effect of glycemic control on depression .

background : depression is common among diabetes , and is associated with poor outcomes . however , the data on this important relationship are limited from india.objective:the aim was to estimate the prevalence of depression in patients with diabetes and to determine the association of depression with age , sex , and other related parameters.materials and methods : the study was cross - sectional carried out in endocrinology clinic of tertiary care hospital in north india . cases were patients with type 2 diabetes mellitus ( t2 dm ) above 30 years of age . depression was assessed using the patient health questionairre-9 ( phq-9 ) . the relationship with sociodemographic profile , duration of diabetes , hypertension and microvascular complications was also analyzed.results:seventy-three subjects ( 57.5% females ) with mean age 50.8 9.2 years were evaluated . the prevalence of depression was 41% . severe depression ( phq score 15 ) was present in 3 ( 4% ) subjects , moderate depression ( phq score 10 ) in 7 ( 10% ) subjects , and mild depression was present in 20 ( 27% ) of subjects . depression was significantly more prevalent in rural subjects ( 57% ) when compared to urban ones ( 31% , p = 0.049 ) . depression increased with presence of microvascular complications , fasting plasma glucose , hypertension , but the differences were not statistically significant.conclusions:our study demonstrates higher prevalence of depression in patients with type 2 diabetes . apart from being belonging to the rural area , no other factor was significantly associated with depression . therefore , depression should be assessed in each and every patient , irrespective of other factors .

caudwell xtreme everest ( cxe ) is a large , healthy volunteer field study investigating human adaptation to environmental hypoxia . the project is organised by the centre for altitude space and extreme environment medicine ( case medicine ) at university college london . during april and may 2007 more than 200 individuals were studied as they were progressively exposed to hypobaric hypoxia on the trek to everest base camp at 5,300 m. most of these individuals were volunteers who gave up their holidays to be participants in the study . the remainder was comprised of doctors and scientists , 15 of whom continued the studies as they ascended up to 8,000 m. eight of these investigators reached the summit of everest and on their descent took the first measurement of arterial oxygen levels above 8,000 m. so what is the relevance of cxe to intensive care medicine ? indeed , it is hard to think of a critically ill patient in whom cellular hypoxia , either local or generalized , is not present . hypoxia may occur as either a cause of or as a consequence of a variety of critical illnesses . systemic inflammation is associated with the development of cellular hypoxia caused by decreased tissue oxygen delivery associated with microcirculatory dysfunction . cellular hypoxia may also be caused by alterations in cellular energy pathways and mitochondrial function , resulting in decreased ability to utilize available oxygen . although our dominant treatment paradigm revolves around maintenance of oxygen delivery to the cells , there are few data to guide the optimal level of inspired oxygen . moreover , in some circumstances increasing oxygen delivery confers no benefit or may even cause harm ; for example , elevating haemoglobin levels or ' optimization ' of oxygen delivery to specific goals in established critical illness [ 4 - 6 ] . might it be that variations in the cellular efficiency of oxygen metabolism account for some of the observed differences in outcome following critical illness ? the high altitude physiology literature gives us an elegant general description of adaptation to environmental hypoxia built around the idea that maintenance of oxygen delivery to the tissues will allow normal cellular function . however , to date none of these adaptations explain observed ( and dramatic ) differences in performance between individuals at altitude . again , the possibility that observed differences are not accounted for by variations in elements of the dominant paradigm raises the possibility that an unmeasured factor or factors may be important . the core hypothesis that cxe is addressing is that variations in metabolic efficiency ( relationship between oxygen uptake and work rate ) may explain , at least in part , observed differences in individuals ' abilities to adapt to hypoxia . if this is true , then it may be possible by examining the genotype and phenotype of the ' rapid adaptors ' to identify mechanisms and thereby develop treatments to benefit the ' slow adaptors ' [ 8 - 10 ] . the studies conducted in cxe involve a variety of techniques , including cardiopulmonary exercise testing on cycle ergo - meters using breath - by - breath expired gas analysis , neuropsychological assessment , near infrared spectroscopy of brain and exercising muscle , blood markers ( inflammatory and neuroendocrine ) and daily recording of simple physiological variables . these measurements and many more were taken in london before departure , in four laboratories in nepal on the ascent to everest base camp , and in two laboratories high on mount everest . the next few years will see whether this new approach to investigating the pathogenesis of critical illness bears fruit . ar , mm , hm and mg were all involved in either ( or all ) of original drafting , review and redrafting of the mansucript . the research was funded from a variety of sources , none of which are public . the entrepreneur john caudwell , whose name the expedition carries , donated 500,000 specifically to support the research . boc medical , now part of the linde group , generously supported the research early on and continues to do so . ely - lilly critical care , the london clinic ( a private hospital ) , smiths medical , deltex medical and rolex have also donated money to support the research and logistics . specific research grants were awarded by the association of anaesthetists of great britain and ireland , and the uk intensive care foundation .

caudwell xtreme everest ( cxe ) is a large healthy volunteer field study investigating human adaptation to environmental hypoxia . more than 200 individuals were studied at sea - level and in four laboratories on the trek to everest base camp ( 5,300 m ) . fifteen physicians climbed high on everest and continued the studies as they ascended ; eight of these individuals reached the summit of everest and succeeded in sampling arterial blood at 8,400 m on their descent . core measurements included cardiopulmonary exercise testing , neuropsychological assessment , near infra - red spectroscopy of brain and exercising muscle , blood markers and daily recording of simple physiological variables . the goal of cxe is to further our understanding of human adaptation to cellular hypoxia , a fundamental mechanism of injury in critical illness , with the aim of improving the care of critically ill patients .

currently , diabetes is known as one of the major public health concerns in the third millennium and is the fifth main mortality cause in the world . this disease kills 4 million people every year , which is 9% of the deaths all over the world . in iran , a national study which investigated the risk factors of non - contagious diseases estimated the prevalence of diabetes as 7.7% in 2008 . today , this disease is being paid more attention due to its high prevalence , imposed costs on health systems , and various negative effects on the patients . suffering from chronic complications of diabetes leads to the decrease in life expectancy and increase in death , imposes high economic burden on the person , family , and society , and affects the life quality of the person and his / her family . thus , many researchers believe that diabetes belongs to the person and his / her family as suffering from this as a chronic disease disturbs the person 's family life and future prospects , threatens their personal independence , and generates a feeling of being different from others . in this regard , self - care is one of the most fundamental strategies in diabetes which can control the disease , and it highly depends on the will of the person for performing self - care and having self - care behaviors . this strategy includes : following the recommended diet , doing regular physical activity , checking blood sugar , and consuming the medication regularly . nevertheless , the results of some studies have indicated that the self - care situation of diabetic patients is not at an appropriate level and the patients have low self - care ability . the results of the studies by dailey showed the non - optimum self - care situation among diabetic patients . in iran , the research conducted by seyedeh roghayyeh jafarian , elham shakibazadeh , mohammad ali morowati , and parvin baghaei revealed the same situation , and the study by alireza shahab jahanloo demonstrated that only 27% of diabetic patients follow the recommended dietary behaviors . although health care providers are responsible for orienting diabetes control programs , their attempts often do not lead to desirable results . the findings have shown that in spite of making the patients aware , healthy function ( self - care ) does not occur , so some researchers believe that increasing patients knowledge of the disease is not sufficient per se for beginning and maintaining self - care behaviors and assuring the long - term control . therefore , many quality studies have measured the reason for lack of implementing optimum self - care among the patients with diabetes , and have introduced various individual , social , and environmental sources as the obstacles for the optimum self - care of diabetics . some studies have also indicated that demographic factors like increased age decrease self - care . moreover , socioeconomic factors like less education , low economic level , and social factors like weak individual and family relationships seriously impede self - management process . as diabetes is a chronic disease which requires extensive behavioral changes and adherence to a complex diet , social support is considered as one of the influential and important factors for performing self - care and for adherence to the treatment and disease control which can facilitate self - care behaviors and compatibility with the disease . on the other hand , a major part of the care for this disease is done at home and inside the family . therefore , diabetes is sometimes called a family disease because its control and demands influence all family members . thus , social support , especially family support , can be a vital component in the successful control of diabetes . this paper attempted to determine the relationship and effect of social support , especially family support , on the self - care behaviors in diabetic patients . this narrative review study was conducted using scientific search engines and information databanks like pubmed , proquest , scopus , and elsevier , and keywords like self - care , diabetes , social support , and family support in order to select studies with cross - sectional , cohort , clinical trial , correlation , and qualitative designs . moreover , persian papers were selected from medlib and iranmedex information databanks and by searching websites of internal research journals . the time range of the reviewed articles was from 1990 until the end of 2011 . the findings of other studies showed that the perceived social support situation is not at an optimum level among diabetic patients ; the research by cooper et al . demonstrated that diabetic patients need others support . gillibrand 's study revealed that social support in diabetic patients is not at an optimum level . the studies conducted in iran have demonstrated that this support is not at an optimum level among diabetic patients ; studies by shiva heidari and mohammad ali morowati sharifabad can be referred to in this regard . as far as the relationship between social support and self - care behaviors is concerned , the following results can be mentioned : in the study by alato which used the developed health belief pattern , it was determined that adherence to the self - care diet had a relationship with social support . wen , who investigated family support , diet , and sports among elderly american mexican men suffering from type-2 diabetes , observed that with the increase in this support , adherence to diet and sports increased . gillibrand 's research and albroght 's study demonstrated a positive significant relationship between social support and self - care behaviors . they reported that social and family fields are strongly accompanied by self - care behaviors , especially diets . also studied psychosocial factors related to glycemic control . in their study , as social support increased for adherence to the self - care recommendations , this kind of adherence increased too . in the study by vijan on 446 urban and rural patients , one of the obstacles reported by patients was with regard to observing dietary recommendations , which was due to lack of family and social support . in that study , those who received more support from their families easily observed and adhered to diets . furthermore , galsgow stated that family support is the strongest determining factor for following treatment diet among type-2 diabetic patients . other studies have demonstrated that social support from diabetic patients affects their tendency toward doing self - care activities . marzili 's research showed that family support had high effect on following diet and sports in diabetic patients . additionally , rafique 's study in pakistan showed that affective stress and lack of social support are among the self - care obstacles for diabetic patients . a study by klomegah indicated that if family members , friends , and others observe a healthy diet , it is easier for the patients to adhere to a healthy diet . in their study on 76 type-2 diabetic patients which lasted for 2 years , trief et al . noticed that quality of marital status ( intimacy and compatibility ) is a predictor of adherence to self - care dimensions ( diet , sports , and doctor 's advice ) . whittemore reported that the most important predicting factor for the metabolic control and diet adherence among type-2 diabetic patients is support and self - confidence . the study by pinar on diabetic patients showed that factors like intimacy among family members , existence or lack of existence of conflict in the family , and current affective status of the family can affect the self - efficiency of patients and can lead to increase of self - efficiency and decrease of stress in the family . garay - sevilla found that adherence to diet and medication was related to the duration of illness and family and social support . moreover , hiroshi showed that social support and its source are influential in the treatment and control of diseases . also , according to the study by fleeson - kreig , the more the receiving support from spouse and others , the more faithful the patient would be in terms of adherence to self - care activities . in fact , the study by chlebowy observed no significant correlation between social support and behavior . murphy also showed that although family support leads to the improvement of self - care programs in diabetic patients , adherence to self - care programs does not automatically lead to more decrease in blood sugar . conducted a study on 98 type-2 diabetic patients and concluded that optimal level of glycosylated hemoglobin had a relationship with the social support received from the family . moreover , schwartz and dai observed a relationship between social support and blood sugar control . the study by ilias and glasgow showed that family support decreased and controlled blood sugar . gholamreza sharifirad conducted a study in iran which demonstrated that lack of social and family support was among the obstacles for observing the diet , as mentioned by the patients . shiva heidari studied diabetic elderly and found a significant relationship between social support and blood sugar control in that those patients who received more support from their family network could optimally control their blood sugar . moreover , the study by akbar zare shahabad indicated a significant direct relationship between the level of perceived social support and the level of adherence to self - care activities . mohammad ali morowati sharifabad also demonstrated that perceived social support had a positive and significant correlation with self - care in that supporting family behaviors predicted 9.1% of self - care changes . in his study , another study by shiva heidari showed a significant inverse relationship between family support and hba1c . in her study , family support led to the improvement in the control of blood sugar among patients and a significant relationship was found between family support and the number of family members . social support is one of the emotion - oriented coping mechanisms with the potential power for influencing life quality . studies have shown a significant relationship between health and social support , so people who receive higher social support have better health . some studies have shown that social support leads to the improvement in health functions and even immunity performance . other studies on aids , indicators of body immunity , and on hemodialysis patients demonstrated a relationship between social support and these diseases in terms of their control and treatment . the findings of the researchers have shown that perceiving social support can prevent the emergence of non - optimum physiological complications in the person , increase the level of self - care and self - confidence , and positively affect physical , mental , and social conditions ; thus , it evidently leads to the increase in the performance and improvement of life quality . in general terms , it should be stated that social support has a great impact on human health . diabetes disturbs daily performance and social activities of the patient , changes his / her capability for performing normal roles and responsibilities , and creates new roles for him / her . the relationship with the spouse , children , parents , sister , brother , friends , and other members of the social network is not like before . these people more or less depend on others and can support others to a lesser degree . therefore , their personal interactions with others are limited and they may be isolated in the society . social support affects the control of diabetes through two processes : a ) direct effect of social support via behaviors related to health , such as encouraging healthy behaviors , and b ) moderating effect of social support which helps in the moderation of acute and chronic nervous pressure on health and increase of compatibility with the nervous pressure of the diabetes disease . social support has been defined as the level of enjoying love , accompaniment , and attention of family members , friends , and other people . in fact , social support is the facilities provided by others for the person . the knowledge which leads the person toward believing that others respect him / her , are interested in him / her , and consider him / her as valuable , dignified , and a person who belongs to a social network of relations and commitment . social support is defined as the functional content of relationships , which can be categorized in the following four groups of support behaviors : affective support including feeling sympathy , love , trust , and attention , which has a strong relationship with healthfinancial support including service and financial assistanceinformation support as recommendations , advice , and information used by the person for being faced with the problemsevaluative support as accessing useful information for self - evaluation . affective support including feeling sympathy , love , trust , and attention , which has a strong relationship with health financial support including service and financial assistance information support as recommendations , advice , and information used by the person for being faced with the problems evaluative support as accessing useful information for self - evaluation . although these four functions are different in conceptual terms , they are not independent from each other in practice . in this regard , family is the first and the most important supportive source which sacrifices itself for providing care for its members . each family attempts to constantly support the person , even if that person is injured and can not compensate for it . moreover , spouses are usually the first people who assist as supportive sources in critical conditions . strong relationships with family , sister , brother , or friends do not make up for the lack of strong relationship with spouse and can not prevent from depression and stress in patients at the time of life problems . other studies have introduced spouses as the most important supportive sources in crises and stressful conditions of life . the use of incorrect support behaviors ( like reproaching him / her for the lack of timely implementation of treatment programs ) by close people in dealing with the patients has an inverse effect on self - care program implementation . an even more interesting point is that when others use positive reinforcing behaviors ( such as accompanying or encouraging ) to force the patients to follow the treatment program , better results are obtained and the patient could better perform the treatment program . nagging and reproaching about lack of performing self - care programs not only does not lead to the increase of these behaviors , but also can lead to the feeling of despair among patients ; as a result , they decrease self - care program implementation . families should consider the point that providing and eating the food that is not appropriate for the diabetic patients can in fact lead them toward avoiding their treatment diet . for instance , eating food which is not a part of the patients diet by family members is among the considerable points in the non - supportive family behaviors . in the health improvement model , pender considered family support as interpersonal effects which can predict health improvement behaviors . in studies which were done based on the health improvement model , 75% supported interpersonal effects as a predicting factor of the behavior . it has been observed that both general social support and diabetes - related support are in correlation with the adherence to self - care behaviors in diabetic patients . since close family support and relationship have a special position in iranian culture , it seems that presenting sufficient information with regard to the disease to the people who are close to the patient and their involvement and cooperation in the treatment and control processes can facilitate the work of treatment team and help the patient in reaching the utmost life quality and health .

background and objectives : diabetes is one of the major concerns in the third millennium , affecting more people every day . the prevalence of this disease in iran is reported to be high ( about 7.7% ) . the most important method to control this disease and prevent its complications is self - care . according to various studies , this method has not found its proper place among patients with diabetes due to several reasons . the present study was aimed at determining the relationship between social support , especially family support , and self - care behavior of diabetes patients.materials and methods : this study was a narrative review in which the relevant papers of cross - sectional , cohort , clinical trial , and systematic review designs were selected using databases and scientific search engines such as pubmed , proquest , scopus , and elsevier , with the keywords diabetes , social support , and self - care . moreover , persian papers were selected from medlab and iranmedex databases and through searching the websites of original research papers published in iran . all the papers published from 1990 to 2011 were reviewed.results:the results of the study indicated that the status of self - care and social support in patients with diabetes was not favorable . all the studied papers showed that there was a positive relationship between social support and self - care behavior . also , some studies pointed to the positive effect of social support , especially family support and more specifically support from the spouse , on controlling blood sugar level and hba1c.conclusion:as social support can predict the health promoting behavior , this concept is also capable of predicting self - care behavior of patients with diabetes . therefore , getting the family members , especially the spouse , involved in self - care behavior can be of significant importance in providing health care to patients with diabetes .

idiopathic pulmonary fibrosis ( ipf ) is a chronic , progressive , fatal form of diffuse interstitial lung disease which is associated with substantial mortality and a median survival of 2.5 to 5 years from the time of diagnosis1 . in spite of acute exacerbations of ipf ( ae - ipf ) being the most common cause of death in this patient population , the pathogenesis of ae - ipf is unknown and diagnosis is reliant upon exclusion of other diseases of respiratory compromise , such as infection , pulmonary edema and embolism2 . given the inherent difficulties in diagnosing pulmonary infections , many patients are treated with prolonged courses of antibiotic therapy even when a causative pathogen is not identified3 . excessive use of antibiotics is associated with increased antibiotic resistance , high costs , and adverse antibiotic reactions4 . a novel approach to assess the presence of an infection and its response to treatment is the use of biomarkers5 . procalcitonin ( pct ) , a calcitonin precursor , is elevated in response to microbial toxins and certain bacteria - specific proinflammatory mediators . in addition , there is a strong correlation between the concentration of pct and the extent and severity of bacterial infection6 . recent studies have shown that pct - guided antibiotic therapy has reduced antibiotic prescriptions and duration of antibiotic therapy in patients with copd exacerbation and community - acquired pneumonia , accordingly7 . the aim of this study was to determine if the same outcomes can be achieved with pct - guided antibiotic therapy of ae - ipf . this study was performed in henan provincial people 's hospital , a 3,000-bed tertiary care hospital . all patients with suspected ae - ipf admitted to the respiratory department were assessed for eligibility from january 2009 to december 2011 . ae - ipf was defined according to the criteria established by the idiopathic pulmonary fibrosis clinical research network8 : ( 1 ) previous or concurrent diagnosis of idiopathic pulmonary fibrosis ; ( 2 ) unexplained worsening or development of dyspnea within 30 days ; ( 3 ) high - resolution computed tomography with new bilateral ground - glass ; ( 4 ) abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern ; ( 5 ) no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage ; ( 6 ) exclusion of left heart failure , pulmonary embolism and identifiable cause of acute lung injury . patients were randomly assigned to either pct - guided antibiotic treatment or a control group receiving routine antibiotic therapy by the statistician using computer - generated random numbers . this process prevents investigator from knowing in advance the treatment to which subjects will be assigned . patients in both groups underwent daily routine laboratory analysis including blood cell count , arterial blood gas analysis and blood biochemical tests . in the pct - guided group , if the physician violated the protocol , the patient was defined as withdrawn . patients whose serum pct value exceeded the threshold of 0.25 ng / ml were administered antibiotics . if antibiotics were initiated , patients were treated until pct value fell to 0.25 ng / ml . in the routine treatment group , patients were treated by antibiotics according to the clinical experience of clinicians typically guided by conventional laboratory tests , such as sputum bacteriology and white blood cell count . serum pct was measured with a time - resolved amplified cryptate emission technology assay ( kryptor pct ; brahms ag , henningsdorf , germany ) with a functional assay sensitivity of 0.06 ng / ml , about fourfold above mean normal levels9 . age , gender , length of hospitalization , the numbers of patients exposed to antibiotics treatment , duration of antibiotic treatment , cases of mechanical ventilation , outcome were retrieved from electronic medical records . discrete variables are expressed as counts ( percentage ) and continuous variables as mean sd . comparability of the control group and the procalcitonin group was analyzed by chi - square tests , two sample t - test or mann - whitney u test . all tests were two - tailed and p - values 0.05 were considered statistically significant . statistical analyses were performed by using the spss version 16.0 ( spss , inc . , this study was performed in henan provincial people 's hospital , a 3,000-bed tertiary care hospital . all patients with suspected ae - ipf admitted to the respiratory department were assessed for eligibility from january 2009 to december 2011 . ae - ipf was defined according to the criteria established by the idiopathic pulmonary fibrosis clinical research network8 : ( 1 ) previous or concurrent diagnosis of idiopathic pulmonary fibrosis ; ( 2 ) unexplained worsening or development of dyspnea within 30 days ; ( 3 ) high - resolution computed tomography with new bilateral ground - glass ; ( 4 ) abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern ; ( 5 ) no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage ; ( 6 ) exclusion of left heart failure , pulmonary embolism and identifiable cause of acute lung injury . patients were randomly assigned to either pct - guided antibiotic treatment or a control group receiving routine antibiotic therapy by the statistician using computer - generated random numbers . this process prevents investigator from knowing in advance the treatment to which subjects will be assigned . patients in both groups underwent daily routine laboratory analysis including blood cell count , arterial blood gas analysis and blood biochemical tests . in the pct - guided group , if the physician violated the protocol , the patient was defined as withdrawn . patients whose serum pct value exceeded the threshold of 0.25 ng / ml were administered antibiotics . if antibiotics were initiated , patients were treated until pct value fell to 0.25 ng / ml . in the routine treatment group , patients were treated by antibiotics according to the clinical experience of clinicians typically guided by conventional laboratory tests , such as sputum bacteriology and white blood cell count . serum pct was measured with a time - resolved amplified cryptate emission technology assay ( kryptor pct ; brahms ag , henningsdorf , germany ) with a functional assay sensitivity of 0.06 ng / ml , about fourfold above mean normal levels9 . age , gender , length of hospitalization , the numbers of patients exposed to antibiotics treatment , duration of antibiotic treatment , cases of mechanical ventilation , outcome were retrieved from electronic medical records . discrete variables are expressed as counts ( percentage ) and continuous variables as mean sd . comparability of the control group and the procalcitonin group was analyzed by chi - square tests , two sample t - test or mann - whitney u test . all tests were two - tailed and p - values 0.05 were considered statistically significant . statistical analyses were performed by using the spss version 16.0 ( spss , inc . , overall , 102 patients with ae - ipf were screened for eligibility . of these patients , 78 patients met the inclusion criteria by fulfilling the definition of ae - ipf and were randomized . thirty - nine patients were assigned to the pct - guided treatment group and 39 patients to the routine treatment group . ten patients were lost to follow up or withdrew from the study ( figure 1 ) . the average age of onset was 72 years in the pct group and 73 years in the routine group ( p=0.63 ) . inspiratory crackles were heard on physical examination in most cases ( 26 in the pct group vs 24 in the routine treatment group ; p=0.20 ) . the two groups were comparable with respect to gender , smoking history , duration of illness and symptoms . no difference was found with regard to blood gas analysis , white blood cell count , duration of corticosteroid and immunosuppressive therapy . as compared with the routine treatment group , the median antibiotic duration was 5.8 days shorter in the pct group ( p=0.0001 ) , and the patients exposed to antibiotics treatment were fewer in the pct group . duration of mechanical ventilation was similar in patients in the pct group and the routine group ( p=0.49 ) . this is the first study to explore the utility of pct - guided antibiotic therapy for treatment of patients with suspected ae - ipf . we found that pct - guided therapy significantly reduced the numbers of patients exposed to antibiotics treatment and duration of antibiotic therapy without adversely affecting patient outcome . during the 30-days follow - up , both the mortality and duration of ventilation were similar between the pct guided group and the routine treatment group . ae - ipf is an acute , clinically significant deterioration of unidentifiable cause in a patient with underlying ipf and associated with a mortality rate of 70%14 . patients with ae - ipf are vulnerable to opportunistic infections , since they are frequently treated by high doses of corticosteroids , immunosuppressive agents and invasive therapy . ae - ipf is difficult to differentiate from infection because both present with similar clinical symptoms and signs including : fever , dyspnea , leukocytosis , elevated c - reactive protein ( crp ) and ground - glass opacities on the ct scan of chest . sputum , blood and bal culture often lack the sensitivity to rule out pulmonary infection . furthermore , patients with ae - ipf are often too ill to undergo bronchoscopy with bal or lung biopsy15 recent data from the literature indicate that antibiotic treatment for more than 7 days increases the risk of fungal infections ; after more than 10 days of treatment , the incidence of drug - resistant organisms is significantly rising10 . it is necessary to seek a highly sensitive biomarker to provide more effective and reliable basis for the differential diagnosis and guide treatment of ae - ipf . inflammatory markers , such as crp or white blood cells ( wbc ) count , lack specificity for bacterial infections16 . reliability of crp for guiding antimicrobial therapy is limited by its protracted response with late peak levels and a suboptimal specificity , especially in patients with systemic inflammation4 . interestingly , crp levels were elevated in infection and systemic inflammation , although they were much higher in infections than in ae - ipf , and crp levels were a significant prognostic factor of ae - ipf17 . in these respects , pct seems more accurate than the currently available biomarkers . to date , the concept of pct - guided antibiotic therapy has been proven in 11 rcts including over 3500 patients18 . it has been shown that pct guidance allows reducing the use of antibiotics in patients presenting with symptoms of lower respiratory tract infection , in patients with acute exacerbation of chronic bronchitis , and in patients with community - acquired pneumonia19,20 . first , the study was a single center with a relatively small sample of patients and it was not sufficiently powered to show significant differences in mortality between the groups . while ae - ipf is clinically important , its rarity makes it difficult to study in a large number of patients . however , considering the short survival of ipf , virginie simon - blancal11 et al reported that death of ae - ipf occurred in the first month after admission . infection is difficult to exclude because of lacking of a standardized approach to rule - out infection . fourth , more variables should be monitored in the study , such as relapse rate , reinfection , cost etc , which are always among the relevant monitored parameters in pct studies21 . in summary , the results of this study suggest that a pct - guided strategy applied in ae - ipf patients reduces exposure to antibiotics and the duration of antibiotics treatment , and this strategy is not associated with worse outcomes . future studies on larger groups and multi - center validation are needed to confirm that monitoring of pct is a valuable tool for therapeutic decision making concerning the length of antibiotic treatment and economic factors . in china with high prescription rates , the reduction in antibiotic use with pct - guided therapy could have a major favorable impact on bacterial resistance , health costs and risks for drug - related adverse events .

object : to assess the clinical value of procalcitonin to guide antibiotic therapy in acute exacerbations of idiopathic pulmonary fibrosis . methods : patients with acute exacerbations of idiopathic pulmonary fibrosis were randomly assigned to the procalcitonin - guided group ( antibiotic use guided by a procalcitonin threshold of 0.25 ng / ml ) or the routine treatment group ( antibiotic use according to routine practice ) . follow up of clinical outcomes were assessed at baseline and 30 days later . results : baseline characteristics including demographics , clinical characteristics and laboratory results were similar between groups . pct guidance resulted in a significant reduction of antibiotic treatment duration ( 8.76.6 compared to 14.25.2 days in the routine treatment group ) . fewer patients were exposed to antibiotics treatment in the pct group ( 26 patients ) compared with the control group ( 35 patients ) . treatment success , mortality rate , days of hospitalization and ventilation therapy were similar between the two groups . conclusion : procalcitonin - guided antibiotic therapy of patients with acute exacerbation of idiopathic pulmonary fibrosis may result in reduced exposure to antibiotics without adversely affecting patient outcomes .

corticosteroids remain the mainstay of treatment for the vast majority of patients with immune - mediated uveitis . however , those patients with active inflammation who are intolerant of or unresponsive to steroids require therapy with other immunosuppressive agents trying to prevent the potential sequelae associated with this vision - threatening condition . the off - label use of biologic agents and particularly those blocking tumor necrosis factor - alpha ( tnf- ) has demonstrated encouraging results when employed for management of patients with immune - mediated uveitis refractory to conventional treatment since their first reported use in 2001 . potential advantages of these agents when compared with traditional immunosuppressors include a substantial efficacy in recalcitrant cases , as well as a lower total immunosuppressive load , a rapid clinical effect , good safety profile , and significant improvement in quality of life . the present evidence shows that infliximab and adalimumab have the highest level of evidence and grade of recommendation , and thus both may be considered as first - line or second - line immunomodulatory agents for treatment of immune - mediated uveitis depending on which systemic immunologic disorder is associated with the intraocular inflammation [ 6 , 8 ] . golimumab ( glm ) ( trade name simponi ) , a fully human anti - tnf- monoclonal antibody , was approved by the us food and drug administration in 2009 for the use with methotrexate ( mtx ) in adults with moderate - to - severe active rheumatoid arthritis ( ra ) and with or without mtx or other biologic disease - modifying antirheumatic drugs in adults with active psoriatic arthritis ( psa ) or active ankylosing spondylitis ( as ) . some other studies have addressed the potential use of glm for treatment of uveitis , mainly associated with rheumatologic conditions [ 11 , 12 ] . we would like to present the results from three uveitis units in spain when using glm for treatment of patients with immune - mediated uveitis of various etiologies that had been resistant to several immunosuppressive agents . patients with different types of active immune - mediated uveitis that had been resistant to local and systemic corticosteroids and at least one additional immunosuppressive agent and who were treated with glm during at least 6 months were included in this study . table 1 lists demographic and diagnostic information for the 13 patients who form the basis of this report . in 12/13 patients ( 92.3% ) glm was at least the second biologic agent used for treatment of uveitis , whereas glm was used as first - line biologic therapy in one patient ( patient 6 ) . table 2 shows previous treatment regimens employed for management of uveitis in all included patients . we defined primary failure as an absence of a two - step decrease in level of inflammation ( e.g. , anterior chamber and/or vitreous cells ) or a decrease to grade 0 . we classified control of inflammation as grade 0 cells in both anterior and posterior segments in addition to absence of other signs of intraocular inflammation ( cystoid macular edema ( cme ) and vasculitis ) . all included patients received 50 mg of subcutaneous glm every four weeks during at least 6 months without modifications during the follow - up . chest x - ray , tuberculin skin test , and quantiferon - tb gold were performed in all patients before treatment . glm was the only immunomodulatory agent used in six of them . in seven patients , topical steroids were used by three patients ( patients 6 , 8 , and 9 ) at the beginning of the follow - up and were slowly tapered and discontinued after one month in all of them . uveitis clinical evaluation was performed at least four times ( before treatment and 1 , 3 , and 6 months after initiation of therapy with glm ) in all included patients . clinical evaluation included visual acuity ( bcva ; best - corrected snellen va ) and ophthalmic examination . anterior chamber was graded according to the classification established by the standardisation of uveitis nomenclature ; whereas the national eye institute system was adopted for grading vitreous inflammation [ 13 , 14 ] . optical coherence tomography ( cirrus hd - oct , carl zeiss meditec , dublin , ca , usa ) was used before and after treatment in both groups of patients to determine the presence of cme . the 1 mm central retinal thickness was evaluated using the macular cube strategy 512 128 in all patients at each study visit . macular edema was defined as central macular thickness > 300 and/or presence of intraretinal cysts in oct . fluorescein angiogram ( fa ) was performed routinely before and after starting treatment ( between 1 and 3 months after initiation of therapy ) to determine the presence or absence of retinal angiographic leakage . treatment - related side effects were assessed on each visit with a thorough review of systems and complete blood - cell counts , blood urea nitrogen ( bun ) level , creatinine level , and liver function test parameters obtained on an every study visit basis . results were expressed as mean sd for variables with a normal distribution or as median ( 25th75th interquartile range ( iqr ) ) when they were not normally distributed . eight men and 5 women ( 22 affected eyes ) with a median age of 30 years ( range 2038 ) and active immune - mediated uveitides were studied . uveitis was anterior in 8 patients ( 61.5% ) , intermediate in 1 patient ( 7.6% ) , and panuveitis in 4 patients ( 30.7% ) . all included patients ( 13/13 ) received previous treatment with systemic steroids ( using intravenous pulses of methyl - prednisolone ) in two of them . in addition , four patients ( 30.7% ) received coadjuvant intraocular steroids ( 2 intravitreal triamcinolone injections and 2 dexamethasone intravitreal implants ) . about traditional immunosuppressors , all included patients had been treated with methotrexate at any time prior to glm therapy , whereas cyclosporine a was used in 2 ( 15.38% ) , azathioprine in 1 ( 7.6% ) , tacrolimus in 1 ( 7.6% ) , mycophenolate mofetil in 1 ( 7.6% ) , cyclophosphamide in 1 ( 7.6% ) , and leflunomide in 1 ( 7.6% ) . only one patient received glm as first - line biologic therapy , whereas 12 patients received previous treatment with at least one other biologic agent . from the latter , 12 patients received treatment with at least one biologic drug prior to glm , 7 patients ( 53.8% ) received treatment with at least 2 biologics , 3 patients ( 23% ) received treatment with at least 3 biologics , and 1 patient ( 7.6% ) received treatment with at least 4 biologics . infliximab ( ifx ) was used as first biologic agent in 8 patients ( 61.5% ) , adalimumab ( ada ) in 3 patients , ( 23% ) , and etanercept ( etn ) in 1 patient ( 7.6% ) . ada was used as second biologic agent in 6 patients ( 46.1% ) and etn in 1 patient ( 7.6% ) . mean time on second biologic agent was 25.5 months ( range 1557 ) . abatacept was used as third biologic agent in 2 patients ( 15.3% ) and certolizumab in 1 patient ( 7.6% ) . etn was used as fourth biologic agent in 1 patient ( 7.6% ) during 7 months . coadjuvant immunosuppressive therapy was used in 7 of the studied patients including methotrexate ( 4 patients ) , azathioprine ( 1 patient ) , mycophenolate mofetil ( 1 patient ) , and leflunomide ( 1 patient ) . glm therapy achieved complete control of inflammation in 12/13 patients ( 92.3% ) after six months of treatment . the mean bcva increased from a basal value ( before initiation of glm ) of 0.60 to 0.68 at the six - month endpoint ( p = 0.009 ) . only one patient , patient number 12 , showed a score of anterior chamber and/or vitreous inflammation different than zero at the six - month endpoint . the mean 1 mm central retinal thickness decreased from a basal value of 317 to 261,2 at the six - month endpoint ( p = 0.05 ) . figure 1 shows changes in mean values of macular thickness ( 1 mm central thickness ) of all included patients over the study period . there was no evidence of active retinal vasculitis before initiation of therapy in any of the included patients . fluorescein angiogram results did not differ from those observed with oct regarding the presence of cme . only a mild and local cutaneous reaction was recorded in two patients ( patients 5 and 9 ) among all included patients over the entire study period . these results suggest that glm is well tolerated and is associated with control of inflammation in 92,3% of a heterogeneous group of immune - mediated uveitis patients resistant to traditional therapy and other biologic agents . the use of glm is also associated with short - term improvement in mean values of bcva and decrease of mean values of central retinal thickness . despite the evident limitations of this study , including its retrospective design , lack of a control group , short follow - up , and limited number of patients , the results suggest that further evaluation of this modality is appropriate . tnf- is recognized as one of the main inflammatory cytokines involved in the pathogenesis of immune - mediated uveitis [ 1416 ] . this ubiquitous cytokine plays a key role in initiating and maintaining the inflammatory processes by orchestrating leukocyte infiltration , dendritic cell maturation , and macrophage activation and driving t - helper lymphocytes ' response . therapy with two tnf- inhibitors , infliximab and adalimumab , has been proven to be effective for treatment of immune - mediated uveitis with considerable levels of recommendation and evidence [ 6 , 8 ] . the clinical efficacy of other tnf- blockers such as glm needs to be demonstrated and thus this drug is considered only as an alternative to those patients who have failed to respond to first - line tnf- inhibitors . however , it is necessary to emphasize that not all patients respond to their first anti - tnf agent , and so it is clearly useful to have a range of effective therapeutic options to treat those patients with severe and refractory immune - mediated uveitis . in this setting , . a potential limitation of these results could be related to the inclusion of less severe uveitis considering that we include 8 patients with anterior uveitis . however , anterior uveitis in these patients was associated with juvenile idiopathic arthritis ( patients 5 , 9 , 10 , and 11 ) and hla - b27 + haplotype ( patients 1 , 4 , 6 , and 8) . despite recent therapeutic progress , jia - associated uveitis has a severe course and the potential for long - term complications , including blindness . hla - b27 positive - associated anterior uveitis is associated with a substantially higher incidence of ocular complications and has a much worse prognosis when compared with hla - b27 negative - associated anterior uveitis . moreover , some of the patients with anterior uveitis ( patients 2 , 9 , and 11 ) had concomitant macular edema , the most vision - threatening complication associated with uveitis [ 20 , 21 ] . in this the seven cases that were included in our paper were severe and vision - threatening cases refractive to conventional and nonconventional treatment for such conditions . of note , patients included in the present study had a severe inflammatory condition which was resistant to several treatment - regimens inflammatory conditions . the positive response observed in almost all included patients needs to be analysed in this mentioned difficult clinical setting . this inclusion bias in addition to the short follow - up may have influenced the limited improvement in visual acuity observed in our study considering the long and severe course of intraocular inflammation in our patients . tnf- is one of the inflammatory cytokines that upregulates intraocular production of vegf [ 22 , 23 ] , which plays a crucial role in the pathogenesis of cme . we have previously reported how another tnf- blocker , adalimumab , induces a reduction in plasma vegf levels when employed for treatment of immune - mediated uveitis , which may correlate with clinical improvement . in our study glm also demonstrated a beneficial effect on cme thus strengthening the idea of a comparable efficacy with first - line tnf- blockers . previous reports on the use of glm for treatment of uveitis have focused on those patients with uveitis secondary to behet disease , juvenile idiopathic arthritis , and/or hla - b27 + haplotype . to the best of our knowledge , this is the first report of glm employed in the treatment of uveitis associated with sarcoidosis , vogt - koyanagi - harada disease , and/or psoriatic arthritis . the increasing potential treatment indications for glm may be of high interest in the therapeutical decision making of chronic uveitis patients . the main aim of this study is to show these encouraging results on the use of glm for treatment of immune - mediated uveitis . although these results are preliminary , further studies including a higher and more homogeneous group of patients are warranted .

objective . to evaluate , in three spanish tertiary referral centres , the short - term safety and efficacy of golimumab ( glm ) for treatment of immune - mediated uveitis resistant to previous immunosuppressive therapy . methods . nonrandomized retrospective interventional case series . thirteen patients with different types of uveitis that were resistant to treatment with at least 2 previous immunosuppressors were included in this study . all included patients were treated with glm ( 50 mg every four weeks ) during at least 6 months . clinical evaluation and treatment - related side effects were assessed at least four times in all included patients . results . eight men and 5 women ( 22 affected eyes ) with a median age of 30 years ( range 2038 ) and active immune - mediated uveitides were studied . glm was used in combination with conventional immunosuppressors in 7 patients ( 53.8% ) . glm therapy achieved complete control of inflammation in 12/13 patients ( 92.3% ) after six months of treatment . there was a statistically significant improvement in mean bcva ( 0.60 versus 0.68 , p = 0.009 ) and mean 1 mm central retinal thickness ( 317 versus 261.2 , p = 0.05 ) at the six - month endpoint when compared to basal values . no major systemic adverse effects associated with glm therapy were observed . conclusions . glm is a new and promising therapeutic option for patients with severe and refractory uveitis .

a 79-year - old man developed persistent right eye blindness after multiple episodes of transient left hemiparesis and right eye amaurosis . brain computed tomography angiography ( angio ct ) disclosed right internal carotid artery ( ica ) plaque with a 8 mm thrombus extending from ica origin to the ophthalmic artery ( figure 1 ) . he was started on aspirin 300 mg , with no further clinical events . follow up visit two months later , the right eye blindness was still present , but no other neurological deficits had occurred . figure 1internal carotid artery ( ica ) thrombosis ( a1 , a2 ) and 3d reconstruction of ica sub - occlusion ( a3 ) at 24 h from symptoms onset ; ica thrombosis resolution ( b2 ) and 3d reconstruction ( b1 ) at 12 days after antiplatelet treatment onset . internal carotid artery ( ica ) thrombosis ( a1 , a2 ) and 3d reconstruction of ica sub - occlusion ( a3 ) at 24 h from symptoms onset ; ica thrombosis resolution ( b2 ) and 3d reconstruction ( b1 ) at 12 days after antiplatelet treatment onset .

a case of a 79-year - old man , affected by persistent right eye blindness after multiple episodes of transient left hemiparesis and right eye amaurosis . brain computed tomography ( angio ct ) well documented right internal carotid artery ( ica ) plaque with a 8-mm thrombus extending from ica origin to the ophthalmic artery , in progressive lysis in the next days .

annual influenza epidemics affect 1020% of the population resulting in substantial mortality and morbidity worldwide . the incidence of influenza in temperate areas of the northern and southern hemispheres is characterized by seasonal cycles with marked peaks in winter , hence , suggesting a role for climate . however , the year round pattern of epidemics observed in tropical countries implies nonuniformity in the factors governing epidemics . in addition , to environmental factors , such as temperature and humidity , fluctuations in host immune response throughout the year , seasonal changes in host behaviors , and overcrowding have also been implicated to play a role in seasonal variation . annual epidemics are attributed to the continuous evolution of influenza viruses resulting from point mutations in its antigenic determinants . despite the availability of extensive time series and developed surveillance systems the influence of interannual climate changes on the incidences and trends of a range of water and foodborne diseases caused by microbiological agents has been reported . , , el nio southern oscillation ( enso ) , which is associated with two extreme events , el nio ( warm ) and la nia ( cold ) , is the most wellstudied climate phenomenon known to have the largest effect on periodic climate variability . , thus , enso can serve as a marker to study the effect of climate variability on disease patterns . despite the strong seasonality , the timing of winter influenza epidemics changes from year to year . influenzalike illness in japan is mainly caused by influenza viruses and thus its incidence is highly representative of influenza activity . , in this study , we utilized influenzalike illness data from 25 epidemics to determine possible effect of enso on the timing of peak influenza activity . influenzalike illness report data were used as a marker of influenza activity . , under the national epidemiological surveillance of infectious disease in japan , clinically diagnosed influenzalike illness cases , defined as sudden fever 38c , respiratory symptoms , and myalgia , are electronically reported on a weekly basis to the infectious disease surveillance center ( idsc ) in the national institute of infectious diseases , tokyo . the number of sentinels is decided on the basis of the size of population of the health center area where they serve . influenzalike illness report data from 1983 through 2007 was obtained from the idsc s webpage ( http://idsc.nih.go.jp/index.html ) . the peak week for each influenza season was then defined as the week during which the most number of cases are reported . largescale epidemics were defined as those for which the peak was 38 cases per sentinel per week , which represents 70% of the largest peak observed during the study period , in 1994/1995 . data on circulating types and subtypes of influenza were also available from the idsc . in japan , enso cycles are identified using a 5 months moving average of the sea surface temperature anomalies . according to the definition of the japan meteorological agency ( jma ) el nio events are associated with positive sea surface temperature anomalies ( 05c ) , while la nia events are associated with negative anomalies ( 05c ) . statistical analyses were performed using fisher s exact probability test ( twotailed ) and scheffe s multiple comparison method . influenzalike illness report data were used as a marker of influenza activity . , under the national epidemiological surveillance of infectious disease in japan , clinically diagnosed influenzalike illness cases , defined as sudden fever 38c , respiratory symptoms , and myalgia , are electronically reported on a weekly basis to the infectious disease surveillance center ( idsc ) in the national institute of infectious diseases , tokyo . the number of sentinels is decided on the basis of the size of population of the health center area where they serve . influenzalike illness report data from 1983 through 2007 was obtained from the idsc s webpage ( http://idsc.nih.go.jp/index.html ) . the peak week for each influenza season was then defined as the week during which the most number of cases are reported . largescale epidemics were defined as those for which the peak was 38 cases per sentinel per week , which represents 70% of the largest peak observed during the study period , in 1994/1995 . in japan , enso cycles are identified using a 5 months moving average of the sea surface temperature anomalies . according to the definition of the japan meteorological agency ( jma ) el nio events are associated with positive sea surface temperature anomalies ( 05c ) , while la nia events are associated with negative anomalies ( 05c ) . statistical analyses were performed using fisher s exact probability test ( twotailed ) and scheffe s multiple comparison method . we analyzed approximately 147 million influenzalike illness cases in japan , which consist of weekly time series of disease incidence from 1983 through 2007 , including 25 influenza seasons . annual influenza seasons began between november and december , peaked between january and march , and returned to the baseline between april and june for the study period ( figure 1 ) . the peak influenzalike illness activity varied between 4th to 10th weeks ( late january and early march ) during 19831994 , between 4th and 5th weeks during 19952000 , and ranged up to the 11th week ( the middle of march ) during 20012007 . data from japan s infectious disease surveillance center . dominant influenza types or subtypes circulating during each season the dashed horizontal line indicates 38 cases per sentinel per week ( representing 70% of the largest epidemic in 1994/1995 ) . epidemics with peak greater than 38 cases per sentinel per week were defined as largescale epidemics . influenza a(h3n2 ) was dominantly circulating during the majority of seasons , followed by a(h1n1 ) and b. largescale epidemics were observed in seven seasons , namely the 1985/1986 , 1989/1990 , 1992/1993 , 1994/1995 ( largest ) , 1997/1998 , 2002/2003 and 2004/2005 seasons . major antigenic drift of a(h3n2 ) occurred in five of these epidemics ( figure 1 ) . the average peak week for the study period was 62 ( figure 2 ) . early peak was observed in six of the largescale epidemics ( figure 2 ) . yearly time series for peak week , defined as that during which the greatest number of influenzalike illness cases was reported , of influenza activity in japan from 1983 to 2007 ( data from infectious disease surveillance center ) . black boxes denote years during which el nio southern oscillation ( enso ) episodes happened ( e and l indicates el nio and la nia , respectively ) , while empty boxes resemble years with normal weather ( nonenso years ) . regarding enso , 10 episodes covering 11 influenza epidemics were identified during the study s period . the peak week of influenza epidemics was earlier than the average in 10 out of 11 enso years ( 909% ) compared to 6/14 ( 429% ) for nonenso years ( p = 003 by fisher s exact probability test , twotailed ) . the average peak week for enso years , 45 09 ( n = 11 ) , was significantly earlier than that for nonenso years ( average = 76 29 , n = 14 ; p = 001 by scheffe s multiple comparison method ) . no significant difference was found between the average peak weeks during el nio ( n = 5 ) and la nia ( n = 6 ) cycles , average = 48 13 and 42 04 , respectively ( p = 085 by scheffe s method ; figure 2 ) . seasonality in disease incidence can often infer an association with weather factors and climate variability . we present here an evidence for a role of interannual climate variability on the temporal dynamics of influenza infections in japan . the evidence is based on longterm timeseries analyses of the relationships between peak influenza activity and enso as a major climate index . el nio southern oscillation arises from fluctuations in sea surface temperature of the tropical eastern pacific ocean . it is well known for its wideranging and prominent consequences on weather around the world . it contributes to the likelihood of extreme weather events , such as strong winds , heavy rainfalls , and droughts . the association between enso and cholera patterns in bangladesh and malaria epidemics in parts of south asia and south america , , were documented . our data demonstrated that peak influenzalike illness activity occurred earlier in 16 out of 25 epidemics spanning 19832007 . early peaks were observed in 10 ( 909% ) out of 11 enso and six ( 857% ) out of seven largescale epidemics ( two of these occurred in enso cylces ) . thus , we conclude that early peak influenza activity occurs in association with enso year or / and largescale influenza epidemics . our observations demonstrated a strong association between the tendency to earlier peak activity and enso in japan . the human response to weather fluctuations involved by enso , as interannual climate variability , may be different from their adaptation to usually experienced weather conditions . changes in immunity , indoor crowding , and behavioral changes could set better conditions for virus transmission and consequently earlier peak influenza activity observed during enso cycles . future studies on what factors of enso correlate mostly to influenza activity could provide better insight on such association . moreover , we demonstrated an association between early peak of influenza activity and largescale epidemics mainly occurring because of a major antigenic drift of influenza a(h3n2 ) , which dominantly circulated during these seasons . although there was an exception in the 2004/2005 season in which influenza activity peaked late though being a largescale epidemic . in this season , both influenza b and a(h3n2 ) were codominantly circulating and their peak overlapped , which could explain high incidence at peak . in a previous study , we similarly reported that the size of epidemic was correlated to the change in antigenicity and that large epidemics were mostly observed with new antigenic variants of influenza a(h3n2 ) . furthermore , the greater the number of cases at peak week the shorter was the increasingtopeak period . thus , in case of a future pandemic we may expect large number of patients within short period , rapid speed of transmission , and early pandemic peak especially in winter season . reported that higher morbidity impact of influenza was shown during cold phases of enso ( la nia ) than in hot phases ( el nio ) . on the contrary , we found no significant difference in the incidence of influenzalike illness cases among the two phases . nevertheless , higher incidence of influenzalike illness was found to be associated with a major drift in a(h3n2 ) ( data not shown ) . influenza s association with winter in temperate regions could be partly attributed to the direct influence of cold weather on virus survival or on the defense mechanisms of the upper respiratory tract . we previously showed that influenzalike illness activity peaked first in westerncentral japan rather than eastern japan where the mean temperatures are lower , suggesting a minor role of temperature in triggering peak activity . however , in tropical countries , temperature and humidity were considered to play an important role in driving the timing of influenza epidemics . different patterns and timings possessed by influenza epidemics in the tropics and temperate areas highlight both its susceptibility to trend modification in response to changing climate and the diversity of its driving factors . the average peak week for the 25 influenza epidemics investigated in this study was in the winter season ( 6th week ) . yet , our data revealed that the peak of influenza activity was delayed until early spring during the 2000/2001 and 2006/2007 seasons . we have previously demonstrated a shift of peak rotavirus activity in japan from winter to early spring , which could be related to global warming . in contrast to the gradual shift observed in the case of rotavirus from 1983 through 2003 , peak influenza activity showed a prompt shift to early spring during two seasons only . the extent to which global warming might affect the timing of influenza epidemics should be carefully followed up in future studies . the importance of influenza as a human disease is well established , and concerns about future pandemics are clearly warranted . , , our study provides evidence of association between the timing of the peak influenzalike illness , as a marker of influenza activity , and enso and antigenic change of a(h3n2 ) , both which can be forecasted half to 1 year ahead and can therefore serve as tools for predicting early peak activity , and consequently improve our preparedness for annual seasonal epidemics . finally , there are clear complexities in trying to understand relations between climate change and disease patterns . knowing that climate change and enso effects on different locations of the globe are not uniform better understanding of global influenza patterns is paramount to improving our control strategies and mitigating the disease burden .

background seasonality characterizing influenza epidemics suggests susceptibility to climate variation . el nio southern oscillation ( enso ) , which involves two extreme events , el nio and la nia , is wellknown for its large effects on interannual climate variability . the influence of enso on several diseases has been described . objectives in this study , we attempt to analyze the possible influence of enso on the timing of the annual influenza activity peak using influenzalike illness report data in japan during 19832007 . materials influenza surveillance data for 25 influenza epidemics , available under the national epidemiological surveillance of the infectious diseases , was used in this study . enso data were obtained from the japan meteorological agency . results influenzalike illness peak week varied largely during the study period , ranging between 4th and 11th weeks ( middle of winter to early spring ) . the average of peak week during enso cycles ( n = 11 , average = 45 09 ) was significantly earlier than in nonenso years ( n = 14 , average = 76 29 ; p = 001 ) , but there was no significant difference in the peak timing between hot ( el nio ) and cold ( la nia ) phases . earlier peaks of influenza activity were observed in 16 , out of 25 , epidemics . these coincided with 10 ( 909% ) out of 11 enso and 6 ( 857% ) out of seven largescale epidemics . conclusion influenza activity peak occurred earlier in years associated with enso and/or large scale epidemics .

the study was approved by the medical ethics committee of jinling hospital and adhered to the tenets of the declaration of helsinki . all donor tissues were obtained within 12 h after enucleated eyeballs from healthy young adults with accidental death without any disease . twenty eyes of 17 patients , who are with moderate to advanced keratoconus without acute keratoconus , the corneas were clear and there was no edema in dm , were enrolled in this study . the patients were divided into femtosecond laser - assisted dalk with 75% of stromal dissection ( predescemetic group ) and using big - bubble technique with total stromal resection ( descemetic group ) . there were 10 eyes of 9 patients ( 8 males and 1 female ) with mean age of 29.4 8.8 years ( range , 2042 years ) in predescemetic group and 10 eyes of 8 patients ( all males ) with mean age of 20.6 6.4 years ( range , 1532 years ) in descemetic group . all treated eyes were examined preoperatively and postoperatively in terms of the uncorrected visual acuity ( ucva ) and best - corrected visual acuity ( bcva ) with the standard logarithm of the minimum angle of resolution chart . anterior segment optical coherence tomography ( oct ) ( carl zeiss meditec , jena , germany ) combined with the 50-mhz ultrasound corneal pachymetry was used to measure the thinnest corneal thickness in the recipient cornea . slit - lamp examination , endothelial cell density ( ecd ) , corneal topography , and dilated fundus examination in dilated pupil were also evaluated . the preoperative data in two groups all procedures of the two groups were performed by a sole fully qualified and highly experienced surgeon ( zhen - ping huang ) . the whole eyeball was placed in the eyeball fixation ( which we previously described ) and received the treatment with the 500-khz visumax femtosecond laser ( carl zeiss meditec ag , jena , germany ) . in the predescemetic group , the mean donor lenticule thickness and diameter were 399 55.27 m ( range , 300510 m ) and 7.73 0.21 mm ( range , 7.38.0 mm ) , respectively ; the mean recipient lenticule thickness , lenticule diameter , and residual stromal bed thickness were 309.5 53.87 m ( range , 230380 m ) , 7.54 0.16 mm ( range , 7.37.8 mm ) , and 84.4 8.67 m ( range , 74105 m ) , respectively . the recipient corneal button was lifted , and the donor lenticule was placed on the recipient residual corneal stromal bed and sutured by continuous or 16 interrupted stitches with 10 - 0 nylon sutures under retrobulbar anesthesia . in descemetic group , we use the laser settings in pkp mode for the donor and recipient to achieve the vertical side cut according to the thinnest corneal thickness . the mean diameter of lamellar was 7.52 0.14 mm ( range , 7.47.8 mm ) in the donor and 7.38 0.10 mm ( range , 7.27.5 mm ) in the recipient . after femtosecond laser procedure , the patient was transferred to the operating room with retrobulbar anesthesia . a 27-gauge needle bent into 60 with a 5 ml syringe filled with air was inserted into the deep stroma . air was then injected into the stroma to achieve a big bubble between the dm and posterior stroma . the anterior chamber paracentesis was performed to lower the intraocular pressure , and a small air bubble was injected into the anterior chamber to check the baring of dm . then , a crescent disposable knife was used to cut the corneal stroma into half , and an ophthalmic viscosurgical device was used to refill the space and protect the dm . the residual stroma was excised by corneal scissors to expose the smoothly transparent dm . after peeling off dm and endothelium using forceps from the donor lamella , prepared by femtosecond laser , the donor lamella was placed on the host stromal bed and sutured by 16 interrupted stitches with 10 - 0 nylon sutures . the antibiotics and corticosteroids of intravenous injection were used once a day for 3 days . tobramycin dexamethasone and ofloxacin eye drops were applied six times and four times / day for 2 weeks , respectively . fluorometholone and cyclosporine a eye drops were instilled three times / day for 3 months to prevent graft rejection . statistical analysis was performed with spss software ( version 17 , spss , inc . , data were calculated as mean standard deviation differences of bcva , myopia , corneal astigmatism , keratometry , central corneal thickness ( cct ) , and ecd between two groups were analyzed using two independent samples t - test . all procedures of twenty eyes were uneventful while one eye has encountered intraoperative dm microperforation in the predescemetic group without converted to pkp operation intraoperatively . 1a ] in the descemetic group , and the regular surface of predescemetic plane was detected in the predescemetic group [ fig . alignment of dm with the donor tissue was much better in the descemetic group at day 2 postoperatively [ fig . the clear and smooth descemet 's membrane was observed after stromal removal in descemetic group . ( b ) the regular surface of predescemetic plane was detected in predescemetic group the excellent alignment of descemet 's membrane with the donor tissue was observed through anterior segment optical coherence tomography at 2 days after surgery in descemetic group the alignment of descemet 's membrane with the donor tissue was detected through anterior segment optical coherence tomography at day 2 postoperatively in predescemetic group the postoperative parameter between two groups was shown in table 2 . the differences of bcva , corneal astigmatism , corneal curvature , cct , and loss rate of ecd between two groups were not statistically significant ( all p > 0 . 05 ) while the loss rate of ecd was slightly higher in the descemetic group ( 6.4% ) than the predescemetic group ( 4.6% ) . however , the mean postoperative myopia was 9.43 7.44 diopter ( d ) in the predescemetic group and 1.03 1.13d in the descemetic group , which was statistically significant ( p = 0.002 ) . the postoperative data in two groups at the last examination in term of postoperative complications , there was one patient with wound dehiscence in the predescemetic group , which has been resutured and one eye with stromal rejection , which has been treated with the application of topical steroids ; there was one eye with high intraocular pressure postoperative induced by the application of steroid in descemetic group , which has been treated by medical therapy . it has gained widespread acceptance that lamellar keratoplasty ( lk ) is necessary for the treatment of moderate to advanced keratoconus , and the acute advanced keratoconus with ruptured dm is required to be treated with pkp . the important benefit from lk is that it can decrease the risk of endothelial rejection . in the previous study , the ucva and bcva have been improved by the femtosecond laser - assisted predescemetic lk for the patients with moderate to advanced keratoconus . as the stroma is unhealthy for the patients with keratoconus , we performed the femtosecond laser - assisted descemetic lk with big - bubble technique for the treatment of keratoconus . dalk with big - bubble technique was first reported by anwar and teichmann in 2002 , which the 60%80% thickness of the cornea was removed first and injected air between deep stroma and dm to separate the cornea with the advantages of shortening the surgical time , reducing the risk of perforation , and exposing the smooth surface . in contrast to anwar 's technique , we use the 500-khz visumax femtosecond laser to cut the donor and host peripheral cornea with regular and smooth incision . our results indicate that the differences of bcva , corneal astigmatism , keratometry , cct , and the loss rate of ecd between two groups are not statistically significant ( all p > 0 . the results of postoperative bcva are similar to results by abdelkader and kaufman , sarnicola et al . , and schiano - lomoriello et al . , which have indicated that no difference in bcva between the predescemetic and descemetic groups is observed , while the visual recovery time is faster in the descemetic group . however , authors have not compared the postoperative myopia between the predescemetic and descemetic groups in their reports . the preoperative mean thinnest corneal thickness , evaluated with ultrasound corneal pachymetry and with anterior segment oct , was 393.90 49.85 m ( range , 319.0454.0 m ) in the predescemetic group and 361.90 51.54 m ( range , 280.0430.0 m ) in the descemetic group . the postoperative corneal mean thickness was 483.40 53.70 m ( range , 389.0598.0 m ) and 471.5 41.68 m ( range , 430.0550.0 m ) in the predescemetic group and descemetic group , respectively . although there was no statistically significant difference in the cct of the two groups , both groups have an improvement of thickness and restoring the corneal optical integrity and structure . the mean postoperative myopia is 9.43 7.44d ( 8 of 10 eyes 6.0d ) in the predescemetic group and 1.03 1.13d ( all of 10 eyes < 3d ) in the descemetic group in our results , which is statistically significant ( p < 0.05 ) . the results of descemetic group are consistent with buzzonetti et al . 's paper , who have reported the mean postoperative myopia was 1.50 1.70d at 12 months after surgery following the 60-khz intralase femtosecond laser - assisted dalk with big - bubble technique for keratoconus . girard et al . reported that the postoperative myopia has been decreased when the diameter of donor graft is 0.25 mm smaller than the recipient graft in pkp for keratoconus . . stated , to some extent , the postoperative refraction could be manipulated toward acceptable ametropia with altering the size of the donor graft button , and they have demonstrated that the average of hyperopic 2.2d would resulted from decreased 0.25 mm of diameter for the graft . some papers have indicated that the diameter of donor graft is depending on the axial length of eyeball . if the axial length is more than 24.5 mm , the diameter of donor graft should be equal to the recipient . if not , the diameter of donor graft should be 0.25 mm larger than the recipient . in addition , when the diameter of donor grafts was smaller than the recipient or the tight sutures were used intraoperatively , there will be hyperopic diopters for the patients and vice versa . have verified that the postoperative visual acuity was better in the patients with same size of the donor and recipient graft than the patients with donor graft 0.25 mm larger of than recipient for the keratoconus patients with longer axial length of eyeball . in this study , we set the mean diameter of donor graft 0.19 mm larger than the recipient in the predescemetic and 0.14 mm larger in the descemetic group referring to mosca et al . 's paper , which they set the average diameter of donor graft 0.2 mm larger than the recipient . wang et al . who performed predescemetic lk and big - bubble descemetic lk for keratoconus manually , which there was no significant difference of postoperative myopic diopter between two groups ( p > 0.05 ) . it was different from our results while it was possible to be significant difference of postoperative myopic diopter between predescemetic and descemetic groups using femtosecond laser as the postoperative corneal pattern is better in the patients with total stromal resection . moreover , ardjomand et al . reported that the postoperative visual acuity following dalk was similar to pkp when the residual stromal thickness was < 20 m , while it would be affected in the case of > 80 m of the residual stromal thickness . in our study , the residual stromal thickness was 84.4 8.67 m in the predescemetic group and 15 m in the descemetic group ( the thickness of dm was about 10 m and the endothelium was 5 m ) ; however , there was no significant difference in terms of bcva and ucva between two groups ( p = 0.758 and 0.445 , respectively ) . the excellent alignment of dm with the donor tissue was noticed in the descemetic group through anterior segment oct at early postoperative examination while there was interface observed between the recipient dm and the donor tissue in the predescemetic group . hence , we believe that there will be different results in different diameters of donor and recipient graft with or without femtosecond laser . in this paper , we have not evaluated the preoperative manifest refraction and axial length of eyeball in the study population , further study should include these data and increase the studied patients . our preliminary results suggest that femtosecond laser - assisted descemetic lk with big - bubble technique could be the alternative procedure to treat the patients with keratoconus rather than femtosecond laser - assisted predescemetic lk . this work was supported in part by young medical talent project grant qnrc2016905 from jiangsu province , china . this work was supported in part by young medical talent project grant qnrc2016905 from jiangsu province , china .

purpose : the purpose of this study is to compare the outcomes following femtosecond laser - assisted deep anterior lamellar keratoplasty ( dalk ) with 75% of stromal dissection ( predescemetic group ) and femtosecond laser - assisted dalk using big - bubble technique with total stromal resection ( descemetic group ) for the treatment of keratoconus.subjects and methods : twenty eyes of 17 patients with keratoconus were studied . there were 10 eyes of 9 patients in predescemetic group and 10 eyes of 8 patients in descemetic group . the postoperative best - corrected visual acuity ( bcva ) , manifest refraction , keratometry , endothelial cell density ( ecd ) , and central corneal thickness ( cct ) were analyzed.results:all surgeries were performed uneventfully . at 1 year after surgery , the bcva , corneal astigmatism , keratometry , cct , and ecd between two groups were not statistically significant ( all p > 0.05 ) . however , the mean manifest refraction was 9.43 7.44 diopter ( d ) and 1.03 1.13d in predescemetic and descemetic groups , respectively , which was statistically significant between two groups ( p < 0.05).conclusions : the results of bcva and corneal astigmatism , keratometry , ecd , and cct were comparable between two groups . however , the mean postoperative manifest refraction was lower in descemetic group .

a 40-year - old caucasian gentleman visited our hospital with complaints of sudden onset of diplopia of two weeks duration . the night before the onset he was at a dance party where he consumed alcohol and cocaine . he visited the eye casualty the next day and was advised a magnetic resonance imaging ( mri ) scan . there was no associated history of decreased vision , eye pain , headache , flashes , floaters , headache , nausea and signs and symptoms of raised intracranial pressure . his personal history included consumption of a bottle of wine daily since 20 years and occasional cocaine use since three to four years . examination revealed visual acuity of 20/20 in each eye with normal anterior segment and fundus in both eyes . neuro - ophthalmic and orthoptic assessment confirmed pupil - sparing iiird and ivth nerve paresis of the left eye [ fig . 1 ] and urgent mri reported an area of increased signal intensity in the brainstem mainly in the left side with mass effect [ fig . 4 ] . magnetic resonance angiography revealed an area of high signal intensity in the vicinity of the posterior communicating region on the left side [ fig . 5 ] . this represented a vascular event probably due to a small bleed arising from the vertebral basilar region . his symptoms and general health had deteriorated in the first week in the interim when we first saw him till he was seen in peripheral hospital . his ocular symptoms started to improve four weeks from then significantly , that there was no diplopia in primary gaze . he was followed in the ophthalmology department in a tertiary hospital eight weeks later and then at six months and was subsequently discharged with complete recovery of eye movements . subsequently , he was doing well and was discharged and is being currently followed by an oncologist / radiotherapist . this patient presented with intracerebral hemorrhage in a distribution commonly seen with hypertensive vasculopathy.1,2 astrocytoma is the most common glial tumor but is more commonly located in the cerebrum , leptomeninges , spinal cord and usually present with other associated focal neurological signs and symptoms . this case represents a rare manifestation of the tumor with only fascicular iii and iv nerve paresis . an important cause of spontaneous ( non - traumatic ) intracranial hemorrhage not due to cerebral aneurysm , vascular malformation or hypertensive cerebrovascular disease is brain tumor which has been reported to represent 0.9 to 11% of spontaneous intracranial hemorrhage according to various studies.3 hemorrhage due to tumor is significantly more common in younger patients with the exception of pituitary adenoma . wakai et al . in their study reported that 42.2% patients showed no evidence of clinical symptoms related to bleeding , 33.3% had preceding history related to brain tumors and in 24.4% the apoplectic syndrome was the initial presentation and out of them only four were astrocytoma.4 kothbauer in their autopsy series of 430 spontaneous cerebral hematomas found that 21 out of 44 tumor - associated hematomas were anaplastic gliomas , 17 associated with metastatic tumors , two with oligodendrogliomas , two malignant lymphomas and one meningioma.5 in another series of 235 surgically verified brain tumors by bromowicz , eight had hemorrhage into the tumor and out of them three had anaplastic astrocytoma.6 the anatomical elucidation of this infrequent palsy is difficult but the possible mechanism here is astrocytoma and associated hemorrhage which was located in the oculomotor nerve fascicle , where the pupillary efferent fibers are anatomically separate from the fibers to the extraocular muscle and also the trochlear nerve fascicle as they transverse the brainstem . therefore , screening for mass lesions using neuro - imaging , preferably mri , is indicated in patients with the presentation of pupil - sparing third and other nerve paresis where diagnosis of hypertensive or ischemic vasculopathy is often made , as timely intervention may carry a favorable prognosis .

a case of spontaneous , painless partial iii ( pupil - sparing ) and iv fascicular nerve paresis as the first presentation of anaplastic astrocytoma is reported . the other ocular , neurological and systemic examination was within normal limits . the literature and possible anatomical location of this atypical presentation is reviewed .

antiproliferative agents should for the time being not be used off - label in pulmonary arterial hypertension.the risk / benefit ratio of tyrosine kinase inhibitors in arterial hypertension remains to be established . antiproliferative agents should for the time being not be used off - label in pulmonary arterial hypertension . the risk / benefit ratio of tyrosine kinase inhibitors in arterial hypertension remains to be established . presently , there are three classes of approved therapies for idiopathic pulmonary arterial hypertension ( ipah ) , namely endothelin receptor antagonists , phosphodiesterase-5 inhibitors , and prostanoids . nonetheless , the prognosis of patients with ipah has remained dismal , with 3-year survival rates around 70 % . although experimentally some antiproliferative properties have been attributed to all of these three drug classes , their main treatment effect is vasodilation . however , except in very early disease , vasodilators remain to be a symptomatic treatment . only recently , the antiproliferative approach has gained clinical interest because of the emergence of the tyrosine kinase inhibitors . by the first experimental proof of concept study in the rat monocrotaline model , schermuly et al . could show that the antiproliferative agent imatinib , which targets mainly the pathogenically important platelet - derived growth factor , was able to reverse pulmonary hypertension . shortly thereafter , the same group started imatinib in a patient already receiving all three classes of the therapeutic agents mentioned above but refusing lung transplantation . six months later , there was a dramatic improvement in hemodynamics , 6-min walking distance ( 6mwd ) and functional class . in the meanwhile , the phase ii trial and the subsequent large randomized trial ( impres ) could demonstrate that imatinib significantly improves hemodynamics within a period of 6 months . about 2 years after the first case report by ghofrani et al . , we commenced imatinib treatment in selected patients on an off - label use basis . herein we present a patient suffering from severe ipah , who could be successfully weaned from intravenous prostanoids within a period of 5 years and attained a persistent hemodynamic normalization . she then had a mean pulmonary artery pressure of 68 mmhg , a cardiac output of 1.9 l / min / m , and a pulmonary vascular resistance ( pvr ) of 2,261 dyn seconds cm ( see table 1 ) . chronic thromboembolic , left heart and pulmonary diseases were excluded by negative ventilation / perfusion scan , normal pulmonary artery wedge pressure , and lung function testing . family history was non - revealing and there were no other diseases known to be associated with pah . , sildenafil 50 mg tid . , inhaled iloprost 100 g daily , oral anticoagulation and diuretic therapy . as depicted in fig . 1 , the 6mwd temporarily improved from 310 to 410 m. however , within 1 year her condition deteriorated dramatically , and in october 2007 the patient became almost bed - ridden . her pvr still was very high ( 1,506 dyn seconds cm ) . treatment with continuous intravenous iloprost was commenced , and its dose was up - titrated to 500 g per day . this resulted in an improvement in her 6mwd up to 444 m until february 2008 . her hemodynamics , however , were still seriously impaired with a pvr over 1,000 dyn seconds cm . hence , we started an off - label treatment with imatinib 400 mg per day . six months later , her pulmonary vascular resistance had decreased to 300 dyn seconds cm.table 1clinical and hemodynamic data over timeoctober 2006october 2007february 2008april 2010october 20116-min walking distance ( m)31070444550580who functional classiviviiiiiimean pulmonary artery pressure ( mmhg)6864532723cardiac index ( l / min / m)1.11.72.64.75.7pulmonary vascular resistance ( dyn seconds cm)2,2611,5061,023259163pulmonary artery wedge pressure ( mmhg)1410567right atrial pressure ( mmhg)1619not done45mixed venous oxygen saturation ( % ) 3729487269n - terminal pro brain natriuretic peptide ( pg / ml)not done1,2041,8229069fig . pvr pulmonary vascular resistance , svo2 mixed venous saturation , probnp n - terminal pro brain natriuretic peptide , 6-mwd 6-minute walking distance clinical and hemodynamic data over time clinical course of the patient . pvr pulmonary vascular resistance , svo2 mixed venous saturation , probnp n - terminal pro brain natriuretic peptide , 6-mwd 6-minute walking distance during the subsequent 3 years of imatinib therapy , the patient further improved her 6mwd and remained stable in functional class ii . except for an episode of central venous catheter infection there were no complications , adverse events or disease - related events . since by april 2010 her pulmonary hemodynamics almost normalized , we decided to reduce gradually intravenous iloprost until complete stop by august 2011 . echocardiography showed a normal size of the right atrium and the right ventricle , and a normal right heart function , i.e. a fractional area contraction of 42 % ( normal > 25 ) and a tricuspid annular systolic plane excursion of 23 mm ( normal > 17 ) . this is to the best of our knowledge the first patient suffering from severe ipah , who could be weaned from intravenous prostanoids , and completely normalized her pulmonary hemodynamics and right ventricular function , remaining solely on continued dual oral targeted drug treatment . we speculate that this normalization can most probably be attributed to long - term imatinib therapy . so far , there are only two case series including 17 adults suffering from ipah , in whom intravenous prostanoids could be discontinued [ 6 , 7 ] . however , it has to be emphasized that all these patients in fact were switched from prostanoids to the new targeted oral or inhaled therapies becoming available at that time . none of them was already receiving targeted treatments at the start of weaning from intravenous prostanoids . after all , it is noticeable that three patients maintained a normal pvr after transition from intravenous to modern oral or inhaled therapy . since the first randomized trial in ipah 1996 , there is an ongoing discussion , what kind of treatment goal is realistic in this otherwise devastating disease . unfortunately , until now , aiming at a normalization of pulmonary hemodynamics has remained to be a search for the holy grail . none of the two largest series of ipah patients on long - term epoprostenol has explicitly reported on any patient with normal hemodynamics on last follow - up [ 8 , 9 ] . the lower 95 % confidence intervals of mean pulmonary artery pressures in these two series were 32 and 40 mmhg , respectively . the same was the case even in prognostically favorable patients on long - term calcium - channel blockers with a lower 95 % confidence interval of mean pulmonary artery pressure of 34 mmhg . foreseeably , because of its mode of action a potential breakthrough effect like in our patient might be expected to occur only after some years of tratment . souza et al . have described two cases , who were on imatinib treatment over a period of 3 years . although not being provable , we strongly believe that the leading effect explaining this extraordinary clinical course of our patient has to be ascribed to a reverse remodeling effect of imatinib . in the rat monocrotaline model , schermuly et al . found a marked increase in cell proliferation in the pulmonary resistance vessels . this could be explained by a lack of apoptosis in the hypertensive animals comparable to the non - exposed control animals . treatment with imatinib resulted a significantly increase in apoptosis in the vessel walls , going along with a reduction of the proliferation rate and a near normal vessel morphology . moreover , these researchers could elegantly show , that platelet - derived growth factor , a known potent inhibitor of apoptosis , which in fact has shown to be increased in the vasculature of patients with ipah , seems to act as the main anti - apoptotic factor in this context . while it was entirely absent in the control animals , it massively increased in the monocrotaline - exposed rats . it could be argued that also the current three targeted therapeutic modalities might have some antiproliferative effect , especially the prostanoids . this has been shown at least in the experimental setting . in humans , however , such a therapeutic effect has never been described so far . of course , the significance of histological examinations of lungs at autopsy or after explantation is hampered by a negative selection bias including only most severe cases . however , there is one interesting study by achcar et al . , who examined explanted lung from 9 patients who had been treated with prostacyclin for a mean of 40 months , and compared them with lungs from 11 patients who had a similar hemodynamic compromise but other treatments than prostanoids . there was not only no difference in vascular remodeling between the two groups , but even a non - significant trend towards a more pronounced medial thickness and a higher number of plexiform lesions in the prostanoid - treated group . in this context , would like to add another interesting report of a patient , who had been on prostacylin for 18 years , and died because of colonic cancer . at autopsy hence , we do not believe that the prostanoid contributed relevantly to the restoration of normal hemodynamics and right ventricular function in our patient . at this point the authors of the impres study reported in september 2011 , that there were two cases of subdural hematoma while on imatinib during the randomized trial phase , and in addition , another six cases were observed in the extension study , summing up to an incidence of 4.2 % per patient year . when we became aware of this serious complication possibly attributable to imatinib in combination with oral anticoagulation , we immediately took two measures . firstly , we confronted all current and subsequent patients treated with imatinib with a range of potential morbidity and mortality rates due to subdural hematoma and the potential benefits of imatinib ( unpublished data ) . all patients were willing to take the worst risk benefit scenario and gave a written informed consent . may be due to the latter measure , we did not observe any case of subdural hematoma over a period of currently around 30 patient - years ( unpublished data ) . notwithstanding , it has to be stressed that we use imatinib off - label , and this treatment is not in accordance with the current guidelines on management of pulmonary hypertension ( 4th world symposium and ers / esc guidelines ) as well as the recommendations made at the last world symposium on pulmonary hypertension , held in nice 2013 , and the statement made by the authors of the impres trial and an accompanying editorial . the increased incidence of subdural hematomas during imatinib treatment may suggest a poor benefit / risk ratio in pah . hence , these authorities stated that until further data are available , the off - label use of imatinib for this indication is strongly discouraged . furthermore , tyrosine kinase inhibitors should generally be used with caution in pah since they may have other unexpected side effects . hence , we fully agree with marc humbert s call for a better understanding of the pathways involved in the efficacy and safety aspects of imatinib in order to design more targeted and better tolerated agents in the field of personalized pah medicine . in conclusion , we presume that the antiproliferative effects of long - term imatinib therapy induced by the clearly described apoptosis of pulmonary vascular smooth muscle cells were the leading effect explaining the clinical course of the current patient , who could be weaned from intravenous prostanoids and attained normal pulmonary hemodynamics parameters . however , we would like to emphasize that at present such an off - label use is strongly discouraged by the authorities until more data on the risk / benefit ratio of tyrosine kinase inhibitors in patients with pah become available .

introduction despite new treatment options targeted at its three main pathogenic pathways , prognosis of idiopathic pulmonary arterial hypertension has remained dismal , with 3-year survival rates around 70 % . antiproliferative agents have emerged as a new therapeutic concept . however , they may exert their effects only after a prolonged period of time . case description herein we present a patient who , despite being on a triple targeted drug therapy including high - dose intravenous prostanoids , still had severe pulmonary hypertension . after 4 years treatment with the tyrosine kinase inhibitor imatinib , the patient could be weaned from intravenous prostanoids and attained a persistent hemodynamic normalization . conclusions antiproliferative agents might be a promising new class of drugs in pulmonary arterial hypertension . however , the occurrence of unexpected side effects like the increased incidence of subdural hematomas , has led to the recommendation that at present such an off - label use is strongly discouraged , and that further studies elucidating the risk / benefit ratio of tyrosine kinase inhibitors are clearly needed .

abnormal oxygen saturation is not detected by pulse oximetry ( spo2 ) in the majority of hb variants . however , some patients inherit an hb variant with a low oxygen affinity that displays low spo2 and arterial oxygen saturation ( sao2 ) ( 2 ) . hb kansas was first reported in 1961 as an hb variant that displays a very low oxygen affinity ( 3 ) . the hb molecule consists of two -globin subunits and two -globin subunits , which maintain the equilibrium between the relaxed state ( r ) , with a high oxygen affinity and the tense state ( t ) , with a low oxygen affinity . hb kansas has an aac to acc mutation at codon 102 of the -globin gene , which results in an asparagine ( asn ) to threonine ( thr ) substitution . the binding between 102 asn and 94 asp ( aspartic acid ) is imperative for the stabilization of r ; however , it is impossible for 102 thr to bind to 94 asp . thus , patients with hb kansas present cyanosis ; however , they are otherwise asymptomatic and do not require any specific treatment . a 65-year - old woman was referred to our hospital for renal dysfunction . she had a history of hypertension and hypercholesterolemia . seven days prior to her admission she had been diagnosed with a facial herpes zoster infection , which was treated with valaciclovir and non - steroidal anti - inflammatory drugs . there were no remarkable symptoms with the exception of cyanosis of the face , lips and nail beds . her spo2 was 70% on room air , despite the spo2 being tested using different oximeter probes on different fingers . her complete blood counts were normal ( hemoglobin ( hb ) , 13.9 g / dl ; hematocrit , 41.6% ; mean corpuscular volume , 89.5 fl ; reticulocyte count , 1.1% ; white blood cell count , 5,160/l and platelet count 23.310/l ) . an arterial blood gas analysis ( room air ) showed that the arterial partial pressure of oxygen ( pao2 ) was 88.7 mmhg , with an sao2 value of 58.1% . a urinalysis showed a ph of 5.0 , a specific gravity of 1.013 , ( ) protein and ( ) blood ( by dipstick ) , and negligible casts . the urine sodium and creatinine concentrations were 21 meq / l and 221 mg / dl , respectively . moreover , the following values were observed : albumin , 4.4 g / dl ; aspartate aminotransferase , 17 u / l ; lactate dehydrogenase , 259 u / l ; blood urea nitrogen , 39 mg / dl ; creatinine , 3.0 mg / dl ; uric acid , 8.6 mg / dl ; creatine kinase , 137 u / l ; sodium , 140 meq / l ; potassium , 4.3 meq / l ; glucose , 128 mg / dl and c - reactive protein , 0.5 mg / dl . sufficient fluid replacement rapidly improved her renal function , with her serum creatinine level reaching 0.74 mg / dl ; after which the patient recovered . however , her spo2 value remained at 78% under both 5 and 10 l oxygen by mask . on the other hand , under 5 l oxygen , her pao2 and sao2 values were 230 mmhg and 77.4% , respectively . thus , we suspected that the patient s condition involved an hb variant with low oxygen affinity . in fact , the patient had looked pale since adolescence ; however , she had no critical symptoms . in addition , the patient s mother also had asymptomatic cyanosis , but she had already died . the hb screening test results were as follows ( table 1 ) : both the percentage of hbf and hba2 were normal ; an isopropanol test , which shows the presence of unstable hb , was within the normal range ; the glycerol lysis time was normal and an hbh inclusion body test was negative ( ruling out thalassemia ) ; hb electrophoresis ( isoelectric focusing ) revealed an abnormal band , at the approximate position of hba ( figure a ) . finally , a dna sequence analysis of the - and -globin genes revealed an aac to acc mutation at codon 102 of the -globin gene , resulting in asparagine to threonine substitution ( hb kansas ) ( figure b ) . hemoglobin screening tests results of the present patient . a : hb electrophoresis ( isoelectric focusing ) of the patient and a control . an abnormal band around the position of hba however , hb variants with a low oxygen affinity should be considered in patients with unexplained cyanosis , if there is dissociation between pao2 and sao2 ( or spo2 ) . these hb variants , in which the alteration of the globin structure due to a genetic mutation causes the low oxygen affinity of hb , are very rare . an increase in the ratio of deoxidized hb to oxidized hb can lead to cyanosis . the oxygen dissociation curve of these patients is shifted markedly to the right in comparison to healthy controls . the delivery of oxygen to peripheral tissues may be enhanced , resulting in the reduction of erythropoietin - mediated erythropoiesis . in addition to hb kansas , hb beth israel ( 6 ) and hb saint mande ( 7 ) are typical hb variants which display a reduced oxygen affinity , and which lead to cyanosis . since ishiguro et al . reported the first case of hb kansas in a japanese family ( 8) , six cases ( four lineages ) , including the case of the present patient , have been reported in japan ( 8 - 10 ) ( table 2 ) . 1 - 2 and 3 - 5 ( table 2 ) were reported from toyama ( mid - west japan ) and hokkaido ( north of japan ) prefecture , respectively . our patient was from hokkaido ; thus , there were three lineages of hb kansas in hokkaido . however , the relationships among the families were unclear . the patients were diagnosed at various ages ( 9 to 65 years of age ) . all of the patients were diagnosed with hb kansas based on investigations for asymptomatic cyanosis and family examinations . hb kansas patients do not require any specific treatments and their prognosis is good ; however patient no . 3 ( table 2 ) who had polycythemia and diabetes mellitus died due to a cerebral infarction . the awareness of hb variants will help ensure a timely diagnosis and avoid unnecessary investigations and managements . mcv : mean corpuscular volume , spo2 : oxygen saturation by pulse oximetry , sao2 : arterial oxygen saturation , pao2 : arterial partial pressure of oxygen , nd : not described , dm : diabetes mellitus , ht : hypertension note : spo2 , sao2 , and pao2 were all measured under room air

hemoglobin ( hb ) kansas is an inherited hb variant with a low oxygen affinity that is associated with low oxygen saturation on pulse oximetry ( spo2 ) . it leads to asymptomatic cyanosis . patients with hb kansas do not require any specific treatment and the prognosis is good . in patients with unexplained cyanosis , we should thus consider hb variants , including hb kansas and avoid unnecessary investigations and managements . we herein report the case of 65-year - old woman with hb kansas and review five other cases ( three lineages ) that have been reported in japan .

posterior lumbar interbody fusion ( plif ) is one of the various methods to surgically manage degenerative spondylolisthesis.123 cloward1 was first to describe original technique . several surgeons have modified the original plif technique described.123 however ; it had been associated with a high incidence of fusion complications such as a graft collapse and nonunion.23 hence plif is not a standard surgical procedure . since the development and improvement of spinal instrumentation , however , plif is not a standard treatment for progressive degenerative spondylolisthesis . while plif with pedicle screw fixation and interbody devices has shown satisfactory clinical results , a solid fusion using spinal instrumentation has been reported to accelerate the degenerative changes at the adjacent levels.234567 however , in almost all of them , the surgeons used several surgical procedures such as plif with or without cage . the purpose of this study was to evaluate the long term outcome of plif using the same surgical procedure in patients with l4-l5 degenerative spondylolisthesis . 45 patients underwent a single level plif at l4-l5 for degenerative spondylolisthesis between 1995 and 2003 . eight of these patients were excluded because their postoperative followup period was < 60 months . the remaining 37 patients ( 16 male and 21 female ) were included in the study . the mean age of the patients at the time of surgery was 61.8 years ( range 26 - 77 years ) and the mean followup period was 121 months ( range 66 - 175 months ) . this study was approved by the ethics committee of our university . written informed consent was obtained from all patients . a routine posterior midline incision was used for , thus exposing the l4 and l5 vertebrae . laminectomy was performed , for almost all the caudal two - thirds of the l4 spinous process and lamina , including both inferior articular processes of l4 . these procedures enable total resection of the ligamentum flavum and exposure of the neural elements . the reduction was initiated by distraction at the l4 pedicle screws using the distraction device . after the l4-l5 disc was resected as much as possible , the anterior part of the disc space was packed with cancellous iliac bone , and titanium cages ( harms cage , depuy spine , raynham , ma ) packed with grafted bone chips were inserted . radiologic assessment was performed using plain lateral view radiographs before surgery , immediately after surgery , and at the last followup examination . we evaluated the % slip , the lordosis at l4-l5 , the lumbar lordosis and the adjacent segment degeneration . the % slip was measured using the taillard method.8 the lordosis at l4-l5 was defined as the angle subtended by the superior end plate of l5 and the inferior end plate of l4 . lumbar lordosis was measured from the superior end plate of l1 to the inferior end plate of l5 using the cobb method.9 the adjacent segment degeneration was defined as imaging evidence of one or more of the following lesions adjacent to a fused segment that was not present preoperatively : ( 1 ) posterior opening > 5 ; ( 2 ) narrowing of the disc height <3 mm ; ( 3 ) progression of the slippage > 3 mm . the japanese orthopedic association 's ( joa ) evaluation system for low back pain syndrome ( joa score ) was used before surgery and at the last followup examination , to evaluate the outcome of subjective symptoms ( low back pain and leg pain ) , clinical signs ( sensory and motor disturbance ) , and urinary bladder function . a normal score is 29 points and the worst score is 6 points [ table 1 ] . the recovery rate of the joa score that indicates the degree of normalization after surgery was calculated at the last followup examination using the formula described by hirabayashi et al.10 statistical evaluation was performed using one - way analysis of variance ( anova ) to compare the radiologic measures before surgery , immediately after surgery , and at the last followup examination . post hoc tests performed were indicated by anova results using tukey 's test for multiple comparisons . a routine posterior midline incision was used for , thus exposing the l4 and l5 vertebrae . laminectomy was performed , for almost all the caudal two - thirds of the l4 spinous process and lamina , including both inferior articular processes of l4 . these procedures enable total resection of the ligamentum flavum and exposure of the neural elements . the reduction was initiated by distraction at the l4 pedicle screws using the distraction device . after the l4-l5 disc was resected as much as possible , the anterior part of the disc space was packed with cancellous iliac bone , and titanium cages ( harms cage , depuy spine , raynham , ma ) packed with grafted bone chips were inserted . radiologic assessment was performed using plain lateral view radiographs before surgery , immediately after surgery , and at the last followup examination . we evaluated the % slip , the lordosis at l4-l5 , the lumbar lordosis and the adjacent segment degeneration . the % slip was measured using the taillard method.8 the lordosis at l4-l5 was defined as the angle subtended by the superior end plate of l5 and the inferior end plate of l4 . lumbar lordosis was measured from the superior end plate of l1 to the inferior end plate of l5 using the cobb method.9 the adjacent segment degeneration was defined as imaging evidence of one or more of the following lesions adjacent to a fused segment that was not present preoperatively : ( 1 ) posterior opening > 5 ; ( 2 ) narrowing of the disc height <3 mm ; ( 3 ) progression of the slippage > 3 mm . the japanese orthopedic association 's ( joa ) evaluation system for low back pain syndrome ( joa score ) was used before surgery and at the last followup examination , to evaluate the outcome of subjective symptoms ( low back pain and leg pain ) , clinical signs ( sensory and motor disturbance ) , and urinary bladder function . a normal score is 29 points and the worst score is 6 points [ table 1 ] . the recovery rate of the joa score that indicates the degree of normalization after surgery was calculated at the last followup examination using the formula described by hirabayashi et al.10 statistical evaluation was performed using one - way analysis of variance ( anova ) to compare the radiologic measures before surgery , immediately after surgery , and at the last followup examination . post hoc tests performed were indicated by anova results using tukey 's test for multiple comparisons . the % slip decreased from 17.0% before surgery to 9.7% at the last followup examination [ figure 1 ] . the mean lordosis at l4-l5 was 3.6 before surgery , 8.2 after surgery and 6.9 at the last followup examination [ figure 2 ] . adjacent segment degeneration occurred at the cephalad level in 14 patients [ figure 4 ] and at the caudal level in one patient [ table 2 ] . bar diagram showing the % slip significantly improved from 17.0% before surgery to 9.7% at the last followup ( * p < 0.05 ) bar diagram showing the lordosis at l4/l5 significantly improved from 3.6 before surgery to 8.2 after surgery . at the last followup , the lordosis at l4/l5 was restored ( * p < 0.05 ) bar diagram showing that the lumbar lordosis did nt significantly change x - ray lumbosacral spine lateral view of a 72 year old male ( a ) preoperative showing l4-l5 degerative spondylolisthesis , ( b ) immediately after the first surgery showing pedicle screws and cage in situ . lordosis improved to 9 at l4l5 ( c ) 8 years after the first surgery showing adjacent segment degeneration at l3l4 level ( d ) immediately after the second surgery plif showing pedicle screws in l3 and cage between l3l4 also ( e ) 10 years after the first surgery showing adjacent segment degeneration at l2l3 level ( f ) after third surgery ( at final followup ) showing fixation at 2 more proximal levels with plif at l2l3 level ( joa score improved 17 to 21 points at final followup ) the mean joa score was 13.4 points ( range 4 - 20 points ) before surgery and 24.5 points ( range 16 - 29 points ) at the last followup examination . no immediate postoperative neurological complications were observed , although an incidental dural tear was observed in two patients ( 5.4% ) . reoperation was required in three patients ( 8.1% ) due to intolerable symptoms in their lower extremities caused by adjacent segment degeneration . anterior column augmentation with plif using intervertebral spacers in addition to pedicular screw fixation was found to have superior fusion rate and improved clinical outcomes in spondylolisthesis.11121314 recently , transforaminal lumbar interbody fusion has also been reported to produce a high fusion rate and excellent clinical outcomes . however , plif is more advantageous in achieving solid fusion by removing intervertebral material and cartilaginous endplates through bilateral wide annulotomy and harvesting a greater amount of local autograft.15 evaluation of the long term outcomes of plif is important . previously conducted studies had limitations in terms of different diagnoses , different levels and number of fused segments and different fusion techniques . therefore , we evaluated the long term outcomes of plif using the same procedure in patients with degenerative spondylolisthesis . in this study , the mean recovery rate of the joa score was 71.2% , and the clinical result was satisfactory . degenerative changes at the levels adjacent to the lumbar spinal fusion have been well recognized.56 the factors thought to be involved in the increase of degeneration at adjacent levels are the stiffness of the fixation , the number of fused levels , the natural course of degeneration at the adjacent level , and any postoperative lumbar sagittal malalignment . the importance of sagittal realignment and maintenance of lordosis during fixation have been documented in clinical studies,1617 and clinical experience suggests that lumbar fusion in a nonanatomic sagittal alignment can cause a deleterious effect at the adjacent level . akamaru et al.18 in their study have reported the effects of fixing the l4-l5 segment in different sagittal alignments on the adjacent motion segments using human cadavers . their study showed that sagittal malalignment fusion is considered a risk factor for adjacent segment degeneration after plif.18 therefore , we have always ensured adequate lordosis at the fusion site in plif . in this study , the mean lordosis at l4-l5 was 3.6 before surgery , 8.2 after surgery , and 6.9 at the last followup examination . we thought that we achieved good local alignment at the fusion site but adjacent segment degeneration occurred in 15 patients and reoperation was required in three of the 15 patients . performed plif both with and without a cage , and reported that adjacent segment degeneration occurred in 57.5% and reoperation was required in 27.5% after a minimum followup period of 10 years.19 greiner - perth et al . have reported in a study of instrumented plif that the reoperation rate was 12.9% for mono - or bi - segmental plif and 14.4% for multisegmental plif after a 5-year followup period.13 from our results , the reasons for adjacent segment degeneration occurrence are not understood . their study showed that coexistence of horizontalization of the lamina at l3 and facet tropism at l3-l4 may be a risk factor for neurologic deterioration resulting from accelerated l3-l4 degenerative change after l4-l5 plif . they used computed tomography and radiographs in their assessment.20 on the other hand , we used only plain lateral view radiographs for our evaluation because our study data was > 10 years old and was insufficient . we need to evaluate the risk factors for adjacent segment degeneration using computed tomography in the future . therefore , we could not evaluate the degenerative changes in the discs of nonsurgical patients . van horn and bohnen , in a retrospective matched pair study of 16 patients with a minimum followup period of 16 years after anterior spinal fusion , found radiographic degenerative changes in the adjacent discs at a rate similar to that in the corresponding levels of the control group.21 second , this study was a small case series . we conclude that at a mean followup period of 10 years outcomes of plif using the same surgical procedure for l4-l5 degenerative spondylolisthesis have shown the satisfactory clinical results . the adjacent segment degeneration occurred in 15 patients ( 40.5% ) and reoperation was required in three patients ( 8.1% ) .

background : posterior lumbar interbody fusion ( plif ) has become the standard in the treatment for degenerative spondylolisthesis since improvement of spinal instrumentation however , few published studies have reported long term outcomes of plif using a same surgical procedure . the purpose of this study is to evaluate a long term outcome of plif using a same surgical procedure for l4-l5 degenerative spondylolisthesis.materials and methods : out of 45 patients who underwent l4-l5 plif for degenerative spondylolisthesis between 1995 and 2003 , 37 patients ( 16 males and 21 females ) were evaluated in this study . mean age was 61.8 years . the average followup period was 121 months . we evaluated % slip , lordosis at l4/l5 , lumbar lordosis , japanese orthopedic association 's ( joa ) score and adjacent segment degeneration.results:the % slip significantly improved from an average of 17.0% before surgery to 9.7% at the last followup . lordosis at l4/l5 averaged 3.6 before surgery , 8.2 after surgery and 6.9 at the last followup . although patients experienced some loss of correction at last followup , their lordosis at l4/l5 at last followup still was significantly different from their lordosis at l4/l5 before surgery . lumbar lordosis did not significantly change . mean joa score was 13.4 before surgery and 24.5 at the last followup ; mean recovery ratio was 71.2% . adjacent segment degeneration occurred in 40.5% of patients , almost all of which occurred in the cranial adjacent segment . three patients ( 8.1% ) required reoperation due to adjacent segment degeneration , at an average of 76 months after their initial surgery.conclusions:with more than 10-year followup after l4-l5 plif for degenerative spondylolisthesis , the adjacent segment degeneration occurred in 40.5% and reoperation was required in 8.1% .

cancer diagnosis is an important event in an individual s life which has considerable outcomes and implications for patient and his / her family . meanwhile , receiving assistance and support from family and friends has a significant impact on patients to help them to cope with disease - related stress and its treatment . this study aimed to assess the received social support and its correlation with demographic and medical variables . this was a cross - sectional descriptive study on two hundred cancer patients referred to sayed al - shohada medical center in isfahan , iran . the study subjects were selected through convenient sampling method and required information collected by questionnaire containing demographic and medical data and multidimensional scale of perceived social support ( mspss ) . some of the inclusion criteria included age over 18 with no history of mental disorders and not being at final stages of the disease . content validity of mspss was confirmed by experts and its reliability was evaluated by test - retest ( r > 0.85 ) . the majority of cancer patients ( 94.5% ) perceived a high rate of social support from their families , friends and relatives . furthermore , the findings indicated a statistical significant correlation between the numbers of children with social support ; however , no significant correlation was found between other demographic and medical variables with social support . the findings of this study indicated receiving the maximum acceptable social support from family , especially children , in patients with cancer . however , conducting further extensive studies is recommended to find effective factors on social support of patients with cancer . cancer diagnosis is an important event in the life with significant physical , psychological , social and economic consequences for patient , his family members and relatives . inasmuch , thus far cancer is known as an incurable and chronic complication that rarely cures ; therefore , after the primary diagnosis and its confirmation by a physician , patients will be shocked or suffer from psychological complications . the incidence of these symptoms leads to lose abilities , feel weakness and pain and believing the fact that death gradually is close and closer . patients and families that face cancer diagnosis would experience various levels of stress and emotional concerns . fear of death , disruption of life plans , change in imagination and self - confidence , change in social roles , lifestyle and financial concerns are important aspects of every cancer patient . flanagan and holmes stated : encountering with a life threatening and risky disease such as cancer requires physical and emotional adaptation and adjustment with new situation and in this context , social support and relations effect as important factors for adaptability with disease and achieving mental health . while social relations act as a major source in positive adjustment with disease ; on the contrary , inappropriate social relations may have negative effects in adjustment with the disease . it should bear in mind that social support with facilitation in the process of cognitive and stressful events cause patients adjust with their situation ; now if social reacts are negative and non - supportive against disease , the process will be inhibited . social support is defined as received assist and support from others , particularly certain people . it has been suggested that social support has a mediating role in the effect on adaptability style . if social support can reduce the effect of life s difficult stress and incidence of mood disorder , cancer patients certainly need such supportive mechanisms . for years , scientists have identified the positive correlation between social support and health . in this regard , meyerowitz et al . found that received social support from family members is associated with flexibility and emotional vitality in women with cervical cancer . furthermore , ashing - giwa et al . also found that in order to increase disease improvement , american women have faith in god and rely on their families . the results of another study about experiences of patients after prostatectomy showed that men consider their spouses as an important supportive source to control their anxiety . in addition , many studies indicate the fact that more survival , better adaptability and mental health and higher quality of life are seen in cancer patients receiving social support . conversely , inadequate or unsatisfying social support leads to negative outcomes such as more stress and concern , more psychological and mental pressure and communication disorders . in this regards , previous studies indicated some relationship between some of the demographic characteristics and its disease - related variables with the quality of a good adjustment with cancer . for example , researchers have realized that married people show lower distress and higher adjustment than single patients . however , considering to the importance of social support in cancer patients , currently there are very few studies in iran in this regard and it has been less discussed about its association with demographic characteristics and disease - related variables such as cancer type , treatment and duration of therapy . in this respect , this study was dome based on the level of received social support from family and friends and its association with some demographic and medical characteristics so that herewith obtaining more information about the related causes with social support in cancer patients , healthcare and medical team , particularly nurses , can provide more support and care . this was a descriptive cross - sectional study done during 2007 to 2009 in seyed al - shohada hospital in isfahan , iran . the study population included all he patients admitted in internal wards of males and females , surgical and intensive as well as patients referred to outpatient chemotherapy and radiation therapy of this hospital . some of the inclusion criteria included age of over 18 , no history of mental disorders ( with diagnosis of physician and no history of antidepressants in the past or present ) , ability to read and write or speak , passing at least one month since diagnosis and not being at the final stages of the disease . a questionnaire was used in order for data collection consisted of two parts : the first part was the medical and demographic characteristics and the second part was multidimensional scale of perceived social support ( mspss ) . the demographic survey contained questions to evaluate age , sex , marital status , occupation , and education , number of children , average income of spouse and place of living . medical information was about duration of disease since being diagnosed , disease site and treatment type obtained through interviewing and also patients records and files . content validity of mspss was done through comments of ten faculty members and experts by some modifications and its reliability was confirmed by test - retest method with correlation coefficient over 0.85 . the data were analyzed by spss software with descriptive ( frequency ) and inferential statistics ( chi - square ) . the average age of patients was 40 years most of whom were between 21 to 60 years old . most of them were housekeeper which probably was due to high number of women among the study subjects . furthermore , they had the least level of literacy and were mostly high school graduates . the studied patients suffered from different types of cancers : breast cancer ( 33.5% ) , gastrointestinal ( 16.5% ) , leukemia ( 7% ) , bone cancer ( 7% ) , lung ( 5% ) and kidney ( 4% ) and others ( 27% ) . moreover , most of the patients passed less than 6 months from their diagnosis . the most common treatment method of the study subjects was combined method ( including surgery , chemotherapy and radiation therapy ) . the results showed that most of the cancer patients ( 94.5% ) received a high rate of social support from family , friends and relatives . moreover , the results of chi - square test showed that there was a statistical significant correlation between the variable of the number of children with social support in cancer patients ( = 0.039 ) ; however , there was no significant correlation between other demographic or medical characteristics with social support . the findings showed that the majority of cancer patients received maximum social support from their family , friends and relatives . in this respects , the results of previous studies also indicated receiving the maximum acceptable social support from family . because social support received by parents , spouse , children and other healthcare givers is the most important source of social support for adolescents and adults with cancer . furthermore , the results indicated that patients with more children generally received higher social support than others . in this regard , han et al . also found that adequacy of social support through larger channel is associated with lower depression of cancer patients . in addition , the findings suggested that receiving support from family , particularly children , plays an important role in relieving depression symptoms in cancer patients . the results showed that statistically there was no significant correlation between age and social support which was not in accordance with the results of the previous studies in this regard ; for instance , the results of a study in pakistan showed that age of patients with breast cancer significantly correlated with social support . it seems that the reason is due to difference in the limited number of study subjects and/or due to cultural differences between iran and other countries ; because in iran , young and old people almost receive similar level of high social support from others . besides , the majority of the study subjects were males and in iranian culture , woman is given high attention as mother and/or wife . thus , there was no significant difference between men and women with cancer regarding social support receive . in this regard , krishnasamy implemented a study about social support and its effect on cancer patients defined three parts of support as follows : 1 . tool support ( i.e. providing money , facilities and services ) , 2 . informational support ( i.e. providing guidance and information ) and 3 . emotional support ( i.e. expressing the positive effect and awareness from patient s feelings ) . considering the effect of age on each of the above parts , conducting further studies on how male and female cancer patients benefit from social support in iran is recommended . besides , there was no significant difference between scores of social support in single and married patients which was not in accordance with the results of previous studies . usually single individuals live with their parents before marriage and receive their supports similar to supports of children and spouse for married patients . however , it seems that not only the number of people around patient , but also the quality of interaction is important too . furthermore , the results indicated lack of a significant correlation between educational levels with social support . the results of previous studied were in accordance with the results of the present study ; so that tan and karabulutlu in a study found that there was no correlation between education level of cancer patients with social support . besides , there was no significant correlation between average income level of family and social support . while previous studies have proven the opposite . for example , according to hilton s study , financial support is an important way for adjustment improvement for patents . financial problems limit adjustment of cancer patients and may confront them with many problems to providerequired medications and reduce cancer healing . the reason of this difference might be because the average income of the study subjects was not determined accurately based on related indices . because provided to do so , the correlation might be significant . in addition , this difference can be attributed to low number of subjects which requires conducting more extensive studies with higher study population and more accurate statistical indices . in addition , this study evaluated the association of place of living with social support which showed no significant difference in mean score of social support among urban and rural patients . the results indicated lack of a significant correlation between disease - related variables ( disease duration , treatment type and disease site ) with social support . for example , the study of tan and karabultlu also supported this correlation . furthermore , a study by nausheen and kamal on patients with breast cancer indicated the fact that there was no correlation between social support with those who either underwent or did not undergo mastectomy . however , most of the results in some studies also were slightly different with this finding . e.g. a study titled as the contribution of attachment security and social support to depressive syndrome in patients with metastatic lung cancer and gastrointestinal cancer on 326 patients showed that disease - related factors inversely correlated with social support . however , it should be mentioned that one of the inclusion criteria for selection of the study subjects in this study was no history of metastatic disease which this was not considered in the study of rodin et al . therefore , re - implementation of such a study with higher study samples is recommended . the results of this study showed that received social support form friends , family and relatives was in an acceptable extent ; however , it seems that in order for higher social support in cancer patients , some continuous care interventions in clinical environments should be done for patients with new cancer diagnosis in iran including reviewing the presence of supportive individuals in the family network and relatives as well as providing adequate information for more support from others by clinical nurses and psychiatric nurses . ultimately , it can be said given that nurses practice and performance in cancer health medical centers still is discussable and controversial , therefore development of specialist cancer nurses based on needs of patients and in order to provide specialized and comprehensive care as well as providing permanent interventions seems necessary so that patients can better adjust with their disease . furthermore , it is recommended that effective factors on social support of cancer patients investigated through more extensive studies . in addition , repeating the present study with more sample size and using systematic sampling method among iranian men and women with different cancer is recommended to access generalization and more evidence .

background : cancer diagnosis is an important event in an individual s life which has considerable outcomes and implications for patient and his / her family . meanwhile , receiving assistance and support from family and friends has a significant impact on patients to help them to cope with disease - related stress and its treatment . this study aimed to assess the received social support and its correlation with demographic and medical variables.materials and methods : this was a cross - sectional descriptive study on two hundred cancer patients referred to sayed al - shohada medical center in isfahan , iran . the study subjects were selected through convenient sampling method and required information collected by questionnaire containing demographic and medical data and multidimensional scale of perceived social support ( mspss ) . some of the inclusion criteria included age over 18 with no history of mental disorders and not being at final stages of the disease . content validity of mspss was confirmed by experts and its reliability was evaluated by test - retest ( r > 0.85).findings : the majority of cancer patients ( 94.5% ) perceived a high rate of social support from their families , friends and relatives . furthermore , the findings indicated a statistical significant correlation between the numbers of children with social support ; however , no significant correlation was found between other demographic and medical variables with social support.conclusions:the findings of this study indicated receiving the maximum acceptable social support from family , especially children , in patients with cancer . however , conducting further extensive studies is recommended to find effective factors on social support of patients with cancer .

acquired neuromyotonia ( nmt ) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome , and is thought to be caused by antibodies to voltage - gated potassium channels ( vgkc ) . a case of acquired nmt accompanied by exertional weakness without coexistence of seropositive mg is reported herein . clinical and electrophysiological observations suggest that the cholinergic overactivity in nmt can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission . acquired neuromyotonia ( nmt ) is a rare condition of spontaneous and continuous muscle fiber activity that is thought to be caused by voltage - gated potassium channel ( vgkc ) antibodies that functionally block the neuronal potassium channels at the distal motor axons.1 exertional weakness is unusual without coexistence of autoimmune myasthenia gravis ( mg).1 a patient with nmt who developed exertional weakness without coexisting seropositive mg is reported herein . a 19-year - old man presented with generalized muscle stiffness and cramps of 5 weeks duration . he also noticed moderate limb weakness , and complained of difficulty climbing stairs , elevating his arms , and handwriting . 1a ) , diffuse fasciculation , and myokymia . repetitive nerve stimulation ( rns ) of the ulnar nerve at low frequencies revealed marked reductions in compound muscle action potential ( cmap ) amplitudes ( fig . 1b ) , but there was neither postexercise facilitation nor abnormal increase at a stimulation frequency of 50 hz . the findings of a conventional nerve conduction study were normal except for abnormal stimulation - induced afterdischarges ( fig . antibody tests against vgkc , acetylcholine ( ach ) receptor , and muscle - specific kinase were all negative . all other laboratory tests yielded no other unusual findings . with a presumed diagnosis of seronegative generalized mg superimposed on nmt , this patient was treated with high - dose intravenous immunoglobulin ( ivig ) along with oral carbamazepine and a low dose of pyridostigmine bromide ( 30 mg three times per day ) . within 2 days , even before the ivig treatment was completed , the patient had responded so dramatically that not only the muscle stiffness but also the weakness had improved to a near - premorbid state . however , a follow - up nerve conduction study at that time was not fully consistent with the clinical recovery , revealing the occurrence of repetitive cmaps ( repcmaps ) along with more prominent afterdischarges ( fig . the repcmaps disappeared after discontinuation of pyridostigmine , but the abnormal afterdischarges persisted in the peroneal and tibial nerves . abnormal cmap decrements continued to be present in a follow - up rns study , but to a lesser degree with larger cmaps ( fig . the patient continued to receive carbamazepine treatment only , and his clinical improvement was maintained during the next 2 years of follow - up . it was initially assumed that the patient had two separate conditions : nmt and mg . however , subsequent clinical and electrophysiological observations seemed to discount this , raising another possibility that the observed myasthenia was related to the pathophysiology of nmt . indeed , it has been suggested that the constant and rapid motor unit firing in nmt reduces the amount of immediately releasable quanta in the nerve terminals , causing a decrease in the quantal content.1 the quantal response may also be impaired , since the prolonged and repeated exposure of ach receptors to their agonist can result in prolongation of the endplate current , leading to receptor desensitization and depolarization block.2 the initially quite low cmap amplitudes in the present patient may be explained by such defects in neuromuscular junction transmission in nmt . the rapid therapeutic response of the myasthenia in this patient , in terms of both clinical and electrophysiological aspects , could support this explanation . the " neural " repcmaps , also called m - wave afterdischarges , have been reported in two other cases with nmt.3 unlike " synaptic " repcmaps , " neural " repcmaps are known to occur in the supernormal phase of repolarization , triggered at about 10 ms after the passage of an impulse.4,5 this is in contrast to synaptic repcmaps , which begin 3.5 - 4.0 ms after the primary discharge.4 interestingly , there were both " neural " and " synaptic " repcmaps in our patient , with the latter observed after treatment with pyridostigmine at a very low dose . the occurrence of " synaptic " repcmaps might be attributable to the pyridostigmine - induced additional excess of ach in the synaptic space , which in our case was already fullycharged . previous findings are not consistent with the presence of neurophysiologically detectable neuromuscular transmission defects in patients with nmt.3,6,7 this discrepancy may be attributable to heterogeneity in the severity and extent of the pathological processes underlying nmt.1 coincident autoimmune mg might have further complicated the issue of the origin and pathophysiology of exertional weakness in nmt . although the mechanism involved remains to be elucidated , the findings of the present case report suggest that 1 ) exertional weakness can develop in nmt without coexisting autoimmune mg , and 2 ) the constantly rapidly firing motor units in nmt may compromise the safety factor at the neuromuscular junction sufficiently to cause a neuromuscular transmission defect .

backgroundacquired neuromyotonia ( nmt ) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome , and is thought to be caused by antibodies to voltage - gated potassium channels ( vgkc ) . exertional weakness is unusual unless autoimmune myasthenia gravis ( mg ) is superimposed.case reporta case of acquired nmt accompanied by exertional weakness without coexistence of seropositive mg is reported herein.conclusionsclinical and electrophysiological observations suggest that the cholinergic overactivity in nmt can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission .

the discovery of coagulation factor xiii ( fxiii ) dates back to 1940s when a serum factor was found to make the fibrin clot insoluble in concentrated urea solution . in 1960 , a case report demonstrated that the severe bleeding of a patient was due to the deficiency of fibrin stabilizing factor . soon after this clinical finding , such fibrin stabilizing factor was formally termed fxiii in 1963 . fxiii is a transglutaminase ( tg ) that circulates in tetrameric form ( fxiii - a2b2 ) , consisting of two a subunits ( fxiii - a ) and two b subunits ( fxiii - b ) . the a subunit , as the pro - tg , is made up of 732 amino acids with a molecular mass of 83,000 . fxiii - a comprised five domains : the n - terminal activation peptide ( ap - fxiii ) ( amino acids 137 ) , -sandwich ( 38184 ) , catalytic core ( 185515 ) , -barrel 1 ( 516628 ) , and -barrel 2 ( 629731 ) . fxiii - b is a glycoprotein consisting of 641 amino acids ; its molecular mass is 80,000 . it is a typical mosaic protein consisting of 10 short tandem repeats , called sushi domains . fxiii - b serves as a carrier protein and is essential for the stabilizing of fxiii - a . it accelerates cross - linking of fibrin by promoting the formation of a ternary complex between proenzyme fxiii , prosubstrate fibrinogen , and activator thrombin . the catalytic site of fxiii - a2 is cys314 , which is normally occluded by ap - fxiii . initiated by thrombin , ap - fxiii is cleaved and plasma fxiii - a2b2 is converted to fxiiia2 b2 . after further disassociation of fxiii - b2 as a result of conformational change after ca binding , fxiii is finally transformed into activated fxiii ( fxiiia ) [ figure 1 ] . fxiii - a is mainly formed by cells originated from the bone marrow . in plasma , all fxiii - a exists in a complexed form of fxiii - a2b2 . while the free form , fxiii - a2 is only found intracellularly , mainly in platelets , megakaryocytes , monocytes , and macrophages . fxiii - b , synthesized by the hepatocyte , presents both as free form of fxiii - b and a complexed form of fxiii - a2b2 in the plasma . ( b ) after the initial conversion of fibrinogen into soluble fibrin by thrombin , fxiiia cross - links gln and lys residues of fibrins , which further leads to the formation of insoluble fibrin network . ap - fxiii : activation peptide factor xiii ; fxiii : factor xiii ; fxiiia : activated factor xiii ; gln : glutamine ; lys : lysine . as a tg the substrates of fxiii add up to more than 140 , including fibrinogen , fibronectin , and vitronectin . the whole complement system , including c3 , c4b , c5a , can be cross - linked and immobilized by fxiii ; hence , a pro - inflammatory environment is created , providing a suitable microenvironment for cellular growth . interaction between these proteins and signal molecules on the cellular surface may activate signal pathways . fxiii is transformed to activated fxiii by thrombin with the help of ca and catalyzes cross - linking of fibrin , converted from fibrinogen by activated thrombin [ figure 1 ] . fibrin cross - linking is a highly specific acyl transfer reaction consisting of two steps : ( 1 ) glutamine of the substrate forms a binary complex with the active site cysteine of the enzyme through the thioester linkage , accompanied by ammonia release ; ( 2 ) the acyl group of the binary complex is transferred to the acyl acceptor amine and form an isopeptide , releasing the enzyme at the same time . fibrin included two -chains , two -chains , and two -chains , linked by the disulfide bond . fxiiia cross - links fibrin chains , during which -chain dimers and -chain polymers are formed . -chain dimer formation between lysine of one -chain and glutamine of the other -chain is fast , followed by the formation of -polymers . -chain multimers from progressive cross - linking of -chain dimers , accompanied by cross - linking between -chain and -chain , further stabilize the fibrin clot . 2-antiplasmin ( a2 at ) is one of the substrates of fxiii that can be cross - linked to fibrin , further strengthening its antifibrinolytic ability . other substrates of fxiii include plasminogen activator inhibitor 2 , plasminogen , and thrombin activatable fibrinolysis inhibitor , whose roles in fibrinolysis and thrombosis remain to be studied . fxiii deficiency is a rare type of disorder that often causes bleeding manifestations , sometimes life - threatening central nerve system ( cns ) bleeding . a research of 190 patients with congenital fxiii deficiency revealed that major clinical manifestations include umbilical bleeding of neonates , deep soft tissue hematoma , prolonged wound bleeding , mucosal bleeding ( gum bleeding , epistaxis , prolonged menstrual bleeding ) , and cns bleeding . patients may develop antibodies for fxiii - a or fxiii - b from autoimmune or neoplastic disease and usages of certain medications . fxiii deficiency has been found in children with malignant disease including acute myeloid leukemia and acute lymphoblastic leukemia ( all ) , and solid tumor such as neuroblastoma , non - hodgkin lymphoma and disseminated alveolar rhabdomyosarcoma , with the presence of bleeding manifestations . one research focused on pulmonary embolism ( pe ) demonstrated that patients with pe ( n = 71 ) have lower fxiii levels than patients without ( n = 4 9 ) . similar results were observed in fibrinogen level , indicating that lower level of fxiii in patients with pe might be a result of consumption during clot formation . studies have also shown that the role of fxiii in thrombosis may be affected by factors such as age and gender . two studies with 955 and 278 patients , respectively , reported that increased fxiii plasma concentration was associated with increased incidence rate of myocardial infarction and peripheral artery disease in female patients . inflammatory cells such as macrophages and neutrophils will migrate to the wounded area due to the chemotactic effect induced by cytokines . angiogenesis then starts under the influence of growth factors such as vascular endothelial growth factor ( vegf ) , fibroblast growth factor , and transforming growth factor - g . the newly synthesized small vessels , together with fibrin , will form the granulation tissue . fxiii also plays an important part in the process . besides the significant role in the coagulation cascade , immobilized fxiiia in the tissue of the wound supports platelet adhesion through integrins ( iib3 and v3 ) on the surface of the platelet , a process independent of fxiiia tg activity , thus stabilizing the provisional matrix at the very early stage of wound healing . bacteria are immobilized via cross - linking to fibrin fibers by the action of fxiii . fxiii is also able to cross - link with many molecules such as fibronectin and vitronectin , which adheres to the integrin of inflammatory cells that would migrate to the wound later . as a result , adhesion of the inflammatory cells is enhanced , and integrin - related signal pathway is activated . it is found that fibronectin plays a potential role in the activation of macrophage , and cross - linked vitronectin can inhibit apoptosis of neutrophils . vegf receptor-2 ( vegfr-2 ) and v3 on the surface of vascular endothelial cells are both signal molecules in angiogenesis , which can be activated by fibronectin and vitronectin when cross - linked with fxiii . the role of fxiii in wound healing is supported by research in both animal studies and clinical cases . exposure to dextran sulfate sodium ( dss ) causes mucosa damage of colon in mice . the colon damage of wild - type mice was found to recover better than fxiii mice after dss exposure . a research study including 31 patients of crohn 's disease ( cd ) reported that plasma fxiii level was lower in patients with active cd than patients in remission , indicating fxiii consumption during the healing of damaged colons . another study including 249 patients of ulcerative colitis showed that plasma fxiiia was lower in more severe patients ( measured by clinical activity index , endoscopic and histologic scores ) . immunohistochemistry also reported fxiii localization in extracellular matrix of damaged mucosa , a strong evidence of fxiii participating in wound healing process . researchers have found abnormal fxiii expression level or activity in patients with leukemia and solid tumors . the cellular form of fxiii ( fxiii - a2 ) is present mainly in platelets , megakaryocytes , monocytes , and macrophages . it was found that fxiii - a2 expression level of tumor cells was significantly elevated in patients with acute myelomonocytic leukemia ( aml - m4 ) and acute monocytic leukemia ( aml - m5 ) . abnormal fxiii activity has been found in patients with solid tumors . a research including 28 patients of nonsmall cell lung cancer ( nsclc ) found that fxiii activity level of patients in advanced - stage is higher than that of patients in early - stage and healthy controls , indicating that fxiii activity level could be potentially used as a marker of advanced nsclc . vairaktaris et al . analyzed 130 patients of oral squamous cell carcinoma and 135 healthy controls and found that l allele was associated with higher oral cancer risk . it was observed that patients with ll homozygotes had a 3-fold higher risk for oral cancer , while in vl , the risk was 2-fold higher . fibrins are found in neoplastic tissues , as well as many tumor - associated macrophages ( tams ) which express fxiii - a2 . fxiii - a2 released from damaged tams was involved in the stabilization of fibrin network which facilitated tumor growth . fxiii was found to be involved in tumor metastasis in the research of mice by limiting natural killer cell - mediated clearance of micrometastatic tumor cell . however , the role of fxiii in tumorigenesis is still unclear , and the relationship between fxiii and leukemia and solid tumors needs to be further elucidated . bone remodeling is a life - long process , involving osteoclasts that resorb bone and osteoblasts that form new bone tissues . bone extracellular matrix is essential in the process by facilitating cell attachment , cell differentiation , and bone mineralization . researches in mice have reported the activation of fxiii - a gene in osteocytes of long bones ( femur ) and flat bones ( calvaria and mandible ) . a 37,000 protein expressed in bone and was confirmed to be the active product of fxiii - a after posttranslational proteolytic processing . the protein was able to stabilize the interaction of microtubules with the plasma membrane , making it possible for the secretion of exosomes which contain collagen and fibronectin , both of which were predominant composition of bone extracellular matrix . collagen and fibronectin secreted outside the cell could form stable interaction with osteonectin and osteopontin , catalyzed by tg . the deposition of ca and collagen would decrease after suppression of tg activation , indicating the important role tg played in the mineralization and collagen deposition of bone extracellular matrix . however , other researches have observed mineralization and collagen deposition of extracellular matrix in tg2 and fxiii - a knockout mice . another protein of 37,000 , with similar function to the active product of fxiii - a mentioned above , has been found . it is reasonable to believe that other kinds of protein may also be involved in bone remodeling . a systemic review by sharief and kadir found 127 ( 66% ) miscarriages in 192 pregnancies of 63 women with congenital fxiii deficiency . for those without prophylactic therapy , as high as 91% of 136 pregnancies resulted in miscarriage . fxiii - a is present in normal uterus , implantation tissues , and placenta in normal pregnant women , but missing in women of congenital fxiii deficiency . extravillous cytotrophoblasts formed the cytotrophoblastic shell which stabilized the interaction between embryo and decidua of uterus . it was reported that fxiii - a was missing in the placenta in woman with fxiii deficiency , leading to insufficient formation of the cytotrophoblastic shell . the cross - linking between proteins such as fibrin and fibronectin was also important for the attachment of placenta to uterus . however , a research including 536 cases reported that the plasma level of fxiii could not predict recurrent miscarriage . one potential explanation is that fxiii in plasma is not equal to that in placenta tissues while the latter is the key to pregnancy loss . fxiii has been treated as merely a coagulation factor for a long time by the medical community . recent studies have shown that fxiii , with the essence of tg , is involved in many more processes besides coagulation such as wound healing , bone extracellular matrix stabilization , and the interaction between embryo and decidua of uterus , as well as some rare processes [ table 1 ] . the expression and activity level of fxiii also changes in leukemia and solid tumors , but its underline mechanism is still unknown and more research is needed .

objective : to provide a comprehensive literature review on roles of coagulation factor xiii ( fxiii ) in coagulation , wound healing , neoplasm , bone metabolism , and pregnancy.data sources : all articles in pubmed with key words coagulation factor xiii , wound , leukemia , tumor , bone , and pregnancy with published date from 2001 to 2016 were included in the study . frequently cited publications before 2000 were also included.study selection : we reviewed the role of fxiii in biologic processes as documented in clinical , animal , and in vitro studies.results:fxiii , a member of the transglutaminase ( tg ) family , plays key roles in various biological processes . besides its well - known function in coagulation , the cross - linking of small molecules catalyzed by fxiii has been found in studies to help promote wound healing , improve bone metabolism , and prevent miscarriages . the study has also shown that fxiii concentration level differs in the blood of patients with leukemia and solid tumors and offers promises as a diagnostic indicator.conclusions:fxiii has many more biologic functions besides being known as coagulation factor . the tg activity of fxiii contributes to several processes , including wound healing , bone extracellular matrix stabilization , and the interaction between embryo and decidua of uterus . further research is needed to elucidate the link between fxiii and leukemia and solid tumors .

the incidence of preeclampsia is 57% , making it the foremost cause of maternal and fetal morbidity and mortality in industrialized countries . the pathogenesis of preeclampsia is complex , involving the interaction of genetic , immunologic , and environmental factors . the patient was a 28-year - old woman with polycystic kidney disease and known arterial hypertension since her first pregnancy 5 years earlier , for which she was taking methyldopa . the hematuria resolved in 2448 hours , but high blood pressure ( 150/90 mmhg ) persisted despite initial treatment with hydralazine . proteinuria ( 0.93 g/24 h ) and impaired renal function ( creatinine 1.3 mg / dl ) were present , but no evidence of hemolysis , elevation of transaminases or uric acid , or thrombocytopenia was found . in view of the patient 's preeclampsia and a nonreactive fetal pattern , the patient , who intended to breast - feed , was assessed by the nephrology department for high blood pressure postpartum . she was started on nifedipine , but labetalol was later added due to poor control . on postpartum day 4 , the patient presented a headache , vision loss that progressed to bilateral amaurosis , and bilateral nonreactive mydriasis . cerebral nuclear resonance imaging ( mri ) with a diffusion sequence revealed cytotoxic / vasogenic edema of the cortex and subcortical white matter [ figure 1 ] , which is consistent with posterior reversible encephalopathy syndrome ( pres ) . the cortex and , to a lesser extent , the subcortical white matter of the territories of the posterior cerebral circulatory system ( occipital and parietal lobes ) and the territories bordering the anterior cerebral circulatory system ( frontal gyri ) present cytotoxic and vasogenic edema the patient was admitted to the intensive care unit and treated with antihipertensive agents with infusion of labetalol , nitroprussiate and valsartan , to which an alpha - adrenergic blocker , amlodipine , and hydrochlorothiazide were added . examination of the ocular fundus revealed optic discs with clean , symmetrical margins and good coloring . proteinuria and hypertension dominate the clinical manifestations of preeclampsia because the kidney is the target organ of the disease . even when full eclampsia does not develop , preeclampsia may lead to kidney failure , liver damage , intracranial hemorrhage , delayed fetal intrauterine growth , and fetal death . despite the criteria for definition , many patients present without these clinical manifestations . the traditional criteria are not reliable in women with hypertension and proteinuria before week 20 of pregnancy , especially in women taking antihypertensive medication . the condition is more severe in women with chronic hypertension , pre - gestational diabetes mellitus , pre - existing thrombophilia , multiple pregnancy , or prior preeclampsia . the criteria that define severe preeclampsia include blood pressure 160/110 mmhg , proteinuria 5 g/24 h , oliguria , lung edema , cerebral symptoms , epigastric pain , elevation of liver enzyme levels , microangiopathic hemolysis , thrombocytopenia , delayed fetal intrauterine growth , or oligohydramnios . the three most common visual complications of severe preeclampsia are hypertensive retinopathy , exudative retinal detachment and cortical blindness . cortical blindness refers to reduced vision from bilateral damage to any portion of the visual pathways posterior to the lateral geniculate nucleus . it occurs in up to 15% of preeclampsia and eclampsia . currently , there are two competing theories for the cause of cerebral edema . one theory is that cerebral vasospasm induced by severe hypertension results in cerebral ischemia , and consequently , cytotoxic edema . the second theory is that acute hypertension induces a loss of autoregulation , causing passive dilatation of cerebral arterioles , as well as an increase in vascular permeability , and consequently , vasogenic edema . to date , both vasogenic and cytotoxic edema have been observed in patients with cortical blindness . management of preeclamptic patients who develop cortical blindness is the same as for women without this visual complication . the goal of treatment of a patient with preeclampsia is to minimize organ damage and prevent the development of eclampsia while maximizing fetal viability . the decision to induce delivery or proceed conservatively with the aim of improving the prognosis of the neonate which depends on stage of pregnancy , fetal status , and clinical situation of the mother . corticoids are safe and effective in reducing neonatal complications in women with severe preeclampsia before week 34 of pregnancy . antihypertensive medication in women with preeclampsia and high blood pressure prevents cerebrovascular complications but does not change the course of the disease in women with mild preeclampsia . hydralazine , labetalol , and nifedipine are the drugs most recommended for the control of acute severe hypertension in women with preeclampsia . magnesium sulfate prophylaxis may be useful before and after delivery in some women with severe preeclampsia ; its benefits are not clear in women with mild preeclampsia . reported here , prompt diagnosis led to immediate energetic treatment of the factor that triggered the condition , arterial hypertension , and the condition resolved clinically with 14 days of aggressive antihypertensive management in the icu . in this clinical case , we found predisposing factors known to be associated with pres . the most common clinical presentation is new - onset seizures , encephalopathy , headache , and visual disturbances . there may be abnormalities of vision such as hemianopia , visual neglect and cortical blindness . this patient did not present seizure or changes in consciousness , which is not frequently reported in the literature . the syndrome may not be completely reversible , is not always limited to the posterior regions , and may involve gray as well as white matter . patients with an innocuous clinical picture may develop organ damage as a result of arterial hypertension .

the maternal and perinatal fetal prognosis of preeclampsia depends on the gestational age of the fetus at onset , the severity of the disease , the quality of care , and the presence of pre - existent medical conditions . one of the uncommon effects of severe preeclampsia on the eye is sudden loss of vision . the present case report is of a woman with severe preeclampsia exacerbated by delivery that coursed with difficult - to - control arterial hypertension and reversible cortical amaurosis without impaired consciousness or seizures .

some ectoparasites of hedgehogs such as ticks and fleas have zoonotic importance ( khaldi et al . hedgehogs may act as reservoir hosts for some diseases for instance salmonellosis , leptospirosis and pulmonary capilloriois ( mccarthy and moore 2000 , riley and chomel 2005 , marie et al . ticks and fleas are blood feeding arthropods that act as vector for transmitting many bacterial , viral , rickettsial and parasitic infection among both domestic and wild animals as well as between animals and humans ( mullen and ocanner 2002 ) . ticks are the most important ectoparasites affecting wild - life as they transmit many important diseases in the wildlife , among the livestock and humans ( mclean 2008 , castellaw et al . ticks are vectors carrying a number of diseases named tick - borne diseases including lyme disease , rocky mountain spotted fever , tick - borne meningoencephalitis , babesiosis and crimean - congo hemorrhagic fever ( cchf ) ( service 2012 ) . also several flaviviruses are transmitted by ixodes ticks , that cause encephalitis and haemorrhagic fever among humans ( capinera 2010 ) . ticks are common in eurasia and africa and are usually found in similar habitat to that of hedgehogs ( causey et al . hedgehogs are a frequent host of hard tick i. hexagonus ( gern et al . an enzootic transmission cycle of b. burgdorferi involving hedgehogs and i. hexagenus , another tick vector , has been described in urban environment ( gern et al . fleas such as ticks transmit many diseases to humans and animals , viral , bacterial , rickettsial and protozoal diseases , in addition some helminths are transmitted by fleas ( boris 2008 ) . fleas can transmit yersinia pestis , rickettsia typhy , r. felis , bartonella henselae , myxoma virus and some helminthic diseases , such as hymenolepis nana and dipylidium caninum ( tapeworms ) . rodents are predominant host and 74 % of fleas feed on rodents ( otranto and wall 2008 , capinera 2010 ) . the aim of our study was to detect the infestation rates of east hedgehogs ( erinaceus concolor ) with ticks and fleas in van province , eastern region of turkey . hadgehogs were captured between june and sebtember 2013 with the aid of spotlight nightly walks through parts of the study area . in order to estimate flea and tick infestation of hedgehogs , we immobilized the ectoparasites by polluting the body with a insecticide including trichlorphon ( neguvon-bayer ) . immobilized fleas were removed from the hedgehogs by gently shaking the animal over a sheet of paper and then all the fleas counted . we collected all ticks from hedgehogs and conserved them in 70 % ethanol for post identification . hadgehogs were captured between june and sebtember 2013 with the aid of spotlight nightly walks through parts of the study area . in order to estimate flea and tick infestation of hedgehogs , we immobilized the ectoparasites by polluting the body with a insecticide including trichlorphon ( neguvon-bayer ) . immobilized fleas were removed from the hedgehogs by gently shaking the animal over a sheet of paper and then all the fleas counted . we collected all ticks from hedgehogs and conserved them in 70 % ethanol for post identification . throughout the investigation , 60 ixodid ticks and 125 fleas in total were collected from 21 hedgehogs , collected seven hedgehoges each locality , from three different localities . all the collected ticks belonged to rhipicephalus turanicus species and all fleas belonged to archaeopsylla erinacei species ( fig . 1 , fig . 2 ) . other ectoparasites , apart from this kind of species , were not observed in this investigation . table 1 and table 2 shows localities where hedgehogs were obtained and the numbers and gender distribution of the fleas and ticks that were collected from these hedgehogs . a ) dorsal view of male rhipicephalus turanicus , b ) spiracular plate of male rhipicephalus turanicus , c ) dorsal view of female rhipicephalus turanicus , d ) spiracular plate of female rhipicephalus turanicus a ) female archaepsylla erinacei , b ) male archaepsylla erinacei , c ) , d ) adult ticks on the hedgehog locality names and numbers of hedgehogs numbers and gender distribution of fleas and ticks obtained from hedgehogs one of the most important arbovirus transmitted by ticks is crimean - congo hemorrhagic fever viruse ( cchfv ) believed to be survived mainly by hyalomma ixodid ticks in the nature . ticks and fleas are important vectors of several patogens and majority of this patogens are zoonotic . but cchfv has been isolated in nature among at least 30 tick species including i. ricinus , r. sanguineus , r. turanicus , r. bursa and dermacentor spp . adult of r. turanicus normally infest cattle , sheep and dogs in mediterranean region but it can also effect humans ( chochlakis et al . its immature forms generally infest hedgehogs , gerbils and murid rodents ( estrada - pea et al . rhipicephalus turanicus is a vector of q - fever and north asian tick typhus caused by rickettsia sibirica ( ioffe - uspensky et al . some studies performed on hedgehogs ticks , prevalence of r. turanicus infestation was detected respectively 67.70 % in urmia city and 5.26 % tabriz city of iran ( gorgani - firouzjaee et al . 2014 ) , and 77.80 % tokat city , central anatolia region of turkey ( bursali et al . rate of the tick infestation in present study ( 66.66% ) was detected approximately similar to studies of gorgani - firouzjaee et al . it is also hosted by cats and dogs other than hedgehogs and it may be transferred from hedgehogs through direct contact . human cases with fleabite eruption reported in some countries ( pomycal 1985 , naimer et al . prevalence of a. erinacei in hedgehogs was detected 55.90 % in iran , neighboring country of turkey ( gorgani - firouzjaee et al . we detected ticks ( r. turanicus ) and fleas ( a. erinacei ) in hedgehogs at fairly high rates . many ticks and fleas species may harbor on hedgehogs and transmit some tick - borne and flea - borne patogens . therefore , hedgehogs sharing the same habitates with humans in especially urban and suburban regions may be transmission of some tick - borne and flea - borne diseases from hedgehogs to humans . at least , hedgehogs ticks and fleas

background : ixodid ticks ( acari : ixodidae ) and fleas ( siphonaptera ) are the major vectors of pathogens threatening animals and human healths . the aim of our study was to detect the infestation rates of east hedgehogs ( erinaceus concolor ) with ticks and fleas in van province , eastern region of turkey.methods:we examined fleas and ticks infestation patterns in 21 hedgehogs , collected from three suburbs with the greater of number gardens . in order to estimate flea and tick infestation of hedgehogs , we immobilized the ectoparasites by treatment the body with a insecticide trichlorphon ( neguvon-bayer).results : on the hedgehogs , 60 ixodid ticks and 125 fleas were detected . all of the ixodid ticks were rhipicephalus turanicus and all of the fleas were archaeopsylla erinacei . infestation rate for ticks and fleas was detected 66.66 % and 100 % , respectively.conclusion:we detected ticks ( r. turanicus ) and fleas ( a. erinacei ) in hedgehogs at fairly high rates . since many ticks and fleas species may harbor on hedgehogs and transmit some tick - borne and flea - borne patogens , this results are the important in terms of veterinary and public health .

the estimated lifetime risk of osteoporosis is approximately 50% in women and 20% in men , making it one of the most commonly encountered conditions in primary care . the risk of death during the first year following a hip fracture is increased 3.17 times ( 95% confidence interval [ ci ] 1.35 , 7.42 ) , while the risk of death during the second year following vertebral fracture is increased 2.71 times ( 95% ci 1.12 , 6.57 ) . vitamin d plays a critical role in maintaining bone health and preventing fragility fractures [ 37 ] . lower serum vitamin d levels have been shown to be associated with decreased bone mineral density of the total hip and hip trochanter , increased risk of hip fracture in older men and women , and reduced response to bisphosphonate treatment in postmenopausal women with osteoporosis [ 69 ] . conversely , though a recent meta - analysis suggests there is no clear association between vitamin d supplementation and bone mineral density in patients without vitamin d deficiency , vitamin d supplementation has been shown to reduce the risk of nonvertebral and hip fracture in a dose - dependent manner . in accordance with these findings , it has been suggested that vitamin d may work through bone density - independent mechanisms to improve bone health . supplementation with vitamin d to increase serum 25-hydroxy vitamin d ( 25[oh]d ) levels is thus considered an integral part of osteoporosis therapy [ 1316 ] . despite the importance of vitamin d for bone health and recommendations for supplementation , there is some evidence to suggest vitamin d levels are frequently lower than the 75 nmol / l recommended in patients with osteoporosis by the osteoporosis canada and american association of clinical endocrinologists guidelines . for instance , in a study of 1536 north american women receiving osteoporosis therapy , serum 25(oh)d was less than 75 . however , there is limited information regarding how these data translate into clinical practice . this chart review initiative was undertaken to better understand how vitamin d levels are assessed and managed in canadian patients with osteoporosis . canadian physicians involved in the management of osteoporosis were invited by fax and e - mail to take part in this initiative . invitations were sent to 166 specialists , mainly rheumatologists , and 582 primary care practitioners from the canadian provinces of ontario and quebec . the physicians who accepted this invitation used either a secure online tool or paper forms to complete a practice profile questionnaire and profiles for each of approximately 20 patients in their practice who were being treated to prevent fractures and whom they had last seen between november 2008 and april 2009 ( see additional file 1 , practice profile form , and additional file 2 , patient profile form in supplementary material available online at http://dx.doi.org/10.1155/2015/312952 ) . information collected in the patient profiles included demographic data , bone mineral density ( bmd ) and other fracture risk factor information , availability and level of serum vitamin d measurements , current osteoporosis medications , and levels of calcium and vitamin d supplementation . participants were also asked to evaluate patients ' current regimens and detail any proposed changes . in order to maintain confidentiality , no identifying information ( e.g. , name , birth date , and postal code ) was collected . bivariate generalized estimating equations ( gee ) were used to investigate factors potentially associated with physician perception of satisfactory vitamin d levels and with suggested addition or dose increases of vitamin d supplementation . all variables associated with a p value of < 0.2 in the bivariate analyses were then included in multivariable gee analyses . the gee method was conducted to factor in the clustered nature of the data given that individuals managed by the same physician will be treated similarly . all analyses were performed with sas statistical software version 9.2 for windows ( sas , north carolina ) . this chart review initiative was designed and reviewed by the authors to ensure compliance with the world medical association declaration of helsinki regarding ethical principles for medical research . given the retrospective design and anonymous nature of the data collected , no approval from an official ethical review board was sought . of the 582 primary care practitioners invited to take part in this initiative , 36 primary care physicians agreed to participate , for a response rate of 6.4% . a total of 36 physicians ( 28 primary care practitioners and 8 specialists ) were from ontario , while the remaining 16 ( 8 primary care practitioners and 8 specialists ) were from quebec . most ( 78.8% , n / n = 41/52 ) of the participating physicians worked in an urban area and just over half ( 55.8% , n / n = 29/52 ) were in solo rather than a group practice . approximately 80% ( n / n = 42/52 ) had been practicing for over 20 years . the number of patient cases related to osteoporosis seen by the physicians each week varied greatly , with 30.8% ( n / n = 16/52 ) seeing 10 or fewer cases and 23.1% ( n = 12/52 ) seeing over 20 cases each week . profiles were completed for a total of 983 patients who were being treated for osteoporosis and who were last seen by participating physicians between november 2008 and april 2009 . as shown in table 1 , over 85% ( n / n = 863/983 ) of patients were female and 64% ( n / n = 626/983 ) were 60 to 79 years of age . mean bone mineral density ( bmd ) and the standard deviation ( sd ) based on most recent lowest t - score were 2.16 ( 1.55 ) . over a quarter of patients ( n / n = 272/983 ) had had a previous fragility fracture , including 38% ( n / n = 57/151 ) of those with bmd 1.0 and 27% ( n / n = 151/563 ) of those with bmd 2.5 . almost all patients had been receiving treatment for osteoporosis for over a year , as shown in table 1 . bisphosphonates , prescribed to nearly 80% ( n / n = 777/983 ) of patients , were the most commonly used pharmacotherapy and 85% ( n / n = 834/983 ) of patients were prescribed calcium and vitamin d supplements . most patients ( 77.2% , n / n = 759/983 ) received more than 600 mg / day of supplemental calcium , as seen in figure 1 . as shown in figure 1 , approximately half ( n / n = 495/983 ) of patients were prescribed 5600 iu per week of vitamin d supplementation , in accordance with osteoporosis canada recommendations . serum 25(oh)d levels were available in charts for 61.2% ( n / n = 602/983 ) of patients and were measured during the course of the initiative for a further 11.8% ( n / n = 116/983 ) of patients , meaning serum 25(oh)d levels were available for 73.0% ( n / n = 718/983 ) of patients . in those patients for whom measurements were available , the mean serum 25(oh)d level ( sd ) was 85.0 ( 29.0 ) nmol / l and approximately half of these patients had levels less than 80 nmol / l ( see figure 2 ) . over 60% ( n / n = 136/215 ) of patients prescribed less than 2800 iu / week of vitamin d had serum 25(oh)d levels less than 80 nmol / l , as compared to 46% ( n / n = 68/147 ) and 37% ( n / n = 133/356 ) of those prescribed 28005599 iu / week and at least 5600 iu / week , respectively ( see figure 3 ) . participating physicians evaluated the osteoporosis treatment regimens for 769 patients , 37% ( n / n = 287/769 ) of whom were considered to have unsatisfactory change in bmd and 37% ( n / n = 286/769 ) of whom were considered to have unsatisfactory just over half ( n / n = 162/287 ) of patients considered to have unsatisfactory vitamin d levels , as compared to 25% ( n / n = 124/482 ) of those with as shown in table 2 , multivariable gee analysis suggests that serum 25(oh)d level and body mass index were the only factors significantly associated with physicians ' perceptions of whether vitamin d levels were satisfactory . of the patients who were considered by physicians to have n = 294/411 ) were thought to require changes to their osteoporosis regimen ( see figure 4 ) . additional vitamin d supplementation was the most common change suggested , occurring in 78.3% ( n / n = 224/286 patients ) of these patients . physicians did not recommend increases in vitamin d supplementation in 46.9% ( n / n = 158/337 ) of patients with known serum 25(oh)d less than 80 nmol / l . based on multivariable gee analyses , suggested changes to vitamin d supplementation were significantly associated with a perception of unsatisfactory vitamin d levels . other suggested changes to osteoporosis therapy for the 294 thought to require changes included counselling regarding lifestyle modifications ( 40.8% ) , additional calcium supplementation ( 30.6% ) , changing medication to a bisphosphonate ( 21.4% ) , and increasing the dose of current medication ( 13.6% ) . in addition , 62.8% of the 385 patients for whom a question about combination therapy was answered were felt to possibly benefit from combination therapy with vitamin d. this chart review initiative found that a significant proportion of patients treated for osteoporosis in clinical practice have insufficient vitamin d levels , as approximately half of those with known serum 25(oh)d levels had a level less than 80 nmol / l , in many cases despite supplementation with at least 5600 iu of vitamin d per week . in addition , the facts that physicians did not recommend increases in vitamin d supplementation in nearly half of patients with serum 25(oh)d levels less than 80 nmol / l and that serum 25(oh)d level was not significantly associated with changes to vitamin d supplementation suggest that management of vitamin d levels may be a potential gap in practice . this finding is not surprising as , until recently , there has been little guidance for canadian physicians regarding how vitamin d levels should be monitored and measured in clinical practice . osteoporosis canada guidelines published in the fall of 2010 recommend serum 25(oh)d levels be measured in individuals with osteoporosis after three or four months of receiving adequate vitamin d supplementation to ensure levels are 75 however , earlier canadian osteoporosis recommendations did not provide guidance regarding whether vitamin d levels should be measured or what levels should be considered optimal [ 18 , 19 ] . conversely , more recently , several publications have suggested cut - off serum 25(oh)d levels of as low as 50 nmol / l might be adequate to promote optimal bone health [ 16 , 20 ] , though the 2011 us institute of medicine recommendations also cite > 75 nmol / l as the optimal level . in this regard , it should be noted that the 80 nmol / l threshold for vitamin d sufficiency used in this initiative reflects canadian reference values used prior to the publication of the osteoporosis canada guidelines . nmol / l ) seen in patients prescribed vitamin d supplementation may indicate that adherence to supplementation may be an issue for many patients . in fact , adherence to calcium and vitamin d supplements has been shown to be significantly poorer than for pharmacologic osteoporosis therapies , such as bisphosphonates . in an italian survey of 9851 postmenopausal women with osteoporosis , approximately half of women prescribed supplements took less than 80% of the prescribed supplementation pills , while about 20% of patients took less than half of the required pills and one in five patients discontinued use of supplementation within one year . such nonadherence might be one explanation for some of the low serum 25(od ) levels seen in patients prescribed supplementation . for instance , obese individuals often suffer from vitamin d inadequacy [ 23 , 24 ] , likely due to sequestration of fat - soluble vitamin d in body fat compartments and a resulting decrease in bioavailable vitamin d . in this context it is interesting that bmi was one of the two factors significantly associated with physician perception of vitamin d status in this initiative . however , no data on other conditions known to impact vitamin d absorption , such as intestinal malabsorption syndrome , were captured in the chart review process . other limitations of this study include the fact that participation was restricted to physicians in ontario and quebec and the low response rate . in addition , participating physicians were not instructed to select consecutive patients for chart review , thus creating the potential for patients to be selectively chosen . indeed , the high proportion of patients with serum 25(oh)d levels available in file may indicate a selection bias either towards physicians with a greater than average interest in monitoring vitamin d levels or towards patients considered at risk for low vitamin d levels in whom serum 25(oh)d might be more likely to be measured . although most physicians recommend calcium and vitamin d supplementation , vitamin d levels appear to be insufficient in half of patients , including over 40% of patients prescribed at least 2800 iu per week of vitamin d supplementation . this , when added to the fact that physicians did not recommend increases in vitamin d supplementation in nearly half of patients with known serum 25(oh)d less than 80 recent changes to the canadian osteoporosis guidelines clarifying when to measure serum vitamin d and what levels should be considered optimal may help promote monitoring of serum vitamin d status and adequate vitamin d supplementation . however , underlying causes of vitamin d insufficiency , including comorbidities and nonadherence , will also need to be addressed . the results underscore the importance of considering vitamin d status when looking to optimize bone health .

though vitamin d is important for bone health , little is known about the monitoring and management of vitamin d levels in patients with osteoporosis in clinical practice a deficit this chart review initiative aimed to remedy . a total of 52 physicians completed profiles for 983 patients being treated for osteoporosis between november 2008 and april 2009 . information collected included demographics ; fracture risk factors ; availability and level of serum vitamin d measurements ; and information on osteoporosis medications and calcium and vitamin d supplementation . physicians also evaluated patients ' current regimens and detailed proposed changes , if applicable . nearly 85% of patients were prescribed calcium and vitamin d supplements . serum 25-hydroxy vitamin d levels were available for 73% of patients . of these patients , approximately 50% had levels less than 80 nmol / l , which contrasts with the 37% thought to have unsatisfactory vitamin d levels based on physician perceptions . physicians felt 26% of patients would benefit from additional vitamin d supplementation . however , no changes to the osteoporosis regimen were suggested for 48% of patients perceived to have unsatisfactory vitamin d levels . the results underscore the importance of considering vitamin d status when looking to optimize bone health .

lack of suspicion , non - specific clinicoradiological presentation ( often mimicking tuberculosis and fungal infections ) , diagnostic intricacies , and lack of systematic reporting are the probable reasons that have hindered the true estimation of its incidence , worldwide . we present a case series of three patients of pulmonary nocardiosis , who had different clinicoradiological presentations and also responded differently to treatment . difficulties in their management have been discussed in light of the available literature that may help in improving disease management . in view of the rising incidence of cancer , organ transplant surgeries , and use of parenteral steroids , a 50-year - old female presented with complaints of breathlessness at rest , cough , and right - sided chest pain since 15 days . breathlessness was present since five years , for which she was on inhaled steroids and bronchodilators . she had completed successful anti - tubercular treatment ( att ) eight years ago and was again advised att for her current condition . on examination , she was tachypneic , with decreased intensity of breath sounds over the right hemithorax , and bilateral expiratory wheeze . hematological investigations revealed leukocytosis and neutrophilia and the values of the arterial blood gases showed type ii respiratory failure . on a chest radiograph , there was right - sided non - homogenous opacity involving all zones with air - fluid levels and left lung mid - zone infiltrates [ figure 1a ] . however , it revealed weak , acid - fast , filamentous bacilli resembling nocardia spp . the patient was started on two drugs , co - trimoxazole ( dose 40 mg / kg / day of sulfamethoxazole ) and amikacin ( sensitive to nocardia spp . ) . contrast - enhanced computed tomography ( cect ) of the thorax showed right lower lobe and left lingular necrotizing consolidation , with loculated hydropneumothorax [ figure 1c ] . , the patient developed pancytopenia , due to which , cotrimoxazole and linezolid were replaced with doxycycline . ensuring persistent improvement she successfully completed seven months of antibiotics with negative serial cultures and satisfactory clinicoradiological improvement [ figure 1d ] . ( a ) x - ray chest , pa view , showing non - homogenous opacity involving all zones on the right side and in the left para - hilar region ; ( b ) photomicrograph showing nocardia species ( black arrow ) stained with modified ziehl neelsen stain ( under 100 ) ; ( c ) axial cut section ct thorax showing a right - sided , loculated , hydropneumothorax and basilar necrotizing consolidation ; ( d ) x - ray chest pa view , showing clearing of shadows with residual fibrotic scarring over the left lung field a 72-year - old male , presented with a three - month history of progressive shortness of breath and productive cough . he had been on multiple courses of oral steroids for recurrent breathlessness , present for over five years . cect of the chest showed areas of necrotizing consolidation with a few cavitating nodules involving the upper lobe on both sides , with a background of emphysema [ figure 2 ] . on suspicion of pneumonia / tuberculosis , the sputum was subjected to microbiological tests and cytology , which was inconclusive . the patient was started on antibiotics , cotrimoxazole and linezolid ( 600 mg b.i.d . ) , along with oral steroids . however , he got readmitted after 12 days in emergency with complaints of loose stools and deranged consciousness . he had severe electrolyte imbalance , hyponatremia ( serum na : 111meq / l ) , and hypokalemia ( serum k : 1.7meq / l ) , and died due to sudden cardiac arrest . two axial cut sections of the ct thorax , with contrast showing patchy areas of necrotizing consolidation and few cavitating nodules a 42-year - old male smoker presented with cough , increased breathlessness , and high - grade fever since 20 days . the patient had been self - medicating with oral steroids for the last three years due to persistent breathlessness . the x - ray chest pa view and cect thorax showed bilateral mass - like consolidations with air bronchograms [ figure 3a and b ] . on suspicion for lung carcinoma / pneumonia , bal was performed , which showed the growth of nocardia spp . cotrimoxazole ( 40mg / kg / day of sulfamethoxazole ) and injection ceftriaxone 3 g / day were started and the steroids were continued in tapering doses . the patient completed six months of treatment with marked clinicoradiological improvement [ figure 3c ] . ( a ) x - ray chest , pa view , showing homogenous opacity involving all zones over the right hemothorax , as well as , over the mid and lower zones on the left side ; ( b ) axial section of the ct thorax below the carina showing three areas of mass - like consolidations , involving the bilateral hemothorax ; ( c ) x - ray chest , pa view , showing marked resolution of the opacities with residual fibrosis a 50-year - old female presented with complaints of breathlessness at rest , cough , and right - sided chest pain since 15 days . breathlessness was present since five years , for which she was on inhaled steroids and bronchodilators . she had completed successful anti - tubercular treatment ( att ) eight years ago and was again advised att for her current condition . on examination , she was tachypneic , with decreased intensity of breath sounds over the right hemithorax , and bilateral expiratory wheeze . hematological investigations revealed leukocytosis and neutrophilia and the values of the arterial blood gases showed type ii respiratory failure . on a chest radiograph , there was right - sided non - homogenous opacity involving all zones with air - fluid levels and left lung mid - zone infiltrates [ figure 1a ] . however , it revealed weak , acid - fast , filamentous bacilli resembling nocardia spp . the patient was started on two drugs , co - trimoxazole ( dose 40 mg / kg / day of sulfamethoxazole ) and amikacin ( sensitive to nocardia spp . ) . contrast - enhanced computed tomography ( cect ) of the thorax showed right lower lobe and left lingular necrotizing consolidation , with loculated hydropneumothorax [ figure 1c ] . , the patient developed pancytopenia , due to which , cotrimoxazole and linezolid were replaced with doxycycline . ensuring persistent improvement she successfully completed seven months of antibiotics with negative serial cultures and satisfactory clinicoradiological improvement [ figure 1d ] . ( a ) x - ray chest , pa view , showing non - homogenous opacity involving all zones on the right side and in the left para - hilar region ; ( b ) photomicrograph showing nocardia species ( black arrow ) stained with modified ziehl neelsen stain ( under 100 ) ; ( c ) axial cut section ct thorax showing a right - sided , loculated , hydropneumothorax and basilar necrotizing consolidation ; ( d ) x - ray chest pa view , showing clearing of shadows with residual fibrotic scarring over the left lung field a 72-year - old male , presented with a three - month history of progressive shortness of breath and productive cough . he had been on multiple courses of oral steroids for recurrent breathlessness , present for over five years . cect of the chest showed areas of necrotizing consolidation with a few cavitating nodules involving the upper lobe on both sides , with a background of emphysema [ figure 2 ] . on suspicion of pneumonia / tuberculosis , the patient was started on antibiotics , cotrimoxazole and linezolid ( 600 mg b.i.d . ) , along with oral steroids . however , he got readmitted after 12 days in emergency with complaints of loose stools and deranged consciousness . he had severe electrolyte imbalance , hyponatremia ( serum na : 111meq / l ) , and hypokalemia ( serum k : 1.7meq / l ) , and died due to sudden cardiac arrest . two axial cut sections of the ct thorax , with contrast showing patchy areas of necrotizing consolidation and few cavitating nodules a 42-year - old male smoker presented with cough , increased breathlessness , and high - grade fever since 20 days . the patient had been self - medicating with oral steroids for the last three years due to persistent breathlessness . the x - ray chest pa view and cect thorax showed bilateral mass - like consolidations with air bronchograms [ figure 3a and b ] . on suspicion for lung carcinoma / pneumonia , cotrimoxazole ( 40mg / kg / day of sulfamethoxazole ) and injection ceftriaxone 3 g / day were started and the steroids were continued in tapering doses . the patient completed six months of treatment with marked clinicoradiological improvement [ figure 3c ] . ( a ) x - ray chest , pa view , showing homogenous opacity involving all zones over the right hemothorax , as well as , over the mid and lower zones on the left side ; ( b ) axial section of the ct thorax below the carina showing three areas of mass - like consolidations , involving the bilateral hemothorax ; ( c ) x - ray chest , pa view , showing marked resolution of the opacities with residual fibrosis nocardiosis is caused by the aerobic , gram - positive filamentous bacteria of genus nocardia . a majority of the nocardia species responsible for respiratory and disseminated nocardiosis have been re - grouped as the nocardia asteroids complex . the existing literature from india is no better and merely consists of case series and a few case reports . lungs are the most common site of involvement and are affected in 70% of all cases of nocardiosis . the central nervous system ( cns ) , skin , and disseminated disease are other presentations , the likelihood of which depends on the individual 's immune status , time to diagnosis , and virulence of the nocardia species . all three patients in our series had isolated pulmonary involvement , as dictated by the absence of extrapulmonary symptoms . pulmonary nocardiosis usually affects patients with leukemia , human immunodeficiency virus ( hiv ) infection , organ transplantation , diabetes , or patients receiving prolonged corticosteroids . although unlikely , copd has been found as a predisposing factor in 23 - 70% of pulmonary nocardiosis . all patients in the series also had underlying airway disease consistent with chronic obstructive pulmonary disease ( copd ) and two of them had a history of prolonged steroid intake . however , it may be difficult to quantify the relative contribution of each factor in predisposing the disease . pulmonary nocardiosis may present as an acute , subacute or chronic disease , with remissions and exacerbations . symptoms include fever , cough , breathlessness , hemoptysis , and weight loss , which are often attributed to tuberculosis or community - acquired pneumonia . apart from these , nocardiosis may also mimic fungal pneumonia , anti - neutrophil cytoplasmic antibody ( anca)-associated vasculitis and lung cancer . nodules , necrotizing consolidation , cavities , and mass shadows are some of its varied but non - specific presentations . one patient in our series had a mass shadow mimicking carcinoma and the other two had non - specific consolidations . isolation and identification of the organism from the clinical specimens form the backbone for diagnosis of pulmonary nocardiosis . requirement for invasive sampling ( bal , biopsy ) , a slow growth , and varying degrees of acid fastness of the bacteria cause a hindrance to the microbiological confirmation . typically , nocardia are weak , acid - fast organisms , visualized by a modified ziehl - neelsen stain , using 1% sulfuric acid ( instead of 20% , which is used for tubercle bacilli ) . hence , the laboratory should always be notified about its suspicion so as to optimize recovery . moreover , isolation of the organism should be interpreted under the light of a relevant clinical background , as bacteria can also be isolated from colonized airways of apparently healthy individuals , like bronchiectasis . in the present series , species identification could not be done in our patients because of a lack of the requisite infrastructure . once confirmed , the extra - pulmonary spread of disease should be explored , if clinically indicated . owing to the paucity of prospective trials , there is a lack of standard treatment guidelines for pulmonary nocardiosis . in view of the difference in virulence and in vitro drug susceptibility of bacterial subtypes trimethoprim - sulfomethoxazole is the most common drug combination used , in a dose of 25 - 50 mg / kg per day of sulfamethoxazole , in divided doses . amikacin , imipenem , ceftriaxone , minocycline , levofloxacin , linezolid , and amoxicillin - clavulanic acid are the alternate drugs that have activity against nocardia . usually , the treatment is recommended for a total duration of six to twelve months , which may be prolonged in immunocompromised patients . two patients in our series were treated successfully with six and seven months of treatment , respectively , while one died during the course of treatment . the disease should always be considered in the differential diagnosis of pneumonia , not only in the immunocompromised , but also in the immunocompetent , especially when they are not responding to the standard therapy . in tuberculosis endemic countries like india ,

pulmonary nocardiosis is a rising bacterial infection , with a high propensity for misdiagnosis . on account of a paucity of prospective studies , there is limited understanding on various aspects of its diagnosis and treatment . we present three patients with pulmonary nocardiosis , with emphasis on the predisposing factors , variable disease course , and treatment issues . there is a need to understand the basis of these discrepancies so as to rationalize the management of this potentially fatal infection .

these neoplasms are classified from grade i to iv ( 1 , 2 ) . the who grading scheme is based on numerous pathological criteria including mitosis , cell morphology , atypia , endothelial proliferation and tumor necrosis . the prognosis varies dramatically from uncommon grade i ( pilocytic astrocytoma ) which is curable with surgery alone in most cases to the most common variant , grade iv ( glioblastoma ) which is usually incurable despite exploiting multi - modality treatments . the central brain tumor registry of the united states reported overall survival rate at 5 years for pilocytic astrocytom and fibrilary astrocytom around 94% and 48% respectively . in this report a retrospective study in the north - east of iran on 324 patients shows compatible results ( 4 ) . previous trials have investigated the effects of different factors that can influence the prognosis of these patients ( 1 , 2 ) . this study aimed to investigate treatment results and prognostic factors in patients with low grade and high grade astrocytoma separately in our centers in iran . this retrospective cohort study was performed on patients with brain astrocytoma who were referred to our oncology departments , between october 2000 and december 2011 . subjects less than 16 years of age and patients with insufficient data regarding their clinico - pathological characteristics , treatment and follow - up were excluded . surgical resection was considered in cases with removing more than 50% of lesion , while residual more than 50% of primary lesion ( based on lesion size on imaging ) was classified as biopsy . regarding the performance status , patients were classified into two groups of ambulatory and not ambulatory ( having major neurological deficit and/or karnofski performance status score of less than 60 ) . 415 patients with astrocytoma with a median age of 43 ( range ; 16 to 84 ) and a male to female ratio of 252:163 ( 1.54 ) were recorded . the median age for patients with low grade and high grade tumors was 33 ( range ; 16 - 74 ) and 50 ( range ; 16 - 84 ) respectively . from all cases , 40(9.6% ) were grade i , 88 ( 21% ) grade ii , 71 ( 17.1% ) grade iii and 216 ( 52% ) were grade iv . the tumor locations were as follows : 388 cerebral hemispheres ( 93.5% ) , 11 midbrain ( 2.7% ) , 3 pineal region ( 0.7% ) , 9 cerebellum ( 2.2% ) and 4 brainstem ( 1% ) . 131 patients ( 28% ) had a history of seizure . among patients with high grade and low grade astrocytoma , 284/287 ( 99% ) and 118/128 ( 92.2% ) were supratentorial respectively . 231 cases ( 55.7% ) were non - ambulatory which was significantly more frequent in patients with high grade than those with low grade tumors ( 60.6% vs. 44.5% , p = 0.002 ) . surgical resection had been performed in patients with grade i and ii tumors in 24/40 ( 60% ) and 55/88 ( 62.5 % ) of cases respectively . all cases had undergone radiation therapy with a median radiation dose of 54 gy ( 50 - 56 gy ) . among patients with high grade astrocytoma , 41/71 ( 57.7% ) with grade iii and 99/215 ( 46% ) with grade , 67 ( 94.4% ) and 198 ( 91.7% ) could complete their radiation therapy courses with a median dose of 58 gy ( range ; 45 to 60 gy ) and 46 ( 64.8% ) and 145 ( 67.8% ) cases had received adjuvant chemotherapy respectively . concurrent chemoradiation and adjuvant t chemotherapy with temozolomide was administered in 5 ( 7% ) of patients with grade iii and 29 ( 13.4% ) of patients with grade iv tumors 5-year overall survival in astrocytomas with grades i to iv were 90% 4.7% , 69% 5.5 % , 49.2% 6.6% and 14.4% 3% respectively . in patients with low - grade astrocytoma , with a median follow up time of 37 months ( ranging from 3 to 140 months ) , the rate of recurrence among grades i and ii was 4/40 ( 10% ) and 28/88 ( 31.8% ) respectively with a 5-year survival rate of 90% 4.7% , 69% 5.5 % . in these cases , tumor grade ( i vs. ii ) , being ambulatory ( p < 0.001 ) and performing optimal surgery ( p < meanwhile , age ( p = 0.3 ) and sex ( p = 0.4 ) were not associated with overall survival . multivariate analysis showed that tumor grade , performing optimal surgery and performance status were independent prognostic factors in these patients ( table 1 ) . in high grade gliomas , with a median follow up time of 13 months ( range ; 1 - 91 months ) , the number of documented recurrences among patients with grade iii and iv tumors was 33 ( 46.5% ) and 166 ( 76.6% ) respectively . grade ( grade iii vs. grade iv ) , age less than 50 ( p < 0.001 ) , being ambulatory ( p < 0.001 ) , performing optimal surgery ( p < 0.001 ) and receiving chemotherapy ( p = 0.02 ) were significantly associated with higher overall survival . in these patients , sex ( p = 0.8 ) was not correlated with overall survival . in patients with low - grade astrocytoma , with a median follow up time of 37 months ( ranging from 3 to 140 months ) , the rate of recurrence among grades i and ii was 4/40 ( 10% ) and 28/88 ( 31.8% ) respectively with a 5-year survival rate of 90% 4.7% , 69% 5.5 % . in these cases , tumor grade ( i vs. ii ) , being ambulatory ( p < 0.001 ) and performing optimal surgery ( p < meanwhile , age ( p = 0.3 ) and sex ( p = 0.4 ) were not associated with overall survival . multivariate analysis showed that tumor grade , performing optimal surgery and performance status were independent prognostic factors in these patients ( table 1 ) . in high grade gliomas , with a median follow up time of 13 months ( range ; 1 - 91 months ) , the number of documented recurrences among patients with grade iii and iv tumors was 33 ( 46.5% ) and 166 ( 76.6% ) respectively . grade ( grade iii vs. grade iv ) , age less than 50 ( p < 0.001 ) , being ambulatory ( p < 0.001 ) , performing optimal surgery ( p < 0.001 ) and receiving chemotherapy ( p = 0.02 ) were significantly associated with higher overall survival . in these patients , sex ( p = 0.8 ) was not correlated with overall survival . in this retrospective study , the most common histological type of astrocytoma in adult cases was glioblastoma astrocytoma . the median age for patients with malignant astrocytoma was higher as compared to cases with low grade tumors . however , we found a favorable outcome in these cases . in patients with low grade the importance of surgical resection has been proved in previous studies ( 5 - 9 ) . being non - ambulatory as having major neurological deficit and/or karnofsky performance status of less than 60% can be a reflection of larger tumors and probably bigger residual tumor following surgery . these factors have been shown to be unfavorable prognostic factors in the previous studies ( 7 , 10 , 11 ) . in a turkish study by durmaz et al . ( 12 ) , 53 patients with low - grade glial tumor were investigated between 1980 and 2006 . the efficacy of age , sex , location of tumor , the extent of resection , the presence of seizure , radiotherapy and performance status using karnofsky score were evaluated on survival rates of patients . there was not found a significant association between tumor location and overall survival ( p = 0.65 ) . in this study , survival rate was independently affected by the extent of resection ( p = 0.36 ) ( 12 ) . in the study by durmaz et al . ( 12 ) , overall survival was not associated with gender ( p = 0.19 ) . these findings were consistent with the present results that there was not an association between gender and overall survival ( 80 5 for men vs. 70 7 for women ) , ( p = 0.04 ) in durmaz et al.s study ( 12 ) , the patients were divided into two groups based on karnofsky performance score : patients who were scored 70 or less and patients who were scored over 70 that the patients with performance scores in durmaz s study , the survival values of the patients who were under the age of 40 were significantly better ( p = 0.02 ) . the median survival rate for the patients who were over the age of 40 was significantly ( 108 months ) better than that of the patients under the age of 40 ( 168 months ) . patients with performance status of over 70 survived longer than those with scores 70 or less ( p = 0.03 ) . ( 13 ) was undertaken on patients with low - grade tumors during 17 years follow - up . the patients who had performance scores higher than 70% survived longer than those with performance scores 70% or below ( p < 0.001 ) . in our series with malignant astrocytoma , patients with glioblastoma had a dire prognosis with a 5-year survival rate around 9% . as compatible with previous studies ( 14 , 15 ) , patients with grade iii astrocytoma had much better outcome with a 5-year survival of around 49% . the extent of surgical resection had also significant effect on survival in patients with high grade astrocytoma ( 14 - 20 ) . in a study by buckner ( 20 ) , the survival rate for the patients who were treated with biopsy was lower than that of the patients who underwent surgical resection . these results were compatible with the results of previous trials ( 14 , 15 , 19 - 21 ) . in the present study , patients with malignant astrocytoma who were younger than 50 had significantly better survival rate than older cases . more favorable results have been also shown in younger patients in previous studies ( 15 , 16 , 22 ) . the effect of adjuvant chemotherapy on survival in patients with high grade astrocytoma has been investigated in multiple trials . in a review article by stewart investigated the effects of radiotherapy and radiotherapy plus chemotherapy on survival values of patient with high - grade tumors . survival rate was significantly better in patients who were under chemotherapy plus radiotherapy treatment than patients who were under radiotherapy alone ( p < 0.001 ) ( 23 ) . based on the cox proportional - hazard analysis , age , receiving chemotherapy , surgery types and performance status were significant predictors of survival . performing optimal surgery and good performance status were associated with more favorable survival in both low and high grade astrocytomas . in high grade astrocytomas ,

backgroundastrocytomas are the most common primary adult brain tumors.objectivesin this study , we investigated the impact of some potential prognostic factors on survival in patients with low and high grade astrocytomas.patients and methodsthis retrospective cohort study was performed on patients with brain astrocytoma who were referred to oncology departments , omid and ghaem hospitals , mashhad university of medical sciences ( 2000 - 2011).results415 patients with a median age of 43 and a male to female ratio of 252:163 ( 1.54 ) were recorded . grade i to iv astrocytoma were found in 40 ( 9.6% ) , 88 ( 21.2% ) , 71 ( 17.1% ) and 216 ( 52% ) patients . with a median follow up time of 37 months for low grade and 13 months for high grade astrocytoma , the 5-year survival in grades i to iv was 92.1% , 69.1% , 49.2% and 9.6% respectively . in low grade astrocytomas , patients with grade i tumors , being ambulatory ( 5-year survival : 88% vs. 60.3% , p < 0.001 ) and performing optimal surgery ( 5-year survival 86% vs. 59.3% , p < 0.001 ) were associated with more favorable survival . in high grade astrocytomas , patients with grade iii tumors , age < 50 ( 5-year survival 29.6% vs. 14.6% , p < 0.001 ) , being ambulatory ( 5-year survival 39.4% vs. 10.5 , p < 0.001 ) , performing optimal surgery ( 5-year survival 46.1% vs. 4.3% , p < 0.001 ) and receiving chemotherapy ( 5-year survival 23.7% vs. 18.7% , p = 0.02 ) were associated with significantly higher overall survival.conclusionsperforming optimal surgery and good performance status were associated with more favorable survival in both low and high grade astrocytomas . in high grade a strocytomas , patients younger than 43 and those who received chemotherapy had better overall survival .

we for the first time reporting a case of ocd with redundant clothing as the primary manifestation of the disorder . the present case report is regarding a 15-year - old school - going girl , coming to the hospital with the complaint of wearing multiple layers of clothes at a time . on probing , she came with the explanation that the problem started 1 year ago , after she started moving closely with a senior boy in her school . since the boy was she started getting this thought again and again even during her routine tasks and failed to control it , even though she considered it to be irrational . to reduce the anxiety , she started wearing 4 - 5 layers of clothes , even during hot climate and would cover maximum part of her face with head scarf . she hid this clothing pattern from the knowledge of others but could not forego her parents notice . on further probing , she came out with other symptoms comprising washing , checking , repeating questions , fear of telling wrong , which were distressing to her , for the last 5 years . current unusual behaviour of redundant clothing compelled them to seek psychiatrist advice . she was treated with tab . psycho education was also given to alleviate anxiety of the patient and family . during the first follow - up after 2 weeks objectively , her children 's yale - brown obsessive compulsive scale ( y - bocs ) score dropped from 33 to 14 . redundant clothing is often noted in patients with psychotic illnesses . some have even cited it as an observable marker for diagnosing schizophrenia with hypothesis of dysfunctional central and peripheral thermoregulation as well as circadian rhythm , cognitive decline and antipsychotic use . present case is a clear cut manifestation of ocd with no signs of physiological / autonomic disturbance . the current case must encourage psychiatrists to restrain from diagnosing before evaluating the behavioural phenomenon .

this is a case report of a 15-year - old girl who presented with redundant clothing . on evaluation , it was found that she had obsessive compulsive disorder ( ocd ) , and redundant clothing was a symptom of ocd , which has hitherto not been reported .

with an incidence of 1 out of 3,500 live births , cystic fibrosis ( cf ) is the most common life - threatening autosomal recessive genetic disease in caucasian children . half of the affected patients show a deletion of a specific phenylalanine residue ( f508 ) , but the genotype - phenotype relationship is complex . it has been proposed that the strikingly high prevalence of this deleterious mutation could be due to a higher resistance to toxin - induced diarrhea or tuberculosis among heterozygotes . cf affects the gut and the pancreas ( exocrine pancreas insufficiency leads to malabsorption and failure to thrive ) , but for most cf patients , life expectancy is determined by the development of lung disease . the failure to clear thick and abundant mucous secretions from the lung leads to chronic coughing at a young age , followed by frequent lung infections , including repetitive episodes of pneumonia . however , for most cf patients , recurring lung infections finally lead to end - stage lung disease , which can be treated only with lung transplantation . the median survival age for cf patients small , slow - growing colony variants displaying antibiotic resistance , including methicillin - resistant s. aureus ( mrsa ) strains , are characteristically found . in early adolescence , the lungs typically become chronically infected with pseudomonas aeruginosa ; up to 80% of adult cf patients are colonized with this pathogen . nonmotile , anaerobic , mucoid variants of p. aeruginosa grow in a biofilm within the lungs , a structure that confers resistance to antimicrobials . since today s cf patients reach adulthood , still other facultative pathogens have a chance to enter the lung . bacteria of the burkholderia cepacia complex , for instance , are now recovered from 10% of the lungs in adult cf patients . burkholderia infections can transform a mild pulmonary case into a rapidly deteriorating lung infection associated with bacteremia and death within 6 months . even among patients with a less dramatic course , some surgeons consider burkholderia infections to be a contraindication for lung transplantation . in hospital settings , burkholderia - infected patients should be segregated from other cf patients to prevent nosocomial spread of the pathogen . since lung infections are the life - limiting factor for cf patients and since the major cf pathogens are increasingly difficult to treat with antibiotics , alternatives or adjuncts to antibiotics are urgently needed . the mbio article by colin hill and his colleagues ( 1 ) provides an encouraging outlook in this regard . the authors explored the possibility of treating p. aeruginosa infections with bacteriophages , an attractive potential therapeutic option for several reasons . first , s. aureus and p. aeruginosa are classical targets of the soviet phage therapy approach . the russian company microgen currently sells phage preparations against both pathogens , either singly or in combination , for treatment of pyogenic infections . second , it is relatively easy to isolate virulent ( as opposed to temperate ) phages against the three major pathogens of cf patients . large collections of phages of s. aureus , p. aeruginosa , and b. cepacia exist , many of which are fully sequenced . this is not a trivial statement , since phages are not isolated easily against any bacterial species . third , the aforementioned phages have a broad host range . unlike antibiotics , most phages are strain specific , making them targeted to the pathogen of interest and preventing collateral damage to commensal bacteria . however , this specificity can be a problem for treatment , and often a cocktail of different phages is needed to achieve a reasonable coverage of a given pathogenic species . fortunately , phages against cf pathogens have a good , if not an excellent , pathogen coverage . phage k , for instance , infects nearly half of s. aureus isolates from large collections , and phage stau2 infects 80% ( 2 ) . fourth , the efficacy of phage therapy approaches has been demonstrated in animal infection models with cf pathogens . for example , b. cenocepacia bacterial density in the lung was reduced after intraperitoneal but not intranasal phage application to mice . the lytic effect was specific to the replication - competent phages , since no lytic effect was seen with uv - inactivated phages or a phage that had no in vitro lytic activity against the infecting burkholderia strain . phages showed amplification in the lung and reduced pathogen - induced inflammation signs . in treated mice , phages were colocalized with degraded bacteria in perivascular lung areas and alveolar septa ( 3 ) . ( 1 ) provides suggestive evidence that bacteriophages might also be of use against p. aeruginosa infection . they showed that suitable phages can be isolated from sewage , a common starting material for phage isolation . by sequencing the phage , they demonstrated the absence of undesired genes in their therapeutic phages , an essential condition for later phage application in human subjects . finally , the authors demonstrated the efficacy of intranasally applied phages in a p. aeruginosa lung infection model using state - of - the - art imaging techniques ( although it should be noted that mice do not get chronically infected with p. aeruginosa , so biofilms are thus not formed in this transient infection model ) . mice treated with intranasal phage at a phage - to - bacterium ratio of 1:1 , but not with lower ratios , survived a lethal p. aeruginosa infection . ( 1 ) confirm previous observations from other groups and therefore represent important steps toward developing effective cf phage therapy . fittingly , work on phage therapy for p. aeruginosa infection continues at the pasteur institute in paris , where phages and phage therapy were first described by felix dherelle nearly 100 years ago . using bioluminescent p. aeruginosa , debarbieux et al . ( 4 ) demonstrated a rapid killing of bacteria in phage - treated animals and a reduction in inflammatory markers . the researchers selected phages which grew well on clinical p. aeruginosa isolates from cf patients and showed that they achieved dose - dependent protection in a mouse lung infection model ( 5 ) . phages showed in vivo replication , decreased the alveolar pathogen load , and prevented histopathologic lesions . phage treatment could be delayed for a few hours with the same results , and administering the phages a day before pathogen challenge also prevented the infection . when phages were administered to uninfected mice , they persisted for 5 days in the lung , suggesting the potential for preventive phage use . british researchers found that phages had bacteriocidal effects on pseudomonas in biofilms ( 6 ) . when using excess phages , a 100-fold bacterial titer decrease was observed . pseudomonas phages could also diffuse through 8% alginate gels , which mimic the conditions in pseudomonas biofilms . phage researchers from the republic of georgia and structural biologists subsequently showed that the depolymerizing enzyme is part of the phage particles ( 7 , 8) . researchers at the centers for disease control and prevention ( cdc ) in atlanta , ga , demonstrated that pretreating catheters with a cocktail of pseudomonas phages prevented biofilm formation . intact but not heat - killed phages achieved a 1,000-fold titer reduction of the bacteria in the biofilm grown on a catheter in the presence of human serum ( 9 ) . the latter observation is important , since in the transition from bench to bed , the devil is in the details . the lead authors of the alemayehu article observed this for themselves in earlier work , in which they explored the potential of s. aureus phages for treating bovine mastitis . in that study , they found that milk contained an inhibitory activity that inactivated the broad - host - range s. aureus phage k ( 10 ) , a fact that explains the observations from canadian researchers who failed to detect an in vivo inhibitory effect of phages on bovine mastitis . despite the setbacks with s. aureus phage use in farm animals three clinical trials that address pseudomonas infections in venous leg ulcers ( intralytix ) , burn patients ( belgian military ) ( 11 ) , and the outer ear canal ( causing diseases ranging from mild swimmer s ear to necrotizing otitis externa in diabetics and aids ) ( biocontrol , united kingdom ) have been registered . so far , no adverse effects of phage treatment have been observed . in a controlled phase ii clinical trial , 24 otitis externa patients received either a single small dose of pseudomonas phage cocktail or a placebo . the researchers found evidence for in vivo phage replication , a decrease in pseudomonas counts in some patients , and symptom amelioration in most of the treated patients ( 12 ) . one might criticize the study for its small size and for the fact that only patients with pseudomonas ear infection susceptible to the applied phage were enrolled , but the study set a standard for a detailed combined clinical , microbiological , and statistical evaluation of phage therapy approaches . the three senior authors of the mbio article ( 1 ) are members of phageworks , a phage solution company recently founded in cork , ireland , by scientists working in two important research organizations of the irish government : the teagasc food research centre and the alimentary pharmabiotic centre . the current study relies on years of research in the dairy field , but one hopes that the knowledge acquired in the food sector on practical aspects of phage research can eventually serve the biomedical research community and the development of therapeutic applications for phages as well . this reminds me of the words of louis pasteur , who wrote , there are similarities between the diseases of animals and humans and the diseases of beer and wine . looking beyond the fences of one s own professional specialization can lead to important cross - fertilization .

abstractin contrast to usual laboratory conditions , most bacteria in the human body grow in biofilms . encased in a structured matrix , many pathogens display heightened resistance to antibiotics . pseudomonas aeruginosa lung infections in cystic fibrosis patients represent a prime example of the clinical challenges that antibiotic resistance in biofilms can represent . in the march 6 , 2012 issue of mbio , colin hill and his colleagues report on experiments that add to the evidence that pseudomonas phages are a potential treatment option for these infections .

the reference laboratory for hepatitis e at the health protection agency s centre for infections reported 17 cases of non travel - associated hepatitis e in england and wales from 1996 through 2003 ( 5 ) . during 2004 , that laboratory and the other hepatitis e reference laboratory in birmingham received an increased number of samples for hev testing with a corresponding increase in numbers of hepatitis e cases diagnosed by testing for hev immunoglobulin ( ig ) m and igg by using elisas ( genelabs technologies inc , redwood city , ca , usa ) . these observations led to this study , the aims of which were to describe the epidemiology of hepatitis e in england and wales , estimate the number of non travel - associated cases , and identify risk factors for hev infection in indigenous cases . during 2005 , this number represented a substantial increase from 125 cases in 2003 and 150 in 2004 . information on the age groups and sex of all patients who received a diagnosis during 2003 , 2004 , and 2005 is shown in figure 1 . this figure shows a progressive increase in the number of acute cases of hepatitis e in older male patients over the period , and panel b demonstrates the overrepresentation of older men among those with established indigenous cases during 2005 compared with those who were known travelers . a ) age and sex distribution of acute hepatitis e patients , 20032005 ( n = 604 ) . b ) age , sex distribution , and travel associated with indigenous acute hepatitis e case - patients ( n = 143 ) . nr , not recorded . the travel history of the 329 patients is summarized in figure 2 . for 102 ( 31% ) patients , travel status was obtained for 44 additional patients through follow - up , and 33 patients who had not traveled outside the united kingdom were considered to be indigenous case - patients . twenty - three ( 70% ) indigenous case - patients were > 55 years of age , compared with 26 ( 24% ) of 110 travel - associated case - patients ; the median age was 65 years ( interquartile range [ iqr ] 5074 years ) and 41 years ( iqr 2954 ) ( p<0.0001 ) respectively . thirty - two of the indigenous case - patients ( 97% ) had caucasian names ( name classification was used as a proxy for ethnicity ) compared with 21 ( 19% ) of 110 travelers ( p<0.001 ) . * contact with hepatitis e patients who recently returned from hyperendemic countries ; 24-year - old woman infected with hev genotype 1 ; 45-year - old caucasian man who traveled to iraq . the number of indigenous hev infections was estimated for those with an unknown travel history by fitting a logistical regression model that used caucasian name and age as predictor variables . an estimated 67 ( 95% confidence interval 5875 ) of the 176 patients ( when the date of birth was known ) in this group acquired their infection in england and wales . twenty - eight indigenous case - patients were available for telephone interview in which a detailed structured questionnaire was used to identify potential risk factors over the 9-week period before illness . all patients were white , and 23 ( 82% ) were male , with a median age of 65 years . twenty ( 71% ) were referred from southern england and wales ; a similar proportion of interviewed patients lived at inland or coastal addresses , and a high proportion of patients lived in densely populated urban areas . no common risk factors were identified apart from 17 ( 60% ) owning pets . * n = 28 ; some respondents did not answer all questions , so not all cells add up to 28 . hev rna was detected in 14 of the 33 patients with indigenous hepatitis e , and all virus strains belonged to genotype 3 . all but one of the genotype 3 nucleotide sequences clustered with previously described strains from the united kingdom and europe . three distinct sequence groups were noted , but subsequent detailed analysis showed no correlation between these groups and geographic distribution or time , which indicated that a common source was unlikely . the number of hepatitis e cases diagnosed in england and wales began increasing substantially after 2004 . in 2005 , acute hepatitis e was diagnosed in 329 patients ; 33 of these definitely had acquired their infection in england and wales , and a further 67 were estimated to have acquired their infection there . these figures may nevertheless be an underestimation since we also found that a high proportion of clinicians do not test for hev unless the patient reports a recent history of travel to a disease - endemic area . this practice may be changing , and the progressive increase in the number of older patients with diagnoses of hepatitis e may reflect a greater awareness among clinicians . the demographic features of patients who acquired their infection in england and wales are striking . men infected with hev are more likely to access healthcare than women in both disease - hyperendemic and non disease - hyperendemic countries ( 5,10 ) . some researchers have suggested that risk factors for disease may be linked to male occupational or societal roles ( 2 ) . these unique demographic findings need to be emphasized to the medical community because older caucasian men may not be perceived as being at risk by physicians . the epidemiology of hepatitis e in non disease - endemic countries remains poorly understood , and the results from seroprevalence studies vary greatly , which suggests that commercially available serologic tests may not be reliable for population surveys on genotype 3 infections . despite in - depth telephone interviews , we did not identify a likely common source of infection , and genotyping data suggest multiple sources of exposure to hev . we found that 60% of patients reported owning pets , a higher proportion than the proportion of animal - owning households in the united kingdom for cats ( 25% ) and dogs ( 21% ) ( 11 ) . although this difference might just reflect the fact that pet ownership is higher among older persons , a high prevalence of anti - hev antibodies has been found among dogs in india ( 13 ) and cats in japan ( 14 ) , and a patient with hepatitis e from japan owned a pet cat who was positive for antibodies to hev ( 15 ) , all of which indicate that domestic animals may be a potential reservoir for infection . with the growing recognition of hepatitis e as an increasingly important zoonotic infection in england and wales , hev should be considered an etiologic agent of acute and fulminant hepatitis even in patients who report no travel history . we need to raise awareness among health professionals to consider hepatitis e when investigating non travel - associated cases of hepatitis .

in 2005 , 329 cases of hepatitis e virus infection were confirmed in england and wales ; 33 were confirmed indigenous infections , and a further 67 were estimated to be indigenous infections . hepatitis e should be considered in the investigation of patients with hepatitis even if they have no history of travel .

head and neck cancer is the sixth most common type of cancer in the world , representing about 6% of all cancer cases . worldwide , more than half a million head and neck cancer cases and 320,000 deaths due to head and neck cancer are estimated to occur each year , and it is the eighth cause of cancer mortality in the world . head and neck cancer has a higher incidence in older people , primarily due to its relationship with chronic exposure to tobacco smoking and alcohol drinking . fifty - seven per cent of all newly diagnosed malignancies and 71% of all cancer deaths occur in those 65 years of age . more than 40% of head and neck cancers occur in patients older than 65 years . with increasing life expectancy , it is estimated that by 2030 , nearly 70% of the cancer cases would be diagnosed in adults with age 65 years or older . in india , 30,831,190 males and 33,998,613 females are in the age group of 65 years and above , accounting for 5.5% of the nation s population . one of the most challenging tasks for the practicing oncologist today is the care of the elderly cancer patient . in recent years , management of cancer in elderly population has not been adequately addressed as these patients have often been under - represented in clinical trials of new cancer treatments and most clinical cancer trials have had arbitrary upper age limits . majority of elderly cancer patients are less likely to receive definitive or adequate cancer - directed therapy . this has been seen not only for head and neck cancers , but also for other common malignancies . advancing age may be associated with progressive loss of stress tolerance , decline in functional reserve of multiple organ systems , high prevalence of co - morbid conditions , limited socioeconomic support , reduced cognition , and higher prevalence of depression . however , aging is highly individualized , and chronologic age may not reflect the functional reserve and life expectancy of an individual . compliance of elderly patients to intensive multimodality cancer therapy can be challenging due to significant treatment - related toxicities , the logistical demands involved in treatments , and unplanned treatment gaps introduced between the treatments . all these factors can decrease treatment compliance and prolong overall treatment time , which is known to be a detriment to therapeutic outcomes to cancer directed therapy . the present study evaluated compliance of elderly hnscc to cancer - directed therapy . to our knowledge this study is one of the first studies evaluating compliance and overall treatment time of elderly hnscc patients to cancer - directed therapy from a developing nation . our study included a total of forty - seven elderly hnscc patients ( age 65 years or older ) referred for radiotherapy from the various multi - disciplinary clinics at our institute in one unit of department of radiotherapy from july 2010 to june 2011 . the patients were assessed per stage and site of the disease , general condition , performance status , and any pre - existing co - morbidities . for the purpose of study , compliance was defined as all patients who were able to complete the stipulated treatment as intended at the primary clinic . the key factors evaluated for compliance and overall treatment time included date of registration at cancer centre , radiotherapy registration date , surgery date , radiation start and completion date , and treatment completion date . compliance was evaluated with regard to age , stage , general condition , performance status , presence of co - morbidity , and intention of treatment . for possible factors affecting compliance , statistical analysis was done using stata 9.1 software , chi - square / fischer s exact test were used to see the strength association between the two categorical variables . for all compliant patients , overall treatment time was calculated from the day of initiation of cancer - directed therapy to completion of treatment . further , to study the pattern of non - compliance , patients were divided into early non - compliance ( patients that were non - compliant during the investigation and staging work up period ) , mid - course non - compliance ( patients non - compliant after complete diagnostic work up and treatment decision , but before radiation delivery ) , and late non - compliance ( patients non - compliant during radiation delivery ) . in this cohort of 47 patients , treatment decision taken at the multi - disciplinary clinic was for radical treatment in 68% ( 32/47 patients ) , whereas the remaining 32% ( 15/47 patients ) were planned to receive palliative treatment . radical treatment included either radical radiation with or without chemotherapy in 55% ( 26/47 ) of the patients or surgery followed by postoperative radiotherapy in 13% ( 6/47 ) of the patients . in this retrospective analysis , patient and treatment characteristics the salient features were that majority ( 42/47 ) of the elderly hnscc presented in loco - regionally advanced stage ( iii iv ) , the most common site of malignancy was oropharynx ( 21/47 ) , followed by oral cavity ( 11/47 ) , larynx ( 9/47 ) , and hypopharynx ( 6/47 ) . with regard to age distribution , 72% ( 34/47 ) of the patients were between the age group of 6574 years , whereas ( 13/47 ) 28% were 75 or older . general condition was fair in most of the elderly patients ( 38/47 ) ; only ( 5/47 ) of the elderly patients were in good general condition , while the remaining ( 4/47 ) were in poor general condition . out of the 47 elderly patients , analysis of compliance to treatment decision revealed that 62% ( 29/47 ) of the elderly hnscc patients were compliant to cancer - directed therapy , whereas 38% ( 18/47 ) of the patients were not able to complete the stipulated treatment . for all compliant patients , overall treatment time was calculated from the day of initiation of cancer directed therapy to completion of treatment . the median overall treatment time for patients subjected to radical radiation therapy was 52 ( range 4799 ) days , and for radical surgery and adjuvant radiotherapy was 109 ( 95190 ) days . twenty - two per cent of the elderly patients had one or more associated co - morbidities . factors affecting compliance and the association between the categorical variables using statistical analysis by chi - square / fischer exact test are mentioned in table 2 . compliance to treatment decreased as the stage of disease increased ( 80% for early stage versus 62% in loco - regionally advanced stage ) . compliance was better for elderly patients with good to fair general condition ( 63% ) versus 50% patients with poor general condition . fifty - seven per cent of the patients having one or more co - morbidity were compliant to treatment , whereas compliance increased to 63% when patients had no co - morbidity ( p value ns ) . compliance was similar with regard to intention of treatment ( radical 63% vs. palliative 60% ) , advancing age ( age group 6574years 62% vs. 75 or older 62% ) . a further analysis on pattern of non - compliance revealed that early non - compliance to therapy was seen in 5% ( 1/18 ) of the patients , whereas majority ( 14/18 ) of elderly patients showed mid - course non - compliance . only 17% ( 3/18 ) of the patients were non - compliant to treatment during the course of radiation delivery . non - compliance to treatment has been reported to determent all parameters of disease control and survival . the assessment of patients receiving definitive concurrent chemoradiation for either locally advanced or medically inoperable nsclc treated in rtog studies revealed that prolongation of ott was associated with significantly poorer survival , with a 2% increase in the risk of death for each day of treatment prolongation . interruptions more than one week during post - operative irradiation of breast cancer adversely affected overall survival in these patients . for head and neck cancer analysis of treatment compliance in all radiation therapy oncology group ( rtog ) prospective randomized trials between 1978 and 1991 , reported a significantly reduced three - year loco - regional control ( 13% vs. 27% ) and three - year absolute survival ( 13% vs. 26% ) in patients with prolongation of treatment by 14 days or more . similarly , numerous studies have demonstrated non - compliance to treatment protocols impedes local control of head and neck cancers . these studies describe a loss of local control of 0.4% to 2.9% for each day the treatment course is prolonged , with an average of 1.7% per day . a recent analysis of critical impact of radiotherapy compliance in treatment of advanced head and neck cancers , the trans - tasman radiation oncology group ( trog 02.02 ) trial , revealed that patients with major deficiencies in their treatment plans had a markedly inferior outcome(i.e . , for deviations versus compliance as regards the treatment results2 years overall survival 50% vs. 70% and freedom from loco - regional failure , 78% vs. 54% ) . head and neck squamous cell carcinoma may have geographical variation with regard to site and stage at presentation , treatment compliance , and survival . amidst the pre - existing geographical variation with inferior treatment compliance and survival in the asian population , compliance of elderly hnscc patients is of utmost importance , as advancing age may be construed ( i ) with progressive loss of stress tolerance , ( ii ) decline in functional reserve of multiple organ systems , ( iii ) high prevalence of co - morbid conditions , ( iv ) limited socioeconomic support , ( v ) reduced cognition , and ( vi ) higher prevalence of depression all of which may be the reasons for poor treatment compliance . in the present study , elderly hnscc patient compliance in our study is comparable to overall treatment compliance for hnscc patients previously reported from the subcontinent . overall treatment time was prolonged for patients subjected to radical surgery and adjuvant radiotherapy ( median ott 109 days ) , whereas there were no such delays for patients receiving radical radiotherapy ( median ott 52 days ) . elderly patients with cancer may often have other preexisting medical co - morbidities especially related to chronic exposure to tobacco smoke and alcohol . the secondary aim of the study was to see the burden of co - morbidities in elderly hnscc patients . associated co - morbidities were present in 23% of the elderly hnscc patients , and this burden of co - morbidity was less when compared to those reported in literature . presence of co - morbidity in these patients was associated with decreased compliance ; however , the difference in compliance was not statistically significant . similarly , the study did not find a statistical significant association of compliance with age , stage , performance condition , general condition , and intent of treatment . the factors influencing compliance is elderly patients remain complex and need to be further elucidated . the highlights of this study can be : the pattern of elderly hnscc patient non - compliance revealed that majority of the elderly patients ( 83% ) were non - compliant to treatment before the initiation of radiation therapy . this was a bit surprising result as elderly patients were expected to be non - compliant to treatment during the course of radiation therapy because of development of increased acute radiation morbidity , worsening of performance status , and poor tolerance.to our knowledge the present study is the first study to report early to mid - course non - compliance to cancer - directed therapy in elderly hnscc patients . as per available records , the reasons for this early to mid - course non - compliance finding the probable explanation could be a long median radiation waiting of two months at our cancer center , during which some elderly patients may have preferred early cancer - directed therapy at some other cancer centers . further the possibility of upstaging and disease progression during the radiation waiting period can not be ignored ( majority of the patients were already in a loco - regionally advanced stage ) . this aspect of early to mid - course non - compliance to cancer - directed treatment that emerged as predominant factor in our study needs to be further evaluated , especially in developing countries where there is much load on the available machines and where the cancer patient population has probably outnumbered the available resources . the pattern of elderly hnscc patient non - compliance revealed that majority of the elderly patients ( 83% ) were non - compliant to treatment before the initiation of radiation therapy . this was a bit surprising result as elderly patients were expected to be non - compliant to treatment during the course of radiation therapy because of development of increased acute radiation morbidity , worsening of performance status , and poor tolerance . to our knowledge the present study is the first study to report early to mid - course non - compliance to cancer - directed therapy in elderly hnscc patients . as per available records , the reasons for this early to mid - course non - compliance finding could not be evaluated . the probable explanation could be a long median radiation waiting of two months at our cancer center , during which some elderly patients may have preferred early cancer - directed therapy at some other cancer centers . further the possibility of upstaging and disease progression during the radiation waiting period can not be ignored ( majority of the patients were already in a loco - regionally advanced stage ) . this aspect of early to mid - course non - compliance to cancer - directed treatment that emerged as predominant factor in our study needs to be further evaluated , especially in developing countries where there is much load on the available machines and where the cancer patient population has probably outnumbered the available resources . limitations of our study include : retrospective nature of the study and small number of patients.in view of the retrospective nature of the study , all factors for non - compliance could not be elicited . other factors which could influence non - compliance and were not available include ( a ) poor socio - economic status , ( b ) lack of social or family support , ( c ) distance from the treatment centre.elderly patients were not subjected to comprehensive geriatric assessment before treatment decisions.while the medical record documented non - compliance , the underlying reasons behind non - compliance could not be determined . retrospective nature of the study and small number of patients . in view of the retrospective nature of the study other factors which could influence non - compliance and were not available include ( a ) poor socio - economic status , ( b ) lack of social or family support , ( c ) distance from the treatment centre . elderly patients were not subjected to comprehensive geriatric assessment before treatment decisions . while the medical record documented non - compliance , the underlying reasons behind non - compliance could not be determined . in recent years , the improvements in treatment modalities and techniques have made the delivery of cancer - directed therapy safe and feasible in elderly hnscc patients . non - compliance to treatment in these patients could pose an obstacle to delivery of effective health care . our findings from india in a small cohort of elderly hnscc patients showing the issues of early mid - course non - compliance pattern need to be evaluated further . a larger prospective study , performing a comprehensive geriatric assessment and evaluating the role of comprehensive interventions combining cognitive , behavioural , and affective components to improve compliance in elderly patients , is warranted .

backgroundtreatment compliance of elderly patients to intensive multi - modality cancer therapy can be challenging and has not been adequately addressed in developing countries . the present study evaluated compliance of elderly head and neck carcinomas patients to cancer - directed therapy.methodsforty-seven elderly hnscc patients were evaluated in the present study . patients were assessed as per stage and site of disease , general condition , performance status , and any pre - existing co - morbidities . compliance was defined as patients who were able to complete cancer therapy as intended at primary clinic . non - compliance to therapy was stratified as early , mid- and late - course non - compliance . statistical analysis was done using stata 9.1 software , chi - square / fischer s exact test to see strength of association between two categorical variables that could possibly affect compliance in elderly patients.resultssixty-eight per cent of elderly patients were subjected to radical treatment , majority ( 42/47 ) presented in loco - regionally advanced stage ( iii iv ) , most common site of malignancy was oropharynx ( 21/47 ) . sixty - two per cent of elderly hnscc patients were compliance to cancer therapy . median overall treatment time for patients subjected to radical radiation therapy was 52 ( range 4799 ) days , and for radical surgery and adjuvant radiotherapy was 109 ( 95190 ) days . compliance to therapy for elderly hnscc patients was not significantly associated with advanced stage , poor general condition , intent of treatment or presence of co - morbidity . as regards to non - compliance , majority ( 14/18 ) of elderly patients showed mid - course treatment non-compliance.conclusionsnearly two - thirds of elderly head and neck carcinoma patients were compliant to cancer - directed therapy .

, we conducted a retrospective study of bilateral disc swelling in patients at kitasato university s department of neuro - ophthalmology in an attempt to identify the etiology . using kitasato university s department of neuro - ophthalmology medical records and fundus photographs of the period december 1977 through november 2010 , we retrospectively identified 121 outpatients who had been initially confirmed with bilateral disc swelling . this study population consisted of 54 males and 67 females with an average age of 38.2 years ( range 276 years ) . we defined terms as follows : disc swelling was the collective term used to describe disc swelling or protrusion ; papillitis denoted optic neuritis with inflammatory findings on the optic disc such as swelling / redness or dilatation of the retinal vessels ; and papilledema indicated bilateral disc swelling with elevated intracranial pressure . the final diagnosis was judged by ophthalmologic examinations ( including light reflex of the pupil , visual acuity , visual field , critical flicker frequency , and fundus angiography ) and intracranial examinations by magnetic resonance imaging ( mri ) , magnetic resonance venography ( mrv ) , or computed tomography ( ct ) , and consultation with the kitasato university department of neurology or department of neurosurgery . in this study cohort , the most common etiology of bilateral disc swelling was increased intracranial pressure ( icp ) ( 59% ) ; followed by pseudopapillitis ( 16% ) ; uveitis ( 8% ) ; hypertensive retinopathy ( 5% ) ; bilateral neuritis , acute disseminated encephalomyelitis ( adem ) and optic disc drusen ( all at 2% ) ; and leukemia ( 1% ) . unknown etiology accounted for the remaining 6% ( figure 1 ) . when examining the etiology according to patient age group ( eg , 020 years , 2150 years , and 51 years ) , increased icp was found to be the most frequently - appearing condition . in the 020 patient age group , which constituted the smallest age demographic ( 27/121 ) , increased icp and pseudopapillitis were present in the vast majority of patients presenting with bilateral disc swelling . in the 2150 age group , which contained the majority of the patients ( 62/121 ) , an increased icp was the leading cause of bilateral disc swelling , followed by pseudopapillitis , uveitis , and hypertensive retinopathy . a larger number of etiologies were found in the 2150 group than in the 020 group . there were 32 patients in the 51 group who exhibited similar etiologies to the 2150 group , despite the group containing around half the number of patients ( table 1 ) . the most common etiology responsible for the increased icp ( n=72 ) was brain tumor ( 32 patients ; 44.4% ) , followed by cerebral hemorrhage , chronic subdural hematoma , cerebral venous sinus thrombosis ( cvst ) , and other cardiovascular diseases . a form of osteodystrophy known as craniosynostosis was also observed in a few rare cases ( table 2 ) . although characterized by the absence of intracranial space occupying lesions , idiopathic intracranial hypertension ( iih ) was also included in the intracranial event category due to its clinical feature of increased intracranial pressure . categorization of brain tumors in the patients revealed nine metastatic brain tumors and 22 primary brain tumors . the most common type of tumor was meningioma ( n=7 ) followed by astrocytoma ( n=5 ) , glioma ( n=3 ) , glioblastoma ( n=3 ) , acoustic neurinoma ( n=2 ) , olfactory neuroepithelioma ( n=1 ) , pineal tumor ( n=1 ) , and choroid plexus papilloma ( n=1 ) . the tumors occurred most frequently in the frontal lobe followed by the cerebellum ( table 3 ) . the most common primary cancer site among the nine subjects with metastatic brain tumors was lung ( n=4 ) ( table 4 ) . although brain tumors and other forms of increased icp are mainly diagnosed by mri or ct , some conditions may involve elevated icp despite normal imaging findings . these conditions can include iih and cvst , each of which accounted for 6.9% of increased icp in our present study ( table 2 ) . the etiology for three of these patients included a form of nephrotic syndrome , antiphospholipid syndrome and systemic lupus erythematosus . after mri confirmed the absence of intracranial lesions , the results of lumbar puncture demonstrated that all patients had noticeably elevated cerebrospinal fluid pressure ( table 6 ) . koyanagi harada disease , with the majority having redness and swelling of the optic nerves in both eyes as well as inflammation of the anterior chamber , macular edema , and serous retinal detachment ( table 7 ) . in terms of visual performance , the group of patients diagnosed with corrected distance visual acuity ( cdva ) ( 0.05 logmar [ logarithm of the minimum angle of resolution ] ) at the first consultation had pseudopapillitis , adem , optic disc drusen and leukemia , while the group with cdva ( 0.2 > logmar > 0.05 ) had increased icp and an unknown etiology . the group with cdva ( logmar 0.2 ) had uveitis , hypertensive retinopathy , and idiopathic optic neuritis , the latter of which was characterized by significantly reduced flicker values relative to the other diseases ( table 8) . we studied the etiology of patients initially confirmed with bilateral disc swelling . increased icp accounted for approximately 60% of the etiology while the remaining etiology was non - increased icp diseases . although many medical texts list the etiology of bilateral disc swelling , there have been no recently published studies that have listed the percentages of each etiology recorded at hospitals and clinics . therefore , we compared our current findings to two studies that were published in 1971 and 1984 , respectively.1,2 results of this comparison indicated that increased icp was the most common etiology observed at each study site , with optic neuritis , adem , and optic disc drusen only seen at our facility . it is possible , however , that these other studies may have intentionally excluded optic neuritis , among other etiologies . on the other hand , anemia , lead poisoning and thyroid ophthalmology were not observed within our department , but were seen at the other study sites ( table 9 ) . thyroid ophthalmology appears to have been excluded from the scope of our study , as it would have initially been classified at our facility as thyroid ophthalmology or compressive optic neuropathy , rather than bilateral disc swelling . walsh and hoyt s clinical neuro - ophthalmology3 includes a description of the frequency of onset of bilateral disc swelling in various diseases . specifically , papilledema was observed at the following frequencies : brain tumor , 80% ; subdural hematoma , 50% ; acute cerebral abscess , seven of 26 cases ; chronic cerebral abscess , 15 of 23 cases ; subarachnoid hemorrhage , 16% or 10%24% ; meningitis , 2.5% of 2,178 cases or 12 of 530 cases ; viral encephalitis , 19% of 68 cases ; and craniostenosis , 15% of 171 cases . intra cranial pressure was elevated in 13 of 14 cerebral arteriovenous malformation patients , but disc swelling was only observed in three . with the exception of cerebral arteriovenous malformation ( avm ) and encephalitis , all the diseases described above were seen in the results of the present study . in children , optic neuritis is typically bilateral.4,5 although our study found two adult patients with bilateral optic neuritis , the current study identified no children who presented with this condition . however , bilateral optic neuritis occurred in 13 children admitted to our hospital for treatment between 1999 and 2010.6 this was thought to be because only subjects with bilateral disc swelling were targeted in this study , and the disease name listed for these patients from the beginning was bilateral optic neuritis . with regard to funduscopic differentiation between true optic disc edema ( disc swelling ) and pseudo optic disc edema ( pseudopapillitis ) , carta et al7 describe that peripapillary retinal folds seem to be related exclusively to optic disc edema . in our study , the diagnosis of pseudopapillitis was done with all normal patient indications of light reflex , visual acuity , critical frequency , and visual field . one disease that typically involves elevated icp despite normal ct or mri findings is cvst . thus , combining mrv with these standard imaging modalities would be useful when attempting to diagnose this condition . mrv can be used to confirm venous filling defects because it enables clear visualization of the major intracranial veins and cranial sinus without the use of a contrast agent.8 de bruijn et al9 reported finding papilledema in 23 of 56 cvst patients ( 41% ) , with poor outcomes observed in those patients who presented with intracerebral hemorrhage or with some degree of impaired consciousness . although previous studies have asserted that behet s disease is complicated by cvst10,11 and al - fahad et al12 reported finding papilledema in eleven of 40 patients with neuro - behet s disease ( 25.7% ) , none of the cvst patients in the present study had behet s disease ( table 5 ) . another representative disease that leads to intracranial hypertension , although general ct and mri may appear normal , is iih . this condition is generally said to occur commonly among obese women of reproductive age,13 but has also been reported in children and individuals aged 40 years.1416 thus , caution is warranted when examining patients over a wide range of age groups . although follow - up may prove difficult in pediatric patients due to the inability to examine cerebrospinal fluid on a regular basis , several recent studies have determined that optical coherence tomography ( oct ) may be an effective future modality for determining intracranial pressure via measurement of the retinal thickness.1719 headache has also been reported to be a frequent symptom of intracranial pressure.20 even so , a study by de simone et al21 described cases in which no headaches were present , suggesting the need for caution on the part of the diagnosing physician . furthermore , in a study on iih and cvst by lin et al22 106 patients diagnosed with iih were further examined by mrv , which resulted in the discovery of cvst in ten of the patients ( 9.4% ) . daif et al23 used angiography to examine cases previously diagnosed with iih and reported finding 19 of 40 patients had cvst . these findings indicate that , when diagnosing iih , it is essential to use mrv or other imaging techniques to rule out the possibility of cvst . the most common etiology for bilateral disc swelling is intracranial pressure , but it can also be triggered by a variety of other causes . in studies of japanese patients , pseudopapillitis is the most important differentiating disease . when attempting to diagnose the etiology of bilateral disc swelling , patients should be immediately examined for the possible influence of other diseases which increase intracranial pressure .

purposeto investigate the etiology of bilateral disc swelling in japanese.methodsusing kitasato university s department of neuro - ophthalmology medical records and fundus photographs of the period december 1977 through november 2010 , we retrospectively identified 121 outpatients who had been initially confirmed with bilateral disc swelling.resultsthe most common cause of the bilateral disc swelling was increased intracranial pressure ( icp ) ( 59% ) ; followed by pseudopapillitis ( 16% ) ; uveitis ( 8% ) ; hypertensive retinopathy ( 5% ) ; bilateral optic neuritis , acute disseminated encephalomyelitis ( adem ) and optic disc drusen ( all at 2% each ) ; and leukemia ( 1% ) . unknown etiology accounted for 6% of the cases.conclusionalthough increased icp is the most common etiology for bilateral disc swelling , it can also be triggered by a variety of other causes . pseudopapillitis is the most important progenitor of bilateral disc swelling in japanese .

nonalcoholic fatty liver disease ( nafld ) is acknowledged as a ( public ) health issue with an estimated prevalence of 30% in adults , of which approximately 25% progresses to nonalcoholic steatohepatitis ( nash ) . sedentary lifestyle and high - fat and high - caloric dietary intake are strongly associated with nafld and nonalcoholic steatohepatitis ( nash ) . nafld and nash occur not only in adults but also increasingly in childhood [ 35 ] , accounting for a tremendous economic health burden . the pathways of nafld / nash and their alcohol - induced counterpart diseases are multifactorial , involving the liver metabolism key players : cytokines , adipokines , and apoptosis . alternative tools such as ultrasound or magnetic resonance imaging ( mri ) are becoming common in clinical routine ; anyway in nafld / nash diagnostics liver biopsy still remains the golden standard [ 9 , 10 ] . in the context of personalized medicine , the research on biomarker to identify nafld and its development and progression is high priority for clinical routine . our systematic data analysis of nafld research conducted in the last year , based on evaluation of extensive literature search , provided an overview of the most commonly published potential biomarkers for nafld . we performed an extensive literature assessment to evaluate known and novel biomarkers for progression and prognosis of nash / nafld . in this context , we extracted and evaluated cohorts and parameters and consolidated scientific findings from the literature . we limited our keywords to nafld or nash , 2010 , 2011 , accounting for a total of 1,833 articles , 1,517 articles from pubmed and 316 articles from isi web of knowledge ( figure 1 ) . cohorts meeting the selection criteria were included : english language;human subjects;adults;cohort size > 60 subjects;sufficient and reliable data;good scientific practice;positive plausibility proof;balanced grouping;proven diagnosis ( was not performed by an invasive liver biopsy at all studies).those cohorts not meeting the criteria were nevertheless scanned for potential parameters . studies with cohorts below 60 subjects and presenting rare parameters such as potential biomarkers ( e.g. , ferritin , adiponectin , or rarely documented diabetic probands of nafld studies ) and meeting all other criteria were included . cohort size > 60 subjects ; sufficient and reliable data ; good scientific practice ; positive plausibility proof ; proven diagnosis ( was not performed by an invasive liver biopsy at all studies ) . we transferred the cohorts of included studies in our subtypes ' classification according to the definitions listed in table 1 . data - analysis approach is based on several requirements including studies with paired controls and balanced cohort size . the plots require an identical statistical summary measure , which means either using only the mean or only the median and requires the standard deviation known to derive confidence intervals . the information on deviations ranges or standard deviations ( sd ) proved not to be useful for further analysis and was omitted . to analyze a larger set of publications and to overcome limits of balanced cohort size , we included studies that had no paired control and pooled cohorts in several studies to ensure a comparable set . the extracted mean values are displayed in boxplots by exploratory data analysis ( eda ) and show median and 25 and 75 percentiles . mann - whitney test was applied to compare the values between diseased and control groups ; kruskal - wallis test was used to compare subjects of more than two groups . statistical analysis was performed in r version 2.13.1 ( r foundation for statistical computing , vienna , austria ) . p values < 0.05 were considered statistically significant . though a graphical representation of a small number of observations can be performed , finally , we used boxplots to visualize the measurements in arithmetic mean and the comparison between disease and relevant control groups . based on the inclusion criteria , we comprised 62 studies , accounting for 157 cohorts and 45,228 subjects . including gender was impossible because most studies showed no gender separation , but fulfilled all required criteria . the noteworthy results are summarized in figures 2 , 3 , 4 , and 5 . the 62 included studies are listed in table 2 and depicted results of different parameters given in arithmetic mean ( 75.8% ) , in median ( 11.3% ) or mixed in mean and median ( 12.8% ) . in our scope of evaluation , we focused on the analysis of ( 1 ) available data , ( 2 ) significant results , and ( 3 ) potential use of parameters . our data analysis considered conventional parameters such as bmi , age , and systolic and diastolic blood pressure ( figure 2 ) . the bmi results of the healthy control group ( 1 ) were significantly lower than those of different disease groups , whereby the bmi appeared also significantly lower in ( 1 ) control group than in the related nafld - nash group ( p value : 7.8 10 ) . likewise , a significant bmi difference occurred between the diabetic group ( 3 ) and its control group ( p value : 1.48 10 ) . the results of age showed that the subjects of the ( 1 ) nafld - nash group ( p value : 4.6 10 ) and similarly of the ( 3 ) dm group ( p value : 2.1 10 ) were significantly older in comparison to their control groups . the results of blood pressure depicted in the different groups demonstrated an increase of systolic ( sbp ) and diastolic blood pressure ( dbp ) with the degree of nafld , displaying significant differences between ( 1 ) nafld - nash and the relevant ( 1 ) control group ( p value at sbp : 1.4 10 and p value at dbp : 4.0 10 ) . lipid status included total cholesterol ( tc ) , low - density lipoprotein ( ldl ) , high - density lipoprotein ( hdl ) , and triglycerides ( tg ) ( figure 3 ) displayed significant differences only between ( 1 ) nafld - nash group and the ( 1 ) control group ( p value at tc : 2.4 10 , p value at ldl : 4.0 10 , and p value at hdl : 2.6 10 ) . merely , triglycerides showed significantly higher levels in the ( 1 ) nafld - nash group ( p value : 8.8 10 ) and in the ( 3 ) dm group ( p value 1.17 10 ) as compared to respective control groups . we analyzed traditional liver parameters aspartate transaminase ( ast ) , alanine aminotransferase ( alt ) , ast / alt ratio , and the fasting blood glucose ( fbg ) ( figure 4 ) . significant differences of alt levels occurred in the ( 1 ) nafld - nash group ( p value : 2.3 10 ) , the ( 2 ) nash ( p value : 3.37 10 ) , and the ( 3 ) dm ( p value : 9.3 10 ) as compared to control groups . ast levels displayed a significant difference between ( 1 ) nafld - nash group and the ( 1 ) control group ( p value : 1.8 10 ) . fbg levels demonstrated significant differences in the ( 1 ) nafld - nash group ( p value : 2.6 10 ) and the ( 3 ) dm group ( p value : 2.53 10 ) compared to their relevant control groups . finally , we considered serum uric acid ( sua ) and serum ferritin as potential novel biomarkers for nafld diagnostics ( figure 5 ) . the ( 3 ) dm group and respective ( 3 ) control were eliminated due to inconsistent data . both , sua and serum ferritin were significantly different between the ( 1 ) nafld - nash and the ( 1 ) control group ( p value at sua : 4.6 10 and p value at serum ferritin : 6.9 10 ) . despite of the huge amount of assessed data from 157 cohorts , our data analysis mostly revealed the already known and in clinical routine implemented results . first : our results demonstrated that no individual biomarkers are path - breaking , but a composition of biomarkers / biomarker grouping may be successful in clinical detection of nafld and its progression . our analysis lies in ( 1 ) its scope of literature review , ( 2 ) the magnitude of cohorts included , ( 3 ) the number of parameters collected , and ( 4 ) its global approach [ 1230 , 4183 ] . second : overall , europe [ 1222 ] presented smaller cohorts than usa [ 23 , 24 ] and asia [ 2530 ] , due to larger population size and no geographical boundaries . third : the selected parameters included standard nafld / nash parameters such as liver enzymes and lipid profile . bmi and blood pressure were significantly lower in healthy control groups than in the disease group , which similarly confirmed the existing results . furthermore , the results substantiate the theory of previous studies that the risk of nafld increases along with overweight and advanced age . differences of ldl between nafld subjects and their healthy control group as well as between diabetic subjects and their control group are lower than expected . in contrast , hdl levels of both the nafld healthy control group and the diabetic healthy control group are significantly higher as compared to their disease groups . this suggests a lower hdl level on the basis of disordered liver metabolism by nafld . furthermore , the triglyceride level of nafld subjects was significantly higher than that of healthy controls . this may be the result of ( a ) reduced formation of vldl and a disordered beta - oxidation , leading to lower ldl levels than expected , despite an increased triglyceride level , ( b ) triglyceride level of diabetic subjects is significantly higher than that of the nafld - nash subjects ( p value : 2.04 10 ) and suggests the effect of insulin resistance on triglyceride metabolism by increased adipolysis . in contrast , ast and alt were increased by nafld , but diabetic subjects presented no pathological ast and alt elevation as the healthy group . our data analysis of alt , ast , and fbg showed an increase attributable to the degree of nafld . fourth : parameters such as c - reactive protein ( crp ) , procollagen , or hyaluronic acid may not qualify as single biomarker because of their ubiquitary presence . serum uric acid ( sua ) differed significantly between the ( 1 ) healthy control and both liver disease groups . this finding supports the theory that patients with liver disease often receive diuretics or suffer from hepatic - renal syndrome , which both may lead to reduced renal sua elimination and increased sua levels . an association between nafld and sua is most plausible explained through the two - hit theory , which suggests that fat accumulation in hepatocytes presents the first hit and leads to an increased vulnerability of liver . insulin resistance plays a crucial role in this vicious circle , which promotes lipolysis of the peripheral adipose tissue and increases the influx of free fatty acids into the liver . this insulin resistance leads to hyperinsulinemia , which increases the synthesis of uric acid and decreases its renal excretion . although high levels of uric acid were a consequence of metabolic disorders , but it does not lead direct to nafld . other recent studies showed that serum uric acid is independently associated with nafld presence and development . furthermore , a possible gender effect can influence the development and progression of nafld and studies showed that the incidence of nafld increases after menopause . ferritin results showed a significant difference between the ( 1 ) healthy control and the ( 1 ) nafld - nash group . this may be explained by inflammation leading to a serum ferritin increase due to macrophages ' redistribution and by liver tissue damage due to macrophages redistribution . the increased serum ferritin level may serve as independent predictor of liver damage in patients with nafld and is useable to identify patients at risk for nash and fibrosis [ 35 , 36 ] . recent studies suggest the possibility of utilizing serum ck-18 and ferritin levels together to distinguish nash from nafld . recent studies showed that mrna , protein expression , and the serum concentration of fetuin - a were increased in nafld patients . the gene expression of fetuin - a seems to be coregulated with key factors in the glucose and lipid metabolism . furthermore , the oral antidiabetic metformin was able to decrease the fetuin - a level . gamma - glutamyl transpeptidase ( ggt ) was found rarely documented and could not be considered . though the traditional parameter results did not reveal surprising findings , they confirm the impact of lifestyle . during our search on biomarkers we noticed , between the period of april to september 2011 , a doubling of publications on nafld / nash from 1,500 to over 3,000 articles in pubmed . despite these tremendous research efforts , our findings did not display clinical innovation . the results also confirmed that at this point there is no one single biomarker detecting or differentiating nafld . thus , our analysis suggests coordinated , standardized scientific research and the need for a collective look at biomarker groups and their link along with lifestyle , nutrition , exercise , genetics , and other factors . the topic of nafld / nash is so complex and interdisciplinary that there is much space for further research in nafld development and its process of diagnosing , treatment , and prevention . in addition , our findings suggest the necessity of harmonized data acquisition and publishing as well as data visualization in meta - analyses for an effective nafld biomarker identification for future clinical practicability .

background . nonalcoholic fatty liver disease is now acknowledged as a complex public health issue linked to sedentary lifestyle , obesity , and related disorders like type 2 diabetes and metabolic syndrome . aims . we aimed to retrieve its trends out of the huge amount of published data . therefore , we conducted an extensive literature search to identify possible biomarker and/or biomarker combinations by retrospectively assessing and evaluating common and novel biomarkers to predict progression and prognosis of obesity related liver diseases . methodology . we analyzed finally 62 articles accounting for 157 cohorts and 45,288 subjects . results . despite the various approaches , most cohorts were considerably small and rarely comparable . also , we found that the same standard parameters were measured rather than novel biomarkers . diagnostics approaches appeared incomparable . conclusions . further collaborative investigations on harmonizing ways of data acquisition and identifying such biomarkers for clinical use are necessary to yield sufficient significant results of potential biomarkers .

hydroxypropylmethylcellulose ( hpmc ) k4 m and ethyl cellulose ( ec ) were purchased from qualikems pvt ltd . hpmc k4 m polymer was used as hydrophilic matrix forming agent while solution of hydrophobic polymer ec in ethanol was used as granulating agent . 32 full factorial design was applied to the experiment and total 9 batches of 500 mg tablets were formulated . the two independent factors selected were concentration of matrix forming agent ( x1 ) and concentration of solution of granulating agent ( x2 ) . the dependent variables considered , to optimize the tablets were hardness , % friability and in vitro drug dissolution profile . the granules prepared were evaluated for flow properties and the compressed tablets were evaluated for hardness , % friability , drug content uniformity , weight variation and in vitro dissolution profile . results of all the parameters are mentioned along with the standard deviation in table 2 . it can be seen from the result that granules have flow properties within the range of good flow properties and therefore the blends are suitable for wet granulation . tablets of each formula were sufficiently hard that they all passed the test of friability . results of in vitro drug dissolution showed that as the concentration of the hpmc k4 m increases , release of drug is retarted ; moreover the increase in concentration of ec solution further retarded the release and so , zero order release could be achieved . the sustained release matrix tablets of captopril , prepared by wet granulation method , showed acceptable pre - compression properties , post compression properties and satisfactory drug release up to 24 hrs in controlled manner . the multiple regression analysis of the results led to be equations that describe adequately the influence of the selected variables , concentration of hpmc k4 m and concentration of ec in ethanol on the responses under study . the check point analysis led to the optimum values ( x1 at + 1 and x2 at 0 level i.e. formula f6 ) of the factors at which the produced tablets showed drug release up to 24 hrs in controlled manner .

sustained release matrix tablet is a delivery system by which the drug can be delivered at a controlled rate for long period of time . the present study aims at formulation , evaluation and optimization of captopril matrix tablets . a 32 full factorial design was adopted and all 9 batches were prepared by wet granulation method . prepared granules and tablets were evaluated for precompression and postcompression characteristics respectively . check point analysis was applied to the observations and the formula of the tablet was optimized . optimized formula , f6 showed zero order drug release kinetics for the time period of 24 hours i.e. 17.55% release at the end of 2 hours , 53.4% release at the end of 12 hours and 100.24% release at the end of 24 hours . the results revealed that concentration of matrix forming agent and solution of granulating agent significantly affected in vitro drug release profile .

traumatic injuries related to muscles and tendons of the shoulder girdle are common among athletes ; however , injury to the latissimus dorsi ( ld ) muscle is quite rare . in this case report , we will present acute traumatic tear of the ld muscle close to the myotendinous junction in a female track and field athlete ( 100 m hurdler ) . ld tears related to a sports activity have been reported in rock climbers , rodeo steer wrestlers , golfers , skiers , body builders , baseball players , tennis players , gymnasts , volleyball and basketball players ; but , extensive literature search has not revealed any track athletes . this is the first ld tear ever reported in a track athlete . unlike other cases , ultrasound ( us ) was used to depict the ld tear in detail and the tear was managed non - surgically in a conservative manner . the patient was a 27-year old female elite track and field athlete ( 100 m hurdler ) who has been competing for the last 10 years in many games , including the olympic games . she felt contraction around the right axillary region during a weight - training workout ( snatch ) and a week later , she felt sudden tearing pain after a vigorous start from the crouched position in the blocks . pain , ecchymosis and swelling at the axilla were the most apparent complaints when she visited a physician 4 days later . however her symptoms continued and she was referred to sports medicine department of a tertiary medical center with the presumptive diagnosis of axillary lymphadenopathy 6 weeks after the injury . a soft tissue swelling ( 35 cm ) with a gap in the mid portion and ecchymosis along the right posterolateral axillary region was noted on physical examination ( figure 1 ) . us revealed a complete ( 17 mm long ) tear of ld muscle close to the myotendinous junction on the right axillary region . ld muscle is a large fan - shaped muscle that covers the whole posterolateral aspect of the trunk . the fan - shaped edge originates from multiple sites such as the thoracic , lumbar and sacral spinous processes and the iliac crest then tapers superiorly to insert as a single long tendon to the intertubercular groove of the humerus . therefore , injuries often occur close to the insertion site ( figure 3 ) . in our case , a mild grade i muscle sprain to ld , which occurred during snatch exercises , most likely predisposed the muscle to consequent tearing injury . the actual tear ( grade ii ) occurred later when the patient was trying to generate power to run from the crouched position in the block by pushing her trunk forcibly forward while arms were extended , adducted and fixed on the ground . similar mechanisms were described for slam - dunking in basketball and vaulting in gymnastics . on the basis of patient preference , a conservative approach was preferred rather than surgery ; because competitions were close and requiring immediate treatment plan . presence of an intramuscular tear in an auxiliary muscle , not actively and dominantly involved in running , increased the likelihood of a successful conservative treatment . this was a late admittance case in which 6 weeks had already passed from the time of initial injury ; therefore classic physical treatment modalities [ protection , rest , ice , compression and elevation ( price ) ] were not closely followed . three - plane shoulder range of motion ( rom ) exercises were initiated ( 10 - 15 times 2 sets per day ) . within a week , complaints subsided , rom was full and movements were pain free . the patient resumed full athletic activity after two weeks of treatment , which made 8 weeks in total after the initial injury . the patient did not have any complaint in the follow - up exam 6 weeks later . latissimus dorsi muscle is one of the largest and strongest muscles of the back , having the main function of adduction , internal rotation and extension of the shoulder . the muscle is used to pull the trunk up or to lift or to pull an object forcefully towards the body and it is these exercises that render the muscle prone to traumatic injuries combined with overtraining , incompetent technique and inadequate rehabilitation . ld is used widely as a free flap for reconstructive surgery and a mild decrease ( a decrease of approximately 15 - 25% ) in strength is noted if harvested in the normal population . most probably , injuries to ld muscle are either misdiagnosed or neglected due to lack of serious functional disturbance and problems . but in elite athletes of competitive sports , such mild decreases of strength may become important . the main difference of our case from others is that this is an intramuscular tear close to the myotendinious junction in a field / track athlete . myotendinous junction involvement has been reported by parks et al . in a tennis player . tears involving the muscle belly are quite rare , reported in a series of traumatic injuries related to baseball and as a complication of anterior spinal surgery . intramuscular tears tend to respond well to conservative treatment whereas surgery is often reserved for tears involving the tendon , for complete tears and avulsions in elite athletes ; however , case series suggest that conservative treatment may also be a successful option in this setting . whether ld muscle is actively involved or not , as in pitchers , also affects the recovery and indications for surgery . ld is often an auxiliary muscle working synergistically with teres major , posterior muscles of the deltoid and long head of triceps brachii . spinner et al . reported an ld and teres major muscle tendon tear in a 38-year old golf player that eventually resumed full activity in one month with conservative treatment . butterwick reported a steer wrestler who resumed to competition successfully after two weeks of conservative treatment involving exercises and immobilization . in two separate case series consisting of 10 patients with teres major and latissimus dorsi injuries , including elite baseball pitchers , successful recoveries were reported with a conservative treatment of approximately 2 to 3 months . henry and scerpella et al . reported an acute traumatic avulsion tear of ld muscle tendon in a water skier who returned to sports activities within 6 months after surgery . return to physical activity tends to take longer time after surgery ( 4 - 6 months ) in comparison to the conservative treatment ( 1 - 3 months ) . outcomes of surgical and nonsurgical management are both good . surgical treatment may be opted in patients when full recovery of muscle function is intended and if the patient is willing to devote time to surgery and rehabilitation away from activities . in our case , the patient opted for conservative treatment including anti - inflammatory , analgesic management and physical therapy . most ld tears present a burning sensation and axillary pain along the posteromedial region of the arm , lasting for days . generally , trauma and a shearing sensation are present and injury mechanism has sudden and forceful resisted arm adduction . hurdling technique in athletics requires a strong pull down of contralateral arm of leading leg . starting from the block , a strong - arm action provides inertia for an effective forward rush and ld muscle plays an important role in both actions . anderson et al . have analyzed 5 cases with us , between the years 1998 - 2002 , which were perceived as sarcoma or as a lymphadenopathy as in our case . magnetic resonance imaging is widely used to diagnose ld rupture , has a larger field of view ( fov ) , can better differentiate the teres major and ld tendons from each other , may better depict avulsion injuries with large bone fragments and may also rule out bone edema , tumors of the humerus or scapula ( osteosarcoma or osteoid osteoma ) or additional injuries on the shoulder girdle . us is a useful diagnostic tool in the imaging of soft tissue anatomy , especially for tears and hematomas and it allows dynamic imaging while it is highly operator - dependent with a relatively small fov . ld tears may occasionally be seen in track / field athletes and may go unrecognized . conservative treatment is quite successful especially if ld maintains auxiliary function and if the tear is intramuscular .

soft tissue injuries constitute 30 - 50% of all sports related injuries ; however , injury to the latissimus dorsi muscle is quite rare with only a few cases reported in the literature . herein , we describe an acute traumatic tear of the latissimus dorsi muscle in an elite track athlete , which has not been reported in the track and field sports before . the injury was caused by forceful resisted arm adduction that took place at hurdling and starting from the block . a pseudotumor appearance in the axillary region was misdiagnosed as a mass . the diagnosis was made by ultrasound alone and the patient was managed conservatively .

an osteoid osteoma is a solitary , benign bone tumour , most commonly seen in the long bones of the lower extremities of patients in the second and third decade . patients often present with increasing pain , pain at night with pain relief by use of nonsteroidal anti - inflammatory drugs ( nsaids ) . when an osteoid osteoma is located intraarticular , it may cause swelling , joint effusion or decreased range of motion . besides the clinical characteristics , an osteoid osteoma may have a clear radiological feature , in 85% of cases , there is a small lytic nidus surrounded by reactive bone sclerosis on computer tomography ( ct ) . an osteoid osteoma of the acetabulum is rare ( 0.5% ) [ 7 , 14 ] and difficult to diagnose . in recent literature , we found six case reports of arthroscopic removal of an osteoid osteoma of the acetabulum [ 1 , 4 , 8 , 9 ] . a 20-year - old man visited the outpatient clinic with increasing groin pain on the right side 1 year after a high - speed traffic accident . physical examination revealed a healthy young man with antalgic gait and a stiff right hip with a predominant endorotation position . an additional mri scan showed bone oedema of the acetabulum and femoral head ( fig . 1 ) . at this stage , the possible diagnoses were transient osteoporosis of the hip joint , osteonecrosis , stress fracture ( dashboard trauma ) , infection or a bone tumour . the subsequent ct scan showed a small sclerotic lesion in the acetabulum . with this information , the lesion is also visible on the mri , just underneath the cartilage ( juxta - articular ) . because of this localization , the osteoid osteoma might cause a weak spot ( locus minoris resistentiae ) in the cartilage and might progress to an osteochondric lesion.fig . 1mr arthrogram with gadolinium , a axial view , b coronal view , c sagittal view mr arthrogram with gadolinium , a axial view , b coronal view , c sagittal view radio frequent ablation of the osteoid osteoma with close approximation cartilage was not an option , because this would not treat the osteochondric lesion . in our experience , the open surgical procedure with dislocation of the femoral head has a higher chance of complications than the arthroscopic one . routine hip arthroscopy was performed on the extension table . the femoral head , labrum and acetabulum were without abnormalities . we found a soft spot in the acetabulum just anterior of the fovea of the acetabulum . the cavity that remained was cleaned with curette , and micro - fracturing was performed with a chondropick . after the operation , no further imaging was performed , due to the lack of symptoms . the most important finding of the present report was that an osteoid osteoma of the acetabulum can be treated by arthroscopy . another advantage of the arthroscopy is the possibility of subsequent micro - fracturing of the remaining lesion . as shown in this case report of a juxta - articular located osteoid osteoma , presentation is often atypical and might mimic intraarticular pathology [ 11 , 13 , 18 ] . delayed treatment of a juxta - articular osteoid osteoma may cause secondary osteoarthritic changes [ 12 , 16 ] or make the patient become medically retired at a young age . we were also on the wrong track by first requesting for an mri scan . in our case , the ct scan eventually showed the characteristics of an osteoid osteoma , and after this , a lesion was also observed on the mri scan . ct scan remains the modality of choice but the scan of an osteoid osteoma on a juxta - articular location may not always have such clear features as in the long bones , there may be complete absence of sclerosis . although the mri was not helpful in making the diagnosis , in later stage , it was of great help in locating the nidus close to the cartilage . in recent literature , different treatment options for osteoid osteoma are described such as : open surgical excision , percutaneous ct - guided resection and ct - guided radio frequent ablation [ 2 , 5 , 10 , 14 , 15 , 17 ] . because of the location of the osteoid osteoma close to the cartilage , we decided to perform an arthroscopy to remove the nidus and also for treatment of the overlying chondral lesion . though for adequate pain control , the full nidus has to be removed in total [ 3 , 17 ] ; this could be a disadvantage of arthroscopic removal . the advantages of arthroscopy are lesser surgical approach , evaluation and treatment of the cartilage defect . disadvantages of the technique are failure of arthroscopic approach , possibility of nerve injury and incomplete excision of the lesion or nidus . although an mri is not the diagnostic tool of first choice , it is helpful in describing the relation of the nidus to the articular cartilage .

in this case report , we describe the arthroscopic removal of an osteoid osteoma from the acetabulum in a young adolescent . after identifying the osteoid osteoma close to the cartilage with mri and ct investigations , we decided that in this case , arthroscopic removal was the best treatment . in the case of an osteoid osteoma in the acetabulum close to the cartilage , arthroscopic removal should be considered as one can treat the associated osteochondritic lesion during this procedure.level of evidence iv .

solitary fibrous tumour ( sft ) is a rare mesenchymal neoplasm , first described in 1931 by klempere and robin in a patient with a distinctive pleural lesion as a mesothelial tumour arising from the pleura . sft is distinguished into two entities , pleural and extra pleural . in the thoracic cavity , they are usually asymptomatic and discovered incidentally on a routine x - ray of the chest or during check - up for other abnormalities . extra pleural sfts are observed in middle - aged adults ( median age 50 years ) and affect both sexes equally ( male : female = 1:1.2 ) . in recent years , increased interests for this type of tumour led to its recognition in a large number of extra thoracic sites , including the meninges , orbit , upper respiratory tract , salivary glands , thyroid , peritoneum , liver , retro - peritoneum and pelvis , adrenal gland , kidney , spermatic cord , urinary bladder , prostate , uterine cervix , spinal cord , periosteum and soft tissues . clinically , it is generally a slow - growing , painless , well - delineated exophytic mass ; large tumours can cause compressive symptoms and rarely paraneoplastic syndromes ( i.e. hypoglycemia secondary to insulin - like growth factor ) . the dimensions of sft can vary from 1 to 25 cm in diameter . like pleural sfts , extra - thoracic sfts usually have a benign prognosis , however , a small number of cases with atypical histological features has been reported to develop local recurrence or metastasis . in july 2007 , a 63-year - old white woman referred to a first - level hospital for a palpable lesion in correspondence of right gluteus . she had not fever neither pain , but only a swollen area in perianal region . she was submitted to ultrasounds ( us ) , that showed an hypervascularized swelling that was interpreted as a voluminous hematoma ( size 13 10 cm , thickness 45 cm ) , partially organized in the context of muscular structures of right gluteus ( fig . 1 ) . after antibiotic therapy without any size regression , the patient was submitted to a computed tomography ( ct ) of abdomen and pelvis . figure 1:the abdominal ultrasound ( us ) shows an ovoid swelling , misinterpreted as a partially organized hematoma in the contest of the right gluteus maximus muscle . the abdominal ultrasound ( us ) shows an ovoid swelling , misinterpreted as a partially organized hematoma in the contest of the right gluteus maximus muscle . ct showed an hyperintense and inhomogeneous solid lesion taking up the right ischiorectal fossa ( maximum diameter of about 10 cm ) , extended cranially until impressing the wall of the rectal ampulla , with no apparent infiltration ( figs 2 and 3 ) . the lesion presented an intense contrast enhancement , sign of a rich vascularization ( fig . 4 ) . figure 2:the ct scan demonstrates a solid neoformation in the right ischiorectal fossa . figure 3:the lesion extends cranially until impressing the wall of the rectal ampulla , with no apparent infiltration . the lesion extends cranially until impressing the wall of the rectal ampulla , with no apparent infiltration . the lesion was in close proximity of elevator ani muscle and lateral rectal wall , that were not macroscopically infiltrated . the lesion area was marked with surgical clips because of the close proximity with rectal wall , for eventual post - operative chemotherapy or radiotherapy and for follow - up . surgical specimen was an oval , soft tissue mass of 11 7.5 5.5 cm in size , capsulated , hyper - vascularized , with a inhomogeneous aspect , multi - lobed ( fig . microscopically , the tumour was composed by a proliferation of spindle cells crossed by stromal collagen and giant plurinucleate cells . the patient was discharged home on fifth post - operative day , and she did not receive any further therapy . in december 2008 , she presented an hypo - dermal recurrence in the same area demonstrated with ct - scan ( fig . after 1 year , a magnetic resonance ( mri ) demonstrated the surgical scar without sign of recurrence . after a 7-years follow - up the patient is still alive , without any clinical or radiological evidence of recurrence , she did not need any chemotherapeutic or radiotherapeutic treatment . figure 10:the ct scan demonstrates an hypodermal recurrence of the lesion in the side of resection marked with a metallic clip . the ct scan demonstrates an hypodermal recurrence of the lesion in the side of resection marked with a metallic clip . the histological appearance of sfts may overlap with other benign and malignant diagnostic entities , such as hemangiopericytoma , leiomyoma , nodular fasciitis , inflammatory myofibroblastic tumour , fibromatosis and benign peripheral nerve sheet tumour . in the past , sfts were considered rare tumours originated from mesothelial cells . this has been recently proved using immunohistochemical analysis , particularly positive staining for cd34 and bcl-2 is an indication of sft . usually , microscopic features are the presence of relatively spindled cell set in variably collagenous , cellular and in some cases myxoid matrix . an hemangiopericitoma - like vascular pattern in seen at least focally in most cases . mitotic activity is low ( < 23 mitoses/10 hpf , high - power fields ) in most cases , but some tumours show overtly sarcomatous features with a high mitotic activity . malignant sfts are characterized by large tumour size ( more than 50 mm ) , infiltrative margins , greater cellularity with an infiltrative growth pattern , moderate to marked cellular atypia , and high mitotic activity ( > 4 mitotic cells/10 hpf , high - power fields ) [ 5 , 6 ] . the tumour is difficult to detect because it has no typical radiologic features : on x - ray it appears as a moderately radio - opaque mass , on us as a nodule with generally well - defined borders and an homogenous echo - structure . however , clinical findings , mri and us are not sufficient for a definitive diagnosis . in this case report , the lesion appears like a voluminous hyper - vascularized hematoma , but patient 's anamnesis was negative for traumatic events . patient 's anamnesis took distant from an inflammatory process , because the patient had not fever or leukocytosis . ct scan and mri usually reveal a well defined capsule surrounding an homogenous mass with progressive enhancement from the arterial to venous phase and occasionally multiple small non - enhancing portions . positron emission tomography ( pet ) may be helpful to distinguish between a malignant and a benign variant of the tumour , but the gold standard for diagnosis remains the incisional biopsy . systemic symptoms such as hypoglycemia , arthralgia , osteoarthritis and clubbing have also been reported . lesions located in mediastinum , abdomen , pelvis or retroperitoneum are usually more aggressive than those in the limbs . surgery is considered the first choice of treatment and the use of chemotherapy is reserved to metastatic or symptomatic and non - resectable sfts , but there are no standard chemotherapeutic regimens . generally , to avoid recurrences a local wide resection of these tumours may be recommended .

solitary fibrous tumour ( sft ) is a rare benign tumour that occurs most frequently in the pleura . it is considered rare in soft tissues . we report a case of a middle - aged woman that presented a solitary fibrous tumor of gluteus . the tumour was composed of mesenchymal spindle - shaped cells positive for cd34 and bcl-2 . although rare , sft should be included in the differential diagnosis of mesenchymal soft tissue tumours . the clinical presentation and imaging can be helpful for a better pre - operative diagnosis .

aggressive angiomyxoma ( aa ) is a rare benign soft tissue tumour usually affecting the pelvis and perineum of young women . magnetic resonance imaging ( mri ) is crucial in the management of aa patients for its diagnostic contribution and for the preoperative assessment of the actual tumour extension . given the current development of less aggressive therapeutics associated with a higher risk of recurrence , close follow - up with mri is fundamental after treatment . in this context , diffusion - weighted ( dw ) imaging has already shown high efficacy in the detection of early small relapses in prostate or rectal cancer . we report here a case of pelvic aa in a 51-year - old woman examined with dynamic contrast enhancement and dw - mri , including apparent diffusion coefficient mapping and calculation . to our knowledge , this is the first description of dw - mri in aa reported in the literature . here , aggressive angiomyxoma ( aa ) is a benign soft tissue tumour with myxoid and vascular components that arises mostly in the lower pelvis and perineum in women of reproductive age . most of them ( > 90% ) occurred in young women , usually in the second to fourth decade . the risks of local extension and postoperative local relapse justify surgical excision of the tumour . imaging and particularly magnetic resonance imaging ( mri ) are fundamental for the clinical management of aa . precise preoperative assessment of local extension is crucial to plan the best surgical approach for tumour removal involving as little mutilation as possible . mri allows the monitoring of the response to possible preoperative treatment such as hormone therapy . finally , it is also crucial during the patient 's follow - up after initial treatment . for a few years now , classical mri coupled with diffusion - weighted ( dw ) sequences has developed in oncology , leading to improvements in the detection and characterization of tumours , treatment response monitoring , and detection of recurrence [ 3 , 4 ] . to our knowledge , we report here the first case of pelvic aa explored with dw - mri and dynamic contrast enhancement ( dce)-mri . in july 2011 , a 51-year - old woman presented to her general practitioner with an incidentally discovered renitent mass in the internal part of the left buttock . initial ultrasound ( us ) showed a well - circumscribed mass initially evoking a lipoma . due to the large volume of the mass , she was otherwise asymptomatic with a performance status score of 0 on the who scale . us showed a superficial , soft , hypoechoic , well - limited , solid mass . mri showed a bulky perineal and intrapelvic tumour displacing rather than infiltrating the vagina , anal canal , and rectal structures . the mass was well limited , hourglass - shaped and had a maximum diameter of 11 cm ( fig . t2-weighted imaging showed typical high signal intensity with layered strands of lower signal intensity and swirled architecture . a fat linear structure of high signal intensity on t1- and t2-weighted images was present inside the mass . its significance was unknown , perhaps representing neighbouring tissues trapped when the tumour was growing . after intravenous contrast injection , the mass was greatly and heterogeneously enhanced , exhibiting a layered pattern ( fig . regions of interest located in the layers demonstrated the same profile curves of progressive enhancement with variable intensity . apparent diffusion coefficient ( adc ) mapping showed a high value in the tumour , estimated at 2 10 ( 0.15 ) mm / sec . it also showed disease extension , notably through the pelvic diaphragm , which made a combined transperineal and laparoscopic abdominopelvic approach necessary . before surgery , the examination under general anesthesia showed that the mass was soft , renitent , and seemed to come from the pelvic cavity through the levator ani muscles . tumour excision was monobloc and macroscopically complete , without any rectal or vaginal resection or tumour capsular rupture . macroscopic examination of the surgical specimen showed a firm , partly circumscribed tumour measuring 16 12 6.5 cm . a cut section showed a homogeneous , glistening , and gelatinous appearance without any hemorrhagic or necrotic areas . microscopic analysis showed a monotonous hypocellular proliferation of small nonatypical stellate - shaped cells arranged in a myxoid stroma , along with numerous , variably sized vessels . no mitosis or necrosis could be seen . in its periphery , the proliferation infiltrated the nontumour adipose tissue , and resection margins were focally involved by the tumour cells . immunohistochemical analysis showed strong expression of cd34 , and estrogen and progesterone receptors by tumour cells , without expression of desmin , cd117 , -catenine , and mdm2 , nor epithelial ( pancytokeratin , ema ) , smooth muscle ( -smooth actin , h - caldesmon ) , and schwann cell ( ps100 ) markers . after surgery , no adjuvant treatment was given , and the patient was regularly monitored clinically and radiologically . at her last visit , in october 2012 , more than 1 year after the diagnosis , the patient was alive with an excellent performance status and without any recurrence of the disease on pelvic dw - mri . aa is a compliant tumour that grows slowly in the perineal or pelvic region and can cross the pelvic diaphragm . classically , the tumour shows finger - like projections at the periphery and into the surrounding tissue without infiltrating or invading adjacent organs . in general , the tumour is well limited and large ( often more than 10 cm in diameter ) at the time of diagnosis , and its consistency is soft or renitent [ 1 , 6 ] . histologically , aa is a benign hypocellular tumour , composed of scattered spindle or stellar cells , embedded in a loose myxoid matrix with a few collagen fibers and abundant vessels of varying sizes . frequently , tumour cells show positive immunohistochemical staining for desmin , smooth muscle actin , muscle - specific actin , and hormone receptors . rare and recent molecular analyses have identified translocation in the 12q1315 region involving the hmga2 gene . aggressiveness is related to the high rate of local recurrence after surgery because of frequent incomplete excision . this can be due to the absence of a preoperative diagnosis and estimation of the actual extent of the tumour , or to a particular strategic location of the mass near the urethra , vagina , anal sphincter and rectum , with frequent extension through the pelvic diaphragm , making complete resection difficult . the formerly high rate of relapse has decreased from ~75 to 1030% during the last 20 years thanks to improved imaging techniques , which allow a more complete surgical resection . aa in men is unusual and affects the genitourinary tract especially the scrotum and inguinal region [ 1 , 4 ] . most patients present with a slow - growing palpable or visible mass in the pelvi - perineal region . other signs may include discomfort or pain due to the mass , or signs related to pressure effects on adjacent organs such as dyspareunia and dysuria . morphological imaging like computed tomography ( ct ) checks for the absence of pelvic hernia , gynaecological prolapse or myoma . vaginal cysts , gartner cysts and bartholin cysts are frequent and easy differential diagnoses that do not show significant enhancement except if infected . in that case , mri will usually show peripheral enhancement of the wall of the cyst with variable thickness , which is totally different from the aa pattern of enhancement . the lack of macroscopic fat on ct and mri sequences with and without fat suppression can rule out infiltrating angiolipoma and lipoma or liposarcoma with or without myxoid component [ 7 , 8 ] . endometriomas and melanomas show typical high signal intensity on t1-weighted images without signal intensity dropout on fat - suppressed images . myxoma is mainly an intramuscular tumour that occurs in older patients , and whose enhancement does not show the same features as aa . mri is also a helpful diagnostic tool with in - phase and opposed - phase sequences showing microscopic fat inside the angiomyofibroblastoma . other diagnoses such as myxoid neurofibroma , myxoid - type malignant fibrous histiocytoma , myxofibrosarcoma , vaginal botryoid pseudosarcoma , and rhabdomyosarcoma are made by histological analysis of the tumour . in general , mri will help with the preoperative diagnosis by showing typical images of aa , as in our case . this is all the more important because , if the final diagnosis is obviously based on histology and immunohistochemistry , a preoperative diagnosis may be difficult to obtain from a percutaneous biopsy . typical images show the lesion as a well - limited mass , displacing rather than infiltrating adjacent organs and muscles , with content rich in water , loose myxoid matrix , and hypervascularity . finger - like projections into neighbouring adipose tissue can be present and are relatively characteristic of aa . classically , us without contrast injection shows a homogeneous and hypoechoic mass , sometimes cystic , that may be misleading . ct scan shows an enhanced mass , which is iso- or hypoattenuating relative to muscle [ 7 , 11 ] . mri shows very characteristic aspects : an isointense tumour ( more rarely hypointense ) relative to muscle on t1-weighted images , and hyperintense on t2-weighted images ( high water content and loose myxoid matrix ) [ 2 , 5 , 7 ] . the tumour enhances avidly and heterogeneously after intravenous gadolinium contrast administration , reflecting its inherent vasculature [ 2 , 5 , 7 , 8 ] . a typical mri feature of aa is the presence of an internal layered pattern and/or swirled architecture , which is described in 83% of cases on t2-weighted mri or on t1-weighted mri after intravenous contrast injection [ 2 , 5 , 6 , 7 , 8 , 9 ] . our case perfectly illustrated these mri findings , allowing us to suspect the aa diagnosis before surgery . preoperative mri is also crucial to determine the true extent of the disease and plan the most optimal surgical approach . the importance of accurate preoperative diagnosis and extent screening is clearly reported . in our case , an abdominoperineal approach was chosen as the tumour extended above the pelvic diaphragm on mri , allowing complete resection . during treatment finally , mri is very helpful in order to detect local relapses during follow - up . because of its high sensitivity in detecting tumour presence , its noninvasive nature , and its ability to provide valuable qualitative and quantitative information , dwi has become indispensable for characterizing lesions , and for monitoring the response to nonsurgical therapy and the patient 's follow - up after treatment . this is already well documented for the detection of prostate or rectal cancer relapse . to our knowledge the typical architecture of the tumour was seen on t2-weighted images and b0 sequences ; however , it disappeared both as the b value increased and on adc mapping imaging even in a mass more than 10 cm in diameter . dwi also showed a high value of tumour adc measurements in the region of 2 10 mm / sec , comparable with adc calculations in myxoid tumours . the persistence of high tumour signal intensity on dwi with a high b value suggests the possibility of easy and earlier relapse diagnosis using these types of sequences . furthermore , we can hypothesize that normal mri using dw sequences during patients follow - up is probably an effective way to confirm the absence of recurrence . however , aa can theoretically be polymorphous , and more patients in larger case series are needed to confirm these first observations . due to the rarity of this disease , wide surgical resection is the treatment of choice , sometimes after preoperative angiographic embolization to decrease the size of the tumour . but , because of its frequently large size and location in close proximity to vital organs ( urogenital tract and rectum ) , wide excision is not always possible and/or may cause significant morbidity in young patients . furthermore , the prognostic value of extensive surgical resection to obtain clear margins is questioned . a review of over 100 cases published in 2000 by chan et al . showed that patients with clear resection margins have similar chances of remaining disease free ( 50% at 10 years ) compared with those having tumour - involved resection margins ( 40% ) . these observations explain that incomplete resection is acceptable nowadays if followed by long - term follow - up and careful monitoring for timely identification and prompt resection of relapse . treatment involving chemotherapy and radiotherapy has been disappointing , probably due to the low mitotic activity of the tumours [ 1 , 11 ] . aa is likely hormone dependent as suggested by the reproductive age of the patients , the few cases reported during pregnancy , and the frequent expression of hormone receptors . thus , gonadotropin - releasing hormone agonists have been administered to aa patients in the postoperative as well as in the preoperative setting with dramatic responses , facilitating surgery or avoiding mutilating surgery [ 10 , 13 , 14 ] . one case report of aa treated exclusively with gonadotropin - releasing hormone agonists was published in 2003 . two cases of successful control of recurrent aa with relatively high doses of external radiotherapy have been reported , but a literature analysis shows a definite shift towards less morbid treatments . after treatment , long - term follow - up is required since late recurrences have been described up to 14 years following treatment . recurrence rates are variable in the literature and probably depend on when patients were treated ( related to surgical and mri quality ) . . found a recurrence rate in the region of 50% between 1984 and 1998 . . otherwise , 71% of recurrences occurred within the first 3 years , regardless of the initial tumour size and patient 's age . periodic clinical examination may be insufficient and imaging studies , such as mri , are fundamental . they may detect recurrence early , when the tumour is smaller in size , making surgery easier to perform or allowing the use of less morbid percutaneous ablative therapeutic strategies such as radiofrequency ablation or cryotherapy . mri is crucial in the management of aa patients for its diagnostic contribution and preoperative assessment of the actual extent of the tumour . during eventual neoadjuvant treatment , it allows monitoring of the tumour response and , after treatment , it is very useful for detecting recurrences . here , we presented the use of mri in a typical case of aa . however , this case report is also the first description in the literature of aa with complete dce and dwi analysis . we have updated the current knowledge on aa and , furthermore , we recommend the use of diffusion sequences in the follow - up of young patients treated for aa , regardless of what type of treatment they have previously had .

introductionaggressive angiomyxoma ( aa ) is a rare benign soft tissue tumour usually affecting the pelvis and perineum of young women . magnetic resonance imaging ( mri ) is crucial in the management of aa patients for its diagnostic contribution and for the preoperative assessment of the actual tumour extension . given the current development of less aggressive therapeutics associated with a higher risk of recurrence , close follow - up with mri is fundamental after treatment . in this context , diffusion - weighted ( dw ) imaging has already shown high efficacy in the detection of early small relapses in prostate or rectal cancer.case reportwe report here a case of pelvic aa in a 51-year - old woman examined with dynamic contrast enhancement and dw - mri , including apparent diffusion coefficient mapping and calculation.conclusionto our knowledge , this is the first description of dw - mri in aa reported in the literature . here , knowledge about imaging features of aa will be reviewed and expanded .

the ucsd - nature signaling gateway ( http://www.signaling-gateway.org ) is a collaboration between the university of california , san diego and the nature publishing group ( npg ) , designed to facilitate navigation of the complex world of research into cellular signaling . the signaling gateway is made up of three components : the molecule pages ( described in this study ) , the signaling update and the data center . the signaling update is published weekly by the npg to provide topical and timely information about progress in signal transduction research . the signaling gateway was formerly sponsored by the alliance for cellular signaling ( afcs ) ( 1,2 ) , which performed comprehensive experimental analyses of selected signaling systems . the data center section of the web site contains all the data generated by the afcs during the period signaling gateway was part of the afcs . the signaling gateway molecule pages ( sgmp ) database provides essential information on more than 3800 proteins involved in cellular signaling in mammals , with each protein having its own molecule page . molecule page information is presented in two categories : author - entered data and automated data . author - entered data contain expert - authored and peer - reviewed information based on published literature , with both review style free text with citations , and highly structured data for bioinformatic interrogation . the information is linked to appropriate journal citations , and covers areas such as protein interactions and states , transitions between states and protein function . the automated data information is a collection of public bioinformatic data source links and sequence analysis results , derived from the sequence and data record used to define the molecule page . the sgmp base organism is mus musculus ( because of the mouse - centric focus of the afcs ) , though much of the information in the sgmp is derived from homologous proteins in other species , such as homo sapiens . once the author - entered information has gone through a peer review process , the molecule page is published . the published molecule pages are citable and to date npg has published entries for 365 proteins , with nearly 130 submitted molecule pages currently in the review system , and 350 molecule pages in author preparation . new published molecule pages are promoted through the signaling update website pages , e - alerts and linkouts from npg content . the sgmp is a complicated online annotation and publishing system , containing three major subcomponents : ( i ) online pathway curation ( author - entered data ) ; ( ii ) online peer review and ( iii ) public repository data acquisition and display ( automated data ) . the peer review information and the pre - published author - entered information for a given molecule page are only visible to the author , selected reviewers and the editorial staff , and are invisible to all other users . each molecule page is assigned a specific protein sequence , a name , a list of synonyms and a specific protein function category ( based on that information is used to generate the properties of the sequence such as molecular weight , and all the automated data associated with the sequence . a combination of database links and computational methods are used to find the related database records and the parameters of computational matches ( e.g. a domain region ) . this information is displayed in the protein overview section of the molecule page , which is the landing page for unpublished molecule pages . to illustrate the depth of the author - entered data , we choose adenylyl cyclase type 5 ( sgmp i d a000001 ) . because this is a published molecule page , the user first arrives at the abstract section , which gives information on the author ( carmen w. dessauer ) , gives a summary of the role of adenylyl cyclase type 5 , lists the names and synonyms provided by the author and the editors , indicates that a000001 molecule has 32 enzyme functions , exists in 33 states , has 96 transitions between these states , and shows a miniature version of the network map of these transitions . the full text section contains a textual description with published references of protein function , regulation , interactions , subcellular localization , expression , phenotypes , splice variants and antibodies . the states section lists each defined functional state , with links to a constituent list and a transition graph ( if applicable ) to indicate all the transitions that lead to the state . a protein state is defined by the principal proteins interactions with other protein partners , covalent modifications on all protein components , association with small molecule ligands and cellular location . transitions section shows a list of the defined transitions , with a link to detailed information on each transition with initial and final state information , the change that occurred in the transition , process information , other comments and citations ( figure 1 ) . a transition is defined as a biological process that causes the conversion of a protein from one state to another . network map gives a graphical representation of all the states , and the transitions between them , defined by the author for a000001 ( figure 2 ) . functions section shows that a000001 acts as an enzyme , catalyzing the conversion of mg - atp to cyclic amp and pyrophosphate . each state that catalyzes the reaction is listed , with a link to the detailed state information , and a link to detailed function information with reaction information , comments and citations ( figure 3 ) . the protein classes section shows classes defined by the author to aid in data entry and display a class is defined as a group of three or more proteins that behave identically in a particular state . the protein records section displays all the sequence database records related to particular molecule page . a specific record , defined by an ncbi protein gi number ( 3 ) , is assigned to the molecule page as a base sequence . all the other sequence records listed in the same entrez gene ( 4 ) record are displayed , as well as any uniprot ( 5 ) and ensembl ( 6 ) records that refer to those sequence records . the gene info page displays pertinent information related to the molecule from the entrez gene record , including any related ensembl gene records or the sequence records within it . the domains & motifs ( figure 4 ) section contains domain information pfam ( 7 ) and smart ( 8) , pattern / motif information from prints ( 9 ) and interpro ( 10 ) records related to the molecule page sequence . these records are produced using a combination of database record references , computational schemes [ hmmpfam ( 11 ) and fingerprintscan ( 12 ) ] . matching sequence regions are given for the computational matches . the interactions page displays matching interaction database records from the bind database and from the entrez gene database , including bind ( 13 ) , biogrid ( 14 ) and hprd ( 15 ) interaction records . interactions involving likely orthologs of the molecule page base sequence are displayed , to provide additional information . orthologs section shows genes in other select organisms that are likely orthologs of the base gene . this list is constructed using a combination of a species - specific blast against the ncbi protein database , and database analysis of homologene ( 16 ) and ensembl homology databases . blast data section contains a list of the top blast hits against the entire ncbi protein database . the protein structure section displays the pdb ( 17 ) records that are related to the molecule page , either through a database reference to one of the related protein sequence records , or by a sequence match with blast . in addition to all the hyperlinks to the relevant bioinformatic databases , the sgmp base sequence also links directly to the sdsc biology workbench ( http://workbench.sdsc.edu ) . the biology workbench ( 18 ) enables a user to carry out seamlessly a variety of sequence analysis operations . to illustrate the depth of the author - entered data , we choose adenylyl cyclase type 5 ( sgmp i d a000001 ) . because this is a published molecule page , the user first arrives at the abstract section , which gives information on the author ( carmen w. dessauer ) , gives a summary of the role of adenylyl cyclase type 5 , lists the names and synonyms provided by the author and the editors , indicates that a000001 molecule has 32 enzyme functions , exists in 33 states , has 96 transitions between these states , and shows a miniature version of the network map of these transitions . the full text section contains a textual description with published references of protein function , regulation , interactions , subcellular localization , expression , phenotypes , splice variants and antibodies . states section lists each defined functional state , with links to a constituent list and a transition graph ( if applicable ) to indicate all the transitions that lead to the state . a protein state is defined by the principal proteins interactions with other protein partners , covalent modifications on all protein components , association with small molecule ligands and cellular location . transitions section shows a list of the defined transitions , with a link to detailed information on each transition with initial and final state information , the change that occurred in the transition , process information , other comments and citations ( figure 1 ) . a transition is defined as a biological process that causes the conversion of a protein from one state to another . network map gives a graphical representation of all the states , and the transitions between them , defined by the author for a000001 ( figure 2 ) . functions section shows that a000001 acts as an enzyme , catalyzing the conversion of mg - atp to cyclic amp and pyrophosphate . each state that catalyzes the reaction is listed , with a link to the detailed state information , and a link to detailed function information with reaction information , comments and citations ( figure 3 ) . the protein classes section shows classes defined by the author to aid in data entry and display a class is defined as a group of three or more proteins that behave identically in a particular state . the protein records section displays all the sequence database records related to particular molecule page . a specific record , defined by an ncbi protein gi number ( 3 ) , all the other sequence records listed in the same entrez gene ( 4 ) record are displayed , as well as any uniprot ( 5 ) and ensembl ( 6 ) records that refer to those sequence records . the gene info page displays pertinent information related to the molecule from the entrez gene record , including any related ensembl gene records or the sequence records within it . the domains & motifs ( figure 4 ) section contains domain information pfam ( 7 ) and smart ( 8) , pattern / motif information from prints ( 9 ) and interpro ( 10 ) records related to the molecule page sequence . these records are produced using a combination of database record references , computational schemes [ hmmpfam ( 11 ) and fingerprintscan ( 12 ) ] . matching sequence regions the interactions page displays matching interaction database records from the bind database and from the entrez gene database , including bind ( 13 ) , biogrid ( 14 ) and hprd ( 15 ) interaction records . interactions involving likely orthologs of the molecule page base sequence are displayed , to provide additional information . orthologs section shows genes in other select organisms that are likely orthologs of the base gene . this list is constructed using a combination of a species - specific blast against the ncbi protein database , and database analysis of homologene ( 16 ) and ensembl homology databases . the blast data section contains a list of the top blast hits against the entire ncbi protein database . structure section displays the pdb ( 17 ) records that are related to the molecule page , either through a database reference to one of the related protein sequence records , or by a sequence match with blast . in addition to all the hyperlinks to the relevant bioinformatic databases , the sgmp base sequence also links directly to the sdsc biology workbench ( http://workbench.sdsc.edu ) . the biology workbench ( 18 ) enables a user to carry out seamlessly a variety of sequence analysis operations . the advisory board provides high - level guidance and advice concerning the development of the molecule pages database . the editorial board helps the editorial team with several aspects of publishing molecule pages , such as identifying relevant authors , reviewers and adjudication during peer - review . npg manages a rigorous editorial process to ensure that expert - authored molecule pages are accurate and complete , and that structured data is recorded in a consistent manner . authors either apply to contribute and are selected by npg editors , or are commissioned by editors . after an initial editorial evaluation of an author 's submission , the molecule page undergoes anonymous peer - review by two or three experts in the relevant field . following peer - review the author may be required to revise their submission in light of reviewer and editor comments . following revision the molecule page is critically assessed and a decision to publish is made . the molecule page is copy edited before publication and a digital object identifier ( doi ) assigned upon publication . the database tier is an oracle 10 g database instance running on a sun server . the middle tier contains business and web components and is deployed on an oracle components 4 java ( oc4j ) application server that also runs on a sun server . the business components consist of data access objects that encapsulate database access for the web layer . the web layer consists of java servlets and server pages complying with the j2ee ( enterprise java ) 1.3 specifications . the compute and database servers are located at the san diego supercomputer center ( sdsc ) . in addition to the web forms that the general public uses for viewing the data , there are specialized web forms for the authors , reviewers and editors to perform their tasks . a password - protected user access system controls access to the specialized forms and the unpublished data for a given molecule page , but the general public is able to access any published data and all automated data without having to register for an account . local copies of the constituent databases are stored in custom , relational forms on the oracle system , with the computational methods being run on sun systems . the results of the automated data are stored in the database tier , along with the archived results of automated analysis at the time of publication . tab - delimited files relating the molecule pages to protein sequence database records ( e.g. uniprot , refseq , genbank ) and gene database records ( entrez gene and ensembl ) are provided via anonymous ftp . the data is accessed via a browse function , a simple search engine and an advanced search engine . the simple search engine allows users to query the database using the molecule page i d , gene symbols , protein names and synonyms . the advanced search engine allows users to ask complex questions , such as show me all functional states involving molecule a and molecule b. the advanced search engine uses the lucene library ( http://lucene.apache.org/ ) from the apache software foundation ( http://www.apache.org/)an open - source java toolset . a wiki will be added to the web site , allowing for open comments on any given molecule page , as well as a living molecule summary that does not require the rigorous process of a published molecule page . previously published molecule pages will be updated by the authors , and released as subsequent versions . we plan on adding exportable molecule page information , for published molecule pages , in xml form , as well as standard exchange formats such as biopax ( http://www.biopax.org/ ) . we will continue to add to the links provided in the automated data sections , addressing areas such as gene expression and phosphorylation .

the ucsd - nature signaling gateway molecule pages ( http://www.signaling-gateway.org/molecule ) provides essential information on more than 3800 mammalian proteins involved in cellular signaling . the molecule pages contain expert - authored and peer - reviewed information based on the published literature , complemented by regularly updated information derived from public data source references and sequence analysis . the expert - authored data includes both a full - text review about the molecule , with citations , and highly structured data for bioinformatics interrogation , including information on protein interactions and states , transitions between states and protein function . the expert - authored pages are anonymously peer reviewed by the nature publishing group . the molecule pages data is present in an object - relational database format and is freely accessible to the authors , the reviewers and the public from a web browser that serves as a presentation layer . the molecule pages are supported by several applications that along with the database and the interfaces form a multi - tier architecture . the molecule pages and the signaling gateway are routinely accessed by a very large research community .

levamisole , an anthelmintic agent that targets the nicotinic acetylcholine receptors , is usually used as an immunostimulant in combination with 5-fluorouracil ( 5-fu ) to treat colorectal cancer since 1990 . it has been shown that combination of these two drugs decrease the risk of clinical recurrence and to increase survival in patients with stage iii adenocarcinoma of the colon . , we describe multifocal inflammatory leukoencephalopathy in a patient with accidentally consumption of levamisole after 8 months of gastric lavage of the drug . a 53-year - old man was admitted to the neurology department of farabi hospital ( kermanshah , iran ) with walking inability and recognition disorder . patient history showed that he had referred to hospital with vomiting , vertigo and headache 8 months before after consumption of two sachet of levamisole ( for veterinary use ) which each sachet contained 1.5 gram of levamisole hydrochloride . one month later , he had been stricken by progressive walking inability and recognition disorder up to administration to our hospital . the patient had not any previous illness . on neurologic examination , he was confused and did not establish a good relationship with the bystander . on mental and cognitive power examinations , using the mini mental state examination ( mmse ) , he earned 17 points ( out of a total score of 30 ) with no signs of meningeal irritation ( such as stiffness of neck ) . the power of limbs was within normal range but deep tendon reflexes in all of four limbs had increased in conjunction with extensor plantar response and reduced abdominal skin reflex . on cerebellar examination , finger to nose test and heel to shin was impaired and the gait was ataxic . on the initial laboratory tests , complete blood count ( cbc ) , in cerebrospinal fluid analysis , color , pressure , cells , and sugar were normal but protein was increased ( 69 mg / dl ) . on electroencephalography ( eeg ) , bilateral paroxysmal slow waves were seen . in visual evoked potential ( vep ) , there was a bilaterally prolonged p100 latency . brain magnetic resonance imaging ( mri ) showed mild cerebral atrophy and multiple focal lesions distributed in periventricular and cerebellar white matter and also in pons and midbrain ( figure 1 ) . these lesions had low - signal intensity on t1-weighted images and high - signal intensity in fluid - attenuated inversion recovery ( flair ) view and t2-weighted images . initial brain mri in the patient with multifocal demyelinating leukoencephalopathy after accidental consumption of levamisole ; a : brain mri on t1wi revealed multifocal subcortical white matter lesions in the periventricular ; b and c : brain mri on t2wi revealed multifocal subcortical white matter lesions in the periventricular , cerebellar and pons ; d and e : brain mri on flair revealed multifocal subcortical white matter lesions in the periventricular area , cerebellum and pons following clinical examinations and ruling out of other causes , including infectious and vascular causes , trauma and metabolic , central nervus system ( cns ) vasculitis and paraneoplastic syndromes ; and according to the patient 's history , the patient was diagnosed as multifocal inflammatory leukoencephalopathy following levamisole consumption . the patient was treated with intravenous methylprednisolone ( 500 mg ) every 12 hours for 7 days followed by two weeks oral consumption of the prednisolone ( 50 mg / day ) during hospitalization . no change was noticed in cerebellar signs and gait disorder but a brief improvement was seen in mentality and cognition after 1 and 3 months . after a month of treatment ( figure 2 ) the follow - up brain mri in patient with multifocal demyelinating leukoencephalopathy , after 1 month treatment with methylprednisolone disclosed no recovery of the subcortical white matter lesions ; a : brain mri on t1wi revealed multifocal subcortical white matter lesions in the periventricular area ; b : brain mri on t1wi with contrast revealed multifocal subcortical white matter lesions in the periventricular area and no evidence of enhancement ; c : brain mri on t2wi revealed multifocal subcortical white matter lesions in the periventricular area ; d , e and f : brain mri on flair revealed multifocal subcortical white matter lesions in the periventricular area , cerebellum and pons this paper reported the clinical features and mri changes that were occurred suddenly after consumption of high dose levamisole and 8 months later . clinical investigations and also mri imaging showed the drug induced toxicity in the brain after 8 months of treatment . toxicity of levamisole is generally mild , even when levamisole is used alone , and is negligible in a series of patients in whom it is associated with 5-fu ( leucovorin ) . the spectrum of side effects ( partly dose - dependent ) includes myalgia , arthralgia , fatigue , fever , chills , skin rash , nausea , vomiting , anorexia and neurological symptoms . the latter mainly consist of depression , anxiety , insomnia , difficulty in concentration , headache and vertigo . clinical investigations of the patient showed memory loss , confusion , ataxia , dysarthria , and hyperreflexia that can not be considered as the side effects of the drug alone but are the main symptoms of multifocal inflammatory leukoencephalopathy . here , it seems that if a case subjected to only one but high dose of levamisole , the catastrophic effect is such prominent that may induce multifocal inflammatory leukoencephalopathy . on the other hand , mri imaging showed inflammation in many parts of the brain that led us to diagnose the patient as multifocal inflammatory leukoencephalopathy . multifocal inflammatory leukoencephalopathy , a central nervous system disorder characterized by demyelination with perivascular inflammation , has recently been reported in several patients treated with the combination of fluorouracil and levamisole chemotherapy . it has been suggested that the neurotoxicity derived by combination of these two drugs was mainly due to 5-fu rather than levamisole alone . however , some authors confirmed that multifocal inflammatory leukoencephalopathy could be induced by levamisole alone . in parallel with these studies , we also suggest that levamisole alone can induce multifocal inflammatory leukoencephalopathy . on the other hand , in previous studies , levamisole was administered as a drug choice and there was no document in the literature for monitoring the effect of this drug following accidental consumption . in addition , gastric lavage followed by delayed treatment of the patient with methylprednisolone can not diminish the neurotoxicity of levamisole . these data highlights the fact that the drug must be unavoidable to children and the usage of the drug must be used vigilantly .

levamisole is an anthelmintic agent and also immunostimulant drug which is used to treat colorectal cancer . the present study aimed to show accidental consumption of levamisole alone induced multifocal inflammatory leukoencephalopathy . a 53-year - old male was admitted to the neurology department of farabi hospital ( kermanshah , iran ) with walking inability and recognition disorder . following clinical examinations , the patient diagnosed as multifocal inflammatory leukoencephalopathy following levamisole consumption.the patient was treated with intravenous methylprednisolone followed by prednisolone . the magnetic resonance imaging ( mri ) was done 1 month later and did not show a reduction or remission in the lesions . history of the patient showed that he had accidentally consumed levamisole 8 months ago . it seems that the consumption of levamisole can induce multifocal inflammatory leukoencephalopathy and delayed treatment of the patient with corticosteroid can not diminish the neurotoxicity of levamisole . in addition , the cytotoxic dose of levamisole induces irreversible multifocal inflammatory leukoencephalopathy .

according to world health organization ( who ) ( 2012 ) more than 347 million people worldwide suffer from diabetes mellitus ( dm ) , of which 90% have type 2 diabetes ( t2d ) . both the prevalence and morbidity , especially of t2d , continue to grow globally , especially in developing countries . this growth has led to strains on healthcare systems worldwide as t2d remains one of the leading causes of cardiovascular disorders , blindness , renal failure , amputations , and hospitalizations . adiponectin is a circulating protein produced by adipose tissue that is a versatile regulator of energy homeostasis , insulin sensitisation , inflammation / atherosclerotic processes , and anti - ischemic cardioprotection . it is well established that adiponectin plays an important role in t2d , hypertension , multiple sclerosis , and dyslipidaemias . particularly , there is a strong association between hypoadiponectinemia and t2d : both adipose adiponectin mrna expression and circulating adiponectin levels are significantly reduced in most rodent models of t2d , as well as t2d patients ; the degree of glycosylated adiponectin and high - molecular weight / total adiponectin ratio , which correlates with insulin sensitivity , were significantly decreased in t2d patients compared to healthy controls ; high adiponectin levels are associated with reduced risk of developing diabetes . the most significant role adiponectin may play is that of sensitizing the liver and muscles to the action of insulin in both humans and rodents . adiponectin has an ameliorating function on glucose metabolism apart from insulin signalling . in animal models of obesity and diabetes , adiponectin affected both skeletal muscle and liver , promoting fatty acid oxidation in muscle and inhibiting glucose production from the liver , thereby leading to decreases in circulating free fatty acids ( ffas ) , triglyceride , and glucose levels [ 7 , 8 ] . ffas as well as tumor necrosis factor alpha ( tnf ) are factors released from adipose tissue that contribute to insulin resistance . in addition , lipid accumulation in beta - cells might lead to reductions in insulin secretion . in individuals with visceral obesity , there is a decrease in the insulin - mediated suppression of lipolysis , leading to increases in circulating ffas concentrations that contribute to both peripheral and hepatic insulin resistance either by impairing insulin signalling pathways , by competitive inhibition of muscle glucose uptake , by stimulation of endogenous glucose production , thus contributing to hepatic insulin resistance , or by combination of mentioned mechanisms [ 6 , 7 , 9 , 10 ] . also it was shown that adiponectin regulates the expression of several pro- and anti - inflammatory cytokines . its main anti - inflammatory function might be related to its capacity to suppress the synthesis of tnf and interferon gamma ( ifng ) and to induce the production of anti - inflammatory cytokines such as interleukin-10 ( il-10 ) and il-1 receptor antagonist ( il-1ra ) . tnf is a key modulator of adipocyte metabolism , with a direct role in several insulin - mediated processes , including glucose homeostasis and lipid metabolism [ 6 , 7 , 12 ] . the net effect of tnf is to decrease lipogenesis ( ffa uptake and triglyceride synthesis ) and to increase lipolysis . finally , there is substantial evidence of adiponectin effects on beta - cell function and survival , which are well known as key factors in the development of t2d along with insulin resistance . taking into consideration the above mentioned it could be conclude that adiponectin - targeted pharmaceutical strategies increasing circulating adiponectin levels may be therapeutic against t2d . subetta is drug containing release - active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide ( no ) synthase . this novel class of drug was demonstrated to have a fundamentally new proantigen ( cotargeted with antigen ) targeted activity . for the first time in the study of the repeated dilution process , it was found that the resulting ultra - dilution generates a novel activity absent in the starting material , called a release - activity . a distinctive feature of the release - active antibodies is their ability not to suppress , and to modify the activity of the antigen against which they were raised . in two dm animal models , streptozotocin - induced dm and spontaneous t2d in goto kakizaki rats , subetta showed antidiabetic effects similar to that of rosiglitazone . additionally , subetta has shown promising results in its first clinical use in both type 1 diabetes ( t1d ) patients with poor glycemic control receiving intensive insulinotherapy and t2d patients receiving metformin / combination of basal insulin with metformin ( unpublished data ) . subetta treatment led to a significant decrease in fasting plasma glucose and glycated haemoglobin ( hba1c ) levels , exerted a normalizing effect on the daily glycemic levels ( self - control of blood glucose and daily glucose monitoring ) , significantly lowered insulin resistance and plasma insulin levels , as well as lowering total cholesterol and low - density lipoproteins . the aim of this work is to investigate the ability of subetta to affect adiponectin secretion by mature human adipocytes . human preadipocytes ( lot sl0047 ) were provided by zen - bio , inc . human preadipocytes were mixture of subcutaneous depots ( abdomen , thigh , hip , flank , and breast ) obtained from 5 healthy donors ( sex : female ; age : 47.0 5.4 ) undergoing elective surgery that have signed informed consent , under existing institutional review board ( irb ) . the cells were pooled and grown together , then harvested and cryopreserved as the superlot ( multidonor ) that was used in the current study . prior to use the cells undergo quality control in a number of functional assays ( differentiation ( measured by total triglyceride ) , lipolysis , insulin - induced glucose uptake ) and also the results of the quality control have shown that there were not any differences between the depots . preadipocyte medium ( catalog number pm-1 ) , adipocyte differentiation medium ( catalog number dm-2 ) , and adipocyte maintenance medium ( catalog number am-1 ) were provided by zen - bio , inc . enzyme - linked immunosorbent assay ( elisa ) kit ( catalog number adip-1 ) was the product of zen - bio , inc . subetta , release - active dilutions ( rad ) of antibodies ( abs ) to the beta subunit of insulin receptor and abs to endothelial no synthase , rad of abs to cannabinoid receptor type i ( r - cbi ) , rad of rabbit nonimmune serum ( rbs ) , rad of purified water ( placebo ) , and purified water were manufactured and supplied by ooo npf all of ooo npf materia medica holding compounds , except for purified water , were manufactured using the method described previously using routine methods described in the european pharmacopoeia ( 6th edition , 2007 ) . starting substances were mixed with a solvent ( ethanol - water solution ) and shaken for 1 min to produce c1 dilution . all subsequent dilutions consisted of one part of the previous dilution to 99 parts of solvent ( ethanol - water solution for intermediate dilutions and distilled water for preparation of the final dilution ) , with succession between each dilution . solutions were prepared in sterile conditions , avoiding direct intense light , and were stored at room temperature . rabbit polyclonal antibodies to the beta subunit of insulin receptor and to endothelial no synthase were used as starting substances for subetta , rabbit polyclonal antibodies to cannabinoid receptor type i for rad of abs to r - cbi , rabbit nonimmune serum for rad of rbs . in case of placebo , human preadipocytes were plated at 40625 cells / cm in 150 l of preadipocyte medium . the cells were allowed to attach overnight in a 37c humidified incubator at 5% co2 . the following day , the plating medium was removed and replaced with 150 l of adipocyte differentiation medium and the cells allowed to incubate in a 37c humidified incubator at 5% co2 for 1 week . after 1 week , 90 l of the differentiation medium was removed from each well and 120 l of adipocyte maintenance medium was added . the cells were then allowed to incubate in a 37c humidified incubator at 5% co2 for 7 more days . prior to the assay , the cells were incubated in the absence of serum and hormones for three days . after starvation , test compounds ( 75 l ) were added and the cells were incubated at 37c in a humidified incubator at 5% co2 for three days . conditioned media was collected after 72 hours and either frozen for later evaluation or measured immediately . for the elisa , 20 l of the conditioned medium was added to 80 l of pretreatment solution and heated to 100c for 5 minutes . once the samples were cooled to room temperature , 50 l of each sample was added to 200 l diluent buffer to generate a 5-fold dilution . samples were mixed and 100 l was transferred to the coated wells of the elisa plate . samples were incubated at room temperature for 1 hour after which the plate was washed and secondary antibody applied and incubated at room temperature for 1 hour . the plate was washed again and detection antibody was added and allowed to incubate for 1 hour at room temperature . detection reagents were added and absorbance at 450 nm ( spectramax 250 : molecular devices ) was determined . the data are presented as mean value per group ( m ) standard deviation ( sd ) . one - way analysis of variance ( anova ) followed by tukey hsd test was used for statistical analysis and p values less than 0.05 were regarded as significant ( statistica 6.1 software ) . incubation of mature human adipocytes with subetta for 72 hours resulted in a statistically significant increase in adiponectin concentration in the culture medium ( table 1 ) . nonspecific controls , rad of abs to r - cbi and rad of rbs , did not significantly affect adiponectin secretion , resulting in adiponectin levels comparable to background values of the negative controls , placebo , purified water , and 0.1% dimethyl sulfoxide ( dmso ) . the reference drug rosiglitazone stimulated adiponectin secretion but to a lower level compared to that of subetta and its effect was not significant in comparison with dmso value . previously , subetta demonstrated the ability to reduce hyperglycemia and improve glucose tolerance in various experimental models of diabetes mellitus and its effects were similar to that of rosiglitazone [ 14 , 15 ] . subetta was given by oral gavage , when it was studied in vivo but in the current study the direct action of subetta on mature human adipocytes was estimated in vitro . based on the activity demonstrated for the whole class of novel drugs and on data from previous studies , we may conclude that the complex drug mainly exerts a modulating effect on the beta subunit of the insulin receptor regulating the insulin receptor 's kinase activity and consequently activating receptor - associated signal pathways . the ability of direct activation of insulin receptor and activate receptor - associated signal pathways in the absence of insulin was shown for l7 ( merck ) [ 17 , 18 ] . according to shehzad et al . specifically , insulin enhances adiponectin regulation and secretion selectively in adipocytes . while the exact mechanism of action of insulin on adiponectin biosynthesis remains unclear , it has been suggested that insulin binding to its receptor activates a cell cascade inhibiting the activity of foxo1 , a suppressor of peroxisome proliferator - activated receptor gamma ( ppar gamma ) , which in turn results in the induction of adiponectin biosynthesis . it is important that adiponectin has an ameliorating function on glucose metabolism apart from insulin signalling . taking into consideration the above mentioned , it could be assumed that subetta via direct effect on beta subunit of the insulin receptor of mature human adipocytes activates insulin receptor in the absence of insulin in culture medium , which in its turn exerts activating receptor - associated signal pathways . as a result activity of foxo1 is inhibited and thus adiponectin biosynthesis is inducted . to confirm this suggestion , further studies ( both in vitro and in vivo ) should be conducted in order to provide a detailed investigation of the mechanism of subetta influence on the production of adiponectin and also to assess the involvement of this process and its role in the mechanism of drug action . in summary , the novel complex drug subetta , containing rad of antibodies to the beta subunit of insulin receptor and antibodies to endothelial no synthase , stimulates adiponectin production by mature human adipocytes . this effect on adiponectin production is specific ; neither rad of abs to r - cbi nor rad of rbs affected adiponectin secretion by mature human adipocytes . therefore , the ability of subetta to exert its modulating effect on the insulin receptor even in absence of insulin might be the basis for stimulating adiponectin secretion and might serve as one of the mechanisms of the antidiabetic effect of this drug . the results of the current in vitro study give first insight on possible mechanism of action of subetta and serve as a background for further studies .

purpose . to investigate the mechanism of action in peripheral tissues of novel complex drug containing release - active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide synthase ( subetta ) , which has shown efficacy in animal models of diabetes . methods . human mature adipocytes were incubated either with subetta , with one of negative controls ( placebo or vehicle ) , with one of nonspecific controls ( release - active dilutions of antibodies to cannabinoid receptor type i or release - active dilutions of rabbit nonimmune serum ) , or with dimethyl sulfoxide ( dmso ) at 37c in a humidified incubator at 5% co2 for three days . rosiglitazone was used as reference drug . secretion of adiponectin was measured by quantitative enzyme - linked immunosorbent assay ( elisa ) . results . only subetta significantly stimulates adiponectin production by mature human adipocytes . nonspecific controls did not significantly affect adiponectin secretion , resulting in adiponectin levels comparable to background values of the negative controls and dmso . conclusion . increasing adiponectin production in absence of insulin by subetta probably via modulating effect on the beta subunit of the insulin receptor might serve as one of the mechanisms of the antidiabetic effect of this drug . these in vitro results give first insight on possible mechanism of action of subetta and serve as a background for further studies .

as a new class of potential fluorescence probes , quantum dots ( qds ) have attracted great interests of the researchers because of their unique and excellent properties over traditional fluorescent dyes and fluorescent proteins [ 13 ] . compared to conventional organic fluorescent dyes , qds possess higher photoluminescence ( pl ) , excellent quantum yield ( qy ) , size - dependent tunable luminescence wavelength , wide continuous absorption , narrow fluorescence band , and better photostability . over the past two decades , great efforts have been focused on the development of sensors [ 48 ] based on qds , and the detection of metal ions is the active field . some researchers have realized the specific detection of metal ions through modification of qds with different surface - attached ligands [ 913 ] , such as the detection of cu ions through thioglycerol - capped cds qds and mercaptopropionic acid - coated core / shell cdte / cdse qds , the detection of zn ions through l - cysteine - capped cds qds , the detection of ag ions through thioglycolic acid - coated cdse qds , the detection of cu and ag ions through peptide - coated cds qds , and the detection of pb ions through glutathione - capped zncdse and cdte qds . as one of the most toxic heavy metals and persistent contaminants which can not be biodegraded in ecosystem [ 14 , 15 ] , mercuric ion ( hg ) requires new and efficient detection methods . the major challenges in developing qds - based hg probe are the preparation of water - soluble qds with high luminescence quantum yield and the selectivity of the system [ 1619 ] . herein , through hydrothermal route , a series of high - quality n - acetyl - l - cysteine- ( nac- ) capped qds with excellent water solubility , stability , and high qy ( the average qy is 50% ) have been synthesized [ 2022 ] . based on the prepared nac - capped cdte qds as the fluorescence probe , a rapid , cost - efficient , sensitive , and selective detection method for hg(ii ) ions has been developed in which hg(ii ) efficiently quenches the fluorescence of qds and produces a new peak in near - infrared area . since size effect is a basic characteristic of semiconductor nanocrystals , the proposed hg(ii ) detection mechanism was also deduced through fluorescence spectrum , ultraviolet absorption spectrum , and x - ray photoelectron spectrum ( xps ) . cdcl2h2o , hg ( clo4)2 , rhodamine 6 g , and sodium borohydride ( nabh4 ) were obtained from aldrich . deionised distilled ( di ) water prepared from a milli - q - ro4 water purification system ( millipore ) was used and purged with nitrogen ( n2 ) for 30 min before use . nabh4 was used to react with tellurium with a molar ratio of 2 : 1 in di water to prepare sodium hydrogen telluride ( nahte ) . cdcl2 ( 1.25 mm ) and nac ( 1.56 mm ) were dissolved in 40 cm of di water in an ice - water bath . the precursor solution was adjusted to ph 9 by stepwise addition of 1.0 m naoh at 4c . subsequently , a fresh nahte solution at 0c was added to the above prepared precursor solution and stirred vigorously . the molar ratio of cd : te : nac was fixed at 1.0 : 0.2 : 1.2 . finally , the solution was put into a 40-cm teflon - lined stainless steel autoclave . it was loaded in an oven at 200c for a specified time ( 3050 min ) and then cooled to the room temperature by a hydrocooling process . to remove nac - cd complexes at the end of the synthesis , cold 2-propanol was added to the reaction mixture to precipitate nac - capped cdte qds . the as - prepared products were dried overnight under vacuum at 40c for further experiments . 5.0 m of cdte qds in 50 mm tris - hcl buffer at ph 7.8 was used , and the excitation wavelength was 450 nm . rhodamine 6 g in ethanol was chosen as the reference standard ( qy = 95% ) . uv - visible absorption spectra were acquired with a varian cary 100 scan uv / visible spectrophotometer . photoluminescence spectra were recorded on a photon technology international qm4 spectrofluorometer equipped with a thermoelectrically cooled ingaas photodiode for near - infrared ( nir ) region measurement . xps measurements were acquired with a leybold heraeus skl 12 x - ray photoelectron spectrometer . figure 1 shows the fluorescence spectra of nac- capped cdte qds ( em = 565 nm ) in hg(ii ) ions titration experiments ( in 50 mm tris - hcl buffer at ph 7.8 ) . as shown in figure 1 , hg(ii ) ions can efficiently quench the pl intensity of cdte qds . with the addition of hg(ii ) ions , the pl peak intensity at 565 nm decreases with a slight bathochromic shift of pl spectrum . when hg(ii ) ions concentration is increased to 1.0 m , the pl peak intensity reduces to only a few present of its original value . meanwhile , new emission peak appears at 700900 nm , and its fluorescent intensity increases with the addition of hg(ii ) ions ( inset of figure 1 ) . the relationship between fluorescence intensity of cdte qds and concentration of hg(ii ) ions can be described by stern - volmer plot as follows : ( 1)ioi=1+ksv[q ] , where io and i are the pl intensities of cdte qds in the absence and presence of quencher q , [ q ] is the hg(ii ) ion concentration , and ksv is the stern - volmer constant . figure 2 describes a stern - volmer quenching curve with io / i as a function of hg(ii ) ion concentration , and a very good linearity is observed in the lower concentration range . the linear rang is from 20 to 430 nm with ksv at 5.49 10 m. the limit of detection is 8.0 nm which is determined on the basis of three times the standard deviation of six replicate measurements of the quenched pl intensity by the addition of 30 nm hg(ii ) . however , when the concentration of hg(ii ) ions is higher than 430 nm , the line is curved upward because of superquenching effect ( vide infra ) . to study the selectivity of the system , we investigated the influences of common biological metallic ions on the fluorescence intensity of nac - capped cdte qds . as shown in figure 3 , most common metallic ions , including li , na , k , ca , mg , zn , cd , pd , fe , pb , and cu , exhibit no significant effect on the fluorescence intensity of qds even at relatively high concentrations , while hg exhibits strong quenching ability to the intensity even at low concentration . in particular , with the addition of hg ions , there appears a new emission peak at the nir region 700900 nm , and no other metallic ions produce the similar phenomena . different from other traditional fluorescent probes which only rely on the fluorescence change of the qds , the newly appearing pl peak ensures excellent selectivity in detection of hg ions . furthermore , a series of different - sized qds were chosen to study the impact of qds diameter upon the position of the new peak . as shown in figure 4 , the newly appeared peaks appear at the relatively fixed position regardless of the difference of qds diameters , showing that the wavelength of the new peak is irrelevant to the size of qds . however , the smaller - sized qds can be more easily quenched by hg(ii ) ions , and the intensity of newly appeared peak is stronger , which is beneficial to the excellent sensitivity of the system . it is known that the fluorescence intensity of smaller - sized qds can be easily influenced by the environment and other interfering materials , greatly limiting the selectivity of the system . therefore , to ensure both good sensitivity and selectivity , this paper chooses nac - capped cdte qds with their emission peak at 565 nm . to explain the difference in linearity of the system in low and high hg(ii ) concentrations , we proposed two interaction modes between nac - capped cdte qds and hg(ii ) with the increase of hg(ii ) ions . when hg(ii ) ions concentration is relatively low ( < 430 nm ) , the hg(ii ) ions interact with the carboxylate moiety of ligand ( nac ) on the surface of cdte qds by electrostatic forces . when the concentration further increases ( > 430 nm ) , hg(ii ) ions would further interact with cdte qds , displacing the cd in the cdte to form alloyed cdxhg1xte ncs . these surface changes of nac - capped cdte qds , on one hand , increase surface defects of qds and render luminescence quenching of qds ; on the other hand , by facilitating nonradiative e / h annihilation acting as electron - hole recombination centres and decreasing radiative e / h annihilation ( luminescence ) , these alloys cdxhg1xte ncs lead to superquenching of the original qds . meanwhile , the formation of cdxhg1xte ncs increases the original diameter of nac - capped cdte qds and narrows the band gaps of these ncs , producing an obvious bathochromic shift of the pl spectrum at 700900 nm . in which the formation of ultrasmall particle ag2se on the surface of cdse qds was proved after the addition of ag , during their study of functionalized cds qds as selective ag probe . figure 5 displays the absorption spectra of nac - capped cdte qds with the addition of hg(ii ) ions , in which the absorption peak red - shifts with the increase in hg(ii ) concentration , inferring the formation of larger cdxhg1xte ncs . to further confirm our proposition , xps was used to analyze the surface components of qds after the addition of hg(ii ) ions . xps is known as a surface analytical tool that is sensitive to the atomic composition of the outermost 10 nm of a sample surface . a larger amount of hg(ii ) ions was added into qds solution , and the resultant product was precipitated by cold 2-propanol . the product was washed and dried overnight for xps measurement . if hg(ii ) ions combine only with the ligands on the surface of nac - capped qds , they will be removed by the addition of 2-propanol , while if hg(ii ) ions bind directly onto the surface of cdte qds and form alloyed cdxhg1xte ncs , they will be precipitated out . the appearances of characteristic cd ( 3d5/2 ) peak at 404.8 ev and te ( 3d5/2 ) peak at 572.2 ev are depicted in figure 6 . the typical binding energies for the hg ( 4f ) peaks at 101.0 and 105.0 ev confirm the presence of hg on the cdxhg1xte ncs ( figure 6(c ) ) . the selective detection of hg(ii ) ions through the interaction of hg(ii ) ions and nac - capped cdte qds has been realized in our system . the fluorescence intensity of cdte qds can be remarkably quenched by the addition of hg ions , and there appears a new peak at about 820 nm . the linear response range and the limit of detection are 20430 and 8.0 nm hg(ii ) , respectively . the influence of most physiologically important metallic cations upon the system , including li(i ) , na(i ) , k(i ) , ca(ii ) , mg(ii ) , zn(ii ) , cd(ii ) , pd(ii ) , fe(iii ) , pb(ii ) , and cu(ii ) , was tested to prove the selectivity of the system . we further proposed that the possible mechanism for the new peak is that hg(ii ) ions displace the cd in the cdte and form alloys cdxhg1xte ncs , which has been proven by ultraviolet absorption spectrum and x - ray photoelectron spectrum .

a simple , rapid , and specific method for hg(ii ) detection has been proposed based on the fluorescence change of n - acetyl - l - cysteine - capped cdte quantum dots ( qds ) . the presence of hg(ii ) ions could quench the fluorescence of qds at 565 nm and meanwhile produce new peak in 700860 nm wavelength range . the linear response range is 20430 nm with the detection limit at 8.0 nm hg(ii ) . it was found that the position of the new peak was irrelevant to the size of qds . furthermore , the mechanism of the quenching of qds fluorescence by hg(ii ) and the appearance of new peak in near - infrared area were also discussed and deduced through ultraviolet absorption spectrum , fluorescence spectrum , and x - ray photoelectron spectrum .

spontaneous central vein thrombosis is a rare but potentially serious condition as it can present with a fatal pulmonary embolism . activated protein c resistance ( apc - r ) due to homozygous factor v leiden mutation is an exceptional cause of spontaneous central venous thrombosis . we describe here a right - sided internal jugular vein ( ijv ) and subclavian vein ( scv ) thrombosis in a patient due to apc - r and homozygous factor v leiden mutation . the relationship with dengue viral infection and apc - r with central vein thrombus has been explored . a 21-year - old non - obese female patient with no co - morbid illness was referred to our intensive care unit ( icu ) from a private hospital with history of high grade fever with chills 8 days back with respiratory distress for 6 days and altered sensorium for 2 days . she was intubated for altered sensorium and had already received mechanical ventilation for 48 hours . she was referred to us in a state of shock with vasopressors infusions on flow ( dopamine through peripheral line ) . additionally , she had edematous peripheries ( right upper limb swelling was more as compared to the left ) . she had leukocytopenia ( 2,400/cmm ) , thrombocytopenia ( 20,000/cmm ) , and normal prothrombin time , activated partial thromboplastin , and thrombin times and fibrinogen levels . neck ultrasonography ( usg ) prior to an attempt of right ijv cannulation revealed a non - compressible right ijv along with absence of venous flow in color doppler strongly suggestive of right ijv thrombus . her left ijv and scv were compressible ( checked by using linear ultrasound probe supraclavicularly ) and patent , hence we inserted the central line in the left scv for hemodynamic monitoring , fluid resuscitation and vasopressor use . echocardiography showed mild tricuspid regurgitation with ejection fraction < 55% with mild dilatation of main pulmonary arteries . urgent thoracic computed tomography ( ct ) angiography revealed left distal pulmonary artery thrombosis [ figure 1 ] . we immediately started unfractionated heparin ( loading dose : 80 u / kg followed by continuous infusion @ 20 u / kg / hr . ) to achieve a target activated partial thromboplastin time ( aptt ) of 2 - 2.5 times the normal . further investigations demonstrated apc - r using the test kit sta -staclot apc - r ( diagnostica stago , asnieres , france ) and genetic markers for thrombosis using polymerase chain reaction showed homozygous to factor v leiden mutation . after achieving the target aptt , oral vitamin k anticoagulants ( ovka ) in the form of warfarin 5 mg was started along with the heparin to aim international normalized ratio ( inr ) of 2 - 2.5 . her other supportive management included fluids , sedation , vasopressors , broad spectrum antibiotics , enteral nutrition , and mechanical ventilation . in the meantime , dengue igm enzyme - linked immunosorbent assay ( elisa ) ( dengue igm capture elisa , panbio , australia ) was also found to be positive . within the next week after the shock recovered , we did thrombophilia testing of this patient [ table 1 ] . but , her right ijv and scv thrombus persisted with partial recanalization in follow up usg [ figure 2 ] . importantly , her father , mother , and younger sister underwent factor 5 leiden mutation test which was tested negative . computer tomography angiography scan of thorax coronal view showing pulmonary artery thrombus ( arrowed ) usg scan of right ijv ( 1 ) showing presence of partial thickness thrombus ( 2 ) and right carotid artery ( 3 ) ( follow up pictures ) thrombosis screening in our patient apc - r is an autosomal dominant abnormality leading to thrombophilia due to point mutation ( position 1691 ) in the factor v gene . with this mutation , factor v becomes unresponsive to proteolytic action of activated protein c. thus protein c resistance occurs and resulting in uninhibited coagulation and intravascular thrombosis . the clinical picture is of spontaneous intravascular thrombosis at an early age ( > 45 years ) in an unusual venous site or pulmonary embolism or recurrence . hence after radiological confirmation of right ijv thrombus and thoracic ct angiography , thrombophilia testing was initiated . age of the patient and unusual venous site thrombus with distal pulmonary artery thrombus prompted us to send thrombophilia testing for secondary prevention .. additionally , we did testing for homocysteine levels which were very low in our patient . epidemiological studies have proved that increased homocysteine level is a risk for venous thrombosis , but the recent evidence has also challenged this concept . antibodies against dengue antigen nonstructural protein 1 ( ns1 ) can cross - react with endothelial cells , leading to endothelial activation and expression of more cytokine , chemokines , and adhesion molecules , resulting in widespread endothelial cell damage . dengue virus infected endothelial cells can inhibit prostacyclin release and intensify von willebrand factor release from endothelial cells . similar intravascular thrombosis is also known with sepsis of any cause . in our case , we believe that central venous thrombosis was due to dengue infection mediated endothelial injury or dengue virus sepsis syndrome induced . venous thromboembolism in patients with factor v leiden mutation related heritable thrombophilias is managed with anticoagulants . ovka , like warfarin , are preferred with a target inr of 2.5 ( range 2.0 - 3.0 ) . the duration of anticoagulant therapy ( 3 - 6 months ) is based on the risk factors , no of events , recurrence , and area of involvement . after a first episode , like in this case , the british committee recommends anticoagulation for 6 months . this case report elaborates about a rare incidence of spontaneous central vein thrombosis in a patient of acp - r . the relation between dengue infections and dengue viral sepsis with spontaneous thrombosis in a predisposed patient was also explored . this case report also emphasizes the significance of usg as fortuitous detection of central vein thrombosis during usg for venous access .

spontaneous central vein thrombosis is a rare and potentially fatal condition in critical care setting . activated protein c resistance due to homozygous factor v leiden mutation is an exceptional cause of central venous thrombosis . we recently treated a healthy female student who presented with acute febrile illness , septic shock , and encephalopathy . neck ultrasonography ( usg ) prior to an attempt of right internal jugular vein ( ijv ) cannulation revealed non compressibility of the vein along with absence of venous blood flow . right ijv and subclavian vein thrombus was confirmed subsequently in usg doppler by radiologist . radiological evidence of distal pulmonary artery embolism in pulmonary angiography was also evident . further investigations demonstrated homozygous factor v leiden mutation and activated factor c resistance and dengue igm positivity in our patient . intravenous heparin followed by oral vitamin k anticoagulants ( ovka ) aided in her recovery . spontaneous intravascular thrombosis with activated protein c resistance and the relationship of acute dengue infection were explored in our report .

occupational health risks and hazards due to polluted environment have become a serious public health concern where there is unplanned urbanization . pollution due to road traffic is a serious health hazard and thus the persons like traffic police who are continuously exposed may be at an increased risk [ 1 , 2 ] . the traffic police have to undergo physical strain in an environment polluted by fumes , exhaust of vehicles , use of blowing horns , emission from nearby brick factories , and blow of dust in the air by a speeding vehicle . the traffic situation in kathmandu metropolis is dominated by an enormous increase of motorized vehicles . altogether 688,026 vehicles have been added to the bagmati zone from 1990 to 2013 and most of them are being added to the already congested roads of the kathmandu valley . of the total vehicles , only 2.7% of vehicles are public while 92.1% of vehicles are privately owned . according to a report from clean air network nepal , motorcycles dominate the vehicles composition by 73.2% and car / jeep / van by 18.5% . a study shows that vehicle flow in kathmandu is two - wheelers ( motorcycles ) ( 77.5% ) , taxi ( 8.2% ) , car / jeep / van ( 7.6% ) , truck / mini truck ( 1.9% ) , bus / minibus ( 1.7% ) , and microbus ( 1.6% ) . air pollution from vehicles is the complex function of fuel characteristics , extents of combustion , reactions with other gases , and atmospheric condition . . however , adulteration ( mainly with kerosene ) in such fuels can increase ambient air pollution . a study in nepal showed that existing diesel ( commercially dispensed at automotive fuel pump stations ) indicated presence of 3050% kerosene in diesel . in nepal , air quality crisis in cities is mainly due to increased vehicular emission , rampant construction works , and unmanaged factories [ 8 , 9 ] . the world health organization ( who ) has found kathmandu as one of the most polluted cities in asia with regard to pm10 ( particulate matter ) and pm2.5 level in ambient air . adverse health effects due to air pollution range anywhere from minor irritation of eyes and the upper respiratory system to chronic respiratory disease , heart disease , lung cancer , and death . the particles emitted from the vehicular exhaust of more than 10-micron size are held in upper respiratory tract and particles less than 10-micron size accumulate in the lung and produce respiratory abnormalities . according to the who , outdoor air pollution caused about 3.7 million premature deaths worldwide in 2012 , 88% of those occurring in low- and middle - income countries . a study conducted in 2006 in nepal revealed a fact that over 1,900 premature deaths occur per year in kathmandu valley due to air pollution . according to the metropolitan traffic police office in singha durbar , as many as 50 traffic police personnel fall ill daily due to hazardous dust on the recently demolished but yet - to - be - reconstructed roads ( unpublished data ) . similarly , a study showed that the negative effect of air pollution on health of dwellers in kathmandu valley is extreme . therefore , this study aimed to assess the knowledge regarding respiratory problems among traffic police in kathmandu valley and common preventive measures adopted by them to prevent respiratory problems . a descriptive exploratory research was conducted among the traffic police working in six areas of kathmandu city from july to august 2013 . the selected areas were singha durbar , maharajgunj , kalanki , koteshwor , gaushala , and kalimati . these areas were selected randomly with the guidance from the ramshah path , kathmandu , metropolitan traffic police division . the list of all traffic police from each area was obtained from metropolitan traffic police division , ramshah path , kathmandu . the sample was selected as whoever was available in the selected area to fulfill the criteria of the study . however , those traffic police who were involved in administrative work and had less than 6 months of work experience were excluded from the study . close ended / open ended structured questionnaires were developed which included information regarding demography , knowledge , and practice on prevention of respiratory problems . all the questionnaires were translated into nepali language for the ease of respondents ( traffic police ) to answer the questions . the content of the questionnaire was developed by an extensive consultation with the public health experts and metropolitan traffic police division , ramshah path , kathmandu . the internal consistency of the questionnaires was obtained with cronbach 's alpha score of 0.83 for knowledge and 0.6 for practice . a total of nine traffic police officers were enrolled in the pilot study . after taking their feedback , seven out of the nine traffic police officers mentioned use of antipollution mask to protect from air pollution in knowledge - related questions . similarly , information regarding rotation in duty area was added in the final study as five out of nine traffic police officers mentioned it . the respondents were briefed on the purpose of the study beforehand and they were briefed on the details of the questionnaires . the respondents filled the questionnaire in the presence of the researcher and the questionnaire was immediately collected . similarly , permission was obtained from the metropolitan traffic police division , ramshah path , kathmandu . anonymity and confidentiality was maintained through the study and none was compelled to participate in the study . in the evaluation of level of knowledge of the respondents , in addition , multiple choice answer was awarded more than one mark for each correct answer . similarly , in the evaluation of level of practice of the respondents , a total of five questions regarding the preventive practice for respiratory problems were included . the ranking of respondents was done as follows : below average ( score < 50% ) , average ( score of 50% to 69% ) , and above average ( score 70% ) . the data was entered to and analyzed in statistical package for social sciences ( spss inc . , version 18 ) . descriptive statistics were made by using proportions , mean , and standard deviation ( sd ) , while inferential calculation was made using fischer 's exact test . majority of the respondents ( 94.0% , n = 78 ) were male and nearly four - fifth of the respondents ( 79.0% , n = 66 ) were married . regarding educational status , all the respondents had completed slc ( school leaving certificate ) and almost half of them had passed intermediate level . more than half of the respondents had 610 years of work experience , the mean ( sd ) years of experience being 7.9 ( 3.6 ) ( table 1 ) . among the effects of the pollution on respiratory system , the majority ( 84.3% , n = 70 ) responded with lung cancer followed by bronchial asthma ( 78.3% , n = 65 ) . more than ninety percent ( n = 75 ) responded with difficulty in breathing as a major sign and symptom when they get respiratory problems . similarly , among the ways , nearly four - fifth reported that the use of mask and about three - fifth reported that regular health checkup can prevent the effects of air pollution . about three - fourth reported that antipollution mask was a suitable mask to prevent air pollution ( table 2 ) . 88.0% ( n = 73 ) of the respondents had below - average level of practice to prevent respiratory problems . likewise , 41.0% ( n = 34 ) of the respondents had average level of knowledge regarding the prevention of respiratory problems ( figure 2 ) . the majority of the respondents ( 94.0% , n = 78 ) used masks during duty hours while more than half of the respondents had rotation in duty areas in order to prevent respiratory problems . less than one out of 10 respondents had regular health checkup ( table 3 ) . the level of practice was below average ( i ) in majority of respondents having intermediate level of education . in addition , there was no association between education and level of practice ( table 4 ) . the majority of respondents with 11 to 15 years of working experience had level of knowledge above average followed by respondents with 16 to 20 years of experience . 91.3% ( n = 43 ) of respondents with experience of 6 to 10 years had level of practice below average . there was an association between working experience and level of practice ( p = 0.04 ) ( table 5 ) . the present study showed that the traffic police had knowledge regarding the negative effects of air pollution on their health . they had knowledge that air pollution can cause difficulty in breathing , wheezing sound , lung cancer , bronchial asthma , and pneumonia . studies conducted in india have also found that there is increased risk of getting different respiratory problems when traffic police are exposed to polluted air for a longer time [ 2 , 15 ] . it is essential for traffic police to be aware of the problems especially related to respiration in cities like kathmandu . although majority of the traffic police had knowledge that they need to use antipollution mask , fewer of them felt like going for regular health checkup . regular checkups save lives even when there is no specific problem , since the absence of disagreeable symptoms does not necessarily guarantee that one is in good health . some studies have also shown decreased rates of invasive cancers and decreased mortality in people who undergo regular medical checkup [ 1618 ] . therefore , awareness creating activities and policies relating to regular health checkup and protection from polluted environment should be launched effectively . this study showed that the level of knowledge regarding the prevention of respiratory problems among the traffic police was comparatively higher than the level of practice . similar results were obtained in a study done in india ; the level of knowledge was found to be better in majority of traffic police while the level of practice was average . this might be due to financial problems faced by the traffic police as studies have suggested that socioeconomic factors play a role in the health seeking behaviors . in addition , lack of time management during duty periods could prevent attending regular health checkup [ 20 , 21 ] . nonetheless , they should be motivated to have healthy and safe practice against the pollution . a study revealed that the use of facial masks could help to reduce the negative effects of air pollution . a minority of the traffic police implemented rules in vehicles for less emission of gases in this study . this might be due to ineffective rules regarding prevention of vehicular emission . in kathmandu valley , vehicular emission is the major contributor to air pollution . a study done in kathmandu valley showed that the total estimated emission ( co , co2 , hc , nox , so2 , and pm10 ) was 7,231,053.12 tons / year , the majority of which was co2 ( 91.0% ) and co ( 5.0% ) . in addition , at the time of this study , demolition of buildings and construction of roads were in progress . this could have aggravated the condition of air , eventually deteriorating the health of the traffic police . the good health of traffic police and city dwellers is ensured only if the government implements vehicle inspection and emission testing effectively and ban on polluting vehicles . the present study showed that education affected the level of knowledge in prevention of respiratory problems among traffic police . however , there was no association between education and level of practice to prevent respiratory problems . the poor practice of the traffic police , despite better knowledge , has not been fully understood necessitating further research in this regard . this study also showed that working experience had association with the level of practice but not with the level of knowledge . a research work suggests that , with longer experience , people increase their level of performance . it is better to learn preventive measures against air pollution from experience and practice them in daily life . first , all traffic stations in kathmandu metropolis could not be taken into account due to budget limitation . second , it would have been better to observe the practices of the traffic police rather than to provide them with the questionnaires to fill them . in the future , research can be done by providing some interventions like training to the traffic police and observing the outcome in their knowledge and practice . other health effects such as hearing impairment , eye problems , hypertension , and respiratory functions can be studied among the traffic police . more than ninety percent of the traffic police mentioned that difficulty in breathing was a major sign and symptom when they get respiratory problems . among the ways , the use of mask and regular health checkup can prevent the effects of air pollution . the majority of the traffic police used masks during duty hours and had rotation in duty areas in order to prevent respiratory problems . the level of knowledge among the traffic police is adequate , but the level of practice on prevention of respiratory health problems is not satisfactory . association of level of practice was observed with working experience but not with education of the traffic police in kathmandu . it is the responsibility of the government and concerned authorities to deal with the issues and derive effective and sustainable solutions to ensure better health of traffic police in the city .

introduction . traffic police in kathmandu are continuously exposed to air pollution and are at an increased health risk . this study aimed to assess the knowledge and practice regarding prevention of respiratory problems among traffic police in kathmandu . methods . a descriptive exploratory study was conducted among the traffic police ( n = 83 ) working in six areas of the kathmandu metropolis from july to august 2013 . self - administered questionnaires were distributed to all the participants . results . the mean age ( sd ) of the respondents was 28.8 4.3 years . more than half of the respondents had 610 years of work experience , the mean ( sd ) years of experience being 7.9 ( 3.6 ) . the level of knowledge regarding the prevention of respiratory problems was better than the level of practice among the respondents . education of the participants did not affect the level of practice of the respondents while there was association between working experience and level of practice ( p = 0.04 ) . conclusion . since the preventive practice is poor , the government should come up with plans such as distribution of antipollution masks to improve the level of practice among traffic police to prevent respiratory problems .

calcifying fibrous tumor ( cft ) is a rare , usually solitary , benign tumor of uncertain etiology . we report an incidentally detected case of cft arising from the small intestine and associated mesentery . a 45-year - old man with no significant past medical history presented to a local emergency room with severe left groin pain . his evaluation included a ct scan of the abdomen and pelvis , which showed a 5 cm densely calcified right pelvic mass [ figure 1 ] . axial ( a ) and coronal ( b ) noncontrast ct scans show a 5 cm , densely calcified pelvic mass ( arrow ) and its intimate relationship with the adjacent small bowel loops he was subsequently referred to our center for sarcoma and bone oncology with a presumed diagnosis of soft tissue sarcoma . upon initial consultation , the treatment options discussed included obtaining a preoperative , diagnostic , image - guided core needle biopsy or proceeding directly to surgery . when it was explained to him that this mass required resection in any case and that the findings of a preoperative biopsy would not change treatment plans , the patient elected to proceed with surgery . at laparotomy , he was found to have a hard mass involving the distal small intestine . a small bowel resection with an en bloc resection of the involved portion of the mesentery was performed . intraoperative photograph shows a pedunculated mass on the small bowel mesentery histopathologic evaluation was consistent with a cft . the tumor exhibited a relatively hypocellular spindle cell proliferation , with dense collagen fibers and scattered to loosely aggregated lymphocytes and plasma cells [ figure 3 ] . low - power ( 10 ) photomicrograph stained with hematoxylin and eosin shows relatively hypocellular spindle cell proliferation ( bottom right corner ) , with dense collagen fibers ( arrow ) and scattered to loosely aggregated lymphocytes and plasma cells ( curved arrows ) based on this diagnosis , no further treatment was needed or recommended . the most common sites are the soft tissues of the extremities , pleura , or peritoneum.[13 ] involvement of the gastrointestinal ( gi ) tract is rare . the mean patient age is 34 years compared with 16 years for patients with cfts occurring in the superficial soft tissues . cfts have characteristic histologic features of a well - circumscribed mass composed of hyalinized , hypocellular , lamellar collagen ; bland spindle cells ; chronic inflammatory cell infiltrates ; and psammomatous or dystrophic calcifications . thought to represent a reactive process resulting from abnormal tissue healing , the lesions were previously called calcifying fibrous pseudotumor . however , due to a local recurrence rate of approximately 10% , these lesions were renamed cfts in the current world health organization classification . the most important differential diagnosis of cft of the gi tract includes other spindle cell tumors , such as desmoid tumor and gastrointestinal stromal tumor ( gist ) . desmoid tumors have a variable ct appearance depending on fibroblastic proliferation , fibrosis , collagen content , and vascularity . on ct scan , they usually appear as well circumscribed , homogeneous masses that may enhance with intravenous contrast . gists may occur along any part of the alimentary tract that contains smooth muscle , with stomach and small bowel being the most common locations . on ct scan , gists are usually enhancing , well - circumscribed solid masses . with increasing size there may be central necrosis , cavitation , and heterogeneous enhancement . gists have a submucosal origin with exophytic growth and displace rather than invade surrounding structures as they enlarge . calcification is rare , however , a gist of the sigmoid colon with a large calcified component has been reported . other radiologic differential considerations for a calcified pelvic mass include calcified lymph node , carcinoid , inflammatory myofibroblastic tumor ( imt ) , sclerosing mesenteritis , and extraskeletal osteosarcoma . a calcified lymph node may be the result of prior granulomatous disease or a treated lymphoma . correlation with the clinical history is also important . while small intestine carcinoids may extend into the mesentery , calcification in the mass , particularly dense calcification , is unusual . imt and sclerosing mesenteritis are included in a group of benign fibrous tumors / tumor - like lesions of the mesentery , linked histologically by the presence of fibroblasts or fibrosis and anatomically by location within the mesentery . imt is a benign , chronic inflammatory disorder of unknown etiology that may manifest as a solid mesenteric mass . sclerosing mesenteritis is a rare idiopathic disorder characterized by mesenteric masses composed of chronic , nonspecific inflammation . on ct scan , a rare case of extraskeletal osteosarcoma of the mesentery presenting as a large calcified mass in the pelvic cavity has been reported . ct scan findings are nonspecific and overlap with multiple other entities , and therefore warrant biopsy / excision . resection of cft is usually curative but because of the potential for local recurrences , patients should undergo periodic follow - up . there are no guidelines for specific screening or follow - up radiologic imaging . in summary , we present a patient with a rare case of cft of the gi tract discovered incidentally at imaging and treated with surgical resection . the patient is recurrence free at 1 year . in the absence of any distinctive imaging characteristics to distinguish cfts from other rare intra - abdominal soft tissue neoplasms , biopsy and/or resection

calcifying fibrous tumor ( cft ) is a rare benign mesenchymal tumor most commonly found in the soft tissues of the extremities and pleura . it is characterized by hyalinized collagenous fibrous tissue , with bland spindle cells , psammomatous or dystrophic calcifications , and focal lymphoplasmacytic infiltrate . cft of the gastrointestinal tract is exceedingly uncommon . we report a case of cft arising from the small intestine and associated mesentery ; this case was identified incidentally in an otherwise healthy 45-year - old man .

dyke - davidoff - masson syndrome ( ddms ) , reported first in 1933 refers to atrophy or hypoplasia of one cerebral hemisphere ( hemi atrophy ) , which is usually due to an insult to the developing brain in fetal or early childhood period . age of presentation depends on the time of neurologic insult , and characteristic changes may be seen only in adolescence . the clinical features of this syndrome are variable and depend on the extent of brain injury . it is characterized by cerebral hemiatrophy ( ch ) with prominent sulci , contralateral hemiplegia / hemiparesis with homolateral hypertrophy of the skull and paranasal air sinuses , elevation of the sphenoid wing and petrous ridge , facial asymmetry , seizures , mental retardation , and delayed developmental milestones . a 17-year - old female adolescent with a history of recurrent refractory seizures , hemiplegia and mental retardation reported to department of radiology for computed tomography ( ct ) assessment of brain . on examination , the ct brain showed right ch , lateral ventricular dilatation ( lvd ) , prominent sulci , and displacement of falx cerebri attachment with midline shift toward the atrophic side [ figure 1 ] . bone window image showed thick skull vault with widened diplopic space on the right when compared to left side [ figure 2 ] . there was the elevation of the petrous ridge and upward tilting of planum sphenoidale [ figure 3 ] along with narrowed right anterior and middle cranial fossae . the mastoid air cells on the affected side appeared larger than the other side [ figure 3 ] along with larger frontal , ethmoidal , and sphenoidal air sinuses . right cerebral hemiatrophy ( ch ) with prominent sulci , lateral ventricular dilatation ( lvd ) , falx displacement ( fd ) thick skull vault with widened diploic space ( sd ) elevated petrous ridge ( ep ) and larger mastoid air cells ( m ) ddms may be classified as congenital or primary and acquired or secondary . in congenital type , there is usually no apparent etiologic factor but most likely it may be due to intrauterine vascular occlusion involving middle cerebral artery territory and the symptoms are present at birth or shortly thereafter . in acquired type , the symptoms are related to central nervous system damage that occurs in the perinatal period or later . cerebral malaria and encephalitis , vascular abnormality such as coarctation of the midaortic arch , internal carotid hypoplasia or agenesia , reduced or absent middle cerebral artery . the largest series of ddms in the literature concluded male sex dominance ( 73.5% ) with left hemisphere involvement ( 69.2% ) among 26 patients with a mean age 11 . studies have reported delayed appearance of mental retardation and early appearance of seizures associated with cerebral atrophy after the onset of hemiparesis . the finding of right ch with lvd and prominent sulci and displacement of falx attachment with midline shift toward the atrophic side reflect a late onset of brain insult due to any of the acquired causes resulting in abnormal neuronal and glial proliferation or apoptosis during cortical development . prominent sulci will be absent when the brain insult occurs during embroyogenesis , where the formation of sulci and gyri are incomplete , but a shift of midline structures towards the disease side will be seen . the findings of thick skull vault with widened diplopic space , hyperpneumatisation of paranasal air sinuses and mastoid air cells on the affected side , elevation of petrous ridge and upward tilting of planum sphenoidale with a small anterior and middle cranial fossae may be due to insult to brain occurring during first 18 months to 23 years of life and compensatory adaptation to unilateral decrease of brain substance . patient with intractable hemiplegia / hemiparesis and seizures are the candidates for functional hemispherectomy with a success rate of 85% in carefully selected cases . prognosis is good when hemiparesis occurs after the age of 2 years , and there is the absence of prolonged or recurrent seizures . conditions that are associated with ch such as rasmussen encephalitis , silver 's syndrome , linear nevus sebaceous syndrome , progressive multifocal leukoencephalopathy , sturge weber syndrome , and fishman syndrome are to be differentiated from ddms . the present case exhibits classical features of the acquired type of ch involving right cerebral hemisphere . this case has deviated from the usual presentation of male predominance and left sided ddms . in cases of intractable seizures

dyke - davidoff - masson syndrome ( ddms ) refers to atrophy or hypoplasia of one cerebral hemisphere , due to an insult to the developing brain in fetal or early childhood period . age of presentation depends on the time of neurologic insult , and characteristic changes may be seen only in adolescence . male gender and left hemisphere are more frequently involved.a 17-year - old female adolescent with a history of recurrent refractory seizures , hemiplegia and mental retardation reported to department of radiology for computed tomography ( ct ) assessment of brain . on examination , she had facial asymmetry , delayed milestones , and spastic hemiplegia . the ct brain showed right cortical atrophy with ventricular dilatation , prominent sulci , and shifting of falx to the right side . bone window image showed asymmetry in skull vault thickness , the width of diploic space , the size of paranasal air sinuses and inclination of the petrous ridge between the affected and normal sides . as the above case deviates from the usual presentation of male left sided ddms , hence the report .

all procedures were conducted after approval from the cary institute of ecosystem studies institutional animal care and use committee . we conducted our research in dutchess county , new york , a region where human cases of anaplasmosis are rapidly increasing . we trapped hosts on the property of the cary institute of ecosystem studies ( millbrook , ny , usa ) during the peak abundance of larval blacklegged ticks ( ix . we held members of 10 mammal and 4 bird species ( table 1 ) for 3 days in cages with wire mesh floors suspended over pans lined with wet paper towels . ticks feeding on hosts were allowed to feed to repletion and drop from hosts into the pans , from which they were collected . in some cases , if hosts did not drop > 10 ticks within 3 days , we infested them with unfed larval ticks following methods described ( 8) . because no evidence has been found for transovarial transmission of a. phagocytophilum ( 9 ) or of infection in larval ticks , these infestations likely did not affect host exposure to the pathogen . hosts that had been infested were held for an additional 4 days , and engorged ticks were collected each day . all engorged larval ticks were held in moistened glass vials at constant temperature and humidity until they molted into the nymphal stage . newly molted nymphs were flash - frozen in liquid nitrogen and stored at 80c . * number of ticks tested per host can include samples from either natural body loads or experimental infestations , as described in the text , and is not representative of mean total body loads . dna extraction was conducted as described ( 7 ) . to amplify extracted dna , we used protocols reported by courtney et al . briefly , we used primers apmsp2f and apmsp2r and probe apmsp2p , which are specific for the msp2 gene of a. phagocytophilum and generate a 77-bp fragment . real - time pcr was performed by using a cfx96 real - time pcr system ( bio - rad , hercules , ca , usa ) . we used extracted dna from unfed larval ticks and ultrapure water as negative controls to account for potential contamination during the extraction and pcr processes , respectively . ticks were considered positive for a. phagocytophilum if any 1 of 3 replicate samples showed amplified dna for a. phagocytophilum relative to negative controls . ticks with marginal results ( i.e. , moderate fluorescence ) were tested a second time with the same primers and sybr green dye . for these confirmatory tests , we included a melt curve analysis in which we determined the temperature at which half of the pcr products had denatured . pcr products were heated from 70c through 85c , raising the temperature by 0.5c every 10 s. positive controls consistently had melting point maxima of 80.5c . using a topo - ta cloning kit ( invitrogen , carlsbad , ca , usa ) , we cloned and sequenced 140 fragments that had a melting point of 80.5c . identity of sequences was confirmed by conducting blast searches ( national center for biotechnology information , bethesda , md , usa ) of genbank using the blastn algorithm ( 11 ) . one hundred thirty - one of 140 fragments were identified as a. phagocytophilum ; the remaining 9 fragments either had poor - quality sequences or did not have the cloning vector inserted . if any replicate was positive in the confirmatory test , ticks were considered positive for a. phagocytophilum . if all 3 replicates in the confirmatory test showed marginal or negative results , the ticks were considered negative . reservoir competence for each host species was calculated as the average percentage of ticks infected per individual host . using data for 4,640 ticks collected from 254 animals over 3 years , we assessed levels of reservoir competence for 14 host species ( 10 mammals and 4 birds ) ( table 1 ) . short - tailed shrews , white - footed mice , and eastern chipmunks had mean levels of reservoir competence > 10% ( figure 1 ) . all other hosts , including opossums , gray and red squirrels , and all 4 species of birds , had mean levels of reservoir competence ranging from 2% to 10% . reservoir competence differed significantly among these 11 species ( f = 2.294 , df = 10,232 , p = 0.014 , by 2-way analysis of variance ) . southern flying squirrels , striped skunks , and masked shrews all transmitted a. phagocytophilum to ticks , but our sample sizes were too small to draw strong conclusions about reservoir competence . for species that we collected in abundant numbers in multiple years ( > 4 animals in > 2 years ) , reservoir competence of each species did not vary significantly from year to year ( p>0.10 for all species tested , by analysis of variance or kruskal - wallis tests as appropriate ) ( figure 2 ) . mean reservoir competence of 14 host species ( 10 mammals and 4 birds ) for anaplasma phagocytophilum , southeastern new york , usa , 20082010 . error bars indicate se . reservoir competence is defined as the mean percentage of ticks infected by any individual host of a given species . single - letter abbreviations for genera along the left indicate blarina , didelphis , glaucomys , mephitis , peromyscus , procyon , sciurus , sorex , tamias , tamiasciurus , catharus , dumetella , hylocichla , and turdus , respectively . mean reservoir competence of 14 host species ( 10 mammals and 4 birds ) for anaplasma phagocytophilum , southeastern new york , usa , 20082010 . reservoir competence is defined as the mean percentage of ticks infected by any individual host of a given species . for inclusion , no species showed significant variation in reservoir competence across years ( p>0.10 , by 2-way analysis of variance or kruskal - wallis test as appropriate , for all species tested ) . single - letter abbreviations for genera along the left indicate blarina , didelphis , peromyscus , procyon , sciurus , tamias , catharus , and turdus , respectively . our data contradict several assumptions about the role of hosts in infecting ticks with a. phagocytophilum . first , the role of the white - footed mouse in infecting ticks has been controversial ( 2 ) . our data suggest that although the mouse is a major reservoir , short - tailed shrews and eastern chipmunks have comparable levels of reservoir competence . in addition , previous work has suggested that chipmunks , skunks , and opossums do not infect feeding ticks ( 12 ) . at our sites , thus , the potential for these hosts to contribute to human risk for hga should not be ignored . * infected hosts are those that transmitted a. phagocytophilum to > 1 ixodes scapularis tick larva . host species with < 10 individual hosts sampled . because hosts are capable of clearing a. phagocytophilum infections ( 13 ) , surveys of host exposure might not represent species - specific probabilities of transmitting the pathogen to uninfected ticks . instead , the role of particular species in contributing to the pool of infected ticks is best assessed by determining host reservoir competence using field - captured animals that usually carry ticks . on the basis of the community of hosts we sampled , small mammals are most responsible for infecting uninfected larval ticks in nature , and this result is consistent across years .

fourteen vertebrate species ( 10 mammals and 4 birds ) were assessed for their ability to transmit anaplasma phagocytophilum , the bacterium that causes human granulocytic anaplasmosis , to uninfected feeding ixodid ticks . small mammals were most likely to infect ticks but all species assessed were capable of transmitting the bacterium , in contrast to previous findings .

chronic subdural hematoma ( csdh ) is one of the most common disorders in the field of neurosurgery.2 ) the current understanding of the mechanism of development of csdh is that damage to the bridging veins by minor head trauma results in a collection of hematomas in the subdural space.15 ) then , the hematomas form a vessel - rich outer membrane.18,21 ) fragility of this neovasculature leads to repeated microbleeding and increases the permeability of the membrane , resulting in the development of csdh.2,3,13,14 ) the known risk factors of csdh are trauma , old age , brain atrophy , alcohol abuse , seizure , coagulopathy , the use of anti - platelets , and the use of anticoagulants.7,10 ) in this study , we focused on the fact that some patients do not develop csdh after head trauma and proceed through therapy without any complications , while others need additional surgeries to treat csdh . assuming there are differences between the patients who develop csdh and those who do not , we investigated the various known risk factors , along with the computed tomographic findings at the time of the head injury . we conducted a survey of 277 patients who scored over 13 on the glasgow coma scale who received treatment at our institution after minor head trauma in the period from january 2012 to december 2013 . all the patients did not require surgery at the time of their arrival . during the follow - up period , the 20 patients who required surgery to treat csdh were designated as the patient group , while the remaining 257 patients who did not develop csdh after minor head trauma and completed treatment were selected as the control group . head trauma , out of many other factors , was set as the controlled variable . age , gender , and the history of diabetes mellitus ( dm ) , hypertension , cerebral infarction , cardiac disease , hematologic disease , and epilepsy were investigated as the factors contributing to progression of csdh after minor trauma . the medication history of antiplatelet and anticoagulant agents was also surveyed , as well as the smoking and drinking habits of subjects . the presence of acute subdural hematoma ( asdh ) in the convexity , accompanying hemorrhage and encephalomalacia , and the maximum distance from skull to cerebral parenchyma ( figure 1 ) were investigated by examining the patients ' initial computerized tomography ( ct ) scans . in our study , the diseases that could cause coagulopathy , such as hematological malignancies , were defined as hematologic disease . in cases where the patients ' initial brain ct scans showed cerebral contusion , subarachnoid hemorrhage , epidural hemorrhage , or intracerebral hemorrhage , we defined the finding as an accompanying hemorrhage . statistical analyses included chi - square test , fisher 's exact test and multivariate logistic regression analysis to assess the relationship between csdh and various factors . demographic data , medical history , social history , and ct findings are summarized in table 1 . the number of patients enrolled in the study was 277 , with an age range of 0 to 94 years , and a mean age of 53.9 years . the average age of the patient group was 67.5 years , while that of the control group was 52.9 years , showing that the patient group was statistically significantly older than the control group ( p=0.014)(figure 2 ) . thirteen male patients ( 65% ) and 7 female patients ( 35% ) were in the patient group , while 173 male patients ( 67.3% ) and 84 female patients ( 37.7% ) made up the control group with males contributing a little higher number in both groups , without a noticeable significance in the gender difference ( p=0.832 ) . in the patient group , there were 7 ( 35% ) patients with dm and 12 ( 65% ) patients with hypertension , while there were 35 ( 13.6% ) patients with dm and 90 ( 35.0% ) patients with hypertension in the control group . the presence of dm or hypertension showed a statistical significance between groups ( p=0.010 , p=0.026 ) . the numbers of the patients with a history of cerebral infarction were 3 ( 15% ) in the patient group and 11 ( 4.3% ) in the control group , which was also statistically significant ( p=0.035 ) . with regards to medication history , the administration of antiplatelet agents presented a statistically significant difference between the two groups ( p=0.000 ) ; 10 in the patient group ( 50% ) , 45 in the control group ( 17.5% ) . the brain ct scans taken on the time of admission were examined . a higher percentage of subjects in the patient group ( 15 patients , 75% ) had asdh in the convexity from the trauma than that of patients in the control group ( 78 patients , 28.4% ) at a level of statistical significance ( p=0.000 ) . four subjects in the patient group ( 20% ) had encephalomalacia , while 17 patients ( 6.6% ) in the control group had the affliction with statistically significant ( p=0.029 ) . the brain ct scans taken right after the trauma were used to measure the maximum distance between the skull and the cerebral parenchyma . the average maximum distance of the patient group ( 7.15 mm ) was much longer than that of the control group ( 1.35 mm ) and the difference was statistically significant ( p=0.000)(figure 3 ) . the receiver operating characteristic curve was drawn by plotting the occurrence of csdh according to the maximum distance between the skull and the brain parenchyma . it was determined to be reliable test model due to its large area under the curve . we found that the distance between the skull and parenchyma as 3.52 mm can be a cutoff value , yielding 90.0% sensitivity and 90.7% specificity ( figure 4 ) . the multivariate logistic regression analysis was used to verify the correlation between the statistically significant factors and csdh occurrence . as a result , only the maximum distance between the skull and the cerebral parenchyma showed a reliable correlation with csdh occurrence ( p=0.000 ) , while the other factors failed to show any remarkable statistical significance ( table 2 ) . each group was classified according to the type of trauma . slipping down stood out as the most common cause of trauma but with no statistical significance between the two groups ( p=0.236)(table 3 ) . unlike other studies,7,10 ) this study demonstrates that the presence of dm or hypertension significantly influences the occurrence of csdh after minor head trauma . on the contrary , a study conducted by yamamoto et al.22 ) reported that the hyperglycemia in dm patients leads to the hyperviscosity of blood and increases the intravascular osmotic pressure , resulting in a reduced probability of csdh recur . however , considering the fact that one of the major complications of dm is capillary vasculopathy such as retinal hemorrhage , and the fact that micro - bleedings and the exudation of immature capillaries surrounding the csdh outer membrane are the major mechanisms in developing csdh , the capillary vasculopathy in dm patients affects the immature capillaries around the outer membrane of the subdural hematoma after head trauma , and consequently results in the development csdh.20 ) also , in the case of patients with hypertension , higher blood pressures put more pressure on the immature capillaries around the outer membrane have to endure , increasing the probability of repeated capillary injuries and micro - bleedings . even though there are few preexisting studies on the impact of hypertension on the csdh,8 ) additional studies need to be performed to confirm a correlation between hypertension and csdh . it is known that the old age is associated with csdh , as there is a higher csdh prevalence rate among the elderly.1,5,6 ) the fragility of the bridging veins and accompanying cerebral atrophy from the aging process are considered as the major factors causing the increased prevalence.5,19 ) as aging progresses , the volume of the cerebral parenchyma shrinks , resulting in an increase of the subdural space between the skull and the cerebral parenchyma . the enlarged subdural space enables the brain to move around the skull while patient ambulates , and the vulnerable bridging veins can be injured easily with a minor head trauma.9,12,23 ) the correlation between the occurrence of csdh and old age was also confirmed in this study , and there was a tendency to develop post - traumatic csdh among the patients with larger subdural spaces due to cerebral atrophy . the reason why the history of cerebral infarction and the presence of encephalomalacia are correlated with csdh occurrence in this study can be explained by considering the same mechanism described above . the presence of encephalomalacia after the brain injury , such as cerebral infarction , results in the reduction of brain parenchyma volume , which enlarges the subdural space between the skull and brain parenchyma , and consequently results in higher tendency of post - traumatic csdh.16 ) a study from lindvall and koskinen,10 ) which analyzed 71 patients with csdh concluded that the administration of antiplatelet or anticoagulation agents contributed a significant difference in csdh occurrence in the patients without trauma compared to the patients with trauma . another study conducted by reymond et al.17 ) analyzing 198 patients with severe head trauma also reported that there was a statistical significance between the administration of antiplatelet or anticoagulation agents in csdh occurrence . considering the analogous result in the preceding two studies , the same outcome was expected when analyzing our data . however , there was no statistically significant difference between using anticoagulation agents and the occurrence of csdh , while there was a significant correlation between the use of antiplatelet agents and the occurrence of csdh . while the preceding studies analyzed patients who already developed csdh or had severe head trauma , we included all the patients with minor head trauma , which may explain the difference in the outcome . also , the fact that the patient group only had a limited number of the patients may be related to the difference as well . it was expected that there would be a correlation between csdh occurrence and the patients with cerebral infarction or with cardiac disease , as they are commonly administered antiplatelet or anticoagulant agents.10 ) the actual study showed a higher ratio of patients with cerebral infarction or cardiac disease in the patient group than in the control group . however , only the history of cerebral infarction demonstrated a statistically significant difference , while the presence of cardiac disease failed to show a statistical significance . with regard to cerebral infarction , aside from using antiplatelet agents or anticoagulants , other co - factors , such as a decrease in brain volume due to encephalomalacia after infarction , could influence the outcome . also , the insufficient number of the patients analyzed in the patient group is likely the reason why we could not find a significance relationship between csdh occurrence and the presence of cardiac disease . generally , the hematologic diseases that cause coagulopathy are known to be risk factors for post - traumatic csdh occurrence.1,4 ) the history of epilepsy is also expected to be a risk factor of csdh since it can cause repeated seizures.1,11 ) we began our analysis considering these known concepts , but the history of hematologic diseases and epilepsy showed no significant differences in our study . yet , there was no patient with a history of hematologic diseases or epilepsy in the patient group , and a very small number of the patients with a history of hematologic diseases ( 1.1% ) or epilepsy ( 1.4% ) were present among the entire test population . it is assumed that the limited number of patients analyzed in the study impacted the result as well . limitations of the current study include the small number of patient group and the retrospective nature of the study design . however this study creatively demonstrated the predictive factors of csdh in patients with minor head trauma . based on the results of this study , the predictive factors of post - traumatic csdh occurrence are old age , preexisting dm , hypertension , and history of cerebral infarction , the presence of asdh in the convexity found in brain ct scans taken right after the trauma , encephalomalacia , and an enlarged subdural space between skull and brain parenchyma . when treating patients with minor head trauma accompanied by those risk factors , physicians must pay careful attention to the possibility of post - traumatic csdh and need to continuously observe the patients .

objectivechronic subdural hematoma ( csdh ) is relatively common in neurosurgical field . however not all patients develop csdh after minor head trauma . in this study , we evaluate the risk factors of post - traumatic csdh.methodstwo-hundred and seventy - seven patients were enrolled and analyzed in this study from january 2012 to december 2013 . of those , 20 participants had minor head trauma developed csdh afterward . we also included 257 patients with minor head trauma who did not develop csdh during the same follow - up period as the control group . we investigated the risk factors related to the development of csdh after minor head trauma.resultsold age ( p=0.014 ) , preexisting diabetes mellitus ( p=0.010 ) , hypertension ( p=0.026 ) , history of cerebral infarction ( p=0.035 ) , antiplatelet agents ( p=0.000 ) , acute subdural hematoma in the convexity ( p=0.000 ) , encephalomalacia ( p=0.029 ) , and long distance between skull and brain parenchyma ( p=0.000 ) were significantly correlated with the development of csdh after trauma . multivariate analysis revealed that only the maximum distance between the skull and the cerebral parenchyma was the independent risk factor for the occurrence of csdh ( hazard ratio 2.55 , p=0.000).conclusionwe should consider the possibility of developing csdh in the post - traumatic patients with the identified risk factors .

upper gastrointestinal bleeding ia a major emergency and represents a major public health problem , its prevalence being 100170:100000 people . bleeding from esophageal varices is only 511% of all gastrointestinal bleeding and in the u.s . approximately 30% of patients with compensated cirrhosis have esophageal varices when first diagnosed . in cirrhotic patients , life prognosis in a patient with upper gi bleeding from esophageal varices depends on the severity of the bleeding , the hepatic functional reserve ( stage of cirrhosis ) , the extent and location of the varices ( esophageal or gastric ) , their age , the existence of associated diseases and the treatment prescribed . the aim of this study was to monitor the risk factors that trigger variceal bleeding in cirrhotic patients , to assess the severity of the bleeding and the efficacy of the endoscopic hemostasis techniques , to assess the relapses of bleeding episodes and the mortality rate . the study was a prospective one , and it was conducted in the period 11.200412.2006 in the o. fodor regional institute of gastroenterology and hepatology , cluj - napoca ; 273 patients with variceal bleeding underwent upper gastrointestinal endoscopy for diagnosis and treatment in emergency conditions , at the office of digestive endoscopy of the o. fodor regional institute of gastroenterology and hepatology , cluj - napoca ; the study included only patients who had upper gastrointestinal bleeding because of variceal rupture , which was assessed by emergency endoscopic examination , performed within 6 hours of the patient s admission ; after identifying the variceal source of the upper gi bleeding , endoscopic therapy was performed ( elastic ligatures or endoscopic sclerotherapy with hypertonic glucose solution , depending on the possibilities under emergency conditions ) ; during periodical check - ups , the risk factors for variceal bleeding were monitored in cirrhotic patients , along with the efficacy of endoscopic treatment techniques , the relapses of bleeding episodes , the number and cause of deaths of cirrhotic patients who experienced upper gastrointestinal bleeding because of rupture of varices ; the patients included in the study met the clinical , biochemical , endoscopic and ultrasound criteria for liver cirrhosis ; the etiology and the staging of the disease were documented according to the patient s observation charts ; the results of the study were processed using excel ; quantitative data were expressed as median se ; the study was approved by the local ethics board of the prof . the average age of the patients included in the study was 57.86 years , the extremes being represented by 26 and 82 years ( figure 1 ) . regarding the gender distribution of patients , there were 167 male patients ( 61.17% ) and 106 female patients ( 38.83% ) . out of the 273 cases with variceal bleeding , 255 ( 93.4% ) were cases of bleeding from esophageal varices and 18 ( 6.6% ) were cases of gastric varices . thus , it occurs more frequently in patients with varices grade ii and iii . in our series there were 2 patients ( 0.73% ) with bleeding from esophageal varices grade i , 131 patients ( 47.98% ) with hemorrhage from esophageal varices grade ii and 122 patients ( 44.7% ) with bleeding from varices grade iii . gastric varices hemorrhage was found in 18 patients ( 6.59% ) ( figure 2 ) . . however , the risk of variceal rupture increases with the increased severity of the liver disease . thus , variceal bleeding occurred in 63 ( 23% ) patients in child class a , 109 ( 40% ) patients in child class b and 101 ( 37% ) patients in child class c. mortality caused by variceal hemorrhage was 2.93% in the study group . death occurred in 8 patients as follows : 1 was in child class a , 2 were in child class b and 5 in child c class . hence , the mortality of patients with variceal hemorrhage is closely related to the child class . variceal bleeding was more frequent in patients with alcoholic liver cirrhosis - 140 cases ( 51.28% ) ; the next highest frequency was in patients with c virus cirrhosis - 69 cases ( 25.27% ) , b virus liver cirrhosis - 21 cases ( 7.69% ) , followed by other etiologies - 43 cases ( 15.76% ) . some of the 273 patients with variceal bleeding also had significant comorbidities : liver carcinoma ( 45 cases ) , gastric cancer ( 2 cases ) , lung cancer ( 1 case ) , liver metastases ( 1 case ) , pregnancy 28 weeks ( 1 case ) , peritoneal carcinomatosis ( 1 case ) . initial variceal bleeding was arrested in 269 of the 273 patients admitted under emergency conditions , using endoscopic techniques for hemostasis therapy . the failure of the endoscopic techniques imposed the use of the sengstaken - blakemore probe in 4 patients . a number of 148 patients were treated by sclerotherapy and 125 patients by performing elastic ligatures . out of the 148 patients treated by sclerotherapy during the first bleeding episode , in 28 cases sclerotherapy was performed when the first bleeding relapse occurred , while in 16 cases elastic ligatures were performed . out of the 125 patients treated by elastic ligature during the first bleeding episode , in 9 cases sclerotherapy was performed when the first bleeding relapse occurred , while in 12 cases elastic ligatures were performed . three porto - caval shunt interventions were performed , in 3 male patients of 41 , 46 and 71 years of age . each of these three patients presented three episodes of variceal bleeding . in the case of the 71-year old patient bleeding recurrence occurred in 65 ( 23.8% ) patients of the study group , 43 men and 22 women ( figure 3 ) . the average age of those who experienced bleeding relapses was close to the average age of the group , which was 58.69 years . thirty - seven patients underwent endoscopic treatment by sclerosis of varices with 2 ml of hypertonic glucose in 812 points intra- and para - varices , while 28 patients underwent elastic ligatures ( 46 elastic rings ) . there were 17 cases of bleeding recurrence within 7 days of the first bleeding episode , 19 cases in the first month , 11 cases after 6 months and 18 cases after 1 year . the failure of emergency endoscopic treatment is defined as continued or recurrent bleeding within less than five days , in spite of the completion of two sessions of sclerotherapy . there are no predictors of the failure to indicate and require treatment change . in the study group there were 14 cases of bleeding relapses within the first 4 days of the endoscopic hemostasis . bleeding relapses were favored by the presence of hepatocarcinoma ( 26 patients out of the 65 patients with recurrent bleeding ) and by the child class c ( 23 patients ) . in the present study , out of the 65 patients with recurrent bleeding , 13 were not treated with propranolol while 9 were treated with small doses of propranolol . alcoholic cirrhosis was the dominant etiology in patients with recurrent bleeding ( 36 cases - 55.38% ) , while the child class c was found in 22 patients ( 33.84% ) . the results of the current study show that bleeding from esophageal varices is more frequent than from gastric varices ( 93.4% versus 6.6% ) . mention must be made that the rupture of the varices depends on the size of the variceal veins , and thus rupture is more frequent in patients with esophageal varices grade ii and iii . the data obtained in the present study are in keeping or similar to those shown in the speciality literature . variceal bleeding was more frequent in male patients , the data obtained being in keeping or similar to those shown in the specialty literature . the variceal hemorrhage prevailed in each clinical class and the variceal rupture risk increased with the increase in the severity of the liver disease . thus , the majority of patients with variceal bleeding were child class b or c ( 77% ) , our results overlapping those mentioned in literature . variceal bleeding was more frequent in patients with alcoholic liver cirrhosis ( 51.28% ) , the results being similar to those reported in literature . in the current study , 19% of the patients who had variceal bleeding also had significant comorbidities , the most frequent being hepatocarcinoma which has been reported as a significant predictive factor for death in decompensated cirrhosis and early rebleeding in several studies . bleeding relapses were frequent ( 23.8% ) and raised special problems related to the type of treatment ( sclerotherapy or ligation ) , to the therapeutic booster in order to eradicate esophageal varices , to the adjuvant medication therapy for portal hypertension ( beta - blockers ) or to invasive procedures for the treatment of portal hyper - tension ( tips ) or liver cirrhosis ( liver transplantation ) . bleeding recurred more frequently after sclerotherapy than after the application of elastic ligatures ( 29.72% versus 16.8% ) , the results of the current study being similar to those published in literature . approximately 34% of our patients experiencing bleeding relapses did not receive beta - blocker therapy or were given low - dose propranolol . for secondary prevention , a meta - analysis that compared beta - blockers plus isosorbide mononitrate versus endoscopic band ligation showed no significant differences between treatments in preventing rebleeding or in preventing deaths . however , in trials using a mean beta - blocker dose of less than 80 mg / day , endoscopic band ligation significantly reduced rebleeding compared with beta - blockers plus isosorbide mononitrate . in addition , earlier meta - analyses usually included trials in abstract form , of which complete data were not available . therefore , a further update of studies comparing endoscopic band ligation and pharmacological therapy should be performed . the study also showed that the severity and etiology of the liver disease ( cirrhosis ) may play a role in the risk for bleeding relapses . in the study group there were three porto - caval shunt interventions , each patient presenting three bleeding relapses during the period studied . mortality due to variceal hemorrhage was 2.93% in the study group , which was lower than that in the data published in the speciality literature . many studies have reported decreasing incidence and mortality rates of variceal bleeding by progress of treatment modalities . the significant decrease in mortality in other studies is probably due to the improvement in treatment modalities such as endoscopic treatment , transjugular intra - hepatic portosystemic shunt , and pharmacologic treatment including the use of prophylactic antibiotics and vasoactive drugs . the mortality of patients with variceal hemorrhage is closely related to the child class ( 62.5% - child c ) . however , the risk of variceal rupture increases with the increased severity of the liver disease . hence , the mortality of patients with variceal hemorrhage is closely related to the child class . variceal bleeding occurred more frequently in patients with alcoholic cirrhosis stage child c. in our study mortality was relatively low . hence , prevention methods against variceal rupture and the application of elastic ligatures are required as a means of treatment .

objectivesthe aim of this study was to monitor the risk factors that trigger variceal bleeding in cirrhotic patients , assess the severity of the bleeding and the efficacy of the endoscopic hemostasis techniques , as well as the recurrence of bleeding episodes and the mortality rate.materials and methodsthe current study was a prospective one , and it was conducted in the period november 2004 - december 2006 in the o. fodor regional institute of gastroenterology and hepatology , cluj-napoca.it included 273 patients with upper gastrointestinal bleeding because of variceal rupture , assessed by emergency endoscopy . the patients included in the study met the clinical , biochemical , endoscopic and ultrasound criteria for liver cirrhosis . its etiology and staging were documented from the patients observation charts.resultsout of the 273 cases of variceal bleeding there were 255 ( 93.4% ) cases of bleeding from esophageal varices and 18 ( 6.6% ) from gastric varices . variceal bleeding episodes were more frequent in patients with alcoholic liver cirrhosis ( 51.28% ) . most patients with variceal bleeding were in child class b or c ( 77% ) . mortality because of variceal hemorrhage was 2.93% in the study group . a number of 148 patients were treated by sclerotherapy and 125 patients with elastic ligatures . bleeding relapses occurred in 65 ( 23.8% ) patients within the study group , 43 men and 22 women . variceal bleeding relapses were more frequent after sclerotherapy than after elastic ligatures.conclusionsvariceal bleeding occurred more frequently in patients with alcoholic cirrhosis stage child c. in the current study mortality was relatively low . the treatment of bleeding recurrence is more difficult , hence variceal rupture prevention and application of elastic ligatures represent a therapeutic necessity .

it can occur in two separate triangular areas of the flank ( 1 - 3 ) . the superior triangle ( grynfeltt 's lumbar triangle ) is bound by the 12th rib superiorly , the internal oblique muscle inferiorly , and the sacrospinous muscles medially . the inferior triangle ( petit 's lumbar triangle ) is bound by the latissimus dorsi muscle posteriorly , the external oblique muscle anteriorly , and the iliac crest inferiorly ( 4 ) . . this may be because the liver pushes the right kidney inferiorly in development , leading to the protection of the lumbar triangles ( 5 ) . lh may contain a number of intra or retroperitoneal structures including large intestine , small intestine , stomach , kidney , spleen , and mesentery omentum . 25% of all lhs are secondary acquired that may be caused by blunt - penetrating or crushing trauma ; fractures of the iliac crest ; surgical lesion ; hepatic abscesses ; infection in pelvic bones , and ribs or lumbodorsal fascia ( 1 ) . the incidence depends on a number of risk factors including old age , sex , obesity , suture type and wound infection . here , a 55-year - old homeless man came to the emergency department ( ed ) with pain and a mass in his left flank . this mass was appeared about three hours before admission and his flank pain was slight at first but became more severe gradually . on admission , he had 18 per minute respiratory rate , 88 per minute pulse rate , 110/80 mmhg blood pressure , 90% o2 saturation in room air , and 37c auxiliary temperature . the pain score was about 9 to 10 according to visual analog scale ( vas ) . the only positive finding on physical examination was the sphere shaped , firm , mobile , and mild tender mass at his left flank ( figure 1 ) . there was a 5 cm scar on this site because of previous penetrating trauma injury due to a motor vehicle collision . there was an abdominal wall defect about 8 cm in diameter and bowel loop was trapped in the neck of hernia sac on computed tomography ( ct ) ( figure 2 ) . as a result , a petit 's triangle lh was diagnosed . finally , the report of surgery finding confirmed diagnosis . the patient s left flank mass abdominal computed tomography of patients the inferior lumbar hernia is less common because of attachment of external oblique and latissmus dorsi to the iliac crest . complications oflh include irreducibility , incarceration and strangulation ( 9 ) . in lh symptomatology limited to lower back pain . in less than 10% of cases if the defect is small , it can be closed with continuous polypropylene . for large defect , laparoscopic repair has been used in different reports with less pain and good functional result ( 11 ) . motor vehicle accidents are the most common cause of post - traumatic lhs ( 1 , 4 ) . if a lh is found after a motor vehicle accident , it is critical to assume that the patient has other intra - abdominal injuries . these patients should undergo urgent laparotomy because more than 60% of them will have major intra - abdominal injuries . all authors passed four criteria for authorship contribution based on recommendations of the international committee of medical journal editors .

lumbar hernias ( lh ) accounts for less than 1.5% of total hernia incidence . it can occur in two separate triangular areas of the flank . about 300 cases have been reported in the literature . here , we report a 55-year old man with acute painful left side flank mass and final diagnosis of lh . the mass was appeared about three hours before admission and his pain was slight at first but became more severe gradually . he had stable vital sign and the only positive finding on his physical examination was the sphere shape , firm , mobile , and mild tender mass at his left flank .

to report and describe a safe approach to laparoscopic cholecystectomy in patients with situs inversus totalis . we present the case of a 61-year - old male who was diagnosed with gallstones and situs inversus totalis during work - up for epigastric pain . laparoscopic cholecystectomy was performed in mirror - image to the standard approach , with the surgeon standing on the patient s right side . in order to maintain orientation and safety during the operation , anatomical structures were spatially related to each other in a medial and lateral manner , which are preserved in situs inversus ; rather than left and the duration of the operation was 85 minutes , which is slightly longer than our standard laparoscopic cholecystectomy . nonetheless , the patient was discharged on the morning following surgery , which is comparable to other patients undergoing laparoscopic cholecystectomy . he was seen in follow - up on postoperative day 14 and was doing very well . careful attention to unfamiliar anatomic relationships is important . approaching the anatomy in terms of medial and lateral structures , first described in 1600 , situs inversus totalis is a rare congenital anomaly with an autosomal recessive genetic pattern of inheritence , which is usually asymptomatic through adulthood . in the absence of rare cardiac anomalies , life expectancy is normal.1,2 situs inversus refers to a spectrum of mirror image transpositions of the thoracic viscera , abdominal viscera , or both , and is present in approximately 1 in 5,000 to 20,000 live births.2 there is no evidence to suggest that situs inversus predisposes to cholelithiasis or that cholelithiasis occurs with greater frequency in this population.3 similarly , symptoms of gallstone disease probably present with similar frequency as that of the general population . since the introduction of the technique in 1987 , there have been only approximately 30 cases of laparoscopic cholecystectomy performed in patients with situs inversus reported in the literature.4 here we report the unusual case of a patient with situs inversus totalis who presented with an episode of severe epigstric pain , and an eventual diagnosis of gallstone disease . while maintaining basic operative techniques in the dissection of the triangle of calot , but in mirror image , laparoscopic cholecystectomy was performed safely , with little increase in operative time , and a postoperative course comparable to standard cholecystectomy . the patient was a 61-year - old man with hypertension and prior hip replacement , who reported an episode of severe epigastric pain . at that time he presented to his primary care provider with nausea , although he tolerated liquids without difficulty . he was afebrile , his abdominal exam was significant for findings of epigastric tenderness , and liver function tests were abnormal . due to a prior history of acute hepatitis , he was discharged with planned follow - up . however , because of recurrent pain , the patient underwent an abdominal ultrasound examination that revealed a left sided gallbladder and gallstones , without gallbladder wall thickening or pericholecystic fluid . no stones were seen in the bile ducts and no biliary duct dilatation was appreciated . when seen by the surgical service , he was pain free and tolerating a low fat diet . an electrocardiogram demonstrated findings consistent with dextrocardia , including a right axis deviation , qrs complex in lead avr , and a negative qrs in lead i and avl . a computed tomography scan ( figure 1 ) confirmed situs inversus totalis with complete mirror image of thoracic and abdominal viscera . the liver and gallbladder were in the left upper quadrant and the spleen was in the right upper quadrant . multiple gallstones were seen in the gallbladder , and there was no evidence of intrahepatic or common bile duct dilatation . with a diagnosis of symptomatic cholelithiasis , the patient was scheduled for an elective laparoscopic cholecystectomy . at operation , the abdomen was insufflated to a pressure of 15 mmhg using a veress needle that was inserted at the superior umbilical fold . a 12-mm port was inserted into the abdominal cavity , through which a 5-mm , 30 degree laparoscope was inserted and the abdomen explored . situs inversus was confirmed with a right sided spleen and stomach , and left sided liver with a gallbladder in the left upper quadrant . a 5-mm epigastric port was inserted to the left of the falciform ligament , and two 5-mm ports were inserted along the left subcostal line . the surgeon stood to the right of the patient , and calot s triangle was dissected using the operator s left hand and a dissecting instrument through the epigastric port . in essence , the entire operation was performed as a mirror image of the standard laparoscopic cholecystectomy . the cystic duct and artery were clipped only after the critical view was achieved ( figure 2 ) . the gallbladder was dissected from the liver bed using electrocautery , was placed in a bag and removed through the umbilical port . cholecystitis in the setting of situs inversus can pose a diagnostic dilemma.1 however , with the aid of careful physical exam , electrocardiogram , and noninvasive imaging , the diagnosis of situs inversus should be made prior to laparoscopy.5 on physical exam , an apical beat in the right chest and liver percussion dullness over the left upper quadrant both suggest situs inversus . the electrocardiogram is consistent with right ventricular hypertrophy , and findings on chest x - ray , abdominal ultrasound , and computed tomography can each help secure the diagnosis . the first case of laparoscopic cholecystectomy in a patient with situs inversus was in 1991.6 to date , only 32 additional cases had been reported.4 here we report a case in which a patient presented with epigastric pain , but without left upper quadrant pain . although the total number of patients is small , it is suggested that this presentation pattern is present in 30% of patients with cholecystitis and situs inversus.7 there have even been reports of patients presenting with right - sided pain alone.8 there is no clear anatomical explanation for this observation , but it may be related to incomplete inversus of the autonomic nervous system . although some reports suggest adjusting port placement to accommodate for a right - handed surgeon , we opted to perform the operation in complete mirror image to the conventional laparoscopic technique , as previously described.3,5,6 this requires that the entire dissection be performed with the left hand , and thus may favor the left - handed or ambidextrous surgeon . slow and meticulous dissection at the triangle of calot results in safe exposure of the cystic duct and artery ( figure 2 ) . we found it helpful to approach the anatomy in terms of medial and lateral relations , rather than left and right , since the medial and lateral anatomical relations in situs inversus are preserved . strongly right - dominant surgeons have found other port arrangements to be helpful that allow the majority of the dissection to be performed with the right hand.7,9 thus , the right - dominant surgeon can move their body to dissect the triangle of calot using their right hand in the epigastric port , while allowing their assistant to retract hartmann s pouch . alternatively , the lateral ports can be moved slightly caudally and the dissecting hand can be placed in one of those ports , while the left hand retracts the gallbladder fundus through the epigastric port . no matter which configuration is used , it is important to clearly dissect the cystic duct and artery , stay close to the inferior gallbladder edge , and obtain the critical view of safety prior to transecting any structures . this is true of all laparoscopic cholecystectomy , but especially true in this case , in which the patient s anatomic configuration is not familiar . some surgeons may opt to selectively perform a cholangiogram to delineate ductal anatomy.10 we found that following these basic principles , and continually verifying the anatomy with respect to preserved medial versus lateral relationships , allows for laparoscopic cholecystectomy to be performed safely and expediently in patients with situs inversus totalis .

purposeto report and describe a safe approach to laparoscopic cholecystectomy in patients with situs inversus totalis.methodswe present the case of a 61-year - old male who was diagnosed with gallstones and situs inversus totalis during work - up for epigastric pain . laparoscopic cholecystectomy was performed in mirror - image to the standard approach , with the surgeon standing on the patient s right side . in order to maintain orientation and safety during the operation , anatomical structures were spatially related to each other in a medial and lateral manner , which are preserved in situs inversus ; rather than left and right which are reversed.resultsthe duration of the operation was 85 minutes , which is slightly longer than our standard laparoscopic cholecystectomy . nonetheless , the patient was discharged on the morning following surgery , which is comparable to other patients undergoing laparoscopic cholecystectomy . he was seen in follow - up on postoperative day 14 and was doing very well . there were no postoperative complications.conclusionlaparoscopic cholecystectomy can be performed safely in patients with situs inversus totalis . careful attention to unfamiliar anatomic relationships is important . approaching the anatomy in terms of medial and lateral structures , a relationship that is preserved , is helpful to complete the procedure safely .

prescription is the written order of the physician which is directly conveyed to the patient . it contains information pertaining to dose of the drug , route of administration , frequency of administration . prescribing appropriate drugs in right doses is an integral part by which a physician can influence the patient 's health and well - being . drug plays an intrinsic role in maintaining and restoring health as well as to combat diseases . however , irrational use of drugs can lead to adverse drug reaction and negative socio - economic impact . to promote rational use of drugs , international agencies like the world health organization ( who ) and the international network for the rational use of drugs , have emphasized treatment of diseases by the use of essential drugs , prescribed by their generic names . internship is the period where students after passing final mbbs examination undergo medical apprenticeship under the supervision of a consultant . he is expected to learn clinical skills , perform routine clinical procedures and exhibit a good clinical judgment to arrive at patient management decision . most of the budding doctors are unaware of the fact that prescribing errors contribute significantly in escalating occurrence of adverse events . internship is the period where undergraduate medical education can be consolidated through continued learning and acquisition of knowledge and skills under the direct supervision of teachers . their attitude toward good prescribing , rational drug use is of utmost importance as they constitute the future generation of doctors . they should know how to prescribe safely and correctly and for this the knowledge and understanding , skill and attitude is required by medical graduates . a literature search was conducted , which consisted of a medical literature analysis and retrieval system online database search ( accessed on 16.4.2010 ) and a world wide web search ( search engine : google , accessed on 16.4.2010 ) using the following keywords : prescribing pattern and intern and study . the search revealed that very few studies have been conducted to assess the prescribing pattern of interns . our study was conducted against this backdrop with the objective of exploring the prescribing pattern of interns in a medical college . a cross - sectional study was conducted in the primary health center attached to the institute for a period of 2 months ( june 1 2010-july 30 2010 ) . prior permission was obtained from institutional ethics committee for conducting the study . in this study , the primary health center which has been visited by the interns of the institute was considered to be the primary sampling unit . as per who recommendations , a study of a single health facility should measure facility specific prescribing indicators with a 95% confidence limit 10% . accordingly , it has been recommended that at least 600 encounters should be included in a cross - sectional survey with a greater number if possible . in the present study batches of 25 internees of the institute visited the center twice a week accompanied by a faculty member from the department of community medicine and provided medical service to the villagers . a resident from department of pharmacology used to visit the health center during the study period for the purpose of data collection . data collection was done by attaching a plain white paper along with a carbon paper with the original prescription form at ticket registration counter . the carbon copy of that prescription form was taken from the patient before he / she leaves the health center . details of the prescription were entered into a previously prepared proforma . in the current piece of work , who suggested criteria were used to assess the rationality of the prescriptions , which are enumerated below : therapeutic indication of the prescribed drugdose strength and dosage scheduleduration of therapyfixed - dose combinations ( fdcs ) prescribed : rational or not . therapeutic indication of the prescribed drug dose strength and dosage schedule fixed - dose combinations ( fdcs ) prescribed : rational or not . any prescription which fails to comply with any of the above mentioned criteria were considered irrational . the rationality of first three criteria were judged as per standard treatment guidelines , issued by government of west benga and national formulary of india . for the fourth criteria , only those fdcs mentioned in the current version of who formulary ( 17 list , 2011 ) and national essential drug list ( edl ) of india ( 2011 ) were considered rational . data obtained were analyzed in computer by using statistical package for social sciences program version 10 ( chicago , il , usa ) . data analysis was done by using descriptive and inferential statistical methods : frequencies , percentage , and mean standard deviation . a cross - sectional study was conducted in the primary health center attached to the institute for a period of 2 months ( june 1 2010-july 30 2010 ) . in this study , the primary health center which has been visited by the interns of the institute was considered to be the primary sampling unit . as per who recommendations , a study of a single health facility should measure facility specific prescribing indicators with a 95% confidence limit 10% . accordingly , it has been recommended that at least 600 encounters should be included in a cross - sectional survey with a greater number if possible . in the present study batches of 25 internees of the institute visited the center twice a week accompanied by a faculty member from the department of community medicine and provided medical service to the villagers . a resident from department of pharmacology used to visit the health center during the study period for the purpose of data collection . data collection was done by attaching a plain white paper along with a carbon paper with the original prescription form at ticket registration counter . the carbon copy of that prescription form was taken from the patient before he / she leaves the health center . details of the prescription were entered into a previously prepared proforma . in the current piece of work , who suggested criteria were used to assess the rationality of the prescriptions , which are enumerated below : therapeutic indication of the prescribed drugdose strength and dosage scheduleduration of therapyfixed - dose combinations ( fdcs ) prescribed : rational or not . therapeutic indication of the prescribed drug dose strength and dosage schedule fixed - dose combinations ( fdcs ) prescribed : rational or not . any prescription which fails to comply with any of the above mentioned criteria were considered irrational . the rationality of first three criteria were judged as per standard treatment guidelines , issued by government of west benga and national formulary of india . for the fourth criteria , only those fdcs mentioned in the current version of who formulary ( 17 list , 2011 ) and national essential drug list ( edl ) of india ( 2011 ) were considered rational . data obtained were analyzed in computer by using statistical package for social sciences program version 10 ( chicago , il , usa ) . data analysis was done by using descriptive and inferential statistical methods : frequencies , percentage , and mean standard deviation . during the study period , a total of 760 prescriptions were analyzed and the total number of drugs prescribed amounted to 1968 . average number of drugs per prescription was 2.58 , while the number of drugs per prescription varied from 1 to 7 [ detailed in table 1 ] . the frequency of drug administration was mentioned in 726 ( 95.52% ) of the prescriptions , while the duration of therapy was recorded in 586 ( 77.1% ) of them . analgesic was the most commonly prescribed drug ( 25.78% ) followed by antibiotics , drugs used for gastrointestinal symptom ( diarrhea / vomiting etc . ) multivitamins , anti - malarial , antihistaminic , hematinics , etc . , [ table 2 ] . regarding prescribing indicators , in 435 prescriptions ( 22.4% ) , antibiotics were advised . a total of 688 ( 34.97% ) drugs were prescribed by generic name while the percentage of drugs prescribed from edl of india was 58.47% . the present study provides an insight to the performance of interns in several key dimensions related to rational use of drugs . in our study , the average number of drugs prescribed per patient varied from 0 to 7 with the average of 2.58 . the result obtained in the present study is similar to studies conducted in manipal ( 2.76 ) , delhi ( 2.47 ) , madhya pradesh ( 2.8 ) and pune ( 2.8 ) . the most common drugs prescribed in the current study was analgesics followed by antibiotics , drugs for the gastrointestinal tract , multivitamins while it was hematinics followed by analgesics in manipal ; analgesics , antibiotics in delhi , madhya pradesh . the variation in drugs most commonly used can be attributable to differential prevalence of diseases in varied geographical locations . recently , regulatory authorities of different countries are emphasizing on generic prescribing to cut total healthcare cost . similar endeavor has also been taken up by local state government . in this backdrop , the percentage of drugs prescribed by generic name in our study was very low , i.e. 34.97% which is comparable to study reported from delhi ( 49.5% ) , madhya pradesh ( 48.5% ) . in a study conducted in jordon , the percentage was also low ( 5.1% ) . inappropriate sensitization of the interns to generic prescribing and the frequent visit of the medical representatives at health facilities may be the probable cause of the under prescribing of the drugs by generic name . the percentage of prescription with antibiotics was 22.4% as compared to 60.9% in madhya pradesh and 25% in bangladesh and burkina faso . according to who , 15 - 25% prescription with antibiotics is expectable in most of the countries where infectious disease is more prevalent . in a study conducted in india , bapna et al . studies conducted in other parts of india reported that the injection practices comparatively similar results , i.e. 5.2% by bapna et al . the overall percentage of drugs prescribed from an edl is a measure to examine the degree to which the practices confirm to national drug policy , as indicated by prescribing from national edl was 58.94% . the reasons for such wrong practices in our study were inadequate supply of drugs at health centers and unavailability of copy of edl . internship is the period when the prescribing behavior of a doctor usually develops , which determines his / her approach to rational drug use in subsequent medical life . in this perspective , the prescribing pattern of interns , as observed in our study , calls for an urgent intervention to sensitize these young medical graduates with the principles of rational drug use . a further follow - up study is needed to compare the outcome of such intervention on the prescribing behavior of the interns of the institute . however , adequately powered multicentric studies with a similar objective can provide a more meaningful answer . the present study was conducted among medical interns catering patients of a single rural health center attached to a medical college and thus can not be generalized . the present study was conducted among medical interns catering patients of a single rural health center attached to a medical college and thus can not be generalized . the present study shows that irrational prescribing practices are common among interns of the institute . the art of rational prescribing should be taught to them by medical teachers who are adequately trained in rational drug use . the manuals of standard treatment guideline and copy of edl should be made available to every interns .

background : prescription is the written order of the physician which is conveyed to the patient . rational prescription writing is a skill which should be mastered at the earliest . internship is the period where undergraduate medical education can be consolidated through continued learning under the direct supervision of teachers . the attitude of interns toward rational drug use is of utmost importance . the present study aimed to explore the prescribing pattern of interns in a primary health center in india.materials and methods : a cross - sectional study was conducted for a period of 2 months ( june 1 2010-july 30 2010 ) in a primary health center attached to a medical college in india . the main outcome measure was to assess rationality of prescribing pattern of interns was measured as per world health organization enlisted prescribing indicators . data analysis was done by using descriptive and inferential statistical methods : frequencies , percentage , and mean standard deviation.results:a total of 1968 drugs were prescribed in 760 prescriptions analyzed with an average of 2.58 drugs per prescription . analgesic was the most commonly prescribed drug ( 25.78% ) followed by antibiotics ( 22.1% ) , drugs used for gastrointestinal symptom ( 15.78% ) , multivitamins ( 11.84% ) , anti - malarials ( 8.35% ) , antihistaminics ( 6.25% ) , and hematinics ( 5.36% ) . regarding prescribing indicators , in 435 prescriptions ( 22.4% ) , antibiotics were advised . a total of 688 ( 34.97% ) drugs were prescribed by generic name , while the percentage of drugs prescribed from essential drug list of india was 58.47% . injectables were prescribed in 89 prescriptions ( 4.49%).conclusion : the present study shows that irrational prescribing practices are common among interns of the institute . the art of rational prescribing should be taught to them by medical teachers who are adequately trained in rational drug use .

lymphoscintigraphies performed during sentinel lymph node ( sln ) mapping and biopsies in breast cancer have discovered lymphatic extra - axillary drainage in 20 - 27% of cases . extra - axillary nodes most often located are : ipsilateral internal mammary chain ( imc ) ( 17% ) , intra - mammary ( 3% ) , supraclavicular ( 2% ) and interpectoral ( 2% ) nodes . contralateral axillary drainage is an unexpected finding that is a source of controversies in the management of these patients.[310 ] this situation is more exceptional when there is not prior breast surgery,[710 ] especially when internal mammary chain drainage is associated . a 48-years - old woman with no prior surgery of breast or axilla was diagnosed of breast ductal carcinoma in retroareolar region of the right breast with size of 2 cm . lumpectomy and sentinel lymphatic node ( sln ) biopsy was suggested . the day prior to surgery , a lymphoscintigraphy was performed with peritumoral injection of two doses of 74 mbq of technetium-99m - nanocolloid ( volume of 0.1 ml ) each one . planar images were acquired at 120 min of injection , including chest in anterior and lateral projections . we acquired images of 3 min in a 256 256 matrix using a planar source of cobalt-57 in anterior projection and an anatomical point source of tc99 m in order to delineate the body shape and locate the nodes . the images showed drainage to ipsilateral axillary nodes , ipsilateral imc and contralateral axillary nodes [ figure 1 ] . in the left we show anterior image of lymphoscintigraphy after 2 peritumoral injection of tc-99m - nanocolloid in the retroareolar region of right breast . bilateral axilla and ipsilateral ( internal mammary chain ) imc drainage are depicted with at least , 3 nodes in right axilla , 2 in imc and only one in left axilla . in the right upper quadrant , in the left lateral projection we can see tracer injection activity in the breast and the only contralateral axillary node . in the right lower quadrant , right lateral projection shows activity in the breast and in the main axillary node in the operating room , lumpectomy and sln biopsy of the three territories were performed . frozen section and subsequent 2 mm step sections of the paraffin embedded nodes did not reveal metastases in any of the lymph nodes . the patient was treated with chemotherapy , radiotherapy and hormone therapy and no significant complications were observed . there are several works , which show patients with contralateral axillary drainage but with prior history of surgery due to breast cancer , mammoplasty , axillary dissection due to melanoma or excissional biopsy , etc . , these abnormal drainages probably would be caused by surgical disruption of the physiological lymphatic pathway , and the clinical implications of them are different to these cases with no prior surgery procedures in the breast or axilla . we have found only four articles with contralateral axillary drainage and no prior surgery in breast or ipsilateral axilla.[710 ] simultaneous imc nodes were not found in any of them . in two cases , the lymphoscintigraphy showed bilateral drainage and all nodes were selected as sentinel and excised . histological studies did not reveal tumor spread in all nodes and did not impact in the management of the patients . tumor spread of a contralateral axillary lymph node is considered to be due to distant metastasis ( m1 ) by mean of conventional diagnosis procedures , or due to the presence of other occult primary cancer in contralateral breast . differentiation between a systemic metastatic disease and an atypical lymphatic spread would be of great interest in the prognosis and management of these patients . lymphoscintigraphy is the only procedure capable of separating these clinical situations , because extra - axillary lymph nodes are not detectable using blue dye alone.[79 ] metastases to a contralateral axillary lymph node reflect the lymphatic drainage of the tumor as seen on lymphoscintigraphy . so , the patient should be considered to have a node positive and not metastatic ( m1 ) disease . most lymph passes from the breast along interlobular vessels to the subareolar plexus and follows the veins of the breast to the axilla ( 75% ) . lymph from the medial part of the breast , in addition to the axilla , drains into the parasternal lymph nodes . some authors think that lymph from the skin of the breast may pass to the abdominal wall and opposite breast through the subdermal plexus as it is seen in melanoma , but retrosternal crossover to the contralateral side could be the pathway if there is internal mammary involvement . we think that in our patient , the lymph could have passed through the retrosternal pathway to the contralateral side because the tumor was located deep in the retroareolar region as we can see in the figure 1 . krause and colleagues described a case , which showed that the only metastatic lymph node was the contralateral axillary sentinel node , a finding , which may impact on adjuvant therapy , if this situation were ignored . , showed a patient with bilateral axillary drainage in which both axillary nodes were positive ; ipsilateral lymphadenectomy was performed and four more lymph nodes were removed from the left ( contralateral ) axilla . all nodes were free of metastases . a complete level i and level ii axillary lymph node dissection was not performed on the contralateral side because of concerns about bilateral lymphedema . probably , this would be the right choice and could be implemented selecting the contralateral nodes by mean of manual exploration removing all nodes enlarged and/or hardened.[1113 ] we think , as the same of carmon , et al . , that all ectopic nodes should be considered as sentinel nodes and must be biopsied to reach the most complete staging as possible . the knowledge of extra - axillary lymph nodes containing metastases may lead to better selection of patients for various adjuvant treatments such as radiotherapy to extra - axillary sites of metastatic sentinel lymph nodes or alteration of chemotherapy modalities if an extra - axillary sentinel node is the only metastatic lymph node . in our opinion , lymphoscintigraphy should be always used in addition to or instead of dye methods for lymphatic mapping . the only way to find a metastasis in a contralateral axillary lymph node arose from the primary carcinoma in the opposite breast is to use lymphoscintigraphy and perform sentinel node biopsy ( snb ) of contralateral nodes if founded . the distinction between node - positive and systemic metastatic disease is important considering the different treatment objectives and modalities for node positive versus metastatic breast cancer .

lymphatic drainage outside the ipsilateral axilla in breast cancer is discovered in as many as 25% of all sentinel lymph node procedures and it is evidenced by lymphoscintigraphy . contralateral axillary drainage is a rare clinical situation , mostly if there is not prior breast surgery , but this situation is extremely exceptional if we also found internal mammary chain drainage . we have not found such a case published in literature . this atypical finding is source of doubts because it could have clinical implications in the management of patients . we present a woman just diagnosed of breast carcinoma with hot nodes in bilateral axillary and ipsilateral internal mammary chain lymph nodes , shown by preoperative lymphoscintigraphy . we review published cases with contralateral axillary drainage , which enhance the role of scintigraphic procedure in such cases and show induced controversies in selecting the most adequate management .

postoperative endophthalmitis following cataract surgery could have potentially devastating consequences of severe vision loss or even blindness . the average time from surgery to presentation of endophthalmitis is usually 6 - 7 days . this is a rare cause of endophthalmitis in the postoperative setting following cataract surgery , with an incidence of 0.002% in the endophthalmitis vitrectomy study . our case is unique in that this is the first case to our knowledge of s. haemolyticus endophthalmitis following femtosecond cataract surgery , and this rapidly progressive infection produced severe inflammation on postoperative day 1 . his past ocular history was significant for right eye cataract surgery , right eye retinal tear and laser retinopexy , and bilateral high myopia . a right eye slit lamp examination was normal , while a left eye slit lamp examination showed 3 + nuclear sclerotic cataract . a right eye fundus examination showed peripheral laser scars at 10 o'clock , and a left eye fundus examination was normal . cataract surgery was performed using the femtosecond laser to make the limbal relaxing incision , capsulotomy , and nucleus fragmentation . following hydrodissection , an anterior capsular tear was identified with extension to the posterior capsule . a complete anterior vitrectomy was performed , and there was no vitreous to the wounds . a sulcus intraocular lens was placed , and corneal wounds were sutured and well sealed . on postoperative day 1 , vision was counting fingers at 2 feet . the anterior chamber had 4 + cells and 3 + fibrin anterior to the intraocular lens . observation was chosen at this time with the following medications : difluprednate 4 times a day , bromfenac once a day , cyclopentolate 4 times a day , and besifloxacin 6 times a day . six hours later and still on postoperative day 1 , the patient experienced pain and decreased vision to hand motions . b - scan ultrasonography showed 3 + vitritis and attached retina 360. the working diagnosis was now endophthalmitis , and a tap and an injection of vancomycin 1 mg per 0.1 ml and of ceftazidime 2.25 mg per 0.1 ml were performed . a second tap and injection were performed on postoperative day 2 with the same antibiotics , since it was felt to be an aggressive organism that was progressing quickly . on postoperative day 3 , the patient 's vision was still hand motions , and there was no view of the fundus . however , the hypopyon reduced in size and a b - scan showed decreased vitritis . the hypopyon and vitritis continued to improve daily , and vision improved to counting fingers . on postoperative day 14 , the patient complained of painless decreased vision in the left eye . endophthalmitis is a serious complication following cataract surgery that could result in devastating vision loss . the average time from surgery to presentation of endophthalmitis is usually 6 - 7 days . the most common pathogen is s. epidermidis , but rarely other coagulase - negative bacteria are causative agents . coagulase - negative staphylococcus is a normal skin and mucus membrane commensal , most commonly in the axillary , inguinal , and perineal regions . possible virulence factors of coagulase - negative bacteria appear to be protease , lipase , slime production , and hemagglutination , and most cases of coagulase - negative staphylococcus are sensitive to vancomycin . s. haemolyticus is a gram - positive , coagulase - negative bacterium that is uncommonly reported in the literature as a cause of endophthalmitis in the postoperative period . reported 448 cases of endophthalmitis , and less than 6% were caused by s. haemolyticus . in the endophthalmitis vitrectomy study , delima et al . reported a case of endogenous s. haemolyticus endophthalmitis with no light perception vision that resulted in evisceration . our case is unusual because there are very few cases of endophthalmitis caused by this bacterium , and there have been no cases of this bacterium causing endophthalmitis following femtosecond cataract surgery . in addition , the presentation of the endophthalmitis was on postoperative day 1 and progressed very quickly . therefore , if a causative organism could be suspected early by its clinical presentation , the consequences may not be as severe , especially if treatment could be targeted even before culture results are obtained . it may also be beneficial to consider repeat intravitreal antibiotic injections of vancomycin , as was done in our case . we urge clinicians to consider s. haemolyticus as an offending agent , especially when the infection presents immediately and progresses aggressively in the postoperative period .

a 53-year - old caucasian man underwent femtosecond cataract surgery and then presented with pain and hand motions vision 1 day following surgery . anterior segment examination showed a 2-mm - layered hypopyon , a well - centered intraocular lens in the sulcus , and an obscured view to the fundus . b - scan ultrasonography showed significant vitritis and that the retina was attached . a tap and an injection of vancomycin 1 mg per 0.1 ml and of ceftazidime 2.25 mg per 0.1 ml were performed . the tap eventually yielded culture results positive for staphylococcus haemolyticus , which was sensitive to vancomycin . we report a case of endophthalmitis that occurred on postoperative day 1 following complicated cataract surgery . this is an uncommon bacterium that is not widely reported in the literature as a cause of endophthalmitis in the postoperative period . we urge clinicians to consider s. haemolyticus as an offending agent , especially when the infection presents very early and aggressively in the postoperative period .

pertussis or whooping cough is a highly contagious vaccine preventable disease caused by the bacterial species bordetella pertussis . it is estimated that 200 000 - 400 000 cases of pertussis occur annually world wide . there are increasing reports of incidence of b pertussis infections in infants , school children , adolescents and adults . some of the possible explanations for reemergence of pertussis disease in vaccinated children may be poor vaccine quality , improved diagnostic facilities and the antigenic divergence in b pertussis strains than one used in the vaccine in those countries . this third reason has also been confirmed by the studies carried out in many countries including finland , netherlands and united kingdom . pertussis caused by the bordetella species other than b pertussis ( e.g. bordetella parapertussis ) may be another reason[68 ] . the reports of pertussis from vaccinated population may be underestimated , because it is less typical in vaccinated children as compared to unvaccinated children . in last two decades it has been found that bordetella pertussis targets people of all age groups rather than infants and children only . however , the incidence of this disease is highest in children > 6 months old who are not fully immunized . it is clear that childhood vaccination with dtp wanes with time and adolescent and adults are no more protected . adults are not only a source of infection to other adults , but they are also a reservoir for children . it is estimated that a quarter of all adult prolonged cough cases are caused by b pertussis . the rate of pertussis infections in adolescents and adults is 370 - 1500 per 100 000 populations which suggests 0.8 - 3.3 millions cases of pertussis in the united states . the typical whoop is absent in many cases of adult pertussis which makes the diagnosis difficult . serological techniques such as elisa have enabled to us to detect presence of antibodies in the serum sample and an increased level which indicates the exposure of a person to b pertussis with typical or atypical manifestations . high sensitivity of elisa using mixture of antigens as compared to utilizing single antigens such as pertussis toxin ( ptx ) or filamentous haemagglutinin ( fh ) was demonstrated by a study conducted by hanlon et al . the aim of the present study was to determine the level of igg antibodies in the adult population that will indicate the exposure to b pertussis organism . the results of this study may be helpful in getting a picture of b pertussis incidence rate in this area as well as in designing policy regarding the adolescent and adult vaccination in future . the study population consisted of adults of age group 18 - 45 years ( mean age=29.6 years ) . they were further divided into three age groups i.e. 18 - 25 ( mean age=22 ) , 26 - 35(mean age 30.17 ) and 36 - 45(mean age=48.48 ) years and named group a , b and c respectively . we tried to take equal number of male and female participants for each age group . the number of participants for each group was 93 , 64 and 62 for groups a , b and c respectively . relevant information such as age , gender , ethnic background , vaccination status , history of persistent cough etc . informed verbal consent was taken and interested participants were briefed about the details of the study . none of the participants suffered from cough or any other respiratory tract disease at the time of sampling . this study was approved by the ethics committee of comsats institute of information technology islamabad . 5 ml of venous blood was drawn from our university students and staff , their family members and blood donors in holy family hospital rawalpindi . the collected blood was transported to microbiology lab of comsats institute of information technology islamabad . serum was extracted from the blood samples soon after arrival to the lab and stored at -20c until used . igg level to bordetella pertussis antigen was determined by using a commercially available elisa kit from ibl hamburg germany following manufacturers instructions . the kit uses a mixture of b pertussis antigens i.e. filamentous haemagglutinin ( fha ) and pertussis toxin ( ptx ) and results are interpreted as positive , negative and equivocal . participants bearing more than 24u / ml of igg to b pertussis antigens were considered seropositive . the study population consisted of adults of age group 18 - 45 years ( mean age=29.6 years ) . they were further divided into three age groups i.e. 18 - 25 ( mean age=22 ) , 26 - 35(mean age 30.17 ) and 36 - 45(mean age=48.48 ) years and named group a , b and c respectively . we tried to take equal number of male and female participants for each age group . the number of participants for each group was 93 , 64 and 62 for groups a , b and c respectively . relevant information such as age , gender , ethnic background , vaccination status , history of persistent cough etc . informed verbal consent was taken and interested participants were briefed about the details of the study . none of the participants suffered from cough or any other respiratory tract disease at the time of sampling . this study was approved by the ethics committee of comsats institute of information technology islamabad . 5 ml of venous blood was drawn from our university students and staff , their family members and blood donors in holy family hospital rawalpindi . the collected blood was transported to microbiology lab of comsats institute of information technology islamabad . serum was extracted from the blood samples soon after arrival to the lab and stored at -20c until used . igg level to bordetella pertussis antigen was determined by using a commercially available elisa kit from ibl hamburg germany following manufacturers instructions . the kit uses a mixture of b pertussis antigens i.e. filamentous haemagglutinin ( fha ) and pertussis toxin ( ptx ) and results are interpreted as positive , negative and equivocal . participants bearing more than 24u / ml of igg to b pertussis antigens were considered seropositive . the study population consisted of adults of age group 18 - 45 years ( mean age=29.6 years ) . they were further divided into three age groups i.e. 18 - 25 ( mean age=22 ) , 26 - 35(mean age 30.17 ) and 36 - 45(mean age=48.48 ) years and named group a , b and c respectively . we tried to take equal number of male and female participants for each age group . the number of participants for each group was 93 , 64 and 62 for groups a , b and c respectively . relevant information such as age , gender , ethnic background , vaccination status , history of persistent cough etc . informed verbal consent was taken and interested participants were briefed about the details of the study . none of the participants suffered from cough or any other respiratory tract disease at the time of sampling . this study was approved by the ethics committee of comsats institute of information technology islamabad . 5 ml of venous blood was drawn from our university students and staff , their family members and blood donors in holy family hospital rawalpindi . the collected blood was transported to microbiology lab of comsats institute of information technology islamabad . serum was extracted from the blood samples soon after arrival to the lab and stored at -20c until used . igg level to bordetella pertussis antigen was determined by using a commercially available elisa kit from ibl hamburg germany following manufacturers instructions . the kit uses a mixture of b pertussis antigens i.e. filamentous haemagglutinin ( fha ) and pertussis toxin ( ptx ) and results are interpreted as positive , negative and equivocal . participants bearing more than 24u / ml of igg to b pertussis antigens were considered seropositive . the results of our study show that 89.04% of the studied people were seropositive to b pertussis , while 6.48% and 6.48% fell into negative and equivocal category respectively . no significant relation of seropositivity to b pertussis to age and gender or ethnic background of the participants has been found . of all 219 sera samples , seropositivity for each group of participants was 87.1% ( n=81 ) , 90.6 % ( n=58 ) and 90.32 % ( n=56 ) for groups a , b and c respectively . this is the first report on seroepidemiology of b pertussis in pakistan which clearly shows higher level of seroprevalence in pakistani population . as seen in table 1 , all studied age groups show higher level of igg antibodies to b pertussis antigens ( fha and ptx ) . as the immunity conferred by the childhood vaccination with dtp wanes with the passage of time , the higher level of igg to b pertussis in adult population should be due to natural exposure to the organism . adults are not only a source of b pertussis infections for children , but are susceptible to this infection themselves . there have not been many reports of b pertussis infections from pakistan which may be due to the failure of diagnosing from clinical picture and unavailability of laboratory diagnostic facilities in rural areas . at the same time there exists no adequate surveillance system for the monitoring of the infectious diseases like pertussis in pakistan . another possibility may be the shift of the typical pertussis to atypical form in children to which physicians are unaware . in any case , like in many other countries , pertussis seems to be an underreported disease in both children and adults in pakistan . clearly , dtp vaccination has reduced the burden of b pertussis in this region which can be understood by the fact that there is lower recoded morbidity and mortality rate as compared to the past . however , its incidence and the risks still need to be monitored . the clinical manifestation of the adult pertussis differs in reports from different countries . it is reported to have typical paroxysmal cough in some cases , whereas it was difficult to diagnose as pertussis from symptoms alone due to non typical persistent cough . there are reports of outbreak of pertussis with both typical as well as asymptomatic coughing . the results of the study are alarming and clearly indicate the exposure of the local population to b pertussis . we propose adult vaccination with dtp to prevent infants and children from getting this disease .

background : bordetella pertussis is the cause of whooping cough occurring mainly in children . the prevalence of this disease has been reduced largely due to worldwide mass vaccination with dtp vaccine . however , the immunity produced by the vaccination wanes by the passage of time . still this disease kills around 2 - 4 million children annually . adults may be a source of infection for infants and children . furthermore , bordetella pertussis has also been found to be associated with cases of persistent cough in adults in many countries.aim:the aim of this study was to study the exposure of the adult population to the bordetella pertussis by detecting igg antibodies.materials and methods : we performed seroepidemiology of bordetella pertussis infections in multiethnic twin cities of pakistan ( rawalpindi and islamabad ) using a commercially available elisa kit to have a picture of epidemiology of bordetella pertussis in pakistan . we targeted adults of age between 18 - 45 years ( mean age 29.64 years).results : the results of our study show a high percentage of seropositivity to bordetella pertussis ( 89 percent ) , which indicates higher exposure to this organism and risk of infection to infants , children , adolescents and adults.conclusion:a high percentage of seropositive individuals are alarming to health care professionals as well as policy makers . bordetella pertussis infections may be associated with their atypical manifestation in pakistan . adult vaccination with dtp is recommended to reduce the risk of infection in infants and children through adult reservoirs .

chondrosarcoma is the malignant counterpart of the chondroma and , like the benign one , may occur either in the maxilla or in mandible with male to female preponderance of 2:1 . the chondrosarcomas of the maxillofacial region account for 1 - 3% of chondrosarcomas of the entire body . they arise predominately in the maxilla with a predilection for the anterior maxillary region and occur at a lower incidence in the mandible . the preferred site in the mandible is the molar region , and they infrequently occur in the ramus , condyle , coronoid process , or symphysis . roentgenographic findings are not clear unless the lesion is long - standing and has produced considerable destruction of bone . occasionally , tumor appears as radiopaque lesion because of calcification and sometimes shows resorption and exfoliation of teeth . a 60-year - old female patient reported to the department of oral and maxillofacial surgery , with chief complaint of painless swelling at right side of the mandible , which had been present for 6 months . two months back , the growth was excised incompletely by a general dental practitioner ; unfortunately , the excised specimen was not sent for histopathological examination and was discarded , following which the remaining growth grew rapidly . extraoral examination showed a swelling at body of the right mandible measuring 6 6 cm [ figure 1 ] extending intraorally from right mandibular canine to distal aspect of right mandibular second molar . swelling was bony hard , ill defined , and caused obliteration of right lower buccal vestibule . preoperative photograph of the patient showing swelling of right mandible ( or ) extaoral view showing swelling at right side of face a panoramic radiograph revealed a widened periodontal space and an irregularly - shaped osteoblastic lesion with radiopacity . there were signs of sclerosis and new bone formation in the body of right mandible , which was extending to the angle region . there were signs of patchy bony destruction near the root of molar and premolar teeth [ figure 2 ] . orthopantogram showing signs of sclerosis and new bone formation in the body of right mandible along with signs of patchy bony destruction near the root of molar and premolar teeth ( or ) opg showing lesion extending from right side of canine upto ramus of mandible an incisional biopsy was performed which histopathologically revealed areas of hyaline cartilage in lobules with increased cellularity and cellular pleomorphism . a segmental resection under general anesthesia was performed extending from the right lateral incisor and the ramus of the mandible , as the mandibular basal bone appeared to be affected . photomicrograph showing lobular architecture with cellular lobules of chondroid tissue and focal dedifferentiated spindle cell areas ( h and e , 40 digital magnification ) ( or ) histopahological slide showing areas of hyaline cartilage in lobules with increased cellularity and cellular pleomorphism chondrosarcoma of the mandible mostly present as a painless swelling or may appear as mass of long duration with pain , paresthesia , trismus , and loosening of the teeth , which points toward the progression of the disease . radiographically , the appearance of the lesion varies from ill - defined radiolucent to obvious radioopaque shadow . conventional radiograph , computed tomography scan and magnetic resonance imaging are quite valuable in determining the nature and extent of the lesion , but a definitive diagnosis should be made histologically which states significantly that chondrosarcomas are composed purely of hyaline cartilage and fulfill cytologic malignant criteria . in the present case , a hard mass was noticed on the body - angle region of right mandible and presented with loosening of right posterior teeth along with periodontal space widening and resorption of the roots of the teeth which was more prominent in relation to the distal root of right first molar . there are several reports of chondrosarcomas of the jaws and facial skeleton that grew rapidly following incisional biopsy , and the tumor in the current case acted in the same way . radical resection is the most effective primary modality for the treatment of chondrosarcoma , as this is considered to be radioresistant . however , chemoradiation is usually advised for locally recurrent or residual tumor . although the biopsy in the present case report showed the lesion to be of low - grade nature , but a segmental resection of the mandible was performed as the basal bone was also infiltrated by the growth and the resected specimen showed tumour - free margins . the 5-year survival rate for chondrosarcomas of the jaws and facial bones has been reported to be 67.6% . the prognosis of chondrosarcomas depends on the size , location , grade , and surgical respectability of the tumors as chondrosarcomas show a wide variation in time of recurrence and metastasis . the present case is unique as a low - grade chondrosarcoma appeared from a rare site , the body of the mandible and also involved the basal bone which was treated with segmental resection . the unusual presentation of chondrosarcoma described in the present case report will facilitate the medical professionals in the management of such mandibular growths . however , a long - term follow - up is required to assess the nature and long - term outcome of chondrosarcomas of mandible .

chondrosarcomas are the malignant cartilaginous neoplasms rarely seen in the head and neck region . the chondrosarcomas may show an aggressive course and are mostly located in relation with anterior maxilla and base of the skull . chondrosarcomas of the body of mandible are infrequent . we report a case of low - grade chondrosarcoma of body of mandible , which was treated with a simple excision without neck dissection .

fecal microbiota transplantation ( fmt ) has gained worldwide attention in recent years 1 . in 2013 , it was recommended as the clinical choice in guidelines for treatment of recurrent clostridium difficile infection ( cdi ) 2 . in addition , clinical studies have shown that fmt has a therapeutic role in inflammatory bowel diseases , refractory constipation , chronic diarrhea , and metabolic syndrome 3 4 . since 2012 , our group has been evaluating possible applications for and new methods of applying fmt 5 6 7 . previous reports on fmt for delivery of treatment have involved the upper , middle , and lower gut 8 9 10 11 . fmt via colonoscopy is a classic approach , but patients have to endure bowel preparation and colonoscopy , especially when they need repeat treatment over a short period of time 12 . a traditional enema delivers solution only within the rectal and sigmoid colon which is way , in our previous studies of crohn s disease and ulcerative colitis , why we chose to use fmt for delivery through the mid - gut 6 7 . however , patients may find it psychologically difficult to accept fmt through the upper and middle digestive tract . importantly , reflux and aspiration of bacterial liquid may occur and even cause asphyxia 13 14 . there is currently no technique for placing a tube through the anus into cecum for whole - colon administration of treatment that could be maintained for repeat fmts or while awaiting fresh fecal microbiota from the lab . therefore , to solve these problems , we designed a new technique called transendoscopic enteral tubing ( tet ) . as shown in fig . 1 , the tet tube is fixed to the cecum with clips under endoscopic guidance . concept sketch of fmt treatment by tet . a prospective observational study ( nct02560727 ) was conducted at the second affiliated hospital of nanjing medical university from october 2014 to september 2015 . all patients met the inclusion criteria , which were age 10 to 70 years , safety for the pilot study , suitability for endoscopy , and consent to undergo fmt and tet for their diseases and conditions . patients were excluded it they had severe bowel lesions with stenosis , fistula , or the risk of perforation ; complex perianal lesions or serious lesions in the ileocecal junction or ascending colon ; and no proper site for titanium clip fixation . the study was approved by the institutional review board of the second affiliated hospital of nanjing medical university . regular colonoscopy was performed under intravenous anesthesia . after examination and evaluation of the whole colon , the tet tube ( fmt medical , nanjing , china ) was inserted into the ileocecal junction through the endoscopy channel ( fig . 2 ) . the colonoscope was removed from the colon while the tet tube was maintained at the ileocecal junction . the line circle on the tet tube was affixed to the intestinal wall using titanium clips under direct vision ( generally two titanium clips at the first station and one to two clips at the second and/or third station as necessary ) ( fig . 3 and fig . 4 ) . the distal tube was affixed to the skin of the buttocks ( preferably on the left side ) with medical adhesive plaster . a valve was connected to the terminal tet tube . the procedure time and all related adverse events ( aes ) attachment of titanium clips to the tet tube to the cecum mucosa at the first station under endoscopic guidance . the tip of the guidewire can be seen within the tube . the second station of tet tube attachment in the ascending colon mucosa with titanium clips under endoscopic guidance . the guidewire can be seen within the tube . according to the concept shown in fig . 1 , the patient was required to be in the right - lateral position and then 200 ml of suspension was injected through the tet tube . the 200-ml suspension was a mixture of 150 ml saline and 50 cm centrifuged microbiota that was purified following our lab protocol and using the automatic system genfmter ( fmt medical , nanjing ) 6 7 . the duration of the injection was recorded and intended to be more than 1 minute so as to avoid the abdominal discomfort that would be associated with a quicker procedure . after fmt , patients were required to remain in the right - lateral position for 30 minutes . retention of the microbiota suspension for over 1 hour indicated successful delivery of the microbiota through colonic tet . in some cases , fmt was repeated during subsequent days to ensure infusion of the microbiota to the whole colon . reports from patients of discomfort during fmt were recorded and all of them agreed to participate in the post - treatment survey on satisfaction with tet and fmt . a prospective observational study ( nct02560727 ) was conducted at the second affiliated hospital of nanjing medical university from october 2014 to september 2015 . all patients met the inclusion criteria , which were age 10 to 70 years , safety for the pilot study , suitability for endoscopy , and consent to undergo fmt and tet for their diseases and conditions . patients were excluded it they had severe bowel lesions with stenosis , fistula , or the risk of perforation ; complex perianal lesions or serious lesions in the ileocecal junction or ascending colon ; and no proper site for titanium clip fixation . the study was approved by the institutional review board of the second affiliated hospital of nanjing medical university . regular colonoscopy was performed under intravenous anesthesia . after examination and evaluation of the whole colon , the tet tube ( fmt medical , nanjing , china ) was inserted into the ileocecal junction through the endoscopy channel ( fig . 2 ) . the colonoscope was removed from the colon while the tet tube was maintained at the ileocecal junction . the line circle on the tet tube was affixed to the intestinal wall using titanium clips under direct vision ( generally two titanium clips at the first station and one to two clips at the second and/or third station as necessary ) ( fig . 3 and fig . 4 ) . the distal tube was affixed to the skin of the buttocks ( preferably on the left side ) with medical adhesive plaster . a valve was connected to the terminal tet tube . the procedure time and all related adverse events ( aes ) attachment of titanium clips to the tet tube to the cecum mucosa at the first station under endoscopic guidance . the tip of the guidewire can be seen within the tube . the second station of tet tube attachment in the ascending colon mucosa with titanium clips under endoscopic guidance . the guidewire can be seen within the tube . according to the concept shown in fig . 1 , the patient was required to be in the right - lateral position and then 200 ml of suspension was injected through the tet tube . the 200-ml suspension was a mixture of 150 ml saline and 50 cm centrifuged microbiota that was purified following our lab protocol and using the automatic system genfmter ( fmt medical , nanjing ) 6 7 . the duration of the injection was recorded and intended to be more than 1 minute so as to avoid the abdominal discomfort that would be associated with a quicker procedure . after fmt , patients were required to remain in the right - lateral position for 30 minutes . retention of the microbiota suspension for over 1 hour indicated successful delivery of the microbiota through colonic tet . in some cases , fmt was repeated during subsequent days to ensure infusion of the microbiota to the whole colon . reports from patients of discomfort during fmt were recorded and all of them agreed to participate in the post - treatment survey on satisfaction with tet and fmt . as shown in table 1 , 54 patients were included in this prospective study : 32 males and 22 females aged 10 to 70 years ( mean sd , 34.5 10.4 ) . of the patients , 23 cases had ulcerative colitis , 16 had crohn s disease , five had unexplained chronic diarrhea , five had constipation , three had small intestinal bacterial overgrowth , and 2 had irritable bowel syndrome . the mean time from advancement of the tet tube through the channel to the end of the tubing was 14.8 minutes . three clips were used on two fixation stations of the tet tube in 36 cases during our preliminary observational period or in patients who only needed short - term retention of tet tube retaining . in the remaining 15 cases , no complications such as mild to serious abdominal pain and bleeding stool were observed . during the tet tube retention period , 98.1 % of patients ( 53/54 ) were satisfied with tet ; one patient with ulcerative colitis complained of tolerable mild anal discomfort ; no other patients complained of anal pendant expansion . fmt , fecal microbiota transplantation ; tet , transendoscopic enteral tubing ; sd , standard deviation . a total of 200 ml of fecal microbiota suspension was given to each patient and the mean injection time was 3.2 minutes . in all cases ( 100 % ) , fmt through colonic tet was successful . in 88.4 % of cases ( 49/54 ) , patients reported no discomfort during fmt . one patient ( 1.9 % ) with severe ulcerative colitis complained of abdominal pain after infusion through tet tube , and the symptoms were alleviated with rest . four patients ( 7 % ) reported tolerable mild abdominal distension . in one case , we encountered difficult with the infusion because of bending of the tube at an angle in the intestines , which was resolved with injection of normal saline at high pressure . the time from the end of the fmt to the first defecation was 6.3 0.7 hours . in 35 patients with ulcerative colitis or crohn s disease mesalazine was delivered daily to them through the tet tube until the tube fell off . the retention duration was 12.4 2.3 days . in 19 patients , removal of the tet tube reports exist of use of fmt to deliver treatment to the upper gut , mid - gut and lower gut . the capsule dissolves in the small intestine and bacteria are distributed in the gastrointestinal tract . in mid - gut , the microbiota suspension is injected into the small intestine below the second duodenal segment under endoscopic direct vision or via a nasogastric tube , small intestine stoma or percutaneous endoscopic gastrostomy with jejunal extension ( pegj)15 . fecal microbiota can be delivered to the lower gut through colonoscopy , enema , distal ileum stroma , colostomy , and colonic tet . the advantages and limitations of different methods of delivering fmt are shown in table 2 . fmt : fecal microbiota transplantation ; pegj : percutaneous endoscopic gastrostomy with jejunal extension ; sibo : small intestinal bacterial overgrowth ; tet : transendoscopic enteral tubing . in this study , tet and fmt were successfully performed in all 54 cases ( 100 % ) , and fmt retention time was longer than 1 hour . this tet technique and the novel tet accessary devices used demonstrate the feasibility and significance of colonic administration . no serious aes were observed during the tet procedure , infusion of fmt through the tet tube , the period during which the tet tube was left in place , or removal of the device . during the fmt procedure , the mean retention time for the microbiota suspension was enough to meet the requirement for fmt according to our protocol . for patients who required repeat fmt and combined colonic administration of mesalazine , it was a convenient and economic way to use the colonic tet tube . importantly , this method may be less psychologically challenging for patients than delivery of fmt via the upper and middle digestive tract . in 19 patients , the tet tubes were removed after a single fmt or colonic administration . of them , 4 with ibd required removal of the tet tube after fmt and 1-week administration of mesalazine ( 7 enemas in a single package of salofalk ) because there was no need to leave the tet tube in place . according to our lab protocol and clinical flow 6 7 , for consideration of improving possible clinical efficacy , the time from defecation of stool to infusion of microbiota was required to be no more than 1 hour . therefore , 15 patients agreed to the use of tet while waiting for fresh microbiota from the lab and because they preferred psychologically delivery through the lower gut , and their tet tubes were removed after fmt . it should be emphasized that the patients daily lives were not affected by tet , and in 98.1 % of cases ( 53/54 ) , they were satisfied with fmt through tet . for patients with ulcerative colitis that involved the entire colon or crohn s disease , tet should be a wonderful choice for frequently delivering medication into the whole colon . in the current study , all 23 patients with ulcerative colitis and 16 patients with crohn s disease were administered a mesalazine enema through the tet tube . of them , six patients were discharged with the tube and they were able to conveniently infuse medication by themselves at home . besides this pilot study on colonic study for whole - colon administration through a colonic tet tube , a study on the similar concept of tet used for interventional therapy by duodenal or jejunal tet under gastroscopy is ongoing in our center . the sample size of this pilot study was small , but a larger prospective study based on these preliminary results is ongoing . this study did not evaluate clinical responses to whole - colon administration compared with other traditional treatments ; that will be part of our future studies . a cost - efficacy analysis is necessary and the results may vary from country to country depending on policies for medical charges . patients who require only a single fmt ( e. g. cdi ) may not need to generally may not need to undergo colonic tet if use of fresh fecal microbiota is not a consideration and that is why there were no cdi patients in this study . in conclusion , this study is the first report of colonic tet as a convenient and safe way of delivering fmt . the results highlight the significance of colonic tet as a promising technique for single and repeat whole - colon administration of medication .

background and study aims : placement of a tube through the anus into the cecum has not yet been established as a method of administering whole - colonic treatment . the aim of this study was to evaluate the safety , feasibility , and value of transendoscopic enteral tubing ( tet ) for fecal microbiota transplantation ( fmt ) through the colon . patients and methods : a prospective observational study was performed of fmt using a new colonic tet technique . under endoscopic guidance , a tet tube was affixed to the cecum with clips . the safety , value , and satisfaction with the fmt by tet were evaluated . results : a total of 54 patients underwent tet . the success rate of the tet procedure was 100 % ( 54/54 ) . duration of the tet procedures was 14.8 5.8 min . during the tet tube retention period , 98.1 % ( 53/54 ) of patients were satisfied with tet . the retention time for whole - colon delivery of the fecal microbiota suspension was 12.4 2.3 days . in 88.4 % ( 49/54 ) of cases , no discomfort was reported during injection through the tet tube of the microbiota suspension . no adverse events were see in patients who required tube extubation after fmt . conclusions : colonic tet is a novel , safe , convenient , and reliable procedure for fmt that results in a high degree of patient satisfaction .

aseptic necrosis of the femoral head is a disease whose etiology is not completely elucidated , the triggering event being the suppression of blood supply to the femoral head . the disease is common especially among the younger population , patients usually being between the 3rd and 5th decade of life , particularly affecting men [ 7 , 8 ] . for the early diagnosis of aseptic necrosis of the femoral head the physician should have a high index of suspicion , especially in patients with risk factors . the main risk factors of the disease are represented by trauma , chronic alcohol consumption , smoking , corticosteroid treatment [ 1 , 7 ] . this is particularly important in patients where the disease is already present in one femoral joint as aseptic necrosis often occurs bilaterally [ 1 , 3 ] . patient mi , aged 23 , from an urban environment , construction worker , smoker ( 40 cigarettes per day from age 11 ) , chronic alcohol consumption ( beer , wine / daily ) , without significant pathological personal history , presented in june 2014 in the medical rehabilitation clinic accusing pain in the left hip irradiated in the knee with functional impotence of the left lower limb with onset of about 3 months . physical examination of the patient revealed the following aspects- normal weight , discrete erythrose of the cheekbone , bp = 130/70 mmhg , av = 72 bpm , scoliotic attitude , paravertebral muscle stiffness in the lumbar spine , pain when mobilizing the coxo - femoral joint , limitation of flexion , abduction and rotation in the left hip joint , positive left faber test , positive left patrick maneuver , intensely painful trandelenburg positive sign on the left . the results of laboratory tests were normal , except esr = 24 mm / 1 hour 46 mm / 2h , fibrinogen = 423 mg / 100ml , alkaline phosphatase = 138 iu / l , gamma glutamyltransferase = 79 u / l , got ( glutamic oxaloacetate transferase ) = 57 u / l , gpt ( glutamic pyruvate transaminase ) = 62 u / l total cholesterol = 231 mg / dl . the pelvic radiography ( fig.1 ) noted loss of sphericity and collapse of the left femoral head , left joint space narrowing and acetabular changes . imaging investigations continued with a ct scan , which surprised the following aspects : sclerosis , the presence of cysts , microfracture and changes of the trabecular bone , highlighting the femoral head collapse and degeneration of the left coxo femoral joint . it can be seen marked narrowing of the left coxal - femoral joint space , left femoral head deformation , circumscribed areas at the femoral neck , anterior - superior region and subchondral bone attachment aspect . with imaging investigations ( fig.2 ) the patient was diagnosed with aseptic necrosis of the left femoral head stage iv ( arco classification ) and obtained transfer to the orthopaedics - traumatology clinic in order to undergo surgery . the patient underwent surgery for hip arthroplasty with implantation of a left prosthetic bipolar partial hip . upon discharge the following the recommendations were made : physical therapy to recover walking and change of lifestyle : quit smoking and severely limit alcohol consumption . coxal ct - left coxo - femoral articular effusion with edema and bone sclerosis aspect , the presence of cysts , microfractures in the left femoral head . the collapse of the femoral head and joint degeneration in the left coxo - femoral joint . after obtaining the agreement of the patient , the left femoral head taken during hip arthroplasty ( fig.3 ) was fixed in 10% formalin , decalcified and sectioned in order to obtain some histological slices for inclusion in a larger study which followed the morphological changes that occur in patients diagnosed with aseptic necrosis of the femoral head . macroscopic and microscopic images thus obtained confirmed the diagnosis and extension of the area of necrosis to the adjacent cartilage ( fig.4,5 ) . coxal ct - left coxo - femoral articular effusion with edema and bone sclerosis aspect , the presence of cysts , microfractures in the left femoral head . the collapse of the femoral head and joint degeneration in the left coxo - femoral joint . coxal ct - left coxo - femoral articular effusion with edema and bone sclerosis aspect , the presence of cysts , microfractures in the left femoral head . the collapse of the femoral head and joint degeneration in the left coxo - femoral joint . coxal ct - left coxo - femoral articular effusion with edema and bone sclerosis aspect , the presence of cysts , microfractures in the left femoral head . the collapse of the femoral head and joint degeneration in the left coxo - femoral joint . the peculiarity of the case is the appearance of the disease at a very young age , the patient being only 23 years old and diagnosed in stage iv in the left hip and stage i in the right hip and already undergone arthroplasty of the hip . aseptic necrosis of femoral head mainly affects young adults , who are between the 3rd and 5th decade of life [ 1 , 3 , 8 - 11 ] . it is considered that the average age that patients are diagnosed with aseptic necrosis of the femoral head and the timing of the first hip replacement is 38 years old [ 4 , 8 ] . risk factors are represented by chronic alcohol consumption ( beer , wine / daily smoking ( 40 cigarettes per day from age 11 ) trauma and is more frequent in men . it is believed that aseptic necrosis of femoral head affects men 4 times more than women [ 3 , 9 - 11 ] . some authors recorded a male to female sex ratio of 8 : 1 , except that the condition occurs in the context of systemic lupus erythematosus . we can not predict with certainty whether aseptic necrosis of the femoral head to the right is due to suffered trauma in our patient or that the damage occurred at this level as a consequence of long alcohol consumption and smoking . it seems appropriate to conduct an mri exam in detriment of ct in patients with risk factors for aseptic necrosis of the femoral head , even if there are no signs on plain radiography showing the existence of the disease . changes in the early stages of aseptic necrosis of the femoral head are hard to detect on plane x - ray . a normal image obtained by x - ray does not necessarily translate into the absence of the disease [ 1 , 3 , 9 , 12 ] . between the occurrence of hip injury and detection on x - ray suggestive images a 5 year interval usually passes [ 9 , 10 , 12 ] . the sensitivity of the method in the diagnosis of early stages is only 41% . in the early stages , the sensitivity of ct is quite low , being only 55% [ 10 , 12 ] , but can be detect certain alterations in bone density when x - ray images are normal [ 14 , 15 ] . ct is useful in assessing the later stages for lesion extension , such as sclerosis and other events occurring in the state of repair . mri is a non - invasive imaging technique with the highest degree of specificity and sensitivity used in the diagnosis of aseptic necrosis of the femoral head [ 3 , 9 , 10 , 12 , 16 ] . in the early stages is more effective than simple computerized tomography ( ct ) or the single - photon emission ( spect ) , with a degree of increased specificity in the detection of the condition of up to 90% [ 12 , 14 ] . the young age of the patient makes it very likely that they will need additional hip surgery . it is unlikely that the prosthesis used during hip arthroplasty to retain functionality for 40 - 45 years , as is the life expectancy of the patient . long - term results on the use of full or partial dentures ( cemented or uncemented ) in the treatment of this condition is generally unsatisfactory [ 17 - 19 ] . knowing the risk factors involved in aseptic necrosis of the femoral head it is essential for early disease detection , because in the early stages the poor or absent symptoms and laboratory imaging investigations detect no changes . a thorough investigation is particularly important for patients whose disease is already present at one of coxo - femoral joint as in 50- 60% of cases bilateral aseptic necrosis occurs . patients at high suspicion should undergo an mri examination , even if the plane x - ray or ct have not detected significant changes , because the diagnosis of aseptic necrosis of the femoral head in the early stages is a necessity in order to obtain an optimal result when performing conservative treatment .

aseptic necrosis of the femoral head is a disease whose etiology is not completely elucidated and generally affects young adults aged between 30 and 50 years . in a significant number of patients bilateral disease occurs , which makes detection in its early stages constitute an important objective . we present the case of a male patient , aged 23 years , with the following risk factors : smoking and chronic alcohol consumption , who is diagnosed with aseptic necrosis of the left femoral head , arco stage iv , and in just six months after the diagnosis and hip arthroplasty , he suffers an injury which leads to the same diagnosis in the contralateral hip . we want to emphasize that for all patients with a high index of suspicion there should be an mri examination , because the plane radiographs or ct are most often not relevant in detecting early signs of this condition . diagnosis of aseptic necrosis of the femoral head in the early stages is a necessity in order to obtain an optimal result of conservative treatment .

differentiated thyroid carcinoma , especially papillary thyroid carcinoma ( ptc ) , commonly metastasizes to the regional lymph nodes , lungs , and bone . however , the brain is an uncommon site of metastasis , being found only in 0.15%1.3% of cases.1 moreover ; cerebellar metastases from ptc are exceptionally rare , with only 13 reported cases of cerebellar metastasis from ptc having been published so far.2 herein , we describe and discuss the signs and symptoms , diagnostic work - up , differential diagnosis , and management in three cases of cerebellar metastasis from ptc . a 74-year - old female with a diagnosis of ptc , tall cell variant ( pt3n1am0 ) , underwent total thyroidectomy , followed by radioactive iodine ablation ( 150 mci ) in february 2009 . the patient was taking l - thyroxine 125 g as thyroid replacement therapy , and remained in complete remission until june 2013 , when she presented with a 3-month history of left upper neck pain . magnetic resonance imaging of the brain revealed an enhancing mass involving the left side of the clivus and the left occipital condyle ( figure 1 ) . computed tomography ( ct ) showed intense hypermetabolic activity ( standardized uptake volume 138 ) , corresponding to the destructive mass involving the clivus and left occipital condyle ( figure 2 ) . histopathology of the biopsy revealed tall papillary cells ( height at least two or three times their width ) mixed with small fragments of bone , and immunopositivity for thyroid transcription factor-1 and cytokeratin 19 confirmed the diagnosis of metastatic tall cell variant ptc ( figure 3 ) . the patient was treated with external beam irradiation via intensity modulated radiotherapy ( imrt ) . a total dose of 6,600 cgy was delivered to the tumor in 33 fractions over 6.5 weeks . follow - up has been undertaken for 18 months , and the patient has remained clinically asymptomatic without any evidence of recurrence or distant metastases . a 67-year - old female with a diagnosis of ptc insular variant ( pt4n1bm0 ) underwent total thyroidectomy and neck dissection in april 2011 . after surgery , she was treated with radioactive iodine ( 150 mci ) and thyroid bed irradiation via imrt with a dose of 66 gy in 33 fractions , in september 2011 , she developed lung metastasis , and was treated with a second radioactive iodine ablation dose ( 200 mci ) . in august 2013 , neurological findings were cranial nerve ii , iii , and v palsies on the left side . whole body scintigraphy showed intense foci of uptake in the skull base and in both lungs . ct brain revealed an infiltrative enhancing mass occupying the right cavernous sinus and extending to the pituitary fossa and clivus ( figure 4a and b ) . histopathological examination of a transnasal - transsphenoidal biopsied lesion revealed islands of small uniform cells , areas of tumor necrosis , and microfollicles with thyroglobulin , which confirmed the diagnosis of metastatic ptc , insular variant ( figure 5 ) . the lesion was treated with imrt , and a total dose of 6,000 cgy in 30 fractions was delivered to the tumor over 6 weeks without any significant acute toxicity . after completion of imrt , the patient was given a third radioactive iodine ablation dose ( 150 mci ) . at 14 months of follow - up , the patient was alive with progressive in disease in the lungs , an elevated thyroglobulin level ( 5,000 g / l ) , and a stable skull base lesion . a 65-year - old male underwent total thyroidectomy for multifocal ptc , follicular variant ( pt3n1m0 ) , followed by radioactive iodine ablation ( 150 mci ) in july 2006 . the patient was on thyroid replacement therapy with l - thyroxine 150 g , and was in complete remission until december 2013 , when he presented with a 2-month history of headache , dysphagia , hoarseness , dysarthria , and hearing impairment . pertinent neurological findings were cranial nerve ix , x , xi , and xii palsies on the left side ( collet - sicard syndrome ) with moderate sensorineural hearing loss and 100% word recognition on the affected side . ct / magnetic resonance imaging brain revealed a large infiltrative mass involving the petrous , tympanic , and mastoid parts of the left temporal bone with intracranial extension . there was also evidence of invasion of the left sigmoid sinus , left internal jugular vein , and left internal auditory canal ( figure 6 ) . histopathological examination confirmed the diagnosis of metastatic ptc , follicular variant ( figure 7 ) . following surgery , the residual tumor was treated with imrt , using a total dose of 6,000 cgy in 30 fractions . after 12 months of follow - up , the patient remained well without any signs of progression or treatment - related complications . skull base metastasis ( sbm ) of differentiated thyroid carcinoma shows a predominance of follicular thyroid carcinoma ( ftc ) , because ftc is more prone to spread via the hematogenous route to the lungs and bone.2 however , sbm from ptc is rare . to date , only ten cases of sbm from ptc have been reported ( table 1).311 in agreement with the reported cases , sbm in our series were seen in the sixth and seventh decades of life , at a mean age of 68.6 ( range 6574 ) years , and the mean interval between initial diagnosis and sbm was 56.3 ( range 2889 ) years.3,8 in our series , two patients with aggressive variants of ptc ( tall cell and insular ) were recognized . according to the recent literature , these aggressive variants have a worse prognosis than classic ptc , and patients with these variants should be treated aggressively with thyroidectomy , neck dissection , and radioactive iodine , regardless of tumor size.12 the most common symptoms of sbm from ptc in our series were headache and cranial nerve palsies , which is in agreement with reports in the literature.11,12 however , a rare presentation of collet - sicard syndrome ( cranial nerve ix , x , xi , and xii palsies ) was also described , which is the first reported case in sbm from ptc.13 diagnosis of sbm is challenging , because these lesions are often mistaken for chordoma , chondrosarcoma , meningioma , or schwannoma on ct and magnetic resonance imaging.14 biopsies should be performed in such cases for definitive diagnosis . in our series , complete surgical resection is often difficult because of the presence of adjacent vital structures ( brainstem , cochlea , and cranial nerves ) , cerebrospinal fluid leak , and bleeding . in our series , one patient had safe partial resection via a transcranial far lateral approach , which was found in agreement with the literature.15 for unresectable and residual tumors , radiation therapy is feasible option . with the advent of novel techniques in radiation therapy ( imrt , protons , carbon ions , and stereotactic radiosurgery ) , it is now possible to deliver a high dose to the tumor to achieve better local control without any serious acute toxicity , as seen in our series.16 in conclusion , sbm from ptc is a rare clinical entity , and is often associated with cranial nerve dysfunction . histopathological tissue diagnosis should always be attempted to initiate effective treatment , which relies on a multidisciplinary approach to prolong disease - free and overall survival rates .

skull base metastasis from differentiated thyroid carcinoma , including papillary and follicular thyroid carcinoma , is a rare manifestation . herein , we present three cases of skull base metastasis of papillary thyroid carcinoma . the mean age of the patients was 68.6 ( 6574 ) years , and the mean interval between initial diagnosis and skull base metastasis was 56.3 ( 2889 ) months . cranial nerve palsies were seen in all patients . intensity modulated radiation therapy to deliver 6,0006,600 cgy to the skull base metastasis was given to all patients , in addition to partial resection in one patient . at the time of last follow - up , all skull base metastases were well controlled .

there is growing data showing an increased association of seizures with alzheimer s , in both humans and animal models.1,2 estimates of prevalence vary , but it seems that about 1.5% to 10% of people with alzheimer s may experience seizure activity , with the highest prevalence in early onset alzheimers.3 this raises the question as to whether there is a subtype of alzheimer s that is seizure associated and may be linked to differential changes and possibly to differential treatment . quinolinic acid ( qa ) is a possible mediator of both seizures and neuronal loss.4,5 in the brain , microglia are the most likely source for qa . qa mediates neuronal excitotoxicity via the n - methyl - d - aspartate receptor ( nmdar ) and is usually induced by interferon - gamma ( ifny),6 although other factors are known to mediate an increase in the levels of indoleamine 2,3-dioxygenase ( ido ) , and subsequently qa.7,8 one such factor is il-18 . il-18 is induced by stress,9 including in neurons.10 it is cleaved within the cell by caspase-1 , like il-1beta , and when released mediates an increase in ifny.11 such caspase-1 activation has upstream links to inflammasome induction , and therefore to wider models of neurodegeneration.12 it is therefore possible that il-18 , including via ifny , could be associated with an increase in the levels of ido activity and qa induction in microglia . il-18 has been recently shown to increase glycogen synthase kinase 3-beta ( gsk-3b ) and tau hyperphosphorylation.13 would variations in the levels of il-18 be relevant to early onset seizure associated il-18 has been shown to be increased in the brain in alzheimer s , and increased in the cerebral spinal fluid in mild cognitive impairment,14 and il-18 polymorphisms are associated with an increase in alzheimer s susceptibility , showing synergistic interactions with the apoe4 allele.15 interestingly the apoe4 allele , independent of dementia , is associated with an increase in the susceptibility to seizures.16 as to whether il-18 polymorphisms or increases in il-18 would synergistically interact with the apoe4 allele to induce an increase in seizures as well as alzheimer s remains to be examined . it would be expected that il-18 , via an increase in gsk-3b , would increase the hyperphosphorylation of tau and enhance amyloid b ( ab ) production.17 recent data shows that ab may prime microglia - like cells for a sub - threshold concentration of ifny to induce ido / qa.18 60% of ido induction in ab primed cells is mediated by an ifny induced increase in tumor necrosis factor alpha ( tnfa ) , and the subsequent autocrine effects of tnfa . previous data19 in this cell line show that ab effects are prevented when the sphingosine-1-phosphate receptor 1 ( s1p1r ) is k.o.d . would variations in the levels / activity of the s1p1r be a significant modulator of such ab priming for subsequent ifny ? this awaits experimental data , but it would suggest that the effects of ab , like lps or thrombin , in microglia is determined by an increase in the levels of gsk-3b and enhanced nadph oxidase activation.20 this would then modulate the s1p / ceramide ratio , as part of wider oxidant status driven lipid raft re - organization.21 presumably factors that increase the levels of endogenous anti - oxidants will modulate this oxidant driven priming and raft re - organization . a number of factors inhibit gsk-3b and nadph oxidase in microglia , including lithium,22 resveratrol,23 and melatonin.24 all are associated with an increase in the phosphorylation , and inhibition , of gsk-3b , and therefore leading to an increase in nf - e2-related factor ( nrf-2 ) and endogenous anti - oxidants . however , it is possible that il-18 , independent of ifny , can increase ido , as shown in other cell types.25 would il-18 directly mediate an increase in ido ? some unpublished data suggests that this could be so.26 as to whether ab primes microglia for il-18 , as it does for ifny , remains to be determined . il-18 seems to play a role in changing the most relevant factors associated with alzheimer s through its impact on tau , ab and possibly microglia threshold . il-18 is currently being investigated for impacts at the blood brain barrier ( bbb ) . should it induce gsk-3b and alter oxidant status in the bbb , then this could overlap it to the effects of peripheral lps , which mediates changes in rage ( receptor for advanced glycation end products ) and lrp-1 ( low density lipoprotein receptor - related protein-1).27 such changes lead to an increase in the influx and decrease in the efflux of ab over the bbb . would il-18 , perhaps in conjunction with ab , parallel such oxidant associated changes in the bbb ? in human endothelia and pericyte lines , lps leads to an increase in the levels of abluminally released kynurenine.28 this seems likely to be taken up by astrocytic end - feet and rapidly converted to kynurenic acid ( ka ) . would il-18 , with or without ab priming , modulate the ido and kynurenine pathways at the bbb ? such putative increases in ka would likely be anti - epileptic , although it would also induce cognitive impairment , as in schizophrenia as well as in alzheimers.29 this is presuming ka release from astrocytes , perhaps in a targeted manner , to neurons . however , in an inflammatory context , where bbb changes are occurring , then microglia may have closer proximity to the bbb , in conjunction with perivascular macrophages,30 and the kynurenine produced could be driven to qa production , and therefore contribute to excitotoxicity , and seizure induction . an increase in kynurenine , qa and ka would suggest that more tryptophan is being driven down the kynurenine pathway , and less to serotonin and melatonin formation . for example , losartan , via its active metabolite exp 3179 , mediates an increase in the akt / pgsk-3b / nrf-2/anti - oxidant paths . this is achieved via the induction of vascular endothelial growth factor ( vegf ) and its effects at the vegf receptor 2 ( vegf r2).31 ab directly blocks the vegf r2,32 and so some of the anti - hypertensive and importantly anti - oxidant effects of losartan will be lost . a shift to other anti - hypertensives may be useful . this would highlight the need for more dynamic and reactive prescribing , which in turn would be dependent on a more detailed knowledge of the processes of change , including the changes that seizure induction may indicate . melatonin has also been shown to be protective in alzheimers,33 and has been shown to significantly decrease the levels of gsk-3b.34 would a significant decrease in melatonin interact with seizure susceptibility in alzheimer s ? no current data directly answers this , although melatonin is known to have anti - epileptic effects.35 melatonin also reverses some of the other cellular changes that are associated with alzheimer s , including a decrease in the longevity protein sirtuin-1,36 a decrease in pgc-1a ( peroxisome proliferator - activated receptor - gamma , coactivator-1alpha)37 and a decrease in oxidative phosphorylation.38 would variations in melatonin be associated with seizure susceptibility , and perhaps the modulation of the il-18/ifny induced increases in ido / qa in seizure associated alzheimer s ? melatonin is known to modulate bbb permeability , and this may be relevant to changes in brain ab levels , as suggested above . also the kynurenine aminotransferases ( kats ) are sensitive to oxidative stress.39 a decrease in ka arising from such oxidative modulation may allow more kynurenine to form qa . there is one paper showing that astrocytes are able to produce melatonin when adequate serotonin is present.40 given the anti - seizure , anti - cortisol and cortisol modulating effects of melatonin,41 then such induction by astrocytes would be a potential local target for drugs to induce . it would seem likely that such astrocyte derived melatonin would modulate seizures , stress / il-18 as well as microglia and bbb oxidant status and associated changes , as shown in the summary figure . in conclusion , an argument can be made for the role of stress induced increases in il-18 , perhaps via ifny and/or ab priming , in the modulation of ido in both microglia and endothelia . in microglia an increase in the levels of qa would be associated with both seizures and neuronal loss , and these effects may be potentiated by the apoe4 allele . as to whether such pathways constitute a sub - type of alzheimer s , or are differentially activated along a continuum in all people with alzheimer s remains to be determined . further research on the processes may lead to a better treatment strategy for this putative sub - type of alzheimer s .

emergent seizures are common in alzheimer s disease ( ad ) , although the mechanisms mediating this are unknown . it is proposed that stress induced interleukin-18 ( il-18 ) , via interferon - gamma ( ifny ) and independently , increases indoleamine 2,3-dioxygenase ( ido ) and subsequent quinolinic acid ( qa ) in microglia . qa increases seizures and concurrently contributes to neuronal loss via excitotoxicity . the apoe4 allele interacts with il-18 polymorphisms to increase the risk of ad , and seems likely to potentiate the emergence of seizures . concurrent changes in ido and the kynurenine pathways at the blood - brain - barrier ( bbb ) have implications for treatment , including in the efficacy of different anti - hypertensives . melatonin is proposed to inhibit these overlapping excitotoxic and neurodegenerative processes , and would be a useful adjunctive treatment .

neurofibromatosis-1 ( nf-1 ) , previously referred to as von recklinghausen 's disease , is an autosomal dominant disorder with a birth incidence of 1 in 3,500 . although it manifests with variable signs and symptoms , it mainly affects the skin and peripheral nervous system . unusual tumors , including carcinoid , pheochromocytoma , brain tumors , and malignant peripheral nerve sheath tumors occur with higher frequency in nf-1 , but other common tumors , such as lung , breast , colon and prostate , are less frequent . because this disorder involves increased tumor predisposition , the detection of a mass - like lesion raises the possibility of malignancy . in this report , we describe a case of nf-1 presenting with a large intrathoracic mass that was found incidentally . a 41-year - old woman came to the hospital for the evaluation of a lung mass found on a chest radiograph . the patient had no signs or symptoms . however , on physical examination , widespread caf - au - lait spots , cutaneous neurofibromas ( fig . 1a ) , axillary frecklings and reddish brown spots on the iris ( lisch nodules ) ( fig . 1b ) were present , consistent with the diagnosis of nf-1 . among the family members , a 14-year - old daughter and 12-year - old son had similar manifestations of nf-1 ( fig . 4 ) showed a 7 cm homogeneous cystic mass with a thin wall in the left paravertebral area , extending into the spinal canal through the t5 - 6 neural foramen . clear fluid was withdrawn by needle aspiration and the diagnosis of an intrathoracic meningocele was made . a spinal meningocele is a saccular protrusion of the meninges through a dilated intervertebral foramen or a bony defect of the vertebral column . although somewhat common after a laminectomy , a congenital meningocele is relatively rare and usually associated with generalized mesenchymal dysplasia , such as nf-1 or marfan syndrome . andrade et al . found that 69% of intrathoracic meningoceles were associated with nf-1 since the first case was reported by phol in 1933 . in the thorax , lateral meningoceles are more frequent because the paravertebral muscles are relatively weak and the pressure gradient between cerebrospinal fluid and thorax is higher . meningoceles should be differentiated from tumors , especially those that commonly arise from the posterior mediastinum , such as neurofibroma , neuroblastoma , and ganglioneuroma . most patients are asymptomatic , but several clinical manifestations can develop depending on size and location of meningoceles . it can cause paraparesis or pain by involvement of the spinal cord , or may compress the lung and mediastinal structures , causing cough , dyspnea , and palpitations . surgical treatment is indicated only when the size of the meningocele rapidly increases or when patients are symptomatic due to the compression of surrounding structures by the meningocele . although laminectomy and intradural repair of the cyst is sufficient for small lesions , a transthoracic approach is required for larger ones to reduce complications such as cord damage and meningopleural fistula . in conclusion , intrathoracic meningocele is a rare and benign pathology , although surgical treatment is sometimes needed for symptomatic , growing lesions . meningoceles should be considered in nf-1 patients presenting with a mass - like lesion on a chest radiograph .

a large intrathoracic meningocele , a saccular protrusion of the meninges through a dilated intervertebral foramen or a bony defect of the vertebral column , was diagnosed in a 41-year - old female patient showing clinical features of neurofibromatosis-1 ( nf-1 ) , including caf - au - lait spots , cutaneous neurofibromas , and axillary frecklings and lisch nodules on the iris . her daughter and son also had similar manifestations of nf-1 . regular follow - up with periodic imaging was recommended without surgical treatment because there were no signs or symptoms . meningocele should be differentiated from posterior mediastinal tumors such as neurofibroma , neuroblastoma , and ganglioneuroma because nf-1 has a high risk of tumor formation . we report on this case with a brief review of the literature .

workplace health and wellbeing is becoming a major public health issue for employers and at all levels of government initiatives . multidisciplinary strategies to improve health and wellbeing at work have been acknowledged to be very effective in addressing both individual risk and the broader organizational and environmental issues . the workplace is the ideal site for health promotion and a wellbeing initiative as it is a specifically defined community with the benefits of social support and the associated economic and organizational productivity . well planned , comprehensive workplace health and wellbeing initiatives have been shown to be cost - effective , especially when the initiatives are targeted and matched to the health needs of the specific population . furthermore , studies have repeatedly demonstrated that well - resourced workplace health and wellbeing initiatives not only lower healthcare and insurance costs but also decrease absenteeism and improve performance and productivity . the workplace is often an under - utilized setting for promoting employees ' health and wellbeing . most employees spend more than a third of their waking hours at work , and therefore large numbers of employees can be reached and encouraged to acquire the knowledge and skills to live a healthy lifestyle . despite health and wellbeing programs being initiated in organizations , the views of employees on what specific programs and resources are relevant to them are rarely evaluated . in november 2009 , the steve boorman report was launched in the united kingdom to promote the health and wellbeing of employees working in the national health service . one of the report 's recommendations was for organizations to review the health and wellbeing needs and resources within their organization . as a result , this survey was undertaken in order to gather information about the health and wellbeing needs and resources of employees at one british organization . a cross - sectional survey was carried out to explore the health and wellbeing needs and resources of employees at one british organization . all employees were invited to participate in the survey , and , therefore , sampling was not necessary . this survey was within the scope of good clinical practice , and , therefore , ethical approval was not required . a questionnaire was designed for the purpose of the survey and distributed by email in april 2014 . the design of the questionnaire was based on health and wellbeing literature which ensured face validity . in order to ensure content validity , members of the health promotion committee were consulted to scrutinize a draft copy and provide feedback . following initial feedback , any changes made to the questionnaire were discussed with members of the health promotion committee to ensure its accuracy . this included demographic information , factors improving their health and wellbeing , factors affecting their health and wellbeing , and whether or not maintaining a healthy lifestyle in the workplace was achievable . the information from the questionnaires was coded on spreadsheets , and descriptive analysis was carried out . there were 617 ( 74% ) female and 221 ( 26% ) male employees that completed the questionnaire . the highest number of responses that were received according to job profile were registered nurses ( n = 184 , 22% ) , doctors ( n = 154 , 18.4% ) and administration support workers ( n = 153 , 18.3% ) , respectively . the least number of responses were from porters ( n = 2 , 0.2% ) . employees were asked about the factors that were important in improving their health and wellbeing at work . in total , 58% of employees ( n = 485 ) reported " feeling happier at work " was the most important factor . other factors included " wanting to eat a healthier diet " ( n = 411 , 49% ) , " increasing levels of physical activity " ( n = 387 , 46% ) , and " wanting to be a healthier weight " ( n = 331 , 40% ) . a large number of employees ( n = 477 , 57% ) did not feel a " reduction in alcohol intake " was important in improving their health and wellbeing at work . employees were asked about the factors affecting their health and wellbeing at work . in total , 819 ( 98% ) the most common factors were physical tasks , such as " moving and handling " ( n = 434 , 53% ) , " work pressures , such as unrealistic deadlines " ( n = 312 , 38% ) , and " poor relationship with colleagues " ( n = 259 , 32% ) . the issue that least affected employees ' health and wellbeing at work was " inflexible working patterns " ( n = 204 , 25% ) . employees were asked about the types of resources that could be useful to support their health and wellbeing at work . in total , 568 ( 68% ) employees indicated that the " provision of physiotherapy " was the most useful resource at work . other types of work assistance employees felt were useful included " better access to healthy , affordable food " ( n = 551 , 66% ) and activities , such as " subsidized gym membership / cycling scheme " ( n = 536 , 64% ) . the least useful work resources reported by employees were " smoking cessation " ( n = 153 , 18% ) , " advice and support on alcohol intake " ( n = 142 , 17% ) , " literature concerning health topics " ( n = 26 , 3% ) , and " health promotion events " ( n = 25 , 2.9% ) . all employees were asked to indicate whether they agreed or disagreed with the following statement : " i feel maintaining a healthy lifestyle in the workplace is achievable " . a total of 836 ( 99.7% ) employees answered this question , of which 623 ( 75% ) answered " yes " and 213 ( 25% ) answered " no . " of the 213 employees that answered " no " , 145 ( 68% ) gave personal reasons to support why they did not believe a healthy lifestyle was achievable at work . this survey shows that employees had clear expectations about the factors that improved and hindered their health and wellbeing at work . in most organizations , health and wellbeing initiatives are not limited to occupational health professionals but also to physiotherapists and psychologists , providing a wide range of resources . this survey had several strengths , including identifying and documenting those factors that were affecting the health and wellbeing of employees . this provides important information to the organization and occupational health so that a targeted approach can be implemented . many organizations have limited resources , and a targeted approach ensures that available resources are used effectively and future investment is allocated to appropriate resources . in addition , the evaluation of the health and wellbeing needs is likely to demonstrate to employees that the organization is taking their needs seriously . the " provision of physiotherapy " was identified as the most useful resource at work to support employee health and wellbeing . given the high level of moving and handling injuries affecting employee health and wellbeing in this organization , it is not surprising that employees felt that rapid access to physiotherapy services was a valuable resource . studies have shown that rapid access to physiotherapy is both clinically and cost effective in dealing with employees presenting with moving and handling injuries . a quarter of employees did not believe that a healthy lifestyle is achievable at work . this highlights that more needs to be done by the organization and occupational health to improve the working conditions and organizational culture so that employees feel that they can function optimally at work and not perceive the workplace as a contributor to their ill - health . in addition , occupational health can assist with advising both employees and line managers about how to tackle some of the personal issues affecting employee health and wellbeing at work as outlined in table 1 . this could include referral to counseling services , temporary or long - term adjustments to working hours , or risk assessments in areas where the working environment is unsafe . in addition , future health and wellbeing initiatives should be developed taking into account the factors and resources that employees felt would be most beneficial . this approach would ensure that these initiatives appeal to a wide range of employees and possibly increase employee engagement and uptake . as with all case studies , the findings reported in this paper are specific to one british organization , and care should be taken when generalizing the findings to other organizations . however , the details provided in this paper will hopefully enable practitioners to draw conclusions about the applicability of these findings to their own organization or country . firstly , it has evaluated the health and wellbeing needs and resources of employees at one british organization . secondly , it has highlighted the health and wellbeing resources that are most valued by employees at this organization . finally , it has made recommendations for tailoring health and wellbeing initiatives to the needs of employees in order to increase engagement and uptake . in conclusion , it is up to individual organizations or countries to decide if this approach is suitable within the context of their policies , procedures , and legislation in order to inform any future investment in health and wellbeing initiatives for the benefit of their employees . conflicts of interest : none declared . acknowledgments : this study would not be possible without the support of the members of the health promotion committee and all employees that completed and returned the questionnaire .

introduction : workplace health and wellbeing is a major public health issue for employers . wellbeing health initiatives are known to be cost - effective , especially when the programs are targeted and matched to the health problems of the specific population . the aim of this paper is to gather information about the health and wellbeing needs and resources of employees at one british organization.subjects and methods : a cross - sectional survey was carried out to explore the health and wellbeing needs and resources of employees at one british organization . all employees were invited to participate in the survey , and , therefore , sampling was not necessary.results : 838 questionnaires were viable and included in the analysis . employees reported " feeling happier at work " was the most important factor promoting their health and wellbeing . physical tasks , such as " moving and handling " were reported to affect employee health and wellbeing the most . the " provision of physiotherapy " was the most useful resource at work . in all , 75% felt that maintaining a healthy lifestyle in the workplace is achievable.conclusions : more needs to be done by organizations and occupational health to improve the working conditions and organizational culture so that employees feel that they can function at their optimal and not perceive the workplace as a contributor to ill - health .

breast carcinoma in men is uncommon with an incidence report rate of 1.08 per 100,000 . at time of diagnosis , men have a higher median age ; and are more likely to have a more advanced stage of disease and lymph node involvement . forequarter ( interscapulothoracic ) amputation was first performed in 1808 for severe traumatic injuries of the upper extremity . the procedure involves removal of the entire upper extremity with the ipsilateral scapula and total/ subtotal clavicle . the first oncological forequarter amputation was reported in 1836 . since then , it has been used for managing high - grade bone and soft - tissue sarcomas of the shoulder girdle in which salvage of the extremity and the aforementioned bones including the shoulder joint would not be feasible . today , it is very rarely used as effective adjuvant chemotherapy with or without radiation therapy combined with limb - sparing surgery in many cases has replaced radical amputation surgeries . although the majority of forequarter amputations are performed for high - grade bone and soft tissue sarcomas or extensive osteomyelitis of the upper extremities , this radical operation may also be indicated for the curative treatment of recurrent breast cancer and for the palliation of locally advanced breast cancer . axillary tumor recurrence may cause significant morbidity due to pain , limb dysfunction , lymphedema , and varying degrees of paralysis and sensory impairment . it may also cause chest wall invasion , and skin ulceration secondary to invasion of the brachial plexus and axillary vessels by the tumor . further morbidity can be caused by perforation of the overlying skin by the tumor causing bacterial or fungal infections , sepsis , or hemorrhage . in those cases with dysfunctional upper extremities , a need for a more radical surgery may arise in order to improve the patient 's quality of life and daily function [ 3,5 - 7 ] . to date , there have only been 20 published cases of forequarter amputations for axillary recurrence of breast cancer . all of the cases were females and only 4 of these amputations were performed primarily for curative purposes . we are hereby reporting a male patient with metastatic breast adenocarcinoma who underwent simultaneous modified radical mastectomy and forequarter amputation . the axillar mass was 12 7 cm and the mass in the proximal lateral humerus was 6 5 cm . his symptoms had started a number of years prior . before the initiation of these symptoms , he denied having any significant medical problems . he had been referred to a surgerical clinic three years prior in which he had a biopsy of the tumor reported as mucinous adenocarcinoma . it appears that he had been evaluated only for possible intestinal primaries at that time and having failed to identify the primary , had been sent to receive radiotherapy of unclear dosage . after the recurrence of his tumor , he was referred to the medical oncology department at our hospital with a mass in the left thoracic region and another in the left humerus , visible on x - rays ( fig . 1 ) . his examination revealed a mass in his left breast besides the aforementioned ones . his biopsy materials were reevaluated in our pathology department and confirmed to be metastatic adenocarcinoma . the report also indicated that the mass might be breast originated , raising the suspicion towards a possible breast primary . he was then given neoadjuvant chemotherapy consisting of docetaxel and capecitabine for six cycles following the decision of our tumor council . an magnetic resonance imaging ( mri ) scan was obtained following the cessation of his chemotherapy revealing a 140 100 90 mm lobulated mass in the proximal epiphyses , metaphysis and diaphysis of the left humerus , which was destructing the cortices on multiple sides with a large soft tissue component , and invading and protruding out of the skin ( fig . another mass , 123 54 74 mm in size , was located in the axillary region adjacent to the thoracic wall infiltrating the skin , surrounded by multiple nodular masses of different sizes . there were other masses also in his pectoral muscle , as well as in his scapular muscles . medullar intensity of the scapula appeared to be normal . computed tomography scans of the chest , abdomen and pelvis and an mri of the brain failed to demonstrate any other metastasic lesions . at the end of the neoadjuvant chemotherapy protocol , he was under a combination analgesic treatment that consisted of ibuprofen ( 3 400 mg ) , tramadol ( 4 50 mg ) and pethidine ( 1 75 mg ) . his pain scales ( out of 10 ) were 8 to 9 in the mornings and 9 to 10 at night , severe enough to awaken him from his sleep . the status of the patient was discussed amongst the tumor council of our hospital consisting of orthopedic surgeons , radiologists , medical oncologists and radiation oncologists , who decided that amputation would be the best option for the management of the patient 's pain and impaired function . the radical nature of the procedure as well as the risks and benefits were discussed with the patient and his family and the patient consented to undergo the operation . the operation was performed by a team of orthopedic , general and plastic - reconstructive surgeons . the skin incision was marked in close consultation with the general and plastic surgeons ( fig . skins flap were elevated superiorly to the clavicle , inferiorly to the costal arch , and medially to anterior midline . the lateral border of the skin flaps was latissimus dorsi muscle , inferiorly ; and the supero - medial border of the mass , superiorly . dissection of the pectoralis major muscle was started from the medial side at the origin from the sternum as the insertion was also invaded by the mass . dissection was then directed to the thoracic wall to excise all the breast tissue , pectoral muscles and the soft tissues , including the periosteum of the ribs without exposing the tumor . the exposure was continued laterally and posteriorly up to the insertions of rhomboid muscles . finally , the upper extremity , all together with the mastectomy material , was removed including the scapula , inevitably creating a big tissue defect ( fig . 4 ) . the defect was closed with full thickness skin graft and application of vacuum assisted closure ( v.a.c . the specimen consisted of 70 cm of upper extremity and scapula and breast tissue attached to it . there was another ulcerated region of 6 5 cm in the lateral proximal humeral region . the tumor was negative for estrogen receptor , c - erbb2 and gcdfp-15 , and 1% positive for progesterone receptor . in fluorescence in situ hybridization ( fish ) studies conducted with dna probes ( repeat - free poseidon fish dna probes , kreatech diagnostics , amsterdam , netherland ) her-2 gene amplification was not manifested . the patient was monitored in the post anesthesia care unit for a few days until he was stabilized and then transferred to our clinic . in the early post - operative period his pain medication was ibuprofen ( 3 400 mg ) and tramadol ( 2 50 mg ) , with the addition of morphine patient controlled analgesia for the first two days . his pain scales , out of 10 , were between 4 to 6 both during the day and at night . he was discharged from the hospital when the wound healed after two weeks ( fig . his outpatient progress was monitored during the first , third , sixth and twelfth weeks post - operatively . in the third and the sixth week controls , the patient reported that he was experiencing reduced levels of pain and had therefore lessened his intake of pain medication ; he was only taking ibuprofen ( 3 400 mg ) . in the control during the twelfth week the patient reported that he was almost entirely pain - free . the patient , refusing to receive any further chemotherapy , passed away eleven months after surgery . invasive breast cancer is the most common malignancies among women . although the incidence appears to be on the rise , due to earlier detection and adjuvant therapy , declining mortality rates there is a tendency for limited axillary surgery , which may eventually increase the potential risk of future axillary recurrences . a review of the literature reveals only 20 published cases of forequarter amputation for axillary recurrence of breast cancer , most derived from small groups or individual case series . none of these patients were men , and to our knowledge , forequarter amputation as a primary treatment for metastatic and infiltrative breast cancer has never been reported . the status of the disease and possible treatment alternatives were discussed amongst the tumor council at our hospital , which consists of orthopedic surgeons , radiologists , medical oncologists and radiation oncologists . the operation of simultaneous mastectomy , forequarter amputation and skin grafting was performed by a team of orthopedic , general and plastic - reconstructive surgeons . it was well known at the time of treatment that our patient would have a poor short - term prognosis with his extensive metastasis , and the operation was performed with palliative aim , focusing on his quality of life rather than life expectancy . eventually his quality of life improved dramatically after the operation and he lived for eleven more months without suffering from severe pain . similarly , an overall improvement in daily life , physical and emotional well - being and sexual or social life is reported for patients who underwent forequarter amputation for palliation . furthermore , it has also been advocated that local recurrence of breast cancer without a remote metastasis can be an indication for surgery to relieve pain and bleeding , and that in combination with adjuvant therapy the patient 's survival can be prolonged . in conclusion , this case demonstrates that even in grossly advanced stages of breast carcinomas with invasion not only to the chest wall but also to the neighboring axilla and extremity , ablative surgery of a very large magnitude including the excision of the breast and all chest wall muscles as well as the entire shoulder girdle and upper extremity , is not only feasible with a multidisciplinary approach but also advisable in order to decrease patients ' pain and improve the quality of their lives .

although the majority of forequarter amputations are performed for high - grade bone and soft tissue sarcomas or extensive osteomyelitis of the upper extremity , this radical operation may also be indicated for the curative treatment of recurrent breast cancer and for the palliation of locally advanced breast cancer . we report a male patient with metastatic breast adenocarcinoma who underwent simultaneous mastectomy and forequarter amputation for the management of both his primary and metastatic disease .

the patient was a 60-year - old man with a history of smoking 10 cigarettes per day for 35 years . he was found to have a small shadow in the right lower lung field on chest x - ray in 2006 , and was thereafter followed - up at another hospital ( figure 1a ) . chest x - ray in 2007 revealed a cavitating shadow at the same site ( figure 1b ) . a chest x - ray in 2008 showed thickening of the cavity wall , and that in 2009 revealed the tendency of the entire cavity shadow to enlarge ( figure 1c , d ) . computed tomography showed an inhomogeneous thickening of the cavity wall and spiculation from the tumor margin , as well as the presence of lung structures in the cavity ( figure 2a ) . bronchoscopic biopsy of the cavity wall led to a diagnosis of adenocarcinoma . under a diagnosis of lung cancer ( ct2an0m0 ) , right lower lobectomy with hilar and mediastinal lymph node dissection was performed . gross examination of the tumor showed a cavity whose wall was grayish - white , uneven in thickness , and was torn in some areas ( figure 2b ) . interestingly , lung tissue and blood vessels were present in the cavity and were in contact with the extralesional lung through the tears in the cavity wall . histopathologically , the tumor was composed of atypical bronchial epithelial cells proliferating in a tubular pattern ( pt2an0m0 ) . the internal surface of the cavity wall was lined with dilated bronchi and adenocarcinoma cells , and the extensive area of collapsed scars was observed around the dilated bronchi ( figure 3a - f ) . at present , 18 months after surgery , the patient remains free of disease . the frequency of cavity formation in primary lung cancer has been reported to be 2 - 16% , with squamous cell carcinoma and adenocarcinoma accounting for 45 - 63 and 30 - 53% , respectively 1 . the possible mechanisms of cavity formation include : i ) ischemic necrosis due to occlusion of feeding vessels , ii ) check - valve mechanism of the conducting bronchus , iii ) elastic traction by the surrounding lung tissue , iv ) tumor development in pre - existing lesions such as bullae , and v ) neoplastic cell autophagism 2 - 5 . we speculate that the mechanism of cavity formation in this case was as follows : a scar of collapsed elastic fibers was formed in cancer tissue , resulting in the elastic retraction of the bronchi embedded in the scar , and , during the development of bronchiectasis , the bronchial wall was disrupted in some places , with the result that the tumor tissue shared the cavity wall with the bronchus . a small portion of lung tissue and blood vessels stayed inside the cavity through the tears in the cavity wall during the further development of bronchiectasis . cavitary lung cancer which contains lung tissue inside the cavity is a rare entity , but if a tumor shows malignant features on imaging studies , such as wall irregularity , notching , inhomogeneous thickening of the cavity wall , and an enlarging tendency , it is necessary to perform bronchoscopy or surgical biopsy .

reports of cavitary lung cancer are not uncommon , and the cavity generally contains either dilated bronchi or cancer cells . recently , we encountered a surgical case of cavitary lung cancer whose cavity tended to enlarge during long - term follow - up , and was found to be lined with normal bronchial epithelium and adenocarcinoma cells .

leukemic infiltration of breast is rare and may occur as an isolated tumor or as extra - medullary manifestation in systemic disease . we recently came across two cases of acute lymphoblastic leukemia ( all ) presenting as breast masses . breast infiltration was diagnosed on fine - needle aspiration cytology ( fnac ) and later confirmed with other investigations . these cases are reported on account of their rarity , variable presentation , and the fact that there have been few case reports of similar nature elucidating their fnac . a 30-year - old female , 6 weeks after delivery , presented with bilateral painless breast - swellings which she had developed in her 9 month of pregnancy . she complained of early fatigability but had no history of bleeding tendency , weight loss , or loss of appetite . her general physical examination revealed pallor but was otherwise unremarkable . on local examination , a 3 3 cm , firm , irregular , non - tender and partly mobile swelling was felt in the left breast and a similar swelling , 2 2 cm in the right . a complete blood - count revealed a total leukocyte count of 1.21 10/mm with a differential leukocyte count showing 90% blasts , a hemoglobin level of 5.3 mg / dl , and a platelet count of 180 10/l . a mammography was advised and showed diffuse nodular infiltration in both breasts [ figure 1 ] . breast ultrasound revealed a coarse echo pattern with no fixity to any structure and normal ducts . microscopy revealed benign groups of ductal cells , clumps of degenerated cells along with scattered round cells with scanty cytoplasm and inconspicuous nucleoli ( lymphoblasts ) [ figure 2 ] . mammography showing diffuse dense areas in upper and outer quadrants of both breasts but no well - defined mass smears showing abundant round cells with scanty cytoplasm and inconspicuous nucleoli ( lymphoblasts ) amidst a few benign duct cells ( mgg , 400 ) a bone marrow aspirate obtained was hypercellular with > 25% blasts having coarse chromatin , inconspicuous nucleoli and scant cytoplasm . flow cytometry of bone marrow was positive for cd19 , cd10 , cd22 , cd33 , cd45 , terminal deoxynucleotidyl transferase ( tdt ) , hla dr4 , cd34 and negative for t - cell markers . scatter parameters and antigen expression as studied by flow cytometry were suggestive of a b - cell all , common acute lymphoblastic leukemia antigen ( calla ) -positive with myeloid co - expression . the patient received chemotherapy modified berlin frankfurt munich ( bfm ) protocol . she is on regular follow - up and remains disease - free 1 year later . a 14-year old female presented with a 1-week history of a painless swelling in the right breast . she was diagnosed with all - l2 a year - and - a - half back ; flow cytometry had shown calla positive b - cell all with breakpoint cluster region the patient received chemotherapy ( uk all xii protocol with cns prophylaxis ) , and stem cell transplant was declined for financial reasons . clinical examination of her breast swelling revealed a 1.5 cm firm , painless , mobile swelling , in the right breast . a complete blood count revealed a total leukocyte count of 9.4 10/mm , a hemoglobin level of 14.2 mg / dl , and a platelet count of 184 10/l . an aspirate obtained from the lump using a 22-gauge syringe was stained with may - grnwald - giemsa ( mgg ) . microscopic examination revealed highly cellular smears , showing diffuse infiltration by round cells with inconspicuous nucleoli and scanty cytoplasm ( lymphoblasts ) [ figure 3 ] . a 30-year - old female , 6 weeks after delivery , presented with bilateral painless breast - swellings which she had developed in her 9 month of pregnancy . she complained of early fatigability but had no history of bleeding tendency , weight loss , or loss of appetite . her general physical examination revealed pallor but was otherwise unremarkable . on local examination , a 3 3 cm , firm , irregular , non - tender and partly mobile swelling was felt in the left breast and a similar swelling , 2 2 cm in the right . a complete blood - count revealed a total leukocyte count of 1.21 10/mm with a differential leukocyte count showing 90% blasts , a hemoglobin level of 5.3 mg / dl , and a platelet count of 180 10/l . a mammography was advised and showed diffuse nodular infiltration in both breasts [ figure 1 ] . breast ultrasound revealed a coarse echo pattern with no fixity to any structure and normal ducts . microscopy revealed benign groups of ductal cells , clumps of degenerated cells along with scattered round cells with scanty cytoplasm and inconspicuous nucleoli ( lymphoblasts ) [ figure 2 ] . mammography showing diffuse dense areas in upper and outer quadrants of both breasts but no well - defined mass smears showing abundant round cells with scanty cytoplasm and inconspicuous nucleoli ( lymphoblasts ) amidst a few benign duct cells ( mgg , 400 ) a bone marrow aspirate obtained was hypercellular with > 25% blasts having coarse chromatin , inconspicuous nucleoli and scant cytoplasm . flow cytometry of bone marrow was positive for cd19 , cd10 , cd22 , cd33 , cd45 , terminal deoxynucleotidyl transferase ( tdt ) , hla dr4 , cd34 and negative for t - cell markers . scatter parameters and antigen expression as studied by flow cytometry were suggestive of a b - cell all , common acute lymphoblastic leukemia antigen ( calla ) -positive with myeloid co - expression . the patient received chemotherapy modified berlin frankfurt munich ( bfm ) protocol . she is on regular follow - up and remains disease - free 1 year later . a 14-year old female presented with a 1-week history of a painless swelling in the right breast . she was diagnosed with all - l2 a year - and - a - half back ; flow cytometry had shown calla positive b - cell all with breakpoint cluster region the patient received chemotherapy ( uk all xii protocol with cns prophylaxis ) , and stem cell transplant was declined for financial reasons . the patient responded and had been in remission for the last 1 year . on general physical examination , clinical examination of her breast swelling revealed a 1.5 cm firm , painless , mobile swelling , in the right breast . a complete blood count revealed a total leukocyte count of 9.4 10/mm , a hemoglobin level of 14.2 mg / dl , and a platelet count of 184 10/l . a clinical diagnosis of fibroadenoma was made . an aspirate obtained from the lump using a 22-gauge syringe was stained with may - grnwald - giemsa ( mgg ) . microscopic examination revealed highly cellular smears , showing diffuse infiltration by round cells with inconspicuous nucleoli and scanty cytoplasm ( lymphoblasts ) [ figure 3 ] . leukemic infiltration of breast is rare and may occur as an isolated tumor or as an extra - medullary manifestation in systemic disease . only very rarely , is this the primary manifestation of an all . patients with leukemic infiltration of breast usually are present with a palpable lesion that is generally well - circumscribed and rapidly enlarging the mammographic findings are variable and can be unremarkable or reveal an enlarged breast with diffusely coarse breast parenchyma . an irregular mass or a mass with well - defined borders and a benign appearance may also be seen . on ultrasonography , most masses are homogenously hypoechoic with micro - lobulated or indistinct margins . various case reports on fine needle aspiration ( fna ) of all infiltration of the breast the aspirates exhibit dispersed monomorphic blastic cells ranging from small , medium - to - large cells having a high nuclear : cytoplasmic ( n : c ) ratio . ninety percent are t - cell neoplasms and stain for these markers and the remaining 10% are b - cell type . all is the only lymphoma that shows tdt positively . in the absence of a suggestive clinical picture , these include non - hodgkin 's lymphoma , rhabdomyosarcoma , granulocytic sarcoma , lobular carcinoma , neuroblastoma and endocrine carcinoma . our cases had cellular aspirates comprising monomorphic small - to - medium size round cells having high n : c ratio , immature chromatin , inconspicuous nucleoli and scanty cytoplasm . few ductal cells were intermingled between lymphoid cells in the aspirates from the postpartum female . our first case showed myeloid co - expression ( cd33 ) and our second case was bcr - abl positive . in conclusion , breast infiltration by all is rare . it should be considered in the differential diagnosis of breast lumps of sudden onset , especially when there is a significant past history . fnac gives an easy and early diagnosis . in combination with flow cytometry or immunocytochemistry , a definitive diagnosis can be made , avoiding an excisional biopsy and allowing the initiation of early treatment .

extra - medullary leukemic infiltration of the breast by acute lymphoblastic leukemia ( all ) is very rare . we report two cases of all presenting as breast masses and diagnosed on fine - needle aspiration ( fna ) . our first patient , a post - partum 30-year - old female , developed bilateral breast lumps in her last trimester of pregnancy and complained of easy fatigability . our second patient , a 14-year - old girl , presented with a right - breast lump of 1-week duration . she had received treatment for all 1 year back and had been in complete remission for the last 1 year . fna of the breast nodules done in both the cases revealed diffuse infiltration by lymphoblasts . subsequent hematological investigations confirmed bone marrow involvement by all in the first case and extra - medullary relapse in the second case . fine - needle aspiration cytology ( fnac ) is an easy and cost effective method for the early diagnosis of metastatic leukemic infiltration , avoiding unnecessary excisional biopsies in such cases .

recombinant human growth hormone ( rhgh ) is used to treat a variety of growth disorders in childhood / adolescence . adherence to pediatric rhgh therapy is suboptimal ; poor adherence is associated with reduced clinical effectiveness and possible increased economic costs.1 factors affecting adherence to gh therapy include the patients preference for the delivery device , its simplicity and convenience , as well as appropriate education and technique training.2,3 improving patient adherence to long - term gh treatment through enhanced self - administration devices may be important to ensure patients reach their final target height.3,4 gh injection devices continue to evolve and improve ; conventional syringes and needles have been replaced by more sophisticated and user - friendly devices designed to better meet the needs of patients . reliability , ease of use , lack of pain , safety during use / storage , and the number of steps involved in the injection process have been identified as important factors in the design of a gh injection device intended for long - term use.2,58 surepal is a reusable self - injection system that has been developed to support daily administration of omnitrope ( sandoz , kundl , austria ) . approved needle sizes are bd 29 g 12.7 mm , bd 31 g 5 mm , and bd 31 g 8 mm . surepal has been specifically designed to be easy and convenient to use , and to minimize drug wastage.9 key features include ready - to - use cartridges ( no reconstitution necessary ) , auto priming , and a sliding button that requires minimal injection force . in addition , safety features include : an optional needle hider ; pre - assembled cartridges to ensure only the correct dose can be used with each device ; a dose memory function that enables the correct dose to be pre - set and locked into the device which reduces the risk of incorrect dosing ; and a rotating dose knob that provides certainty that a full dose has been delivered.9 a study to validate the usability and assess the ease of use of surepal has been conducted in both adults and children / adolescents ( n=106 ) , in germany and in the usa.9 overall , 92% of participants rated the injection procedure ( into an injection pad ) as very easy or easy . in addition , 99% were able to disassemble the pen device successfully . in this paper we report data from a questionnaire - based cross - sectional survey to evaluate acceptability of , and preference for , surepal in pediatric patients who were prescribed treatment with omnitrope within routine clinical care . a questionnaire - based , cross - sectional , multicenter ( germany and the uk ) , observational survey study was conducted , which was incorporated into the ongoing non - interventional patro ( patients treated with omnitrope ) children study.10 patients eligible for inclusion into patro children are infants , children , and adolescents ( either male or female ) who are receiving treatment with omnitrope and who have provided informed consent . patients who have been treated with another rhgh product before starting omnitrope are also eligible for inclusion . patients ( or their caregivers ) who had provided additional written informed consent were provided with a folder containing the questionnaire , an explanation of the survey and procedures , and timelines for returning the completed questionnaire via a pre - paid and pre - addressed envelope ( completed questionnaires were to be returned 1 month after start of use of surepal , and no later than 7 months after start of use ) . all patients ( or their caregivers ) received training on the use of surepal before the start of the survey . the questionnaire included questions on five main topics ; attractiveness of the device , training received , using surepal , the low drug wastage system , and experience compared with other devices used previously ( where applicable ) . questions were scored on a 5-point scale , with 2 being the worst possible outcome ( eg , very hard or very poor ) and 2 being the best possible outcome ( eg , very easy or excellent ) . i do nt know. all completed questionnaires were sent to the same data collection center , where they were anonymized before data entry and analysis . analyses were conducted for the overall study population and by pre - treatment ( with rhgh ) status . a total of 186 patients were included in this study , 154 from germany and 32 from the uk . twenty - seven per cent of children completed the questionnaire by themselves , and 73% had help from a family member or another person . the majority of participants were male ( 55% ) , and the mean age of all participants was 10.13.5 years . the largest group by diagnosis were patients with gh deficiency ( n=91 , 48.9% ) , followed by children born small for gestational age ( n=55 , 29.6% ) , those with turner syndrome ( n=17 , 9.1% ) , those with prader willi syndrome ( n=5 , 2.7% ) and children with chronic renal insufficiency ( n=1 , 0.5% ) . these proportions are generally consistent with those for the overall patro children population . at the time of completing the questionnaire , the mean duration of surepal use was 75.9 days for the overall study population , 85.5 days for gh treatment - nave patients and 44.3 days for pre - treated patients . almost half ( 49.5% ) of children prepared their surepal for injection themselves , 48.4% had a family member prepare the device , and 1.1% had a nurse do the preparation ( data missing for 1.1% ) . injections were performed by 43.5% of children themselves , by a family member in 52.2% of subjects , and 1.6% had a nurse do the injections ( data missing for 2.7% ) . most patients received training on the use of surepal from their doctor or doctor s assistant ( 31.7% ) ; training was received from a hospital nurse by 29% , and from a homecare nurse by 16.1% ; 22% received their training from another person ( data missing for 1.1% ) . overall , 86% of patients found that learning to use surepal was very easy or easy ; this proportion was slightly higher ( 95.3% ) among pre - treated patients than among treatment - nave patients ( 83.1% ) . the attractiveness of surepal was rated as excellent or good by 87.1% of patients ( 86% among treatment - nave patients and 90.5% among pre - treated patients ) ( figure 1 ) . overall , 86.5% of patients found that using their surepal was very easy or easy ( figure 2 ) . the proportion was slightly higher among pre - treated patients ( 92.9% ) than among treatment - nave patients ( 84.6% ) . almost all patients ( 96.2% ) found that preparing their surepal for injection was very easy or easy , and 89.2% found that injecting with surepal was very easy or easy . again , the proportions were higher among pre - treated patients ( 100% and 95.3% , respectively ) than among treatment - nave patients ( 94.8% and 87.5% , respectively ) . 85.5% of patients recorded that the dose memory function was helpful , and 87.6% thought that taking their surepal apart after an injection was very easy or easy . of the 88 patients who recorded that they had used the low drug waste feature , 89.8% found the feature to be helpful . among the pre - treated patients ( n=42 ) , 81% recorded that surepal was much better / better than their old device ( figure 3 ) . among this same group , 61.9% felt that surepal made their gh treatment plan easier to follow , as compared with their previously used device . most patients received training on the use of surepal from their doctor or doctor s assistant ( 31.7% ) ; training was received from a hospital nurse by 29% , and from a homecare nurse by 16.1% ; 22% received their training from another person ( data missing for 1.1% ) . overall , 86% of patients found that learning to use surepal was very easy or easy ; this proportion was slightly higher ( 95.3% ) among pre - treated patients than among treatment - nave patients ( 83.1% ) . the attractiveness of surepal was rated as excellent or good by 87.1% of patients ( 86% among treatment - nave patients and 90.5% among pre - treated patients ) ( figure 1 ) . overall , 86.5% of patients found that using their surepal was very easy or easy ( figure 2 ) . the proportion was slightly higher among pre - treated patients ( 92.9% ) than among treatment - nave patients ( 84.6% ) . almost all patients ( 96.2% ) found that preparing their surepal for injection was very easy or easy , and 89.2% found that injecting with surepal was very easy or easy . again , the proportions were higher among pre - treated patients ( 100% and 95.3% , respectively ) than among treatment - nave patients ( 94.8% and 87.5% , respectively ) . 85.5% of patients recorded that the dose memory function was helpful , and 87.6% thought that taking their surepal apart after an injection was very easy or easy . of the 88 patients who recorded that they had used the low drug waste feature , 89.8% found the feature to be helpful . among the pre - treated patients ( n=42 ) , 81% recorded that surepal was much better / better than their old device ( figure 3 ) . among this same group , 61.9% felt that surepal made their gh treatment plan easier to follow , as compared with their previously used device . adherence to rhgh therapy among children is sub - optimal.1 several device - related factors have been identified that may impact adherence , including simplicity and ease of use , convenience , and patient preference.2,3 surepal is a reusable self - injection system that has been developed to support daily administration of omnitrope . in the present study , patients overall had a good impression of the device , with 87% rating its attractiveness as excellent / good . the vast majority of patients also found surepal easy to use ( overall , to prepare for injection and to carry out an injection ) . several features of surepal may have contributed to patients rating the device as easy to use . these include the auto priming feature ; cartridges that are pre - assembled and ready - to - use ; a sliding injection button that requires minimum force to perform an injection ; and a dose memory function that enables the correct dose to be pre - set and locked into the device . surepal has also been specifically designed to minimize drug wastage ; if a cartridge in the device does not contain sufficient amount of drug to inject , the device automatically administers the correct amount of additional drug once a new cartridge is inserted ( with no need for priming or adjusting of the dose setting ) . the automated nature of this feature makes it easier to administer a second injection compared with some other gh injection devices , which require the user to calculate the amount of additional dose required and reset their device accordingly.9 eighty to 90% of participants reported that this feature ( and others , such as the dose memory function ) , were helpful . all study findings were generally consistent across treatment - nave and pre - treated patients . the proportion of patients who found surepal easy to learn to use , easy to use overall , easy to prepare for use , and easy to carry out an injection was slightly higher in the pre - treatment group ; this possibly reflects these patients greater experience of using a device to administer gh treatment . among patients who had experience with other gh injection devices , > 80% preferred surepal to their previous device and almost two - thirds felt that surepal would make it easier to follow their gh treatment plan . nevertheless , the findings are consistent with those of an earlier report on the usability and ease of use of surepal , in which the vast majority of patients rated a variety of handling tasks as easy.9 an important distinction is that the earlier study required participants to perform an injection into an injection pad , whereas the present study involved the use of surepal in a real - world clinical practice setting . in summary , this questionnaire - based cross - sectional survey in pediatric patients confirms the ease of use and patient preference for surepal , a reusable self - injection system that has been developed to support daily administration of omnitrope . the continued improvement of gh injection devices may support improved adherence by patients to their long - term treatment .

backgroundsurepal is a reusable self - injection system that has been developed to support daily administration of omnitrope ( sandoz , kundl , austria ) . a questionnaire - based cross - sectional survey was conducted to evaluate acceptability of , and preference for , surepal in pediatric patients who were prescribed treatment with omnitrope within routine clinical care.methodsthis multicenter , observational study was incorporated into the ongoing non - interventional patro ( patients treated with omnitrope ) children study . patients ( or caregivers ) were provided with a questionnaire that included five main topics ; attractiveness of the device , training received , using surepal , the low drug wastage system , and experience versus other devices used previously ( where applicable ) . questions were scored on a 5-point scale , with 2 being the worst possible outcome ( eg , very hard / very poor ) and 2 being the best possible outcome ( eg , very easy / excellent).resultsa total of 186 patients were included in this study ( germany , n=154 ; uk , n=32 ) . the attractiveness of surepal was rated as excellent / good by 87.1% of patients . overall , 86.5% of patients found that using their surepal was very easy / easy . almost all patients ( 96.2% ) found that preparing their surepal for injection was very easy / easy , and 89.2% found that injecting with surepal was very easy / easy . 85.5% of patients recorded that the dose memory function was helpful , and 87.6% that taking their surepal apart after an injection was very easy / easy . of the 88 patients who recorded that they had used the low drug waste feature , 89.8% found the feature to be helpful . among pre - treated patients ( n=42 ) , 81% recorded that surepal was much better / better than their previously used device.conclusionthis questionnaire - based cross - sectional survey in pediatric patients confirms the ease of use and patient preference for surepal , a reusable self - injection system that has been developed to support daily administration of omnitrope.

insertion of the double j catheter into the ureter , which facilitates drainage of the upper urinary tract , is one of the most common urological procedures this medical procedure is generally thought of as quite easy and safe to perform , with a very low rate of severe complications . nevertheless , as any other medical procedure , it is usually associated with some bothersome symptoms such as pain , dysuria , fever , erythrocyturia , mucose membrane injury , or ureter peristalsis disturbances , all of which have a negative impact on the patient s quality of life . other complications include anxiety , sexual dysfunction , sleep disturbances , and absence at work . sporadically forgotten stents should also be mentioned as they may result in serious complications such as marked incrustation , stent fragmentation , urosepsis , or even renal failure [ 15 ] . it must be , however , underlined that bacterial or fungal colonization of both catheter surface and urine is the most frequent complication that is noted . it is observed especially during long term stent retaining [ 6 , 7 ] . king et al . performed a systematic review , which has disclosed that urinary catheterization was the major risk factor of healthcare associated urinary tract infections . the authors have calculated that 79.3% of this complication could have been prevented if catheter insertion had been avoided . many authors therefore investigate the types of pathogens isolated from catheters and urine as well as the correlation between urine and stent culture . the relationship between colonization and stenting duration , as well as some other aspects , such as age , gender , co morbidities , reason for stenting , and the method of catheter insertion , are also found in their field of interest . clinical trials published recently have shown great inconsistency between microbiological analysis of the stent surface and urine . it concerns both the presence of colonization and the type of pathogen cultured from the double j catheters and the urine sample . available data is controversial , therefore it seems that there is a place for further studies in this field [ 9 , 10 ] . the aim of our study was to estimate the relationship between bacterial colonization of the double j catheter , which was dissected into three separate sections , and the microorganisms isolated from urine . we have also examined the rate of urine and catheter colonization as well as the types of pathogens that were cultured . we decided to use microorganism dna analysis while exploring the catheter colonization as this method is thought to possess the highest diagnostic sensitivity . the study sample comprised 60 patients ( 25 women and 35 men , aged 34 to 67 years ) who had double the participants of the trial were recruited from the 2 department of urology of the medical university of lodz between january 2011 and june 2012 . indications for ureteral catheter insertion were the following : urinary tract lithiasis , hydronephrosis due to ureteropelvical junction stricture , ureter stricture , tumors , and the presence of additional blood vessels . the patients were divided for further analysis into three subgroups , according to stenting duration : 1 ) subjects with their stents kept for 20 to 30 days ( 18 cases ) ; 2 ) participants with the catheters retained longer than 30 but shorter than 90 days ( 30 cases ) ; 3 ) patients with their catheters kept for the period longer than 90 days ( 12 cases ) . there were no statistical differences in age and gender distributions between the three subgroups all the participants had their midstream urine samples taken prior to the stent insertion and removal . a negative urine culture before catheterization was mandatory to participate in the study . j stents were inserted via an open or endoscopic manner ( 9 and 51 cases , respectively ) . in our trial , 500 mg of ciprofloxacin twice daily , was administered orally for five days . no episodes of urinary tract infection symptoms were noted in our subjects during the observation period . significant bacteriuria or funguria was defined as a bacterial or fungal count of more than 10 cfu / ml . double after initial analysis of the whole stent it was further divided , under aseptic conditions , into three sections : pelvic , ureteral , and vesicular , which were analyzed separately . bacterial and fungal dna was identified using electrophoresis in polyacrylamide gel with a denaturing gradient ( pcr dgge ) . the trial protocol was approved by the local ethics committee of the medical university of lodz . all the participants have given written informed consent after a complete description of the study . appropriate tests for statistical analysis were used and p values < 0.05 were considered statistically significant . double j catheter dna analyses were positive in all cases . in 2 cases one type of microorganism was isolated from the stent surface . the remaining 58 catheters were colonized by more than one pathogen , including 12 stents with two species and 46 stents with three types of pathogens . each of three sections of double j catheters was analyzed separately . 32 stents were colonized by the same pathogens on all three sections . in 6 cases , stent analyses have shown two types of microorganisms isolated from the different parts , while the remaining 22 catheters were colonized by three different bacteria or fungi species . bacteria species that were most frequently isolated from the catheter surface were the following : staphylococcus aureus , enterococcus faecalis , pseudomonas aeruginosa and escherichia coli . j catheter sections urine cultures were positive in only 8 patients before the catheter removal . only three bacteria species were isolated from the urine specimens : escherichia coli , pseudomonas aeruginosa , and klebsiella oxytoca . the number of bacteria species isolated from urine specimens is shown in table 2 . microorganisms cultured from urine specimens urine and catheter cultures were consistent in 5 cases . in 3 cases urine culture and stent analyses have shown different bacteria species . of 18 urine specimens taken from the subjects with the shortest period of the stent retaining , only 1 was infected ( 5.5% ) . in case of catheters left in the urinary tract for the period of longer than 30 days but shorter than 90 days , 3 of 30 urine samples urine specimens taken from the patients with catheters retained for longer than 90 days were infected in 6 of 12 cases ( 50% ) . gender , reason for catheter insertion , and the method of stenting were not related to variables such as urine culture and the number of pathogens isolated from the stent surface . they are consistent with our previous observations , where we noted that 64 of 65 stents were colonized . also riedl et al have found a 100% risk for colonization while retaining stents long term . similarly , farsi et al . have observed a 67.9% rate of stent colonization . on the other hand , , point to a nearly 44% risk of catheter colonization [ 12 , 13 ] , and kehinde et al . of nearly 42% . urine culture was positive in 8 of 60 patients in our study , which accounts to about 13% . riedl et al . have noted a 45% risk of urine infection during short term stenting and 100% during long term stenting . . a possible explanation for such differences in the rate of stent colonization and urine infection may be the sample of patients ( number , age , sex , concomitant diseases ) , type of catheter , use of prophylactic antibiotic therapy , or different methodology of colonization estimation ( culture , dna analysis ) . the results of many trials show that the rate of catheter colonization is much higher than the rate of urine infection . farsi et al . noted in their study that urine cultures were positive in 29.9% while catheter colonization was found in 67.9% . point to more than 2.5fold higher risk of catheter colonization ( 42% ) than urine infection ( 17% ) . similarly , riedl et al . have noted that short term catheterization is accompanied with catheter colonization in 69% and urine infection in 45% . our previous study has shown that urine infection was detected in 17 of 65 cases while stent colonization was observed in 64 of 65 cases , so the risk for catheter colonization was 4fold higher . we have noted that the rate of stent colonization was 100% , and was 8fold higher than the incidence of urine infection . available data indicate , similarly to our present observation , that the species most frequently isolated from urine is escherichia coli [ 7 , 14 , 16 ] . among others , enterococcus sp . , proteus sp . , klebsiella sp . , and pseudomonas sp . urine specimens were colonized by only 3 bacteria species , while no fungi were observed . however , other authors point to other species as being the most common . kehinde et al . have noted that staphylococcus was isolated most frequently from urine samples . it must be stressed , however , that no antibiotic prophylaxis was administered in these patients , which could have had a significant impact on obtained results . in our study we have noted one such sample . in case of the double j catheters , the most common species isolated were pseudomonas aeruginosa , staphylococcus aureus , enterococcus fecalis , and escherichia coli . it is worth mentioning that species such as staphylococcus aureus , enterococcus fecalis were not isolated from any urine specimen . bacterial colonization seems to depend on the use of antibiotic prophylaxis . in the previously mentioned study of farsi et al . , in patients not given any antibiotic prophylaxis pseudomonas aeruginosa was the most common pathogen found on the stent surface and cultured from urine . have found that colonization of foley catheters was more frequent in patients not receiving systemic fluoroquinolones . he has also quite often observed polymicrobial colonization , with both gram positive and gram negative species . the above findings remain in agreement with our results , as in almost all of our cases ( 58/60 ) we have isolated more than one pathogen . in our previous study , 22 of 65 stents were colonized by more than one species . this is a very important issue as it points to the need for use of a quite broad spectrum of antibiotics in post procedure prophylaxis . this issue is of great importance , as urinary stenting is the procedure most commonly carried out in urology and also because of accompanying complications , especially high rates of urinary tract infections . the current strategies comprise either stent modifications or additional medical interventions both non pharmacologic and pharmacologic . stents ) , design ( distant coil stents vs. loop stents ) , diameter , or type of material that the stent is made of . modifications of stent surface such as silver coating , diamond like coating , hydrophobicity change , or antimicrobial activity molecules ( heparin , triclosan ) have been created , to inhibit or maybe even in the future to prevent , stent colonization and biofilm formation . use of antibiotic releasing biomaterials has additional advantages , as they deliver the drug to target tissues and have a positive impact on both effectiveness ( influencing directly the biofilm that is often resistant to systemic antibiotic therapy ) and lowering the risk of systemic side effects . additionally , it is suggested that increase in patient s fluid intake , augmentation of urine ph value ( via citrate consumption ) , analgesics , anticholinergics , alpha blockers , and/or prophylactic antibiotic therapy may decrease the rate of complications or minimize the complaints . unfortunately , none of the above described strategies has the power to fully prevent catheter colonization , so there is a need for further investigations and technological innovations in this field . it is well known that there are certain groups of patients who are extremely predisposed to this complication . the risk factors include age , sex , lower urinary tract obstruction , co morbidities such as diabetes , chronic renal failure , or impairment of the immune system . therefore , the indications for stenting in these groups of patients should be thoroughly considered . have achieved a significant reduction of the rate of catheterization thanks to educational intervention that was implemented in a teaching hospital in central italy . stenting duration is thought to be a strong risk factor for urine and/or stent colonization [ 9 , 13 , 17 ] . akay et al . observed the relationship between long term stenting and catheter colonization , but not urine infection . in light of these observations it seems that removal of the catheter should be performed as early as possible . on the contrary , in the group of patients presented in our study , no relationship between the duration of urinary stenting and catheter colonization could be observed , as all stents were colonized regardless of the duration . similarly , in our previous study almost all ( 64 of 65 ) double j catheters were colonized . these results point to a rule that stent insertion practically means it will be colonized . double j catheter retention in the urinary tract is associated with an extremely high risk of bacterial colonization , while the associated risk of urine infection is about 8fold lower . there is a great inconsistency between urine infection and catheter colonization , indicating a low predictive value of urine culture for estimating stent colonization . there is also a great heterogeneity of microorganisms colonizing double j catheters , while there were only three bacteria species isolated from urine specimens .

introductionthe aim of the trial was to estimate the relationship between colonization of the double j catheter , and the microorganisms cultured from urine.material and methods60 patients , who had double j catheters inserted , participated in the study . all the subjects had their midstream urine samples taken prior to the stent insertion and removal . a negative urine culture before catheterization was mandatory to participate in the study . the patients were assigned into three subgroups , according to stenting duration : 1 ) 20 to 30 days ( 18 cases ) ; 2 ) 30 to 90 days ( 30 cases ) ; 3 ) longer than 90 days ( 12 cases ) . bacterial and fungal dna was identified using electrophoresis in polyacrylamide gel with a denaturing gradient ( pcr dgge ) . the relationship between the genetic analysis of the catheter and the urine culture was estimated.resultsurine cultures were positive in only 8 patients , while double j catheter analyses were positive in all cases . in 2 cases one type of microorganism was isolated from the stent surface while the remaining 58 catheters were colonized by more than one pathogen . in three cases fungi were isolated . there were only three types of pathogens cultured from urine specimens . urine and stent cultures were consistent in 5 cases . in 3 cases urine culture and stent analysis were not consistent.conclusionsdoublej catheter retention in the urinary tract is associated with an extremely high risk of bacterial colonization , while the risk of urine infection is about 8fold lower . there is a great inconsistency between urine infection and catheter colonization , indicating a low predictive value of urine culture for estimating stent colonization .

a 42 year - old - woman diagnosed with lung cancer ( adenocarcinoma type t4n2m1a , pleural seeding ) was admitted to our institution for pleural seeding related to left chest wall pain ( t8 - 11 nerve dermatome ) causing respiratory difficulty . one month prior , an enhanced chest and abdomen ct had revealed a collapse of the lower left lung and bilateral lung , and hemithoracic pleural metastasis ( the left side showing more severe pleural metastasis ) , with no bone metastasis ( fig . 1 ) . following a consultation for pain control , the intercostal nerves in the t8 - 10 and 11 were blocked with an ultrasound , and there was no motor weakness or side effects . subsequently , the patient 's visual analogue scale score ( vas , with 0 representing no pain and 10 representing the most severe pain imaginable ) dropped from 7 - 8/10 to 3 - 4/10 for 3 days . following her discharge , however , the pain returned with increased severity ( vas 8/10 ) , and she was readmitted through the emergency center . with the aid of an ultrasound , 0.25% chirocaine 2 ml was injected at each level of the t8 - 10 and 11 intercostal nerve . however , the pain relief did not last longer than two days . considering that the patient had experienced brief pain relief from the intercostal nerve block the patient was placed in the prone position on a fluoroscopy - compatible operating table . as alcohol neurolysis could temporarily increase the patient 's pain , monitored anesthetic care ( mac ) and a thoracic epidural block were also scheduled . following aseptic preparation and draping , a t8 - 10 and 11 intercostal nerve neurolysis was conducted using an ultrasound . a 22 g needle was inserted about 5 cm laterally from the lateral tip of each transverse process , under the 8 - 10 and 11 left ribs . the needle was fixed between the internal intercostal muscle and the innermost intercostal muscle . following negative blood aspiration , an alcohol 2 ml solution ( 99.9% ) then , a c - arm fluoroscopy - guided thoracic epidural injection was performed in the left t9 - 10 interlaminar space . using a tuohy needle , 0.125% chirocaine 8 ml and dexamathasone 5 mg were injected . upon completion of the procedure , the patient was moved to the recovery room before being transferred to the admission room . after 1 hour , the patient reported bilateral motor weakness to the ward nurse , although her sensory of lower extremities was normal . the nurse believed these symptoms to have been caused by the block and did not consult the pain clinic . the attending physician was notified and the pain clinic was contacted for consultation . upon physical examination , the neurological tests showed that the upper extremity was intact , but there was significant motor weakness in the lower extremities ( hip flexion 0/0 , abduction 0/0 , adduction 0/0 , knee extension 0/0 , flexion 0/0 , dorsi - flexion 0/0 ) and a sensory decrease below the l2 level . an epidural hematoma or possible spinal cord infarction were suspected , and a magnetic resonance imaging ( mri ) was immediately undertaken . the thoracic and lumbar mri with contrast demonstrated an abnormal spinal cord signal between the t4 spinal cord and the conus medullaris , and bone metastasis at the t5 , t7 - 11 , and l1 levels . 2 ) spinal cord infarction was suspected , and steroid therapy was initiated . upon physical examination on postoperative day ( pod ) 5 , the patient 's entire lower extremity motor grade was 0 , and the pinprick and temperature sensitivity were recorded as 0/0 below the t4 level . despite the intravascular steroid therapy , there was no neurological recovery . on pod 10 , as many as 43% of patients with malignancies do not experience adequate pain relief from systemic medications . in those patients , a plausible interventional approach for patients experiencing the dose - limiting side effects of systemic medications is a nerve block or neurolysis . for chest wall pain caused by a malignancy , l. thefenne et al . encountered a similar case in a 54-year - old male patient who had received right s1 radiculopathy surgery for a l5-s1 slipped disc . immediately after receiving a lumbar injection with prednisolone 125 mg , the patient developed complete , flaccid motor and sensory paraplegia under the t7 level . t. adam oliver et al . also reported the case of a 69-year - old male patient who suffered from lower extremity weakness and paresthesia caused by l2 - 3 and l3 - 4 central spinal stenosis , for which he received a l5-s1 interlaminar epidural injection . the reason for his paraplegia after the epidural injection was thought to have been secondary to vascular trauma , vascular spasm , or the injection of particulate steroids into the artery , which may have caused an embolic effect . although we used non - particulate steroids for the epidural injection and although paraplegia is a very rare complication of epidural injections , there is nevertheless a risk . the second possible cause is an occlusion of the radiculomedullar artery due to hematologic metastasis . there have been a few case reports of paraplegia or neurological deficits following central neuraxial blockades in patients with previously - undiagnosed bone metastases . reported a case of post - operative paraplegia in a previously - undiagnosed case of vertebral metastases originating from endometrial cancer , following a combined spinal - epidural anesthesia . graham et al . also described a case of paraplegia following spinal anesthesia for a bilateral orchidectomy in a case of prostatic carcinoma with spinal metastasis and no pre - existing neurological deficit . as the compliance of the epidural space is restricted by the metastasis , the administration of local anesthetics causes an increase in volume and pressure in the epidural space , leading to symptoms of compressive myelopathy . in our case , the enhanced chest and abdominal ct had shown no evidence of spinal metastasis 1 month prior . however , the mri taken after the onset of the paraplegia showed multiple spinal metastasis , and there might also have been a risk of embolism by hematologic metastasis . the third possible reason for the patients ' paraplegia may have been complications from the alcohol used in the intercostal nerve neurolysis , and which may have caused spinal cord injury . there has been one case report of paraplegia or neurological deficit following intercostal nerve neurolysis . roland kowalewski et al . reported the case of a 55-year - old man with severe scoliosis and chest deformity . the patient was given a 7.5% aqueous phenol solution 6 ml below the 10 rib and 3 - 4 cm outside the spine midline . a few minutes after the injection , the patient felt a heating sensation in his right leg , and decreased motor and sensory functions in both legs . the cause was the diffusion of the phenol through the intervertebral foraminae , which damaged the motor and sensory roots . although we used a smaller drug dose than in this report and the injection site was further away from the spine , we did not know the spreading pattern of the alcohol . if the injected alcohol moved through the paravertebral gutter and the intervertebral foraminae into the epidural space , it could have extended into the intrathecal space . after looking at other reports of similar cases and comparing them with our patient 's mri and the procedures she underwent , we came to the conclusion that the cause of this patient 's paraplegia was most likely to have been spinal cord ischemia , or possibly spinal cord neurolysis . alcohol mixed with contrast media can be useful to confirm the spread of alcohol under fluoroscopy , and a smaller dose of neurolytic drug may decrease the risk of paraplegia . unfortunately , there is no clear evidence as to which of the potential causes discussed above , whether alone or in combination , were responsible for the spinal cord infarction . therefore , physicians should always keep a few points in mind when treating patients with lung cancer for pain relief . first , when performing an intercostal nerve neurolysis , the alcohol injection should be located far away from the spine , and a small quantity of alcohol solution should be used . however , more research is needed to determine the exact location of the injection or the precise amount to be used . second , in epidural injections , contrast media is used to track the placement of the needle . although it may sometimes look as though the tip of the needle is not in the vessel , it is still possible that it may be in the vessel . to evaluate the intravascular injection one should be particularly aware of this and especially careful with patients presenting a history of spine cancer metastasis or spine surgery , as they may feature changes to the epidural space and potential vessel variations . third , when performing an intercostal nerve neurolysis , the patient 's motor power must be examined after the procedure . lastly , if abnormal symptoms such as motor weakness or decreased sensitivity appear after an epidural injection or intercostal nerve neurolysis , a careful physical examination and imaging studies should immediately be taken in order to find the causes of the paraplegia . after identifying the causes , appropriate treatment should be promptly administered in order to minimize the central nerve damage and help the patient recover . in conclusion , when performing block procedures , physicians should always keep the patients ' preexisting conditions as well as the risks of central nerve damage in mind .

the goal of cancer treatment is generally pain reduction and function recovery . however , drug therapy does not treat pain adequately in approximately 43% of patients , and the latter may have to undergo a nerve block or neurolysis . in the case reported here , a 42-year - old female patient with lung cancer ( adenocarcinoma ) developed paraplegia after receiving t8 - 10 and 11th intercostal nerve neurolysis and t9 - 10 interlaminar epidural steroid injections . an mri results revealed extensive swelling of the spinal cord between the t4 spinal cord and conus medullaris , and t5 , 7 - 11 , and l1 bone metastasis . although steroid therapy was administered , the paraplegia did not improve .

portal vein thrombosis ( pvt ) , an event that is associated with a large spectrum of clinical presentations and severity , may be related to cirrhosis , malignancy , local factors or idiopathic . a diagnostic workup to identify an underlying pro - thrombotic condition unrelated to cirrhosis , early anticoagulant treatment is indicated in order to achieve recanalization and , therefore , avoid future complications . with conventional anticoagulant treatments ( low molecular weight heparin ( lmwh ) or vitamin k antagonists ) , recanalization occurs in up to one - third of patients , being more difficult to achieve when ascites or occluded splenic vein are present . in contrast , if anticoagulation is not started , recanalization is exceptional [ 1 , 3 ] . the use of doacs is being generalized , but they are not routinely used in pvt and are not yet mentioned in the latest guidelines as an alternative treatment . recent data , however , indicate that this new class of anticoagulants is increasingly used also in patients with splanchnic vein thrombosis [ 5 , 6 ] . a 28-year - old healthy female , active smoker of 5 pack - year and under oral contraceptive ( ethinylestradiol and gestodene ) presented to the emergency department with severe epigastric pain of 5-day duration . no nausea , vomiting , diarrhea or bloody stools were reported ; she was afebrile , hemodynamically stable and physical examination was normal except for pain on the upper quadrants without signs of peritoneal irritation or ascites . renal function and liver profile were normal ; cbc revealed only discrete anemia ( hemoglobin of 11.8 g / dl ) , with normal platelet count ; d - dimers were elevated ( 948 ng / ml ) , inr and partial thromboplastin time were within the normal range ; c - reactive protein was elevated ( 64.18 mg / l ) with no infection focus found . abdominal ultrasound with doppler revealed thrombosis of more than 50% of the lumen of both right and left portal branches with no extension to the portal vein trunk , superior mesenteric or splenic veins . a computed tomography ( ct ) scan confirmed those findings with normal liver morphology and no ascites . the patient was admitted at the intermediate care unit and unfractionated heparin for 24 h was started with a subsequent relay to lmwh ( enoxaparin ) in the dose of 1 mg / kg twice daily . two days after she was discharged , and after discussion and agreement with the patient , she received rivaroxaban treatment 15 mg twice daily . by that time she was nearly asymptomatic and instructed to stop smoking and to substitute previous oral contraceptive for a progestative one . the 1-month ct scan control showed total recanalization of the left branch and persistence of right branch thrombosis but with partial recanalization . pro - thrombotic workup diagnosis revealed negativity for jak2 and calreticulin mutations , normal homocysteine serum levels , absence of lupus anticoagulant and negativity for paroxysmal nocturnal hemoglobinuria . anti - cardiolipin , anti-2 glycoprotein i , anti - prothrombin and anti - phosphatidylserine antibodies were all negative . factor v - leiden and prothrombin g20210a gene mutations were both found to be positive in heterozygosity . the patient remains under rivaroxaban 20 mg daily , asymptomatic with normal renal function and liver profile with no documented complications of the anticoagulant treatment . extension of pvt at diagnosis ( m0 ) , involving the totality of the right ( r1 ) and segments of the left portal vein branches ( l1 ) . evolution of pvt under rivaroxaban at the end of the first ( m1 ) and sixth ( m6 ) months of treatment . total recanalization is seen at the left portal vein branch and partial at the right portal vein branch . to our knowledge , this is the first case ever reported concerning treatment with doacs for a patient with apvt unrelated to cirrhosis . three other reports using rivaroxaban to treat apvt were published , but all of them in patients with underlying chronic liver diseases [ 7 - 9 ] . in all , total recanalization of the affected segments was achieved after a 1- , 6- and 3-month treatment period , respectively . more recently , another successful case of rivaroxaban use for a recurrent pvt in a patient with a child - pugh class a cirrhosis , with total recanalization was published . in all described cases , none complication related to rivaroxaban use the use of either direct thrombin inhibitors , as dabigatran , or direct factor xa inhibitors , as rivaroxaban , apixaban or endoxaban , may be , at least in theory , even more effective than lmwh or vitamin k antagonists . this because it has been postulated that lower portal flow velocities , which may raise the risk of pvt development , may lead to a lower wash out of active thrombin generated in portal circulation and thus contribute to a other major concern about doacs use is also its safety , since they all are metabolized in the liver . according to current easl recommendations , treatment in the setting of apvt unrelated to cirrhosis should be with unfractionated heparin or lmwh in therapeutic doses with a subsequent substitution for a vitamin k antagonist targeting an inr between 2 and 3 . in this particular case , and under rivaroxaban treatment , a rapid and total recanalization was achieved in left portal branch but not completely in the right , probably linked to a more occlusive thrombosis in the latter . also , in our patient , rivaroxaban proved to be safe , with no bleeding complications reported to date . the dose of rivaroxaban chosen was the one indicated for deep vein thrombosis and pulmonary embolism , which was higher than in almost all of the other case reports , but this patient did not have concomitant liver disease nor acute decompensation / failure . also , rivaroxaban was started 2 days after lmwh was started , as one of the options suggested by recommended guidelines for acute pulmonary embolism . this may reflect a more cautions strategy in the acute setting of pvt , allowing the management of potential complications that may arise in the first hours of hospitalization with the medications that physicians are more used to . two series have been published so far reporting the use of doacs in patients with splanchnic vein thrombosis [ 5 , 6 ] . the results of these two papers strongly suggest that this new class of anticoagulants is safe , since the incidence of major bleedings and other drug - induced side effects was similar as in patients treated with conventional anticoagulation . since doacs are increasingly used off label in this indication , more data about safety and efficacy are eagerly needed . this case report suggests that the treatment of apvt in a patient without underlying liver disease can 1 ) prevent the extension of the thrombus in the portal tract ; 2 ) resolve pvt , at least partially , and most likely when a non - occlusive thrombosis occurs and ; 3 ) be safe . in this setting , randomized controlled studies are needed in order to assess efficacy and safety of doacs compared to lmwh or vitamin k antagonists before its generalization .

in acute portal vein thrombosis ( apvt ) unrelated to cirrhosis , anticoagulant therapy is classically started with low molecular weight heparin or vitamin k antagonists . new direct - acting oral anticoagulants ( doacs ) are used in the treatment of venous thrombosis outside the splanchnic vascular bed , but not in the latter . we report a young female with apvt occurring in a non - cirrhotic liver linked to heterozygosity of factor v - leiden and prothrombin g20210a gene mutations . rivaroxaban was started , with total recanalization of the left and partial recanalization of the right portal vein branches , without complications . new doacs do not need daily subcutaneous injections nor routinely blood coagulation control tests , making its use attractive , eventually increasing patient s compliance . if proved to be safe and effective in the future studies , its use may be extended to pvt treatment . this case shows that rivaroxaban was safe , not only prevented the extension of thrombosis in the portal tract , but also resolved pvt , at least partially .

there are 3 types of blood donors : voluntary / unpaid , family / replacement , and paid . a voluntary blood donor intentionally donates blood without pursuing any remuneration , whereas a replacement donor is requested to do so by the patient or his associates . according to world health organization ( who ) global database on blood safety ( gdbs ) 2008 , but , approximately 48% of these emanate from high - income countries , astringent to 15% of earth 's population . ten nations vouch for 65% of blood collections worldwide , and india is the third highest bidder in this respect following united states and china . with almost 9.8 million units of yearly collections and 84% voluntary donors , india is expected to bang on the who target of 100% voluntary donations by 2020 , much before due date . blood transfusion aggravates the risk of transfusion - transmissible infections ( ttis ) like hepatitis b ( hbv ) , hepatitis c ( hcv ) , human immunodeficiency virus ( hiv ) , syphilis , and less commonly to malaria , toxoplasmosis , brucellosis , other viral infections . as of 2009 , around 2.5 million indians were infected with hiv . succumbing to a prevalence of 0.3% , india presently stands third on planet , in numerical terms of hiv - infected people . globally , hbsag ( hepatitis b surface antigen ) prevalence varies between 0.1 and 11.7% . amongst indian general population and blood donors , it lingers within 28% ; and 12% respectively.8 , 9 , 10 universally around 3% people are infected with hcv . , a low cumulative hcv prevalence below 2% has been reported from this country.9 , 10 , 12 , 13 , 14 darjeeling district in india , has a high hiv prevalence of > 1% , much higher than national distribution . despite that , very little is learnt about the seroprevalence of hiv and other ttis among blood donors here . the present study accomplished at the lone tertiary medical institution in rural sub - himalayan belt of darjeeling , west bengal , india ; was aimed at recollecting the donors ' profile , particularly emphasizing the seroprevalence of ttis amongst them and determination of the suitable population - module to be targeted for upscaling the voluntary blood donors ' strength . consequently , the overall knowledge about blood safety measurements and a rough estimate of the infection burden in rural community can be replenished . the presently discussed , institutional record - based retrospective study was executed in the department of blood bank , north bengal medical college & hospital , darjeeling , west bengal , india . data from three consecutive years of 20102012 , was retrieved from various documents maintained by blood bank authority . various immunological screening methods were performed on all donated samples for hiv-1 & 2 , hbsag , hcv ( by enzyme - linked immunosorbent assay or elisa ) , syphilis ( by venereal disease reference laboratory or vdrl rapid card test from transasia biomedicals limited ) and malaria ( by sd bioline malaria antigen p.f./p.v . rapid diagnostic card test or rdt for pan - malarial antigens ) . recommended donor exclusion criteria were : history of febrile or debilitating illness , weight loss , jaundice , hepatic or cardiovascular or pulmonary derangement , malignancy , epilepsy , bleeding diathesis , past blood transfusion , recent blood donation , consumption of prohibited drugs , surgical intervention , age under 18 or over 60 years , pregnancy or lactation . most of the donors were aged 35 years or less , and a mere 4.27% ( 1210 ) donors were living beyond their mid - forties . males were the dominant cohort , while females constituted only 10.04% ( 2847 ) of the study population ( fig . 1 ) . a sum of 476 blood donation camps were arranged , which collectively compiled 20,985 ( 73.98% ) voluntary donations . astonishingly , the voluntary donors ' strength drastically declined in 2012 than its yesteryears , which actually reflected the reduction in donation camps instituted that year , with profound statistical significance ( p < 0.0001 ) ( fig . 2 ) . as a whole 832 seropositive donors were identified corresponding to a summed - up seroprevalence of 2.93% . however , a statistically significant ( p = 0.0041 ) downgrading trend in overall seroprevalence of ttis , was elicited over observed three years . seroprevalence of hiv , hbv , hcv and syphilis among studied donors were 0.42% , 1.24% , 0.62% and 0.65% respectively . more importantly , a downscaling tendency in seroprevalence of hbv ( p = 0.0126 ) and syphilis ( p < 0.0001 ) , over the projected years was again derived with noteworthy statistical significance . in the final year , the only case of vivax malaria was encountered in a male voluntary donor ( table 1 ) . apart from hcv ( p = 0.0256 ) no significant difference between two principle donor categories could be deducted from their respective individual susceptibility to any other tti . in addition , the overall seroprevalence of ttis was significantly ( p = 0.0398 ) more pronounced amongst replacement donors ( 3.28% ) than their voluntary ( 2.81% ) counterparts ( table 2 ) . altogether the highest prevalence for each tti was observed in the 2635 years age group , followed by the 3645 years age group . age variation of seroprevalence was statistically significant with the likes of hbv , hcv and syphilis particularly during the years of 201011 , 201112 and 2012 respectively ( table 3 ) . gender - wise difference in seroprevalence with hbsag ( p = 0.0064 ) and vdrl ( venereal disease research laboratory test ) ( p < blood transfusion is a life - saving integral remedy in current medical practices , but also carries contemporary risk of transmitting dreadful ttis like hiv , hepatitis b and c. distressed with this disquiet fact , who indoctrinated a detailed strategy in transfusion protocol which potentiates well - orchestration of transfusion services , promotion of voluntary donation with uttermost priority , effective exemption of all seropositive samples particularly those with the four commonest ttis , and establishment of an implicit quality control system . the overall seroprevalence of various ttis among the studied donors figured out as 2.93% with a significant dwindling trend over successive years , which intimately stimulated previous observations by mathai et al ( 3.1% ) , karmakar et al ( 2.79% ) and koshy et al ( 2.9% ) . however , contrasting evidences of significantly lower or higher seropositivity under subcontinental circumstances also prevails at large.19 , 20 , 21 , 22 the infectivity of hbv , hcv , hiv and syphilis amongst indian donors has been documented as 0.6612% , 0.51.5% , 0.0843.87% and 0.853% respectively . hbv was the most frequent ( 1.24% ) tti encountered in presently concluded study , recapitulating earlier indian literatures accomplished in similar context.7 , 16 , 18 , 20 , 23 on the other hand , garg et al and sinha et al reiterated much higher proportion of hbsag seropositivity ; as well as a lower seroprevalence reported by adhikari et al and unnikrishnan et al , contradicts the current elaboration . moreover , mathai et al , gupta et al and koshy et al encountered anti - hcv seroreactivity as the commonest tti in their respective studies . on the contrary , around 0.62% subjects were tested reactive for anti - hcv antibody within the discussed donor population , which lagged third behind hepatitis b and syphilis in the list of ttis . pertinent to present discussion , giri et al and karmakar et al identified 0.74% and 0.59% hcv - positive donors respectively ; though opposing views are also quite obvious.19 , 20 , 21 , 22 serological evidences for syphilis turned out to be affirmative in 0.65% of currently studied donations , which also featured a significantly progressive diminution over the years . most of the previously published indian literatures recorded a much lower incidence of vdrl reactivity.13 , 16 , 18 , 24 but yet gupta et al encountered about 0.85% syphilis patients in their observed group . although hiv - prevalence in darjeeling district ( 1% ) is much higher than whole indian ( 0.3% ) scenario ; still hiv - seroprevalence in discussed donors was quantified as 0.42% only , least of the chief four ttis and more comparable to national seroprevalence . garg et al ( 0.47% ) , kaur et al ( 0.6% ) , sinha et al ( 0.64% ) and karmakar et al ( 0.6% ) traced hiv - seropositivity to similar extent of present study ; whereas gupta et al ( 0.08% ) , agrawal et al ( 0.1% ) and giri et al ( 0.07% ) identified much less number of hiv - infected donors . according to national aids control organization ( naco ) guidelines , the lone malaria - infested donor was detected in the final year of present study . dubey et al successfully detected 0.09% malaria - infected donors using rdt , while the prevalence flourished as high as 17.4% with serological assay for malarial antibody . rdt is associated with high sensitivity and it promptly turns negative 23 days after effective eradication of parasites , in contrast the antibody against plasmodia persists for days after successful therapy . likewise , the donors in the present study were efficaciously screened out for malaria using rdt . in this on - going study most of the donors were males , which beautifully coincided with preceding indian observations . despite the overall seroprevalence hardly differed between genders , the seroreactivity for hbsag and vdrl was found to be significantly higher among males , which is at par with already recommended articles . koshy et al noted most of their studied seropositive donors to be aged between 18 and 30 years , followed by 3140 years . more than two - third seropositive donors belonged to 2140 years age group in the study conducted by karmakar et al . accordingly , most of the infected donors in present study were from 26 to 35 years age - group . more so , the seroprevalences of hbsag , hcv and syphilis were more prevalent among 2645 years aged donors yielding distinct statistical significance . in the earlier studies , replacement donors frequently outnumbered the voluntary ones . whatsoever in correspondence to existing worldwide trend , voluntary donors were profusely predominant in discussed study population . the overall serodominance among voluntary donors was overwhelmed by that of replacement donors , conquering a statistically significant difference . this above - mentioned difference in present study reciprocated the results obtained by kaur et al and koshy et al . in conclusion , the latest study highlights that blood transfusion is one of the major modes to contact hiv , hbv , hcv and syphilis . males as much as the voluntary donors overwhelmingly predominate the donor subpopulation in modern world . hbv is the most and hiv the least common tti affecting blood donors , with a significant downhill tendency in overall seroprevalence through the years . donors aged between 26 and 35 years are significantly associated with ttis as good as the replacement donors do . therefore some immaculate eligibility criteria should be adopted while selecting blood donors to minimize the transmission of potentially fatal infections , to augment the pool of voluntary donors and to increase the feminine participation in nationalized donation campaigns .

backgroundin modern health services , blood transfusion is an essentially life - saving manoeuvre . with this situation healthy donor compilation is the cornerstone of transfusion medicine . henceforth , a provision for strict criterion in recruitment and deferral of blood donors , particularly emphasizing transfusion transmissible infections ( tti ) , may improve safe transfusion practice.objectivesthe present study was executed to assess the prevalence of ttis within blood donors at a sub - himalayan rural tertiary care institution in darjeeling , india ; which can ultimately aid in determination of the population subset to be targeted for enhancing donor pool.methodsthe present study was a three - year ( 20102012 ) retrospective study . data was accumulated and analysed from blood bank records , pertaining to all donors who were screened for various ttis using respective immunological methods . then the tabulated seropositive donors were correlated with relevant epidemiological profiles.resultstotal 28,364 blood donors were examined , comprising of 25,517 ( 89.96% ) males and 20,985 ( 73.98% ) voluntary donors . cumulative seroprevalence of hiv , hbv , hcv and syphilis were 0.42% , 1.24% , 0.62% and 0.65% respectively ; with solitary malaria - infected donor . the overall seroreactivity in present study significantly diminished through successive years.conclusionsdeployment of implicit inclusion - exclusion criteria is high on demand for reducing the prevalence of ttis , to increase the donor subpopulation strength and ultimately to institute a safe transfusion protocol .

long qt syndrome , which is characterized by an increase in qt interval on electrocardiogram ( ecg ) , makes patients susceptible to cardiac arrhythmias , including torsades de pointes ( tdp ) , followed by repeated syncope episodes and even sudden death ( 1 ) . the hereditary form is a familial genetic canalopathy ( 2 ) and the acquired form is a reversible condition induced by an environmental factor , usually a drug from various groups , including some antihistamines , antibiotics , antipsychotic drugs or gastrointestinal prokinetics ( 3 ) . in addition , several risk factors have been identified involved in prolongation of qt interval and the related arrhythmias , which include hypokalemia , hypomagnesemia , hypothyroidism , and hemodialysis . concurrence of these factors can increase the risk of ventricular arrhythmia and the subsequent accidents . therefore , in patients with these risk factors care should be exercised in concomitant prescription of the drugs mentioned above ( 1 ) . corrected qt ( qtc ) and qt dispersion ( qtd ) indexes are used to evaluate the qt index ; qtc is used to correspond the qt interval with the heart rate and both in fact show various dimensions of ventricular repolarization ( 4 ) . cardiac arrhythmias are not uncommon during pregnancy and might create different problems for the mother and the fetus ( 5 ) . on the other hand , female gender is considered as an independent risk factor for long qt syndrome ; in this context , qt interval is almost 10% longer in adult females . various studies have introduced sex hormones ( both male and female ) as a factor effective on the qt interval ( 6 - 9 ) . considering hormonal changes occurring during the pregnancy , it is possible for the qt interval to be affected . although the interval is expected to be decreased in pregnancy due to tachycardia , some studies have shown that the interval increases in pregnant women ( 10 ) . explained the reasons for an increase in qt and qtd intervals in pregnancy as follows : enlarged abdominal organs , hormonal and sympathetic changes , and finally an increase in the impedance of tissues located between the heart and the body surface due to the gradual accumulation of water and sodium during pregnancy ( 10 ) . on the other hand , studies have shown that patients with long qt syndrome ( lqts ) run a higher risk of developing tdp immediately after pregnancy ( 11 - 13 ) . based on above - mentioned , the present study was designed to evaluate and compare the qt interval in pregnant and non - pregnant women to assess the effect of pregnancy on qt interval . study design and setting this prospective cohort study was carried out from april 2011 to december 2012 in shahid behesthi hospital , shiraz , iran . the protocol of the study was approved by shiraz university of medical sciences and the ethics committee of the same university . the subjects were randomly selected from women referring to the clinic for routine pregnancy examinations . in addition , the control group subjects were randomly selected from the individuals accompanying patients referring to the clinic . 40 women in the second and third trimesters of pregnancy ( over 13 weeks of gestational age according to a sonographic examination of the first trimester ) were included in the pregnant women group and 40 non - pregnant women who were in their fertile years were included in the control group . inclusion criteria of the study were an age range of 18 - 35 years , interest in and ability to take part in the study , an interval of at least one year between the present pregnancy and the previous one . in addition , exclusion criteria were the presence of any arrhythmia in ecg , use of any medication influencing qt interval , affliction with any cardiac and renal disease . serial evaluation of ecgs was carried out and the cardiac enzymes , including troponin i and cardiac isoenzymes creatine kinase , were checked . the age , gender , marital status , occupation , living place and phone number of patients were questioned and registered . they were asked to refer to the exercise test unit of imam hossein hospital during one week after discharging . when the patients returned to the exercise test unit , they were asked about the incidence of cardiac symptoms and signs , recurrence of chest pain or referring to the treatment center again . after the exercise test , the results were collected and patients with positive test underwent angiography . , the patients or their relatives received instructions in relation to the symptoms and signs of cardiac diseases . history of medications used and cardiac diseases , the patients demographic data , and the gestational ages were recorded . all the subjects were questioned in relation to the occurrence of any of the symptoms and signs of syncope , palpitation , vertigo , angina , and asthma ( a collection of symptoms and signs , which might have a cardiac origin ) in the six - month period before taking part in the study for the control group and at the beginning of pregnancy for the pregnant group . a standard 12-lead ecg ( paper speed of 25 mm / s and a current of 0.5 mv / cm ) was recorded from each subject . the qt interval , from the beginning of q to the end of t , was measured and recorded . then bazett s formula , qtc = qt/rr , qt dispersion ( qtd ) was also calculated as the difference between the maximum and minimum qt intervals in a 12-lead ecg ( 4 ) . the ecgs were also used to determine the presence or absence of any arrhythmia and the axes of qrs and p waves . chi - squared test was used to compare qualitative data and frequencies of symptoms and signs between the two groups . eighty subjects participated in the present study : 40 in the pregnant women group and 40 in the control group , with mean ages of 292.8 and 283.2 years , respectively . the mean gestational age of pregnant women was 29.217.40 weeks ( 19 - 42 ) . sixteen patients ( 41% ) had their first pregnancy , 134 ( 33.3% ) second pregnancy , eight ( 20.5% ) third pregnancy , one ( 2.6% ) fourth pregnancy and one ( 2.6% ) fifth pregnancy . qrs and p waves of all the subjects were in the normal range , with no significant differences between the two groups ( p>0.05 ) . qtc and qtd were higher in the pregnant group versus the control ( 0.001 ) . it should be pointed out that the means of these two variables were in the normal range . table 1 presents the details of comparisons of qtc , qtd , and heart rates between the two groups . in general , there were no significant differences between the means of qtc and qtd between pregnant women in their second trimesters and those in their third trimesters ( p>0.05 ) ( table 2 ) . the results of present study showed a longer qt interval in pregnant women versus non - pregnant . a research in available library and electronic sources showed only a limited number of studies with similar themes . there are some studies on the effect of pregnancy on patients with lqts ( 12 - 16 ) . ( 2002 ) evaluated qt interval and t - loop morphology in pregnant and non - pregnant women . they compared 37 healthy pregnant women with gestational ages of 36 - 40 weeks with 18 healthy non - pregnant women . finally , it was concluded that qtc and qtd were significantly higher in pregnant women compared to the control group ( 10 ) , consistent with the results of the present study . ( 2004 ) evaluated and compared qt intervals between pregnant women with and without eclampsia . they did not make comparisons with the control non - pregnant women . in general , the mean qtc in the group with eclampsia ( 47.0 milliseconds ) and the group without it ( 43.6 milliseconds ) was higher than that in the present study ( 41.75 milliseconds ) ( 17 ) . seth et al . concluded that pregnant women with a previous definitive diagnosis of lqts run a lower risk of cardiac accidents during pregnancy , including syncope and sudden death due to cardiac arrest . however , during the first nine months after delivery , the risk of cardiac accidents , especially life - threatening accidents , increases . after this period , the risk level returns to the baseline before pregnancy ( 13 ) . none of the two studies above evaluated the question whether the qt interval changes during pregnancy or after it . seth et al . described the reason for a decrease in cardiac accidents due to lqts during pregnancy and an increase in such accidents after pregnancy as follows : pregnancy results in an increase in the referral of women to health and treatment centers , which might lead to prevention of cardiac accidents . on the other hand , although the qt intervals were not different between nulliparous women and those with previous pregnancies , women with no history of delivery before the age of 15 had experienced more cardiac accidents and received more treatments with -blockers , all of which might have prompted them to refrain from becoming pregnant ( 13 ) . comparisons of qtc , qtd , and heart rates between the pregnant and non - pregnant groups comparison of qtc and qtd between the second and third trimesters during the period after delivery , hemodynamic changes occur , which might be related to an increase in arrhythmias . rashba et al . proposed the hypothesis that an increase in cardiac accidents in patients with lqts after delivery might be attributed to a change in adrenergic activity . they also reported that an increase in heart rate during pregnancy could have a protective effect in patients with lqts , who might have a longer qt interval at lower heart rates ; after delivery , this rate returns to the baseline . therefore , this protective role is negated , increasing the odds of qt interval prolongation , and incidence of arrhythmias ( 12 ) . some other studies have shown that other factors such as an increase in stress , fatigue , insomnia , and other environmental factors are effective in increasing the risk of cardiac accidents due to lqts during pregnancy . another opinion about the possible cause of the relationship between pregnancy and a change in qt interval is the relation between sex hormones and ventricular repolarization . one of the risk is that both exogenous and endogenous sex hormones can influence qt interval ( 6 , 7 , 18 , 19 ) . in general , during sexual maturation the qt interval is shortened about 20 milliseconds in males ; however , it does not undergo any changes in females . in fact , the qt interval is not significantly different between the two sexes and the shortening during sexual maturation is responsible for the difference ( 20 ) . some studies have suggested that testosterone is related to shorter repolarization in men ( 21 ) . the qt interval in the luteal phase is shorter than that in the follicular phase , which might be attributed to the effect of progesterone ( 18 ) . therefore , it is possible that the qt interval is influenced by hormonal changes due to pregnancy . however , some studies have shown that hormonal changes in pregnancy decrease the risk of tdp in patients with ltqs ( 13 ) . one of the limitations of the present study was the unavailability of the patients previous ecgs for making comparisons . on the other hand , there were limitations in the selection of controls ; selection of controls from first - degree relatives was more logical and not possible . the qt interval in pregnant women was in the normal range but longer compared to non - pregnant women . therefore , other factors that might be involved in prolongation of the qt interval should be taken into account and care should be exercised to prevent their concurrence with pregnancy as far as possible . all authors passed four criteria for authorship contribution based on recommendations of international committee of medical journal editors .

introduction : prolongation of qt interval might result in dangerous cardiac arrhythmias , including torsades de pointes ( tdp ) , consequently leading to syncope or death . a limited number of studies carried out in this respect to date have shown that qt interval might increase during pregnancy . on the other hand , it has been shown that each pregnancy might result in an increase in the risk of cardiac accidents in patients with long qt interval . therefore , the present study was undertaken to compare qt intervals in pregnant and non - pregnant women . methods : pregnant women group consisted of 40 women in the second and third trimesters of pregnancy and the non - pregnant control group consisted of healthy women 18 - 35 years of age . all the patients underwent standard 12-lead electrocardiogram ( ecg ) . the qt interval was measured for each patient at lead ii . the mean corrected qt interval ( qtc ) and qt dispersions ( qtd ) were compared between the two groups . results : mean heart rates in the pregnant and non - pregnant groups were 98.5514.09 and 72.5313.17 beats / minutes ( p<0.001 ) . qtd and qtc means were in the normal range in both groups ; however , these variables were 49.5012.80 and 43.0318.47 milliseconds in the pregnant group and 39.59.59 and 40.3817.20 milliseconds in the control group , respectively ( p<0.001 ) . conclusion : the qt interval was longer in pregnant women compared to non - pregnant women ; however , it was in the normal range in both groups . therefore , it is important to monitor and manage risk factors involved in prolongation of qt interval and prevent concurrence of these factors with pregnancy .

insomnia , which is difficulty with falling asleep , is more common among aged people . it was found that insomnia occurs in one - third of the general population leading to daytime sleepiness and mental disturbances . it has very serious impacts on individuals health and psychological status which leads to anxiety , depression and poor performance1 . studies have shown that insomnia is also more common among college students and can result in stress , depression and reduced academic performance2,3,4,5,6 . sleep disorders are one of the public health issues that need attention for prevention and early detection , as they are one of the causes of work absenteeism9 . insomnia is defined by the presence of an individual s report of difficulty with sleep10 . subjective assessments includes self- reporting scales like the pittsburgh sleep quality index ( psqi ) , the insomnia severity index ( isi ) , the women s health initiative insomnia rating scale , the basic nordic sleep questionnaire , and the daily sleep log and anxiety index ( stai ) . the insomnia severity index is a valid , reliable and easy to administer tool11 . although pharmacological treatments are effective , they can cause adverse effects such as increased risk of falls , drowsiness , dizziness , cognitive impairment , somnolence , nausea , vomiting and motor vehicle crashes . non pharmacological managements of insomnia include bright light therapy , stimulus control therapy , sleep restriction therapy , sleep hygiene education , cognitive therapy , relaxation therapy , paradoxical intention , and multi- component therapy12 . it has also been found that there is an association between regular exercise or physical activity and the prevalence rate of insomnia13 . most studies have focused on management of clinical insomnia among the middle- aged and elderly , but the aim of our present study was to assess the level of insomnia among female college students , and to determine the association between their physical activity and the insomnia severity index . after obtaining ethical committee approval multiple events were planned at the college of applied medical sciences , king saud university , riyadh , to invite female graduate students to take part in this study . activities like posters , face book events , broadcasts , and lectures were undertaken to motivate the students to participate in the walking program . one hundred and five volunteers as a sample of convenience were included and screened for the inclusion criteria . subjects who had a history of fracture or surgery to the back , pelvis , or lower limb , any contraindications to increased walking , current complaints or conditions affecting their ability to walk , pregnancy or cardiopulmonary disorders were excluded . subjects with insomnia based on the icsd-2 definition , which consists of frequent awakening and difficulty with falling asleep again , difficulty with falling asleep , waking too early , secondary day time impairment due to nighttime sleeplessness were included14 . , medical , socioeconomic and academic details were collected and the isi questionnaire and daily physical log were distributed . in the second stage , a seven- meter distance was taped on the floor to measure stride length , which was calculated by asking subjects to take 10 steps forward , 5 steps with each foot at their natural stride bringing the feet together with the last step . the stride length was calculated by dividing the distance covered by 10 . after recording stride length values , each subject was given a pedometer ( omron model hj-152 ) in the final stage . subjects were instructed to wear the pedometer at the level of the anterior superior iliac spine ( asis ) and also to fill in the daily physical activity log . out of the 105 volunteers , 33 were excluded , and there were 10 dropouts during the 3-week motivation program , leaving finally 62 volunteers who successfully completed the study . the insomnia severity index ( isi ) it is comprised of seven questions which are scored on a likert scale ranging from 0 to 4 . the scores range from 0 to 28 : 0 to 7 , no clinically significant insomnia ; 8 to 14 , sub- threshold insomnia ; 15 to 21 , clinical insomnia ( moderate ) ; 22 to 28 , clinical insomnia ( severe ) . the isi is a valid , reliable , and easy to administer questionnaire both as a screening tool and a measurement tool11 . pedometers are small devices that can be worn at the waist or ankle , and are capable of counting the number of steps taken15 . the participants were given an omron ( model hj-152 ) pedometer , and they recorded their total daily steps for three weeks . out of 105 volunteers , 80 subjects met the inclusion criteria , but only 62 could completed the study . prevalence of insomnia : 50% of the subjects had no clinically significant insomnia ( ncsi ) , 42% had sub- threshold insomnia ( sti ) , and 8% had moderate clinical insomnia ( mci ) . physical activity log : the number of steps taken per day was recorded for 3 weeks . this encouraged the subjects to take as many steps as they could to improve their physical activity ( table 1table 1 . the results show that physical activity increased from the first to the third week . association between insomnia and sleep problems : pearson correlation analysis revealed a significant correlation between sleep problem and the insomnia severity index after the motivation program ( r= 0.353 , p 0.01 ) ( table 2table 2 . relationship between isi and sleep problemcorrelationssleep probleminsomnia severityindex beforeinsomnia severityindex aftersleep problempearson correlation10.4 ( * * ) 0.3 ( * * ) sig . ( 2-tailed).0.00.0n787265insomnia severityindex beforepearson correlation0.4 ( * * ) 10.7 ( * * ) sig . ( 2-tailed)0.0.0.0n727264insomnia severityindex afterpearson correlation0.3 ( * * ) 0.7 ( * * ) 1sig . association between the number of coffee cups drunk and insomnia : pearson correlation analysis of the insomnia severity index before and after the motivation program with the number of coffee cups drunk per day showed a positive correlation with a value of r=0.178 and ( p=0.149 ) which was not statistically significant . association between physical activity and insomnia : physical activity measured as the number of steps taken correlated with the isi values showing a moderately negative correlation , with values of r= 0.396 at week 1 , and r= 0.378 at week 3 ( table 3table 3 . association between physical activity and isincorrelationpair 1pa 1 & isi720.3pair 2pa 3 & isi660.3pa- physical activity in weeks 1 and 3 . this is the first study conducted among saudi female college students to have determined the association between their physical activity and insomnia . the results show that 50% had ncsi ( no clinically significant insomnia ) , 42% had sub- threshold insomnia and 8% had moderate clinical insomnia . the average number of steps taken increased from the first week to the third week . we found a mild negative correlation between physical activity and the insomnia severity index . this is consistent with earlier findings that exercise has a beneficial effect on sleep problems especially insomnia16 . sleep regulates mood and affects learning , memory , concentration and recall , because it is one of the most important processes in a creature s life . on the other hand , poor sleep quality has adverse effects on learning , memory , and awareness adversely affecting work performance , especially among students . students need to show a high level of performance , which may not be achieved with sleep disturbances , because higher mental functions would be affected , leading to unhappiness , irritability , tiredness , depression and decreased level of performance . in 1998 , sherrill et al . associated the level of physical activity and sleep disorders in the middle aged to elderly with obstructive lung airway disease . they reported that women have sleep disturbance and participate in exercise programs more than men , whereas men did regular vigorous activity , and walking at a brisk pace approximately 4.8 to 6.4 km / h . the effect of exercise on sleep is observed when it exceeds 1 hour in duration , and appears to be related to alteration of sleep architecture , e.g. frequency , duration , daytime sleep , quality etc13 . this is consistent with the results of our study that higher physical activity has beneficial effects on sleep quality . researchers conducted a study of patients with end- stage renal disease in saudi arabia . they found that insomnia is common in dialysis patients and was significantly associated with other sleep disorders17 . previous studies also showed that sleep deprivation , and psychological stress are more common among medical students in other countries18,19,20 . moderate intensity aerobic exercise reduced pre - sleep anxiety and improved the sleep of middle - aged and older patients with chronic primary insomnia22 , 23 . previous studies have shown a strong relation between subjective assessment and objective assessment using polysomnography or actigraphy24 , 25 . the insomnia severity index ( isi ) is considered a clinically reliable and valid tool in insomnia treatment research26 . pedometers are considered the most valid and reliable tools for measuring physical activity27,28,29,30 . our present study included a small sample size , and had only a 3-week motivational program for increasing the number of steps taken per day . physical activity was observed to be highest in the second week , and it gradually reduced in the third week . we recommend further research with a longer duration motivation program in a larger group to establish a stronger relationship between physical activity and insomnia .

[ purpose ] insomnia is quite common and it can affect the quality of life of an individual . students undergo stress due to various academic demands leading to sleeplessness and daytime sleepiness . this study was conducted to investigate the association between physical activity and insomnia among female saudi students . [ subjects ] 62 female students with a mean age of 21 1.5 years took part in a motivational program to increase the number of steps taken per day for three weeks . [ methods ] after obtaining subject s informed consent all the subjects were assessed for insomnia using the insomnia severity index ( isi ) , they were then given pedometers to calculate the number of steps they took per day . a physical activity log was kept for three weeks . pre- and post -intervention isi scores were calculated and correlated with the 3-week physical activity log . [ results ] 50% of the subjects had no clinically significant insomnia ( ncsi ) , 42% had sub threshold ( sti ) , and 8% had moderate clinical ( mci ) insomnia . there was a moderate negative correlation between physical activity and isi scores after the 3-week motivation program . [ conclusion ] prevalence of insomnia was common among female saudi students and increase in physical activity appears to improve the sleep pattern .

on november 3 , 2014 , a sudden increase in deaths among 16-week - old turkeys was noticed at an indoor turkey - fattening facility in northeastern germany ( 8) . the affected farm kept 31,000 turkeys and is situated in an area with low density of poultry 1.3 km east of lake galenbeck , a protected , internationally recognized nature reserve frequented by wild birds . the turkeys were kept in stables a and b , each with 3 units ( a13 and b13 ) , all connected by a corridor . on november 1 and 2 , 2014 , 0.5% of turkeys were found dead ( expected number of deaths = 0 ) in unit a3 , which is near the stable complex entrance . on november 3 and 4 , the number of dead turkeys increased sharply ( 731 and 899 , respectively ; 18.4% and 22.6% daily mortality rates ) . when turkeys were culled on november 6 , 2014 , 300 turkeys were alive in a3 ( 93.4% cumulative mortality rate ) . in the adjacent unit , a2 , onset of disease followed the course occurring in a3 with an increased number of deaths delayed by 12 days , but deaths never reached levels found in a3 . units a1 , b1 , and b2 had been little affected when all turkeys were culled ( unit b3 was not in use ) . rna extracted from swab samples of viscous mucus in the oropharynx of dead turkeys and from an organ mixture was positive for influenza a(h5n8 ) virus by using reverse transcription quantitative pcr , conventional reverse transcription pcr , and sequencing ( 9 ) . the polybasic hemagglutinin ( ha ) cleavage site sequence rnsplrerrrkr*glf indicated a highly pathogenic phenotype . pathomorphologic examination of 2 turkeys revealed herds of pancreatic necrosis associated with fibrinous exudates , necrosis of ileocecal tonsils , and discrete petechiae in peri- and subepicardial locations . heavily injected immunohistologic analysis confirmed systemic infection and revealed influenza virus nucleocapsid protein in 1 ) ganglions of the adrenal medulla , 2 ) ependymal cells of the central nervous system ( associated with marked lymphocytic meningitis and perivascular cuffing ) , 3 ) thymus epithelia , and 4 ) epithelia of the exocrine pancreas ( figure 1 ) . a , c ) gross pathology showing acute , focally extensive to diffuse pancreatic necrosis with fibrinous serositis . b , d ) hematoxylin and eosin staining showing acute coagulative necrosis of the pancreas and multifocal staining within the exocrine pancreatic acini for influenza a virus nucleocapsid protein . scale bars indicate 50 m ( b ) and 100 m ( d ) . a virus isolate ( a / turkey / germany - mv / ar2472/2014 ; ar2472/14 ) was obtained in embryonated chicken eggs and in a chicken hepatocyte culture ( lmh , atcc crl-2117 ) . full - genome sequencing ( using sanger technology ) and nontargeted next - generation sequencing , followed by phylogenetic analyses of the sequences ( epi_isl_167140 ) , confirmed a close relationship of all 8 segments of ar2472/14 to hpai virus subtype h5n8 of clade 2.3.4.4 from south korea ( figure 2 , panel a ) . within this clade , 2 sister lineages ( a / breeder duck / korea / gochang1/2014 and a / baikal teal / korea / donglim3/2014 [ donglim3/14 ] ) can be distinguished . the ar2472/14 isolate forms a cluster with the donglim3/14 lineage ( 10 ) , but the derived coding sequences of all segments of ar2472/14 show 14 unique amino acids differing from those of donglim3/14 ( table ) . phylogenetic analysis of hemagglutinin ( ha ) 1 nucleotide sequences of highly pathogenic avian influenza viruses subtype h5 from southeast asia and germany . insert shows the structural model of the ha protein of the german h5n8 isolate ar2472/14 . a ) nucleotide sequences encoding the membrane - distal part of the ha1 of influenza a(h5n8 ) viruses were retrieved from public databases , aligned by using mafft ( http://mafft.cbrc.jp/alignment/software ) and phylogenetically analyzed by using a maximum - likelihood approach ( best fit model : k3pu+g4 ) implemented in iq - tree ( http://www.cibiv.at/software/iqtree ) ( 12 ) . numbers at nodes represent surrogates of branching robustness obtained by an ultrafast bootstrap approach ( 12 ) . green depicts unique mutations distinguishing this virus from other south korea origin avian influenza ( h5n8 ) viruses ; red indicates additional substitutions relative to the closest vaccine candidate within clade 2.3.4.4 . numbering according to a / baikal teal / korea / donglim3/2014 ; sequences were deposited in the gisaid sequence database ( http://gisaid.org ) . pb , polymerase basic ; pa , polymerase acidic ; ha , hemagglutinin ; np , nucleoprotein ; na , neuraminidase ; ns , nonstructural ; , no mutation . three unique amino acid substitutions were found in ha ( s197p , a201e , and i390v , numbered according to influenza a virus subtype h5n8 ) and modeled in the ha structure ( 11 ) ( figure 2 , panel b ) . although s197p is near the receptor - binding site , no ha mutations involve residues previously associated with host specificity , and key residues are in the typical avian configuration : e(190)202 , g(225)237 , q(226)238 , g(228)240 . a201e and s197p are close to antigenic site sb and could have limited influence on the antigenic profile of ar2472/14 . substitution i390v is in the binding interface of some of the universally neutralizing ha stalk antibodies . compared with the most geographically widespread h5 clade in birds in east asia ( 2.3.2.1 ) , several alterations occur in key antigenic regions , possibly promoting spread of the new clade variant 2.3.4.4 . genetically , a / sichuan/26221/2014 ( h5n6 ) appears to be the closest human vaccine candidate in preparation ( 13 ) . although this influenza a virus subtype differs from ar2472/14 by 19 ha mutations , the mutations are scattered over different regions of the structure ( figure 2 , panel b ) , and putative cross - protection requires confirmation . in the neuraminidase protein , unique substitutions a190 t and m470 t were detected in ar2472/14 , but on the basis of the deduced protein sequence , ar2472/14 is expected to be sensitive to current neuraminidase inhibitors . in the internal genes , which are shared with the korean h5n8 subtype , matrix 2 ( m2 ) n31 may confer amantadine resistance , and a c - terminal extension in nonstructural protein 1 masks the pdz binding motif otherwise involved in host interactions . the sequences of the polymerase basic ( pb ) 1 , nucleoprotein ( np ) , matrix 1 and 2 , and nonstructural ( ns ) 1 proteins were similar to the prototype sequence of a donglim3/14 ; however , the matrix protein had no changes , and the pb1 , np , and ns1 genes had 1 aa change each . three unique changes were identified in each of the pb2 and polymerase acidic proteins ( table ) . applying restriction measures according to european union directive 94/2005 ( 14 ) , such as culling affected flocks , epidemiologic investigations revealed no definite route of introduction of the virus but have excluded incursion by infected turkey eggs or poults ; contaminated water , feed , or litter ; and vehicles or persons having contact with infected premises in south korea or east asia . introduction by infected wild birds , perhaps facilitated by contaminated litter , feed , water , fomites , or other substance can not be excluded because an internationally recognized site frequented by wild birds is near the affected turkey farm . shortly before the start of the outbreak , large numbers of migratory birds were observed on harvested fields near the premise . fecal wild bird samples collected from the environment around the farm were negative for influenza a(h5n8 ) virus rna . however , a swab specimen obtained from a healthy common teal ( anas crecca ) shot from a flock of wild ducks on the island of ruegen , germany , on november 17 , 2014 , showed positive results for hpai ( h5n8 ) virus . since this study began , hpai h5n8 subtype outbreaks in poultry and infections in wild birds have been reported in europe ( the netherlands , england , italy , hungary , sweden and germany ) , asia ( russia and japan ) , and north america ( canada and the united states ) . on the basis of available sequences , strains from japan differ only slightly from influenza a(h5n8 ) viruses from europe , suggesting that the common ancestor of this new h5n8 subtype variant likely emerged in asia before recently spreading to europe ( figure 2 , panel a ) . the hpai outbreak in northeastern germany in november 2014 resulted from an hpai ( h5n8 ) subtype virus , represented by isolate ar2472/14 , which is closely related to h5n8 subtype viruses that have hitherto been confined to the far east . fourteen unique coding mutations of ar2472/14 show differences between this virus and previous isolates from south korea , but the mutations are shared with the recent h5n8 isolate a / duck / chiba/26 - 372 - 61/2014 from japan . epidemiologic and phylogenetic data collected so far are insufficient to establish definite pathways of introduction into germany . all possible routes , including relay transmission by subclinically infected wild birds , must be thoroughly examined . enhanced active monitoring of sites frequented by aquatic wild birds and waterfowl is also recommended .

highly pathogenic avian influenza ( h5n8 ) virus , like the recently described h5n8 strain from korea , was detected in november 2014 in farmed turkeys and in a healthy common teal ( anas crecca ) in northeastern germany . infected wild birds possibly introduced this virus .

animal studies have provided valuable clues for understanding the links between vitamin d and the cardiovascular system . rats with experimentally induced vitamin d deficiency ( exposed to a diet low in vitamin d and limited ultraviolet light ) have been shown to develop hypertension and cardiomegaly . mice lacking the vdr develop a fourfold increase in renin expression and angiotensin ii production compared with wild - type mice . vdr - null animals develop hypertension and cardiac hypertrophy , and cardiac - specific vdr knockout models demonstrate cardiac hypertrophy . supplementation with vitamin d has been shown to abrogate endothelin - induced hypertrophy and atrial natriuretic peptide production in cultured rat myocytes . in a study by wong et al . of spontaneously hypertensive rats , 6 weeks of treatment with 1,25-dihydroxyvitamin d3 reduced endothelium - dependent aortic contractions that were accompanied by a lowering of blood pressure and a reduction in reactive oxidative stress . in another study , dahl salt - sensitive rats treated with lower end - diastolic pressures and smaller heart weights were also noted in paricalcitol - treated animals when compared with untreated animals . systemic blood pressures were not significantly affected by paricalcitol therapy , suggesting that the observed cardiac changes were due to direct effects on the myocardium . recently examined the effects of paricalcitol on progression to heart failure after myocardial infarction in mice . paricalcitol attenuated the development of heart failure after myocardial infarction and was associated with improvement in cardiac function and reduction in markers of inflammation and fibrosis . some evidence suggests that the observed effects on cardiac structure and function from animal studies may translate to humans . for example , improvements in cardiac hypertrophy , diastolic function , and septal and posterior wall thickness have been observed in a retrospective pilot study of hemodialysis patients treated with paricalcitol compared with no treatment . animal studies evaluating effects of active vitamin d compounds on uremic vascular calcification offer additional two insights into the actions of these compounds : one related to the dose response relationship and the other related to differential effects of different active vitamin d compounds on the biology of vascular calcification independent of their potential to increase serum calcium . mathew et al . reported that low doses of calcitriol and paricalcitol ( dosages sufficient to correct secondary hyperparathyroidism ) were protective against aortic calcification in a mouse model of ckd and higher doses were noted to stimulate further calcification . in uremic rats , comparable doses of calcitriol , paricalcitol , and doxercalciferol have been reported to have significant differences in mrna expression of runx2 and osteocalcin in aortic tissues ( calcitriol and doxercalciferol treatments resulted in marked increases in these expressions where as paricalcitol did not ) . these dose response and differential effects need evaluation in observational and randomized studies in humans . it is notable that risk of calciphylaxis , one of the most severe forms of vascular calcification seen in patients with esrd , was recently reported to be increased in patients treated with calcitriol but not in patients treated with selective vitamin d analogues such as paricalcitol or doxercalciferol . these findings are preliminary and need confirmation in larger cohorts and also in patients with other forms of vascular calcification . we encourage readers to refer to comprehensive discussion of vitamin d and vascular calcification by dr gerard london in this supplement of kidney international . as early as the 1980s , a number of studies have reported higher blood pressure in patients with low 25-hydroxyvitamin d levels . one systematic review that extracted data from 14 cross - sectional and 4 prospective studies representing 78,028 participants reported that 25-hydroxyvitamin d levels were inversely associated with hypertension . the pooled odds ratio of hypertension was 0.73 ( 95% confidence interval ( ci ) 0.630.84 ) for the highest versus lowest categories of 25-hydroxyvitamin d concentration . response relationship was observed such that , for every 16 ng / ml increment in blood 25-hydroxyvitamin d concentration , the odds ratio of hypertension was 0.84 ( 95% ci 0.780.90 ) . observational studies have also detected associations between vitamin d and left ventricular hypertrophy and incident cardiovascular disease . pilz et al . reported a negative correlation between 25-hydroxyvitamin d levels and impaired left ventricular function in a cross - sectional study of patients referred for coronary angiography . comparing patients with severe vitamin d deficiency ( < 10 ng / ml ) to patients with normal 25-hydroxyvitamin d levels ( 30 ng / ml ) , adjusted hazard ratios for heart failure mortality and sudden cardiac death were 2.84 ( 95% ci 1.206.74 ) and 5.05 ( 95% ci 2.1311.97 ) , respectively . in the framingham offspring study that included 1739 caucasian subjects , subjects with 25-hydroxyvitamin d levels below 15 ng / ml had a multivariable - adjusted hazard ratio of 1.62 ( 95% ci 1.112.36 ) for incident cardiovascular events ( including myocardial infarction , coronary insufficiency , angina , stroke , transient ischemic attacks , peripheral claudication , or heart failure ) compared with subjects whose 25-hydroxyvitamin d levels were 15 ng / ml . vitamin d deficiency is highly prevalent in the ckd and esrd populations , with estimates as high as 7080% in some studies . several observational studies have noted links between vitamin d deficiency and poor cardiovascular outcomes in patients with renal disease . when reviewed systematically , studies suggest that survival in patients with ckd and esrd is positively correlated with increasing 25-hydroxyvitamin d levels . each 10 ng / ml increment in serum 25-hydroxyvitamin d level was associated with a 14% reduction in mortality ( relative risk , 0.86 ; 95% ci 0.820.91 ) . it is noteworthy that the majority of deaths were attributed to cardiovascular causes . in an analysis of data from the necosad ( nederland cooperative study on the adequacy of dialysis ) cohort , significantly higher cardiovascular mortality was observed in patients with severe 25-hydroxyvitamin d deficiency ( 10 ng / ml ) compared with those with 25-hydroxyvitamin d levels above 10 ng / ml . although 1,25-hydroxyvitamin d levels were not reported in this study , the association with cardiovascular mortality was most prominent in patients with high parathyroid hormone levels suggesting that low conversion from 25-hydroxyvitamin d to 1,25-hydroxyvitamin d may predispose patients to the highest risks from adverse consequences of 25-hydroxyvitamin d deficiency . observational studies fall short in their ability to establish a causal relationship between serum 25-hydroxyvitamin d and blood pressure lowering or reduction of cardiac disease risk . this is largely due to the inability of such trials to adjust for possible confounding factors . it is not surprising , therefore , that results suggesting favorable associations between 25-hydroxyvitamin d levels and cardiovascular outcomes have been inconsistent . study design - related factors , population differences , and variations in definitions are also often invoked to explain discrepant results . an alternative and biologically relevant explanation for the inconsistent observations vitamin d is a highly protein - bound hormone with < 1% of circulating 25-hydroxyvitamin d existing in its free form . the majority of circulating 25-hydroxyvitamin d ( 8590% ) is tightly bound to its specific vitamin d - binding protein and a smaller amount ( 1015% ) is loosely bound to albumin ( figure 1a ) . levels of bioavailable 25-hydroxyvitamin d , comprised of the free fraction plus albumin - bound hormone ( figure 1b ) , have been shown to be more strongly associated with serum calcium and parathyroid hormone levels than total 25-hydroxyvitamin d in esrd patients . whether the strength of association between bioavailable 25-hydroxyvitamin d and cardiovascular diseases is also improved needs to be investigated , since most studies to date have reported total 25-hydroxyvitamin d levels and not its bioavailable form . genetic studies demonstrate that vitamin d - binding protein levels are dictated by common genetic polymorphisms . for example , gc suballele frequencies vary considerably by race and are notably different in white subjects compared with non - whites . how circulating vitamin d - binding protein levels and their polymorphisms impact the thresholds used currently to define vitamin d deficiency , and perhaps more importantly , what levels of vitamin d should be targeted in future trials of vitamin d repletion remains open for debate . considering the associations observed between vitamin d deficiency and poor cardiovascular outcomes , a natural question is whether supplementation with vitamin d will provide clinical benefits . a number of observational studies , at least in patients with ckd and esrd , have been supportive and provide rationale for vitamin d therapy in these populations ; however , all have potential limitations that apply to any observational study and this question can only be addressed by randomized controlled trials . in a meta - analysis of 10 randomized trials in healthy adults , supplementation with nutritional vitamin d did not reduce systolic blood pressure ( weighted mean difference , 1.9 mm hg ( 4.2 to 0.4 mm hg ) ) or diastolic blood pressure ( weighted mean difference , 0.1 mm hg ( 0.7 to 0.5 mm hg ) ) . the dose of vitamin d preparations ( either cholecalciferol or ergocalciferol ) varied considerably among these trials ( from 400 to 8500 units / day ) and may explain the discrepancy between the outcomes reported in observational and these prospective interventional trials . albuminuria , an indirect measure of cardiovascular and endothelial health , was significantly reduced upon administration of oral paricalcitol 2 g daily when compared with placebo in patients with diabetic nephropathy . paricalcitol was also associated with lowering of systolic blood pressure ( range 3 to 9 mm hg ; p=0.033 vs. placebo ) during the trial period . a recent meta - analysis of six randomized clinical trials with active vitamin d analogs in ckd patients in which an effect of proteinuria or albuminuria was reported ( n=688 ) , treatment with either paricalcitol or calcitriol reduced proteinuria ( weighted mean difference from baseline to last measurement was 16% ( 95% ci 13% to 18% ) ) compared with controls ( + 6% ( 95% ci 0% to + 12% ) ; p<0.001 ) . whether the improvements in proteinuria seen with active vitamin d therapy correspond with improved clinical outcomes needs further investigation . significant insights into the effects of active vitamin d administration on cardiac structure and function have been provided by the paricalcitol capsule benefits in renal failure induced cardiac morbidity ( primo ) trial . this multinational double - blind placebo - controlled trial was designed to examine the effects of paricalcitol on left ventricular mass index over a period of 48 weeks in stages 3 and 4 ckd patients ( n=227 ) who had mild - to - moderate left ventricular hypertrophy at baseline . changes in left ventricular mass index were determined by cardiovascular magnetic resonance imaging and in left ventricular diastolic function were determined by cardiac echocardiography . paricalcitol therapy did not alter left ventricular mass index , nor did changes in pre - specified measures of diastolic function or systolic blood pressure differ significantly between the paricalcitol and placebo groups . interestingly , paricalcitol treatment was associated with fewer cardiovascular - related hospitalizations and also appeared to attenuate the increase in brain natriuretic peptide levels . in a post - hoc analysis of data from primo , paricalcitol treatment reduced left atrial volume index , a marker for diastolic dysfunction that has been associated with significant cardiovascular risks . one such trial , the japan dialysis active vitamin d trial ( j - david ) , is ongoing and the results are expected in the year 2015 . biological evidence strongly supports the notion that heart structure can be remodeled and function improved with vitamin d intervention . observational studies in humans have stimulated interest and provided important insights into vitamin d therapy , and have been generally supportive , especially with active vitamin d analogs in ckd and esrd populations . however , potential confounding of observational data , limitations of available randomized controlled trials in terms of their sample size , and low intervention doses are possible explanations for discrepancies between observational and experimental data on blood pressure and cardiovascular outcomes . whether future investigations should shift their attention to bioavailable rather than total 25-hydroxyvitamin d

the effects of vitamin d receptor activation on cardiovascular diseases , especially hypertension and cardiac dysfunction , are areas of active investigation . this article reviews the current state of knowledge about vitamin d receptor activation with respect to blood pressure , heart , and vascular health , as well as to chronic kidney disease and end - stage renal disease . potential biological mechanisms , the role of vitamin d - binding protein , and data from observational and randomized controlled trials on this topic are summarized .

synovial sarcoma ( ss ) most commonly affects the para - articular regions of the extremities of young adults , . occasionally , however , ss has been identified in less common locations , including the head and neck , heart , lungs and prostate . herein , we describe a case of primary renal ss , an exceedingly rare diagnosis , in a 52-year - old woman . the diagnosis was established by histology and immunostaining . to our knowledge , based on a review of the english literature , this marks the first case report describing the magnetic resonance ( mr ) features of synovial sarcoma of the kidney . a 52-year - old female presenting with a history of right flank pain underwent computed tomography ( ct ) examination which revealed an amorphous partially cystic right lower pole renal mass with heterogeneous enhancement . further workup with magnetic resonance imaging revealed a 6.0 5.9 6.1 cm mass in the lower pole of the right kidney . three - plane localizer , coronal single shot fast spin echo ( ssfse ) t2 , axial in and out of phase , axial fat suppressed t2 weighted , axial 5-min and 10-min delayed , and axial 3d liver acquisition with volume acceleration ( lava ) sequences were acquired . on t1 weighted imaging ( fig . 1a ) , the mass was heterogeneous , with the posterior region having similar intensity to skeletal muscle and the anterior region with higher signal intensity . axial t2 weighted imaging revealed marked heterogeneity with areas of high , intermediate , and low signal , known as the triple sign ( fig . 1b ) . the mass contained multiple areas of high t2 signal emanating from the center of the mass , with surrounding intermediate and low t2 signal intensity regions ( fig . figure 1axial in - phase t1 weighted gradient recalled echo ( gre ) image ( a ) , showing a heterogeneous mass lesion involving the medial portion of the lower pole of the right kidney ( arrow ) , with a posterior isointense area and an anterior area of higher signal intensity , relative to skeletal muscle . axial fat suppressed t2 ( b ) and coronal ssfse t2 images ( e ) show marked heterogeneity and the triple sign ; : areas of low , intermediate and high signal intensity ( arrows ) . axial post - contrast gre image ( c and d ) shows enhancement of the t2 hypo - intense areas ( arrow ) . axial in - phase t1 weighted gradient recalled echo ( gre ) image ( a ) , showing a heterogeneous mass lesion involving the medial portion of the lower pole of the right kidney ( arrow ) , with a posterior isointense area and an anterior area of higher signal intensity , relative to skeletal muscle . axial fat suppressed t2 ( b ) and coronal ssfse t2 images ( e ) show marked heterogeneity and the triple sign ; : areas of low , intermediate and high signal intensity ( arrows ) . axial post - contrast gre image ( c and d ) shows enhancement of the t2 hypo - intense areas ( arrow ) . the patient underwent right nephrectomy with a pathological diagnosis of high - grade , poorly differentiated spindle - cell synovial sarcoma . immunohistochemical staining showed focal positivity for cytokeratin cam 5.2 and negativity for s100 , ck7 , and epithelial membrane antigen ( ema ) . the most common sarcoma of the kidney is leiomyosarcoma , accounting for 4060% of reported cases . the first set of 15 cases reported was in 2000 , by argani , with few other cases reported in the english literature . there have been no reports to date describing the mr imaging findings of primary ss of the kidney . there is a slight male predominance , with a male - to - female ratio of 1.2 . furthermore , there seems to be a predilection for the right kidney , with a right - to - left ratio of 2.2 . the typical presentation of ss of the kidney is non - specific , and resembles that of other primary tumors of the kidney . patients may complain of localized flank or back pain , hematuria , or a palpable abdominal mass . the imaging modality of choice is magnetic resonance imaging ( mri ) , given its high sensitivity for soft tissue abnormalities . although diagnostic for some soft tissue tumors , mr signal intensity characteristics are usually non - specific for ss . most synovial sarcomas tend to be large masses , averaging 8 cm in size . the most common mr finding is an oval , well - defined nodular mass . on t1 weighted imaging , small lesions are typically homogenous , with a signal intensity similar to that of skeletal muscle , while lesions larger than 5 cm often exhibit intermediate intensity signal and are heterogeneous secondary to hemorrhagic and necrotic areas . on t2 weighted imaging , , lesions are hyperintense , usually with intratumoral hemorrhage ( 73% ) and cystic components ( 77% ) ; 3557% exhibit the triple sign , showing areas that are hyper- , iso- , and hypo - intense relative to skeletal muscle , representing hemorrhage / necrosis , septa / cellular elements , and calcified / fibrotic areas ; however , this is also seen in other soft tissue tumors , namely malignant fibrous histiocytoma , . mr imaging after intravenous contrast injection shows heterogeneous enhancement . histologically , ss consists of round spindle cells with minimal cytoplasm and active mitotic figures . these tumors are further divided into two subtypes , monophasic and biphasic , depending on the absence or presence of a well - develop glandular epithelium . although , synovial sarcoma in any location is regarded as slow growing , it should be considered a systemic disease . indeed , 25% have pulmonary metastases at the time of diagnosis . despite wide surgical resection , local recurrence and metastatic disease however , ss , more than other sarcomas , are more often treated with neoadjuvant chemotherapy followed by surgical treatment . these tumors demonstrate moderate chemo sensitivity , with 50% response rates to ifosfamide - based or doxorubicin - based regimens . studies of extremity ss have shown that ifosfamide - based chemotherapy reduces tumor volume by greater than 50% and improves disease - specific survival . in contrast , renal cell carcinoma is generally considered chemoresistant , although newer drug therapies such as sorafenib and sunitinib have led to some optimism , . multiple studies of ss of the extremity have shown a strong association between tumor size , volume , and histological grade to disease recurrence and patient mortality . high grade ss is favored in tumors that exhibit cystic components , hemorrhage , and fluid levels , as well as the triple sign .

abstractprimary renal synovial sarcoma ( ss ) was first described in 2000 by argani , with only a few subsequent cases being reported in the english literature . herein , we describe a case of a 52-year - old woman who presented with right flank pain . magnetic resonance imaging revealed a 6-cm mass in the lower pole of the right kidney . t1 and t2 weighted imaging revealed a heterogeneous mass with triple sign . there was post - contrast enhancement . imaging , histology and immunostaining together made the diagnosis of ss of the kidney .

although pupil - sparing in acute unilateral complete third nerve palsy is often a sign of ischemic nerve injury , it is not specific for injury outside of the midbrain.13 this report documents acute pupil - sparing complete third nerve palsy in an otherwise - healthy young adult with patent foramen ovale and associated atrial dilatation who suffered cryptogenic focal midbrain stroke , presumably from a paradoxical embolism . a 23-year - old otherwise healthy female with a 2-day history of diplopia and right ptosis after awakening had right complete pupil - sparing third nerve palsy ( complete ptosis , moderate hypotropia , large exotropia and no supraduction / infraduction / adduction ) . ocular examination was otherwise unremarkable in both eyes . directed questioning and physical exam also revealed left dysmetria of the upper and lower extremity , left partial upper motor facial nerve weakness and impaired touch sensation on the right anterior 2/3 of the tongue . the patient underwent extensive medical questioning and investigation . a review of symptoms and history included questioning regarding any recent illnesses , skin rashes , ulcers or sores , insect bites , pains , respiratory symptoms , gastrointestinal symptoms , urinary symptoms , neurological symptoms , trauma , medication history , prior hospitalizations , intravenous needle use , trips abroad and illnesses in family members . the patient had suffered from occasional oral ulcers and minor pain in the left knee over the last few years . laboratory studies included complete blood count , erythrocyte sedimentation rate , platelet count , prothrombin time , activated prothrombin time , bleeding time , lipid profile , plasma homocystine , fasting blood sugar , anticardiolipin ( antiphospholipid ) antibody , lipoprotein a , plasma fibrinogen , factor v leiden , antithrombin iii , protein s , protein c , antinuclear antibody , purified protein derivative standard testing , treponema pallidum hemagglutination assay , venereal disease research laboratory assay , sickle cell testing , prothrombin ( factor ii ) analysis for gene mutation at g20210a and acetylcholine antibody receptor testing . radiological studies included chest x - ray , trans - esophageal echocardiography , brain magnetic resonance imaging ( mri ) , carotid doppler ultrasound and cerebral angiography . mri was significant for a focal t2-weighted hyperintense focal midbrain lesion adjacent to the aqueduct of sylvius and consistent with infarction [ figure 1 ] . echochardiography revealed aneurismal atrial septum with relatively large ( 0.7 cm ) patent foramen ovale . cardiology and neurology consultants agreed that the patent foramen ovale in this setting led to paradoxical embolism and cryptogenic midbrain stroke . the foramen ovale was thus closed surgically via catheterization . in this t2-weighted magnetic resonance image with contrast , an almond - shaped hyperintense lesion can be seen in the right midbrain adjacent to the aqueduct of sylvius . the eyes are in right gaze over the next few months , all signs and symptoms resolved except for a residual right hypotropia and constant vertical diplopia in all positions of gaze . two years after the event , ophthalmic examination was significant for a stable relatively comitant right hypotropia of 25 prism diopters that was slightly greater in upgaze with minimal right supraduction limitation . forced generation and forced duction testing of the right eye were normal . following informed consent , the patient underwent right superior rectus muscle resection of 6 mm and right inferior rectus muscle recession of 6 mm via a fornix technique . postoperatively , the patient was diplopia - free with a slight chin - up position . there was a minimal right hypotropia in the forced primary position , which increased to 10 - 15 prism diopters in upgaze . generally , sparing of the pupil in acute unilateral complete third nerve palsy suggests ischemic extraaxial ( nerve ) injury.1 however , this rule of the pupil is less applicable to younger patients without any ischemic risk factors.12 pupil - sparing in unilateral complete third nerve palsy can occur secondary to focal midbrain injuries that affect third nerve fascicles responsible for extraocular and levator muscles without affecting topographically separated fascicules that carry pupillary fibers.1 directed questioning and physical exam often reveal accompanying neurological signs and symptoms that were not initially volunteered by an affected patient , though very rarely a complete midbrain pupil - sparing complete third nerve palsy can be truly isolated.3 third nerve fascicules maintain their topographical arrangement through and around the red nucleus before exiting the midbrain adjacent to the cerebral peduncle as the third nerve.4 several named syndromes describe the possible neurological associations of midbrain third nerve fascicular injury.5 fascicular injury in the area of the red nucleus can cause third nerve palsy with contralateral hemitremor via damage to cerebral afferents to the thalamus ( benedikt syndrome ) . fascicular injury in the area of the cerebral peduncle can cause third nerve palsy with contralateral hemiparesis including the lower face and tongue ( weber syndrome ) . other named syndromes include nothnagel syndrome ( midbrain third nerve palsy with ipsilateral cerebellar ataxia from injury to the superior cerebellar peduncle ) and claude syndrome ( midbrain third nerve palsy plus contralateral ataxia , asynergy and dysdiadochokinesis due to involvement of the red nucleus and superior cerebellar peduncle ) . in practice , neurological signs and symptoms that accompany midbrain third nerve injury do not usually cleanly compartmentalize into an eponymous syndrome.6 midbrain third nerve injury is typically ischemic in origin and rarely embolic.6 although patent foramen ovale is a common congenital defect that by itself is often of no consequence , it confers a risk for stroke via paradoxical embolism when associated with atrial dilatation.67 a patent foramen ovale can allow particles in the circulation that are normally filtered by small capillaries in the lungs to be transmitted directly from the right to the left atrium and thus gain access to the cerebral small vessel circulation , which is particularly susceptible to embolic phenomena . in the current patient , all signs of midbrain stroke resolved with time except for a relatively comitant hypertropia with associated vertical diplopia . both pre- and postoperatively , there was a slight right supraduction defect . in the setting of grossly normal forced duction and forced generation testing , the preoperative incomitance suggested a minimal residual superior rectus weakness from the midbrain insult .

although pupil - sparing in acute unilateral complete third nerve palsy is often a sign of ischemic nerve injury , it is not specific for injury outside of the midbrain . this report documents acute pupil - sparing complete third nerve palsy in an otherwise healthy young adult with patent foramen ovale and associated atrial dilatation who suffered cryptogenic focal midbrain stroke , presumably from a paradoxical embolism . the patent foramen ovale was surgically closed . over the next several months neurological recovery was complete except for diplopia and relatively comitant hypotropia , which responded well to conventional strabismus surgery .

potassium - titanyl phosphate ( ktp ) laser vaporization of the prostate for treating symptomatic benign prostatic hypertrophy has recently proven to be efficacious with minimal patient morbidity . ktp laser vaporization can create an immediate cavity almost bloodlessly , with the added benefit of little - to - no learning curve and the prospect of successful , same - day , catheter - free discharge . however , longer follow - up studies or reports about possible complications are lacking . dystrophic calcification results from the deposition of calcium in soft tissues despite that there is no generalized disturbance in the calcium or phosphorus metabolism ; this malady is often seen at sites of previous abnormalities or damage . the entity of dystrophic calcification is well described in the rheumatological and dermatological literature , and especially in the setting of dermatomyositis and scleroderma ( 1 ) . we report an unusual case of dystrophic calcification of the bladder neck after performing ktp laser vaporization of the prostate . a 78-yr - old man was presented with 1-yr history of dysuria , frequency and urgency . he had received ktp laser vaporization of the prostate at another hospital 16 months ago . according to past medical history postoperative care had lasted 7 days , which was longer than usual , and then he had been discharged . the laboratory results showed a plasma calcium level of 9.3 mg / dl and a plasma phosphorus level of 4.7 mg / dl , which were both within the normal ranges . the urinary sediment contained 10 - 29 white blood cells / high power field with 5 - 9 red blood cells / high power field , and bacterial culture of the urine was sterile . transrectal ultrasonography of the prostate showed prostate volume of 9 ml and there was diffuse calcification around the internal urethral sphincter ( fig . the cystoscopic findings revealed stones located in the bladder neck , and these were lodged into the previous surgical site . the entire bladder neck was encircled by stones and even in the mucosa of the bladder neck . the stones were so tightly lodged into the mucosa of the bladder neck that they could n't be disintegrated by performing lithotripsy in situ . therefore , transurethral resection was performed on the mucosal - lodged stones and the calcified tissues ( fig . hematoxylin and eosin staining of the surgical specimen showed extensive basophilic staining that was suggestive of calcification within the fibrotic tissues ( fig . foley catheter was removed on the postoperative 4th day and uroflowmetry showed the peak / mean velocity to be 15/11 ml / sec and the self / residual urine volume was 210/30 ml . the bladder irritative symptoms completely disappeared by the postoperative 4 months follow - up . it often occurs in conjunction with such collagen vascular diseases as dermatomyositis , scleroderma and systemic lupus erythematosis ( 1 ) . there have been reported cases of calcium deposition secondary to burn wounds , repeated trauma , needle sticks in the heels of neonates , thumb sucking by children , radiation and surgery ( 2 - 4 ) . although rarely seen in the genitourinary tract , it has been associated with schistosomiasis ( 5 ) , renal and ureteral tumors ( 6 ) , renal parenchymal disease ( 7 ) , churg - strauss vasculitis ( 8) , and polyarteritis nodosa ( 9 ) . however , there have been no reports of dystrophic calcification and stones formation on the bladder neck associated with previous ktp laser vaporization of the prostate . all mammalian extracellular fluids are supersaturated with calcium phosphate , but inhibitors such as matrix gla protein , oseoprotegrin and osteopotin prevent crystal deposition under normal physiological conditions ( 10 , 11 ) . damaged cell membranes leak calcium ions into cells , and these ions are subsequently concentrated by mitochondria to levels that are high enough to form crystals ( 2 , 4 ) . it has also been suggested that necrosis creates an acidic environment that lacks calcification inhibitors ( 12 ) . hydroxyapatite crystals are formed first within the protective microenvironment of the membrane microspace . in rare cases , dystrophic medical therapy , including administering etidronate disodium , sodium warfarin , diltiazem , aluminium hydroxide and intralesional corticosteroids , is the first - line treatment ( 1 ) . the indications for surgery are the presence of painful masses , recurrent infection , ulceration , local functional impairment and cosmetic motivation ( 13 ) . in the present case , ktp laser vaporization of the prostate seems to combine the tissue - debulking properties of transurethral resection of prostate ( turp ) with the well - known hemostatic properties of other laser treatments . it is a safe and relatively bloodless procedure that results in a shorter duration of catheterization , immediate symptomatic improvement and less severe postoperative irritative symptoms . however , concerning the efficacy and safety of this system , the majority of the studies about this deal with the short term results , which were excellent , but longer follow - up studies or reports about complications have been lacking . bachman et al . conducted animal studies using ex - vivo , blood - perfused porcine kidneys , and they compared the hemostatic efficiency of ktp laser vaporization with turp - like tissue resection . the authors showed the zone of coagulation necrosis was larger in the ktp group compared with the conventional turp group ( 0.9 vs. 0.6 mm , respectively , p<0.01 ) and ablation of 16 cm of tissue was accomplished much faster in the turp group ( 20 vs. 100 sec , respectively , p<0.0001 ) ( 14 ) . in this case , the patient had no systemic imbalances of calcium and phosphate metabolism and had n't received any procedures or surgeries that used calcium solution . so , the development of the bladder neck calcification was likely to be due to dystrophic calcification that was caused by the previous operation . additionally , the larger coagulation zone and longer operation time , compared to turp , might have caused relatively more severe injury of the bladder neck and thus promoting dystrophic calcifications .

dystrophic calcification can be defined as a calcification that occurs in degenerated or necrotic tissue . it is associated with multiple clinical conditions , such as collagen vascular diseases . it involves the deposition of calcium in soft tissues despite no generalized disturbance in the calcium or phosphorus metabolism , and this is often seen at sites of previous inflammation or damage . potassium - titanyl phosphate ( ktp ) laser vaporization of the prostate is safe and relatively bloodless procedure that results in a shorter catheterization , immediate symptomatic improvement , and less severe postoperative irritative symptoms . however , longer follow - up studies or reports about complications are lacking . here in we report a case of dystrophic calcification and stone formation on the entire bladder neck after performing ktp laser vaporization of benign prostate hyperplasia . that was treated by lithotripsy and transurethral resection .

a 48-year - old male presented at our clinic with a thoracic mass , which had been incidentally detected on chest computed tomography ( ct ) , and was not clear on routine chest radiography ( fig . chest ct revealed a 3.2-cm flat posterior mediastinal mass at the t8 level ( fig . 1b ) , which led to suspicions of a neurogenic tumor , such as ganglioneuroma or neurilemmoma . however , magnetic resonance images showed slightly lower signal intensity in the bone marrow of all the thoracic vertebrae and a combined finding of myelofibrosis in the bone marrow , which suggested that the posterior mediastinal mass could have been extramedullary hematopoiesis ( emh ) . a technetium-99 m phytate bone marrow scan was performed and asymmetric increased uptake was noted at the 8th thoracic vertebra ( fig . 1c ) . the patient had a history of hereditary spherocytosis , and had undergone splenectomy , cholecystectomy , and distal pancreatectomy 4 years previously . his laboratory findings were as follows : white blood cells 6.0610/l , hemoglobin 14.7 g / dl , platelets 171,000/l , segmental neutrophils 27% , lymphocytes 51.7% , monocytes 15% , and eosinophils 4.6% . although the patient had no specific symptoms and the possible diagnosis was emh , we decided to confirm the pathologic diagnosis to differentiate the mass from neurogenic tumors and other posterior mediastinal diseases , and to remove the potential risk of spinal cord compression because the lesion was located close to the neural foramen . video thoracoscopic surgery was performed and a 2-cm dark - blue pleural mass was found ( fig . a permanent histopathologic examination revealed myeloid tissues composed of hematopoietic cells and confirmed a diagnosis of emh ( fig . the patient 's postoperative course was uneventful and he was discharged without complications on the 5th postoperative day . emh is defined as production of blood components ( hematopoiesis ) outside the bone marrow . it has been hypothesized that emh occurs because of 1 ) hematogenous spread of hematopoietic stem cells , 2 ) a compensatory response to a reduction in blood components during pathologic conditions such as myelofibrosis , and 3 ) the activation of embryonic hematopoietic stem cells in other sites . however , emh is a rare disease and may accompany advanced myelofibrosis in patients with a myelodysplastic , hemolytic disease . in addition , chronic myelodysplastic and congenital hemolytic disorders are also risk factors of emh . during hereditary spherocytosis , an autosomal dominant genetic disorder of red blood cell membranes and cell membrane abnormalities can cause the loss of cellular architecture , and in particular , red blood cells tend to develop spherical features and may subsequently undergo lysis . as a consequence , patients with hereditary spherocytosis can present with symptoms of anemia , hepatosplenomegaly , jaundice , and venous thromboembolism , and may also present with emh as a compensatory response . in terms of its thoracic manifestations , emh should be differentiated from neurogenic tumors arising in the posterior mediastinum . in addition , it can present as spontaneous hemothorax , and rarely , as a lung nodule or mass , or as mediastinal lymphadenopathy or pleural seeding in the presence of a thoracic malignancy . furthermore , paraplegia can develop due to cord compression if emh affects the spinal canal . fine needle aspiration is an acceptable option for differential diagnosis , but it introduces the risk of post - procedural bleeding . surgical excision is recommended in patients with a symptomatic mass or spontaneous bleeding , or when a malignancy is suspected . surgical excision could be achieved using a minimally invasive thoracoscopic procedure , and may be strongly recommended if a patient is symptomatic or when spinal cord compression is anticipated . , we decided on surgical excision because the mass was located in the proximity of the neural foramen and spinal canal invasion was anticipated . causes of death in patients with emh include the following : pulmonary embolism , conversion to acute leukemia , renal failure , and cerebral infarction . we report a surgical case of emh that presented as a paraspinal mass , which was treated by complete resection , in a patient with hereditary spherocytosis .

thoracic extramedullary hematopoiesis ( emh ) is a rare disease entity that is usually associated with hematologic disorders , such as myelodysplastic or hemolytic disease . because thoracic emh is usually encountered as a mass during radiologic examinations , it should be differentiated from posterior mediastinal neurogenic tumors . here , the authors report a case of emh associated with hereditary spherocytosis . the patient underwent a complete excision by thoracoscopic surgery to differentiate it from other mediastinal tumors .

split cord malformations ( scm ) are rare , congenital spinal anomalies involving splitting of the cord . here , a segment or whole of the spinal cord is divided into two parts by a rigid or a fibrous septum . scms into four types , based on the intra - operative location of the bony spur causing the split . the bony septum usually originates from the vertebral body and proceeds posteriorly causing splitting of the cord . individual case reports of nine such cases have been reported in the english literature.[25 ] the authors report four cases of scms with a dorsally located bony spur and the pertinent literature is reviewed . a 2-year - old male child presented to the neurosurgical outpatient services with features of scoliotic deformity of the dorsal spine including urinary and fecal incontinence . a magnetic resonance ( mr ) imaging of the whole spine showed features of scm type i , with a bony spur at the d12l1 vertebral level . a long - segment syrinx and low - lying conus at the l3 vertebral level was observed with tethering of the cord [ figure 1a c ] . further , a plain computed tomography ( ct ) scan of the dorso - lumbar spine confirmed the bony origin of the spur with the spur arising from the posterior elements of the d12 vertebra and ending just short of the vertebral body [ figure 1d ] . the other associated bony anomalies included a hypertrophied posterior arch ( hpa ) at the level of spur and dysraphic spinous process . intra - operatively , the incomplete dorsal bony spur was removed completely , the two dural tubes were converted into a single tube and detethering of the filum was performed . post - operatively , the child developed mild worsening of paraparesis . at follow - up of 1 year following surgery , the child had improvement in paraparesis and autonomic dysfunction . sagittal , axial t1w , axial t2-w mri images and axial ct image of a representative case showing split cord malformation type i with dorsally located bony spur at the d12-l1 vertebral level causing asymmetric division of spinal cord into two separate hemicords with separate dural sheaths . the bony spur proceeds in a dorso - ventral direction and ends just short of the posterior surface of vertebral body a 2-year - old female child presented with gradually progressive paraparesis . mr imaging of the spine showed features of low - lying conus at the l5 vertebral level , split cord from l1 - 3 vertebral level and a bony spur at the l3 vertebral level . detethering of the filum and microsurgical excision of the spur was performed in a single stage . post - operatively , the child developed marked weakness ( power 2/5 medical research council grading ) . she recovered gradually and at the last follow - up 1 year following surgery , the child was ambulatory with support , with lower limb power returning to the pre - surgical state of 4/5 . a 6-month - old male child , presented to our neurosurgical outpatient services with features of hypertrichotic area over the lower lumbar region . mr imaging showed features of split cord at l2 - 5 vertebral level with an incomplete bony spur located dorsally at the l4 vertebral level with a low - lying conus at the s1 vertebral level . exploration , detethering of filum and removal of the dorsal spur was performed in single stage . at the last follow up after 14 months following surgery , the child was doing well and had no deficits . a 3-year - old female child , presented to us with features of deformity of spine and a pigmented patch over her lower lumbar region . imaging showed features of kyphoscoliosis with split cords from the d4-d6 vertebral level and a dorsally located spur at the d4 vertebral level . the post - operative period remained uneventful and at 1 year after surgery , she had no fresh deficits . details of all the four patients have been summarised in table 1 . the summarised clinical data a 2-year - old male child presented to the neurosurgical outpatient services with features of scoliotic deformity of the dorsal spine including urinary and fecal incontinence . a magnetic resonance ( mr ) imaging of the whole spine showed features of scm type i , with a bony spur at the d12l1 vertebral level . a long - segment syrinx and low - lying conus at the l3 vertebral level was observed with tethering of the cord [ figure 1a c ] . further , a plain computed tomography ( ct ) scan of the dorso - lumbar spine confirmed the bony origin of the spur with the spur arising from the posterior elements of the d12 vertebra and ending just short of the vertebral body [ figure 1d ] . the other associated bony anomalies included a hypertrophied posterior arch ( hpa ) at the level of spur and dysraphic spinous process . intra - operatively , the incomplete dorsal bony spur was removed completely , the two dural tubes were converted into a single tube and detethering of the filum was performed . post - operatively , the child developed mild worsening of paraparesis . at follow - up of 1 year following surgery , the child had improvement in paraparesis and autonomic dysfunction . sagittal , axial t1w , axial t2-w mri images and axial ct image of a representative case showing split cord malformation type i with dorsally located bony spur at the d12-l1 vertebral level causing asymmetric division of spinal cord into two separate hemicords with separate dural sheaths . the bony spur proceeds in a dorso - ventral direction and ends just short of the posterior surface of vertebral body mr imaging of the spine showed features of low - lying conus at the l5 vertebral level , split cord from l1 - 3 vertebral level and a bony spur at the l3 vertebral level . detethering of the filum and microsurgical excision of the spur was performed in a single stage . post - operatively , the child developed marked weakness ( power 2/5 medical research council grading ) . she recovered gradually and at the last follow - up 1 year following surgery , the child was ambulatory with support , with lower limb power returning to the pre - surgical state of 4/5 . a 6-month - old male child , presented to our neurosurgical outpatient services with features of hypertrichotic area over the lower lumbar region . mr imaging showed features of split cord at l2 - 5 vertebral level with an incomplete bony spur located dorsally at the l4 vertebral level with a low - lying conus at the s1 vertebral level . exploration , detethering of filum and removal of the dorsal spur was performed in single stage . at the last follow up after 14 months following surgery , the child was doing well and had no deficits . a 3-year - old female child , presented to us with features of deformity of spine and a pigmented patch over her lower lumbar region . imaging showed features of kyphoscoliosis with split cords from the d4-d6 vertebral level and a dorsally located spur at the d4 vertebral level . the post - operative period remained uneventful and at 1 year after surgery , she had no fresh deficits . details of all the four patients scm is an uncommon congenital anomaly in which a segment of the spinal cord is divided into two parts by a fibrous or rigid bony spur . the bony septum usually originates from the vertebral body and passes posteriorly causing splitting of the cord . individual case reports of nine such cases have been reported in the western literature.[25 ] many hypotheses have been postulated for the genesis of these malformations . however , the most widely accepted theory about the embryogenesis of these complex malformations was originally proposed by bremer in 1952 , and subsequently modified by pang et al . as the unified theory of embryogenesis . the basic error appears to be the development and persistence of accessory neurenteric canal ( anc ) . according to the theory , these lesions were divided into two types depending upon the type of the midline mesenchymal derivative and the dural investment of the hemicords . scm - i is characterized by the presence of double dural sacs , rigid extradural bony / cartilaginous spur leading into symmetrical or asymmetrical division of the cord . in scm - ii , there is a single dural sac with a non - rigid fibrous spur and symmetrical division of the cord . scm - ii are slightly more common than scm - i , constituting around 50 - 60% of scms . further proposed a new subclassification for type i scms depending upon the intraoperative location of the bony spur and the splitting of the cord . accordingly , they were subclassified into type ia , ib , ic , i d and they concluded that type i d is the most difficult and challenging . these can range from asymptomatic ones to pain , gait disturbance , motor or sensory deficits , and autonomic dysfunction . in our study , we had one patient ( 25% ) each presenting with dorsal scoliosis with autonomic and motor dysfunction , dorsal scoliosis with cutaneous pigmented patch , hypertrichosis , and two patients had progressive paraparesis . mr imaging is the diagnostic modality of choice and imaging of the whole spine is essential to rule out other associated anomalies . ct scan is complimentary to mri and is helpful in evaluating the nature of the spur and associated vertebral body anomalies . with respect to the bony anomalies , two patients had a hpa and one patient had dysraphic spine . although the unified theory of pang et al . has resolved the pathogenetic classification and clinical significance of these conditions , this theory does not explain the unusual variant such as a dorsally located bony spur . in our study , the bony spur was situated dorsally with two hemicords in a single dural tube as illustrated . in type - i scms , accordingly , these lesions can not be classified as type - i or type - ii scms according to the unified theory . chandra et al . , in their reported case of dorsal bony spur in a lumbar scm hypothesized two mechanisms for the occurrence of this rare variant : ( 1 ) passage of an abnormal cell population dorsally with subsequent loss of contact with the ventrally situated cell population and ( 2 ) migration of cells around the hemicords and subsequent passage between them in a dorso - ventral direction . furthermore , katoh et al . reported a case of scm - ii without a fibrous spur which again is not explainable by the unified theory . hence , although a hypothesis has been proposed for this uncommon variant by some authors , further embryological studies are necessary to validate such proposals . low - lying conus should also be addressed along with the excision of bony spur . in all our cases which were associated with a low - lying conus , exploration and excision of the bony spur midas rex high - speed drill was used in all our cases with gradual drilling of the dorsally located spur in a dorso - ventral direction . the post - operative neurological status was as follows : two patients had no fresh neurological deficits whereas the remaining two patients developed transient worsening of the neurological status ( one developed mild paraparesis which recovered completely and other developed marked paraparesis with good functional recovery to the pre - surgical state ; in both these patients , there was a hpa and low - lying conus ) . the operative steps can be summarized as follows : ( 1 ) midline posterior approach . ( 2 ) laminoplasty should never be performed in these cases for fear of causing increased cord damage because of the dorsally situated spur . hence , laminectomy is preferred and should be done at least one level above and one below the level of the spur as the bony spur is attached to the laminae , they need to be handled with utmost care and should be gradually drilled off using a drill . ( 3 ) the dura is opened in a conventional linear manner with a gentle curve encircling the spur . the dural incision is extended about two levels above and below the level of lesion so that there remains sufficient dura for closure . ( 4 ) the initial work on the bony spur is done by a pneumatic drill and the thinned - out portion removed with microronguers . dura is closed primarily with 5 - 0 vicryl suture and duraplasty is performed when primary dural closure is difficult . dorsally situated bony spur is a very rare entity . mr imaging is the diagnostic modality of choice complemented by ct scan . other associated spinal anomalies should always be looked for , especially a low - lying conus and a syrinx . surgical excision of the spur with detethering of filum , in cases of low - lying conus , is the treatment of choice in which laminectomy with gradual drilling of the dorsally located spur , is preferred . the risk of post - operative worsening of the neurological status is increased in cases in which there is concomitant presence of hpa and low - lying conus . a sound anatomical knowledge coupled with the principles enlisted above can help prevent spinal - cord damage and can help achieve satisfactory results .

split cord malformations ( scm ) with a dorsally located bony spur are a very rare entity . the authors report a series of four such cases . the literature is reviewed regarding the pathogenesis and management of this uncommon variant of scm . the presenting features include scoliosis with motor and autonomic dysfunction ( n = 1 ) , scoliosis with cutaneous patch ( n = 1 ) , hypertrichotic area ( n = 1 ) , and motor deficits alone ( n = 1 ) . the location of spur was thoracic and lumbar in two patients ( 50% ) each . low - lying conus was present in three patients . long segment syrinx was present in one patient . with respect to the bony anomalies , two patients had a hypertrophied posterior arch ( hpa ) and one patient had a dysraphic spine . all patients underwent surgical excision of the spur with detethering , if a low - lying conus was present . two patients developed transient worsening of the neurological status after surgery which recovered at the time of the last follow - up ; in both these patients , there was a hpa and a low - lying conus . surgical excision of the spur with detethering of filum , in cases of low - lying conus , is the treatment of choice . risk of post - operative worsening of the neurological status is increased in cases in which there is concomitant presence of hpa .

on a glass slide , freshly cut surface of the specimen is gently pressed , misrepresentation of the cell 's shape can be prevented by restricting a gliding movement . then the slide is stained with hematoxylin and eosin stain before that it is fixed with 95% of ethyl alcohol for 56 s. however , it is extensively used in the diagnosis of benign and malignant lesions . in tumors such as meningiomas , imprint cytology provides good results without any difficulties in basal carcinomas of the skin . in the diagnosis of ovarian cancers , imprint cytology is used as a diagnostic tool in the study for assessing the salivary gland tumors such as mixed parotid tumors , pleomorphic adenoma and mucoepidermoid carcinoma . the procedure for imprint cytology can be done even in underdeveloped infrastructure and deficient trained technician . it provides an immediate result with minimal artifacts , it is cheaper and so it is most commonly used . a precise diagnosis is received through this technique . tumors and well - differentiated tumors with dense fibrous stroma can not be interpreted through this method . thus , imprint cytology plays a significant role in the quick diagnosis of the lesion . cost effectiveness , rapid results and simplicity are the further criteria promoting it to be a better option when compared with other techniques such as frozen sections .

a valuable information on morphological details of the cell can be obtained through imprint cytology . though it has some pitfalls , it is still considered to be one of the best methods as it provides an excellent cytological clarity in fresh surgical specimens . this article shares knowledge about the procedure , uses , advantages and disadvantages of imprint cytology .

ion channels are integral membrane proteins that govern the passage of ions across cell membranes . encoded by approximately 400 ion channel genes in the human genome , this superfamily of membrane proteins is involved in many important physiological functions such as the regulation of blood pressure , neurotransmission , and hormonal secretion . ion channels are implicated in a wide range of diseases including hypertension , neuromuscular disorders and parkinson s disease . consequently , they constitute the third largest class of targets in drug discovery after protein kinases and g - protein coupled receptors . despite its wide implication in disease conditions , the development of drugs targeting this membrane protein superfamily has remained underexploited , with only about 10% of drugs on the current market known to bind to ion channels . since the advent of high - throughput screening ( hts ) for drug discovery in the 1980s , hts has become an important tool for hit identification in pharmaceutical research . in the past decade , strategies have evolved from traditional diverse hts to the screening of focused libraries for a particular class of biological targets . for example , protein kinase - focused screening libraries have been reported by us and other research groups using well - documented structural motifs to select compounds satisfying a defined pharmacophore . however , in comparison to protein kinases , the assembly of a focused screening library targeting ion channels is more challenging owing to limited structural information about the targets , their structural diversity , and the absence of well - defined pharmacophores required for binding to ion channels.(10 ) the release of the chembl database(11 ) has facilitated open - access to a large volume of small - molecule bioactivity data for various therapeutic target families , including ion channels . here , we describe an efficient workflow for compiling a focused screening library for ion channel targets using a combination of database mining and various chemoinformatics analytical tools for structural class generation and compound selection . the established workflow can easily be adopted to assemble focused screening libraries for other therapeutic target classes with diverse recognition motifs . to enable an efficient assembly of the ion channel - focused screening library , the procedure was divided into five stages ( figure 1 ) . bioactivity data of compounds active against ion channel targets were retrieved from the chembl database.(11 ) this data set ( chemblinitial data set ) contained 25150 compounds reported to be active against 337 different molecular targets . the majority of the classification of ion channel categories followed those as defined in chembl , apart from the groups of ligand- ( lgic ) and voltage - gated ion channels ( vgc ) which were further divided to facilitate data handling . acetylcholine and serotoninergic 5ht3 receptors were grouped together to form the cationic cys - loop channels ( cationiccysloop ) , whereas gabaa and glycine receptors were categorized as anionic cys - loop channels ( anioniccysloop ) . for vgc , each of sodium ( na ) , calcium ( ca ) percentage composition per ion channel category in the chemblinitial , chemblfiltered , and ddu_ic data sets . no desirable bioactive compounds were found for four categories of ion channels ( amiloride - sensitive sodium channels ( asic ) , cgmp - gated channels , ryanodine receptors , and ip3 receptors ) . various filters were applied to the chemblinitial data set for the selection of compounds to form the chemblfiltered data set ( figure 3 ) . first , filters were introduced to exclude compounds for which bioactivity data was reported only for species other than rat , mouse or human . next , the chembl confidence scores for all bioactivity data were checked to ensure there was no experimental data representing activity against nonmolecular or nonprotein targets ( chembl confidence score between 1 and 3 inclusive ) . further , only compounds with reported bioactivity ( ki , kd , ic50 , or ec50 ) of 10 m were kept . although this cutoff value would allow compounds that violate lipinski s rule - of - five,(12 ) it was considered appropriate at this stage of the analysis to minimize loss of core structural information when generating structural classes ( see below ) . finally , compounds containing unwanted groups(8 ) were excluded . this led to a collection of 7102 compounds representing 10 ion channel categories ( figure 2 ) . commercial availability search for compounds of the chemblfiltered data set using our in - house database(8 ) revealed only 329 available compounds . in light of this , bioactive templates representing the different structural classes of ion channel modulators were generated for subsequent substructure searches . bioactive templates were identified by searching for maximum common substructures ( mcs ) of compounds within each ion channel category in the chemblfiltered data set . during this process , singletons and under - represented classes ( see experimental procedures ) afterward , the structures of the bioactive templates were visually inspected , and any synthetically intractable structures were rejected to avoid the presence of synthetically challenging compounds in the final screening library that would not be proceeded as hit or lead candidates . 307 bioactive templates out of 548 generated templates were selected in the final collection and annotated against their respective categories of ion channels ( table 1 ) . after merging identical templates present in multiple categories , 297 unique bioactive templates were used as substructures to search for commercially available lead - like compounds in our in - house database.(8 ) this search identified 92340 compounds representing 149 bioactive templates , forming the commavail data set which contained on average 620 compounds per template . to avoid over - representation of certain templates and to keep the library at an affordable size , a maximum of 50 compounds per bioactive template was imposed.(8 ) in the 77 templates which were represented by more than 50 compounds ( figure 4 ) , molecular diversity of compounds was analyzed using molecular fingerprints and the 50 structurally most diverse compounds were retained in the data set . subsequently , the data set was visually inspected to remove any compounds containing synthetically intractable structures attached to the templates . finally , all bioactive templates which had five or fewer examples remaining were considered under - represented , and therefore these compounds were excluded from the data set . number of compounds per bioactive templates across different ion channel categories in the commavail data set . the 3241 compounds that passed all filter steps were purchased to form the final focused screening library ( ddu_ic data set ) ( figure 2 ) . covering 123 bioactive templates across nine ion channel categories , these compounds were annotated with their respective ion channel category to assist back - tracing of prospective molecular targets from phenotypic screening results . despite the number of templates progressively decreasing from 297 templates in the chemblfiltered data set to only 123 templates in the ddu_ic data set , the percentage composition of each ion channel category remained approximately constant throughout the process ( figure 5 ) . on average , out of the nine ion channel categories represented , only the anioniccysloop category showed a considerable reduction , with eight out of the 36 templates ( 22% ) in chemblfiltered represented in ddu_ic . in contrast , 61% of the 34 templates for transient receptor potential channels were represented in the final library . percentage composition of each ion channel category by number of templates in the chemblfiltered , commavail , and ddu_ic data sets . screening of focused libraries is considered to be a cost - effective strategy for hit discovery . compiling focused libraries requires analysis of relevant chemical space in order to enrich compounds that are likely to interact with the desired target class.(5 ) this is commonly achieved by defining pharmacophoric or structural motifs satisfying specific binding interactions for the desired target class , which consequently requires a thorough understanding of the structural features and patterns of the protein ligand interactions . therefore , focused library construction is more challenging when the recognition motifs of the target class are less established.(10 ) with the first crystal structures of ion channel targets just emerging(13 ) and due to their heterogeneous nature involving 16 subfamilies,(14 ) the assembly of focused screening libraries for ion channels clearly represents a demanding task . the workflow described here ( figure 1 ) provides an efficient protocol to analyze relevant bioactive data for ion channels and to use this information for compiling a focused library . however , since most of the compounds in chembl are not commercially available,(15 ) the identification of bioactive templates using mcs represents an effective method to derive substructures which can subsequently be used to retrieve commercially available compounds that are likely to modulate ion channel activity . in addition to improving compound availability , these bioactive templates , unlike many descriptors derived to predict bioactivity of chemical compounds , are easy to interpret and do not require expert chemoinformatics knowledge , hence synthetically intractable templates can be rejected at an early stage by visual inspection . besides , this mcs approach also allows the identification of promiscuous templates which appear across multiple ion channel categories . indeed , we identified eight bioactive templates which are common to multiple ion channel categories using this workflow . such observation would have been much more difficult if using more traditional similarity - based approaches such as molecular fingerprints comparison . however , promiscuous inhibitors(18 ) in chembl erroneously reported to be active against certain targets are difficult to be detected using this workflow . the selected compounds can be annotated with the respective ion channel category they were derived from , which facilitates target identification when using the library for phenotypic screening . this workflow is not limited to ion channels but can be adapted to any target family for which chemical information is available in chembl or other related databases . the presence of gaps for ion channel - active compounds in lead - like commercial chemical space became apparent when assembling the ion channel library . only 329 compounds ( < 5% ) in the chemblfiltered data set were commercially available based on our in - house database . this is perhaps not surprising , since many compounds in chembl are retrieved from medicinal chemistry literature , which often describes hit or lead optimization efforts . when searching for lead - like commercially available compounds(8 ) using the 297 bioactive templates derived from mcs ( table 1 ) , compound availability was vastly improved , although a significant proportion of the selected templates remained unrepresented ( figure 5 ) . these unavailable templates are present across all ion channel categories ( table s1 in the supporting information ) , and many of them do not appear to be synthetically more challenging than the available ones ( table 2 ) . a similar observation was noted before when we assembled a focused kinase screening library.(8 ) the observed absence of ion channel templates in commercial chemical space is also supported by a recent publication by chuprina et al . who estimated a generally low occurrence of prospective ion channel modulators relative to other target classes from a collection of commercial chemical suppliers similar to those in our in - house database.(19 ) although the collection of suppliers in our database may not represent a comprehensive coverage of the entire commercial chemical space , our observations here , together with that of chuprina et al . , indicate there is still scope for compound vendors to increase the diversity of lead - like compounds on offer in their libraries . we have demonstrated an efficient workflow to assemble a focused screening library for ion channel targets using bioactivity data retrieved from chembl . the workflow is based on the efficient mining of an open - access database containing bioactivity data for structurally diverse therapeutic target families and demonstrates an effective solution using bioactive templates to overcome the problem associated with limited compound availability . the final screening library contained 3241 compounds representing 123 templates across nine ion channel categories . these compounds were annotated with their respective ion channel category to enable efficient back - tracing of prospective molecular targets from phenotypic screening results . the screening library is currently being used in campaigns to identify new chemical starting points toward ion channel targets for various neglected disease programs within the drug discovery unit at dundee . these results will offer valuable data to evaluate the quality of this newly assembled screening library . bioactivity data of compounds annotated with associated ion channel targets ( 337 molecular targets in 14 categories ) were retrieved from the chembl database ( accessed feb 16mar 4 , 2010 ) . all filters applied were carried out using pipeline pilot professional client 7.5 ( accelrys , inc . ) . unwanted groups were described as smarts strings,(8 ) and compounds were matched against the smarts description using substructure mapping . structural classes of the chemblfiltered data set were generated using classpharmer 4.7 ( simulationsplus , inc . ) . the criteria of structural classes were a minimum of 2 rings ( either 2 single rings linked together or 1 fused ring ) , 13 functional groups attached to any ring system , a maximum of 5 bonds between a ring and a functional group , and a maximum of 5 bonds between ring - connected fragments . under - represented classes were defined as those containing fewer than five compounds of which no bioactivities were better than 5 m . these templates were used as substructures to search for commercially available compounds in our in - house database containing 5.9 million unique compounds from 20 commercial chemical suppliers ( as of june 2010 ) . compounds in the commavail data set were chosen according to the lead - like criteria as previously described.(8 ) compound clustering and the selection of representative examples followed the same procedure as previously published.(8 )

the chembl database was mined to efficiently assemble an ion channel - focused screening library . the compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories . compounds in the screening library are annotated with their respective ion channel category to facilitate back - tracing of prospective molecular targets from phenotypic screening results . the established workflow is adaptable to the construction of focused screening libraries for other therapeutic target classes with diverse recognition motifs .

p. linteus was acquired from the chungnam agricultural research and extension service of yesan , in chungnam province . unless specified otherwise , all chemicals and solvents utilized herein were of analytical grade . lipase ( porcine pancreatic lipase , type ii ) , triolein as substrate , tes ( n - tris [ hydroxymethyl ] methyl-2-aminoethane - sulfonic acid ) , taurocholic acid , and gum arabic were purchased from sigma - aldrich ( st . louis , mo , usa ) . the lyophilized powder of fruiting bodies of p. linteus was added to distilled water and 60% ethanol ( 1 : 20 , w / v ) , then shaken for 18 hr at 40. these extracts were centrifuged for 20 min at 8,000 rpm , concentrated with a rotary vacuum evaporator , and lyophilized . lipase inhibitory activity was assessed by determining the rate of release of oleic acid from triolein , via a modified version of the method developed by bitou et al . . a suspension of 120 mg of triolein , 90 mg of gum arabic , 10.16 mg of taurocholic acid in 9 ml 0.1 n tes buffer ( ph 7.0 ) , containing 0.1 m nacl was sonicated for 5 min . a mixture of 50 l of pancreatic lipase ( 500 u / ml , 50 l of mushroom extracts ( 4 mg / ml ) , and 300 l of substrate mixture was incubated for 30 min at 37 , and the quantity of oleic acid generated was determined via the method developed by zapf et al . with some slight modifications . the 400 l incubation mixtures were added to 3 ml of chloroform / hexane ( 1 : 1 ) containing 2% ( v / v ) ethanol , then extracted by 10 min of shaking in a shaker . the mixture was then centrifuged ( 2,000 g ) for 10 min and copper reagent was added to the lower organic layer , and then shaken for 10 min . the mixture was centrifuged ( 2,000 g , 10 min ) , and 1 ml of the upper organic layer , which contained the copper salts of the extracted oleic acid , was allowed to react for 10 min with 0.5 ml of 0.1% ( w / v ) bathocuproine - chloroform solution containing 0.05% ( w / v ) 3-tert - butyl-4-hydroxyanisol , and the absorbance was determined at 480 nm . the inhibition ( % ) was calculated via the following equation : inhibitory activity ( % ) = ( a - b)/a 100 , in which a is the lipase activity in the reaction solution without the sample and b is the lipase activity in the reaction solution containing the sample . the general components of distilled water extract and ethanol extract from the fruiting bodies of p. linteus were determined via the methods of helrich . the mineral contents were analyzed via icp ( varian , nederland ) after wet degradation . the free sugar and organic acid contents of the distilled water extract and ethanol extract were determined by hplc ( 2695 ; waters corp . , milford , ma , usa ) , and the amino acid contents were also determined via hplc ( 2965 ; waters corp . , p. linteus was acquired from the chungnam agricultural research and extension service of yesan , in chungnam province . unless specified otherwise , all chemicals and solvents utilized herein were of analytical grade . lipase ( porcine pancreatic lipase , type ii ) , triolein as substrate , tes ( n - tris [ hydroxymethyl ] methyl-2-aminoethane - sulfonic acid ) , taurocholic acid , and gum arabic were purchased from sigma - aldrich ( st . louis , mo , usa ) . the lyophilized powder of fruiting bodies of p. linteus was added to distilled water and 60% ethanol ( 1 : 20 , w / v ) , then shaken for 18 hr at 40. these extracts were centrifuged for 20 min at 8,000 rpm , concentrated with a rotary vacuum evaporator , and lyophilized . lipase inhibitory activity was assessed by determining the rate of release of oleic acid from triolein , via a modified version of the method developed by bitou et al . . a suspension of 120 mg of triolein , 90 mg of gum arabic , 10.16 mg of taurocholic acid in 9 ml 0.1 n tes buffer ( ph 7.0 ) , containing 0.1 m nacl was sonicated for 5 min . a mixture of 50 l of pancreatic lipase ( 500 u / ml , 50 l of mushroom extracts ( 4 mg / ml ) , and 300 l of substrate mixture was incubated for 30 min at 37 , and the quantity of oleic acid generated was determined via the method developed by zapf et al . with some slight modifications . the 400 l incubation mixtures were added to 3 ml of chloroform / hexane ( 1 : 1 ) containing 2% ( v / v ) ethanol , then extracted by 10 min of shaking in a shaker . the mixture was then centrifuged ( 2,000 g ) for 10 min and copper reagent was added to the lower organic layer , and then shaken for 10 min . the mixture was centrifuged ( 2,000 g , 10 min ) , and 1 ml of the upper organic layer , which contained the copper salts of the extracted oleic acid , was allowed to react for 10 min with 0.5 ml of 0.1% ( w / v ) bathocuproine - chloroform solution containing 0.05% ( w / v ) 3-tert - butyl-4-hydroxyanisol , and the absorbance was determined at 480 nm . the inhibition ( % ) was calculated via the following equation : inhibitory activity ( % ) = ( a - b)/a 100 , in which a is the lipase activity in the reaction solution without the sample and b is the lipase activity in the reaction solution containing the sample . the general components of distilled water extract and ethanol extract from the fruiting bodies of p. linteus were determined via the methods of helrich . the mineral contents were analyzed via icp ( varian , nederland ) after wet degradation . the free sugar and organic acid contents of the distilled water extract and ethanol extract were determined by hplc ( 2695 ; waters corp . , milford , ma , usa ) , and the amino acid contents were also determined via hplc ( 2965 ; waters corp . , to collect data regarding the application of p. linteus lipase inhibitor for use in the functional food industry , the effects of temperature and time on the extraction of the lipase inhibitor from p. linteus by distilled water and ethanol were determined . as is shown in figs 1 and 2 , the lipase inhibitory activities of the fruiting bodies of p. linteus were higher in the ethanol extracts than in the distilled water extracts , and the inhibitor extraction yield increased with increasing extraction temperature and time . furthermore , the optimal ethanol concentration for lipase inhibitor extraction was 80% ( data not shown ) . the lipase inhibitor was optimally extracted when p. linteus was treated with distilled water at 80 for 72 hr ( 52.7% ) and 80% ethanol at 100 for 60 hr ( 73.2% ) , respectively . it has been determined that even when the same inhibitor is used , the optimal extraction temperature between plants and microorganisms differs . for example , the acetylcholinesterase ( ache ) inhibitor from umbilicaria esculenta and job 's tears was optimally extracted at 40 ; however , the ache inhibitors from some plants were most efficiently extracted with hot water [ 17 , 18 ] . the lipase inhibitor - containing distilled water extract and ethanol extract from p. linteus contained crude protein contents of 10.9% and 6.11% , and crude fat contents of 0.96% and 15.86% , respectively ( table 2 ) . the mineral contents of the distilled water extract were higher than those of the ethanol extract -- specifically , the distilled water extract contained 239.5 mg of k , 36.3 mg of mg and 39.3 mg of na ( table 3 ) . the free amino acid contents of the distilled water extract and ethanol extract were determined ( table 4 ) and included tryptophan ( 3,891 mg/100 g solid ) , alanine ( 2,598 mg/100 g solid ) , serine ( 2,066 mg/100 g solid ) and interestingly , asparagines ( 5,139 mg/100 g solid ) . these amino acid contents were higher than those of the ethanol extract , with the notable exception of the asparagine contents ( 6,137 mg/100 g solid ) . however , these amino acid contents were 2.0~6.0 times higher than those of the corresponding tryptophan ( 60 mg/100 g solid ) and serine ( 1,400 mg/100 g solid ) contents in the methanol extracts from umbilicaria esculenta , and were also similar to the alanine contents ( 3,400 mg/100 g solid ) and lower than the glutamic acid contents ( 44,400 mg/100 g solid ) . the glutamic acid ( 17.19 mg / g solid ) and histidine contents ( 6.42 mg / g solid ) of the distilled water extract from p. linteus were similar to those of lentinus edodes ( 15.84 mg / g solid and 7.95 mg / g solid , respectively ) . the principal organic acid detected in the distilled water extract and ethanol extract of p. linteus was malic acid ( 12,312 mg/100 g solid , 8,160 mg/100 g solid , respectively ) . the distilled water extract also contained 590 mg/100 g solid of oxalic acid , and the ethanol extracts contained tartaric acid ( 620 mg/100 g solid ) ; no other organic acids were detected ( data not shown ) . to collect data regarding the application of p. linteus lipase inhibitor for use in the functional food industry , the effects of temperature and time on the extraction of the lipase inhibitor from p. linteus by distilled water and ethanol were determined . as is shown in figs 1 and 2 , the lipase inhibitory activities of the fruiting bodies of p. linteus were higher in the ethanol extracts than in the distilled water extracts , and the inhibitor extraction yield increased with increasing extraction temperature and time . furthermore , the optimal ethanol concentration for lipase inhibitor extraction was 80% ( data not shown ) . the lipase inhibitor was optimally extracted when p. linteus was treated with distilled water at 80 for 72 hr ( 52.7% ) and 80% ethanol at 100 for 60 hr ( 73.2% ) , respectively . it has been determined that even when the same inhibitor is used , the optimal extraction temperature between plants and microorganisms differs . for example , the acetylcholinesterase ( ache ) inhibitor from umbilicaria esculenta and job 's tears was optimally extracted at 40 ; however , the ache inhibitors from some plants were most efficiently extracted with hot water [ 17 , 18 ] . the lipase inhibitor - containing distilled water extract and ethanol extract from p. linteus contained crude protein contents of 10.9% and 6.11% , and crude fat contents of 0.96% and 15.86% , respectively ( table 2 ) . the mineral contents of the distilled water extract were higher than those of the ethanol extract -- specifically , the distilled water extract contained 239.5 mg of k , 36.3 mg of mg and 39.3 mg of na ( table 3 ) . the free amino acid contents of the distilled water extract and ethanol extract were determined ( table 4 ) and included tryptophan ( 3,891 mg/100 g solid ) , alanine ( 2,598 mg/100 g solid ) , serine ( 2,066 mg/100 g solid ) and interestingly , asparagines ( 5,139 mg/100 g solid ) . these amino acid contents were higher than those of the ethanol extract , with the notable exception of the asparagine contents ( 6,137 mg/100 g solid ) . however , these amino acid contents were 2.0~6.0 times higher than those of the corresponding tryptophan ( 60 mg/100 g solid ) and serine ( 1,400 mg/100 g solid ) contents in the methanol extracts from umbilicaria esculenta , and were also similar to the alanine contents ( 3,400 mg/100 g solid ) and lower than the glutamic acid contents ( 44,400 mg/100 g solid ) . the glutamic acid ( 17.19 mg / g solid ) and histidine contents ( 6.42 mg / g solid ) of the distilled water extract from p. linteus were similar to those of lentinus edodes ( 15.84 mg / g solid and 7.95 mg / g solid , respectively ) . the principal organic acid detected in the distilled water extract and ethanol extract of p. linteus was malic acid ( 12,312 mg/100 g solid , 8,160 mg/100 g solid , respectively ) . the distilled water extract also contained 590 mg/100 g solid of oxalic acid , and the ethanol extracts contained tartaric acid ( 620 mg/100 g solid ) ; no other organic acids were detected ( data not shown ) .

in an effort to develop novel mushroom - derived anti - obesity nutraceuticals , water and ethanol extracts containing the lipaseinhibitory compound from phellinus linteus were prepared , and their nutritional components were determined . the optimal conditions for the extraction of p. linteus lipase inhibitor involved the treatment of the fruiting bodies with distilled water at 80 for 72 hr and 80% ethanol at 100 for 60 hr , respectively . the distilled water extract and ethanol extract contained 10.9% and 6.11% of crude protein , and 0.96% and 15.86% of crude fat , respectively . additionally , the distilled water extract contained a large quantity of minerals , including 239.5 mg of k , 39.3 mg of mg , and 39.3 mg of na . the free amino acid content of the distilled water extracts was also higher than that of the ethanol extracts , and in particular , the distilled water extracts contained 5,139 mg of asparagine , 3,891 mg of tryptophan , 2,598 mg of alanine , and 2,066 mg of serine in 100 g of the distilled water extracts . 100 g of the distilled water and ethanol extracts were found to contain 12.31 g and 8.16 g of malic acid , respectively .

staphylococcus aureus is known as one of the most important human pathogens frequently implicated in nosocomial infections . s. aureus has the ability to grow in different environmental conditions and as a part of the normal human flora , it can colonize areas such as the anterior nares , perineum , armpit , and groin . in addition , s. aureus is capable of causing a wide range of infections including skin infections ( folliculitis boils , furuncles , and carbuncles ) , abscesses , toxic shock and scalded skin syndrome , food poisoning , bacteremia , endocarditis , septicemia , osteomyelitis , and pyoarthritis . currently , the increasing resistance against antibacterial drugs is a major public health concern and one of the biggest challenges faced by physicians . in s. aureus , resistance to methicillin occurs because of variations in the alteration of constitutive penicillin - binding proteins ( pbps ) or expression of the meca . because of an increasing prevalence of methicillin - resistant s. aureus ( mrsa ) infections , hospital infection control units , and health authorities should investigate the local mrsa prevalence to provide comprehensive and practical programs to prevent the spread of this organism therefore , providing fast and reliable methods for the detection of mrsa isolates is considered a prerequisite to ensure optimal treatment for patients with mrsa infections . detection of mrsa is based on phenotypic and genotypic characterization of bacterial isolates . in most cases , phenotypic methods are faster and easier than genotypic methods , while genotypic methods may have better accuracy and precision . phenotypic methods include broth microdilution , agar dilution , the agar screening method , disk diffusion , and latex agglutination methods ; while genotypic methods comprises polymerase chain reaction ( pcr)-based detection techniques . this work is approved ( # 0089024 ) by the research ethic committee of kermanshah university of medical sciences ( kums ) . in this way , written informed consent was obtained from all participating patients after careful explanation of the study . one hundred and eighty - six nonduplicate s. aureus isolates were collected from the anterior nares of patients hospitalized in different wards of the kermanshah hospital in the west of iran to be screened for mrsa colonization . cotton swabs soaked in sterile saline were entered into the patient 's anterior nostrils and rotated five times and subsequently transferred to the mannitol salt agar medium . s. aureus isolates were identified by conventional methods , that is , colonial morphology , gram staining characteristics , production of catalase , coagulase , dnase , and mannitol salt agar fermentation . according to the method of anand et al . mrsa atcc 43300 ( oxacillin resistant ) and methicillin susceptible s. aureus ( mssa ) atcc 25923 ( oxacillin sensitive ) were used as positive and negative controls , respectively . susceptibility to oxacillin ( 1 g ) , methicillin ( 5 g ) , cefoxitin ( 30 g ) , cefotetan ( 30 g ) , and cefmetazole ( 30 g ) was determined by disk diffusion testing using the kirby - bauer method . antibiogram results were interpreted according to the clinical and laboratory standards institutes ( clsi ) 2007 standard tables . for all isolates , the broth microdilution method ( microsterile plate ) with oxacillin powder ( sigma - aldrich , germany ) was used to determine the minimum inhibitory concentration ( mic ) . according to the manufacturer 's protocol , each oxacillin tablet was dissolved in 100 ml of nutrient broth medium containing 5% sodium chloride . bacteria were subsequently cultured on this medium and incubated for 24 h. resistance was indicated by bacterial growth after 24 h. bacteria were cultured on nutrient agar medium containing 5% sodium chloride . subsequently , an oxacillin strip was placed on this medium and incubated for 24 h at 37c . observed bacterial growth around the strip indicated resistance . data were described by two - dimensional tables using the k2 test for association and kappa concordance measures for levels of concordance . sensitivity of a certain method was calculated as the number of resistant s. aureus isolates determined using this method , divided by the sum of meca - positive strains . specificity was calculated as the number of mssa strains determined by this method , divided by the sum of meca - negative strains . to calculate the positive predictive value ( ppv ) , the number of true positives ( meca positive ) was divided by the number of positive results by the other tests ; and to calculate negative predictive value ( npv ) , the number of true negatives ( meca negative ) was divided by the number of negative results by the other tests . one hundred and eighty - six nonduplicate s. aureus isolates were collected from the anterior nares of patients hospitalized in different wards of the kermanshah hospital in the west of iran to be screened for mrsa colonization . cotton swabs soaked in sterile saline were entered into the patient 's anterior nostrils and rotated five times and subsequently transferred to the mannitol salt agar medium . s. aureus isolates were identified by conventional methods , that is , colonial morphology , gram staining characteristics , production of catalase , coagulase , dnase , and mannitol salt agar fermentation . mrsa atcc 43300 ( oxacillin resistant ) and methicillin susceptible s. aureus ( mssa ) atcc 25923 ( oxacillin sensitive ) were used as positive and negative controls , respectively . susceptibility to oxacillin ( 1 g ) , methicillin ( 5 g ) , cefoxitin ( 30 g ) , cefotetan ( 30 g ) , and cefmetazole ( 30 g ) was determined by disk diffusion testing using the kirby - bauer method . antibiogram results were interpreted according to the clinical and laboratory standards institutes ( clsi ) 2007 standard tables . for all isolates , the broth microdilution method ( microsterile plate ) with oxacillin powder ( sigma - aldrich , germany ) was used to determine the minimum inhibitory concentration ( mic ) . according to the manufacturer 's protocol , each oxacillin tablet was dissolved in 100 ml of nutrient broth medium containing 5% sodium chloride . bacteria were subsequently cultured on this medium and incubated for 24 h. resistance was indicated by bacterial growth after 24 h. bacteria were cultured on nutrient agar medium containing 5% sodium chloride . subsequently , an oxacillin strip was placed on this medium and incubated for 24 h at 37c . observed bacterial growth around the strip indicated resistance . data were described by two - dimensional tables using the k2 test for association and kappa concordance measures for levels of concordance . sensitivity of a certain method was calculated as the number of resistant s. aureus isolates determined using this method , divided by the sum of meca - positive strains . specificity was calculated as the number of mssa strains determined by this method , divided by the sum of meca - negative strains . to calculate the positive predictive value ( ppv ) , the number of true positives ( meca positive ) was divided by the number of positive results by the other tests ; and to calculate negative predictive value ( npv ) , the number of true negatives ( meca negative ) was divided by the number of negative results by the other tests . of the 186 s. aureus isolates , 95 and 91 were confirmed using pcr as mssa and mrsa , respectively . all meca - positive isolates had a mic of 4 mg / ml for oxacillin . the broth microdilution and a data tab methods indicated 100% sensitivity , and the cefmetazole and oxacillin disk methods had 100% specificity [ table 1 ] . according to our results , the broth microdilution and cefoxitin disk methods had the highest concordance ( 98.9 and 93.6% , respectively ) and the cefmetazole disk method had the lowest concordance ( 47.8% ) . as displayed in [ table 2 ] , 42.8% mrsa had an mic > 2,048 mg / ml for oxacillin . comparison of various laboratory methods for detecting resistant staphylococcus aureus isolates mic distribution of staphylococcus aureus isolates determined by oxacillin microbroth dilution mrsa is a major nosocomial pathogen causing significant morbidity and mortality . because of the necessity and importance of identifying mrsa among s. aureus , it is imperative to apply the appropriate and precise laboratory methods to identify these isolates . because the meca can not be observed in mssa strains , molecular methods such as pcr and hybridization that can detect the meca are considered as the gold standard methods for the identification of mrsa . therefore , the presence and absence of the meca indicates mrsa and mssa , respectively . in the present study , among the phenotypic methods , the microdilution method was observed to be the most sensitive ( 100% ) for the detection of meca - mediated resistance . however , since this method requires oxacillin powder and skilled laboratory staff for its implementation , and as it is time consuming , it can not easily be implemented in routine laboratories . the cefoxitin disk test , which by contrast is easy to perform and does not require special equipment , also demonstrated high sensitivity ( 98.9% ) and specificity ( 94.7% ) for mrsa detection . these findings are consistent with those of broekeme et al . , where the sensitivity and specificity of the cefoxitin disk method were reported as 97.3 and 100% , respectively among 10,611 s. aureus isolates examined . accordingly , clsi has replaced the oxacillin disk with a cefoxitin disk for the detection of mrsa . several studies including the current one have reported that the results of the cefoxitin disk diffusion test correlate better with the presence of meca compared with those of the oxacillin disk diffusion test . cefoxitin is a better inducer of meca expression ; this could explain why heterogeneous mrsa populations variably expressing the meca are better detected by disk diffusion with cefoxitin than with oxacillin , which is a weak inducer of pbp2a production . this is considered to be the underlying mechanism for the higher sensitivity of cefoxitin than oxacillin . reported the sensitivity and specificity of the cefoxitin disk method to be 100% , which was slightly better than that observed in our results . in addition , in that study , the sensitivity and specificity of the oxacillin disk was determined to be 87.5% and 100% , respectively . the lower sensitivity in the present study ( 73.6% ) could be because of differences in the manufacturer 's disk . in the study of sakoulas et al . , the sensitivity and specificity of the oxacillin mic method was 99 and 98.1% , respectively , and the specificity finding was consistent with the results of the present study ( 100 and 98.9% , respectively ) . wallet et al . , compared the mic method with pcr and the sensitivity was 96% , which was slightly lower than results in this study ( 100% ) . in the adata tab method , the medium can be easily made and interpreted , but this test is expensive to perform and not available in all laboratories . because an appropriate and reliable test must have both high sensitivity and specificity , pcr was used as the gold standard to calculate concordance . one feature of the present study was the simultaneous evaluation of the three antibiotics ; cefoxitin , cefmetazole , and cefotetan . these antibiotics are a category of cephamycins and are classified as second generation cephalosporins because of their similarity with cephalosporins . we hypothesized that these three antibiotics would show the same sensitivity and specificity ; however , the results did not support this hypothesis . the present study revealed that the microdilution and cefoxitin disk methods have high sensitivities compared with other methods for detection of mrsa . the cefoxitin disk method may be preferred in clinical laboratories because it is easy to perform and does not require special equipment . however , use of the other investigated methods may not be appropriate because of the relatively lower levels of concordance with pcr .

background : staphylococcus aureus is known as a powerful pathogen that causes various infections . emergence of methicillin - resistant s. aureus ( msra ) is responsible for nosocomial and community - acquired infections worldwide.aims:the present study aimed to evaluate the performance and ability of eight different phenotypic and genotypic methods for the detection of msra.materials and methods : a total of 186 s. aureus isolates were defined as methicillin - susceptible s. aureus ( mssa ; 95 ) and msra ( 91 ) using polymerase chain reaction ( pcr ) as the gold standard . susceptibility to methicillin was investigated using oxacillin , methicillin , cefotetan , cefoxitin , and cefmetazole disks , by oxacillin adata tab and strips . for all s. aureus isolates minimal inhibitory concentrations of oxacillin were determined using the broth microdilution method according to clinical and laboratory standards institute guidelines.results:among the diagnostic methods studied , broth microdilution and the cefoxitin disk had the highest specificity ( 98.9 and 94.7% ) , sensitivity ( 100 and 98.9% ) , and concordance with pcr results ( 98.9 and 93.6% ) . the cefotetan and cefmetazole disks had the lowest concordance with pcr results.conclusion:our results suggest that microdilution and cefoxitin disk methods have high sensitivities compared with other methods for detection of msra . the cefoxitin disk method may be preferred in clinical laboratories because it is easy to perform and does not require special equipment .

hashimoto s encephalopathy ( he ) is an acute or subacute encephalopathy with elevated anti - thyroid antibodies in patients with hashimoto s thyroiditis . the age of onset varies , but most frequently occurs to people in their 40s . its clinical features are as follows ; decreased cognitive function , abnormal behaviors , myoclonus gait apraxia language disorders , confusion and psychosis.1,2 the diagnosis should be considered in patients with encephalopathy with elevated thyroid autoantibody level and without any other etiologies . it is known to show a good response to steroids and other immune therapies.2,3 the cognitive dysfunction of he is often observed and it usually has progressive course . if cognitive dysfunction lasts for a prolonged period of time , it is related with poor response to treatment . it is very rare that it occurs all of a sudden.4 we report a case of he presenting acutely developed cognitive decline and convulsion . a 65-year - old man visited the hospital due to a sudden onset of cognitive decline . two weeks prior to visiting to the hospital , the patient caught a cold for one week . he could nt remember where the razor was and was unable to find the bathroom . he confirmed that he indeed brushed his teeth when asked in case certainly he did nt brush his teeth and did nt use toothpaste when brushing his teeth . at work , he was unable to find the office keys nor able to recognize his co - workers . as well , he was unable to recall the road he routinely walked along , where he parked his car and if he owned a car . he did nt give the hospital staff proper attitude while saying there was something when he saw the electric light turned on . besides , he showed the nervousness as serious as being restless and after that he presented urinary incontinence . he collapsed turning his body around to the left as neurological examination were performed and lost consciousness with the convulsion to move his head to the right for about 20 seconds when he visited the hospital . when he visited to the hospital , his vital signs showed a blood pressure of 135/80 mmhg , respiration rate of 22 times per minute , pulse of 80 times per minute and a body temperature of 36.5c . his physical check - up showed no hair loss , edema , goiter , and etc . korean version of mini - mental state examination ( k - mmse ) showed a 2/5 point in time orientation , 4/5 in place orientation , 0/3 in the three word recall and 4/5 point in serial seven substraction test . there were no abnormal results among complete blood count , serum chemistry and electrolytes , serum tumor markers , paraneoplastic syndrome antibodies , and autoimmune disease and connective tissue disease test . thyroid function test confirmed the asymptomatic hypothyroidism ; the level of triiodothyronine was 62.98 ng / dl ( reference value : 65150 ) , that of thyroxine 0.88 ng / dl ( reference value : 0.781.54 ) , that of thyroid stimulating hormone 5.85 iu / ml ( reference value : 0.554.78 iu / ml ) . the level of thyrotropin - releasing hormone was normal . according to the thyroid autoantibody tests , the level of anti - thyroglobulin antibody was 77 iu / ml ( reference value : 060 ) and that of anti - thyroid microsomal antibody was > 1,300 iu / ml ( reference value : 060 ) . the cerebrospinal fluid ( csf ) showed a slightly increased level of protein ( 58 mg / dl ) and the normal level of white blood cells . and there were no abnormalities in virus including herpes simplex , bacteria and mycobacterium tuberculosis tests . seoul neuropsychological screening battery ( snsb ) carried out 4 days after he was hospitalized revealed a decrease in language and visual memory and language fluency , but there were no abnormalities in the concentration and time and place orientation . 2 ) . single photon emission computed tomography ( spect ) showed decreased in perfusion in the bilateral temporal lobes ( fig . 3 ) . ultrasonography demonstrated an increased vascularity and irregular echoing in the bilateral thyroid lobes . it was diagnosed as hashimoto s encephalopathy based on the clinical features and test results . after oral steroids ( prednisolone 60 mg / day ) and anticonvulsant ( levetiracetam 1,000 mg / day ) administration , he showed a gradual recovery of cognitive function . therefore , on the 14th day after he was hospitalized , the score of k - mmse became normal to 30/30 . since then , the patient s cognitive dysfunction gradually improved and showed no suffering from any convulsions . we presented a patient with hashimoto s encephalopathy who had a sudden cognitive deterioration and convulsion . the sudden decline of cognitive function is a rare clinical feature and it is unusual for the he to affect the old man . the common cold he caught before the onset of the disease is considered to affect the symptoms beginning . its pathophysiological mechanism is not clearly known , but the factors considered to cause it are as follows ; vasculitis by autoimmune mechanism , antineuronal antibody mediated reaction , and the direct toxicity of thyroid stimulating hormone releasing hormone to the central nervous system.2,3 the elevated serum level of anti - thyroid antibody is essential in diagnosing he and it means the autoimmune mechanism of the thyroid gland.2 he may not be related to the functional status of thyroid gland and it can appear in various ways . it shows asymptomatic hypothyroidism 2335% , hypothyroidism 1720% , hyperthyroidism 7% and normal thyroid 1845%.2 it often shows the normal thyroid function , a little decreased function of thyroid gland and a high level of thyroid gland autoantibody.2,3 we presented a case with asymptomatic hypothyroidism and the high titer of autoantibody . clinical manifestations of he are various and non - specific , but it is generally classified into two types . one consists of about 25% presenting focal neurological deficits repeatedly such as stroke and the other consists of about 75% showing diffuse progressive course such as dementia , confusion , and hallucination.1,2,5 two clinical manifestations can occur simultaneously in the course of he.5 here , it occurred in the way that convulsion is added while the sudden decline of cognitive function is the main symptom . it is considered to happen in the way the focal neurological abnormality is combined to the diffuse clinical pattern of the disease . the two thirds of patients with he may have focal or generalized seizure and the generalized one is more common.1,2 it rarely happens to have status epilepticus.2,6 the eeg characteristics are various and mostly show non - specific features.1,2 the slow wave is the most common and appears generally or restricted to forehead or temporal area . focal spike , sharp wave and transient epileptic discharges were rare.1,6 these eegs are related to the severity of the disease and may show improvement according to the response to medical treatment.6 the cognitive decline is often observed in he and it has relatively gradual clinical course . the neuropsychological studies which were carried out before and after treatment are rare . as the cognitive decline starts , all domains of cognition may be affected . with progression , there are high probability of decreased executive function and procedural memory.7 with the worsening of cognition , frontal lobe dysfunction become more common.7 compared with mild alzheimer s disease , he shows impairment in episodic memory concentration , visuospatial function , and executive function but showed normal in naming test.8 in this patient , there were some problems in orientation , recall , concentration , and calculation . on the day and in the snsb carried out 4 days after visiting a hospital , it showed mainly the impairment in memory and partial frontal lobe dysfunction . brain imaging studies frequently reveal non - specific findings.4,9 the brain mri is sensitive to find the lesion and it is likely that signal changes can appear in subcortex , basal ganglia , cerebellum , and medial temporal lobe.1,2,4,9 spect may show focal , multifocal , or global hypoperfusion.10 the brain imaging may show reversible improvement after treatment for he.9,10 this case handles he with sudden onset of cognitive deterioration and convulsion , which abruptly appeared after the patient caught a common cold without the clinical evidences of hypothyroidism . when the sudden cognitive function decrease or convulsion appears , he should be considered regardless of age and gender .

hashimoto s encephalopathy is an immune - mediated disorder characterized by acute or subacute encephalopathy related to increased anti - thyroid antibodies . clinical manifestations of hashimoto s encephalopathy may include stroke - like episodes , altered consciousness , psychosis , myoclonus , abnormal movements , seizures , and cognitive dysfunction . acute cognitive dysfunction with convulsion as initial clinical manifestations of hashimoto s encephalopathy is very rare . we report a 65-year - old man who developed acute onset of cognitive decline and convulsion due to hashimoto s encephalopathy .

patients with autosomal dominant polycystic kidney disease ( adpkd ) may have intracranial aneurysm , hypertensive intracerebral haemorrhage or cervicocephalic arterial dissection . although arachnoid cysts have been associated with adpkd [ 15 ] with a prevalence rate of 8% ( 10 times higher than in the general population ) , we report a case of bilateral sacral radicular cysts in a patient with adpkd discovered incidentally by magnetic resonance imaging ( mri ) . a 46-year - old woman was referred in october 2008 for a routine follow - up for adpkd diagnosed 8 years before . two months earlier , she presented an episode of macroscopic haematuria that was controlled by conservative treatment . her serum creatinine was 2 mg / dl ( 176.8 mol / l ) and creatinine clearance 34 ml / min/1.73 m ( 0.56 ml / s/1.73 m ) . mri of the abdomen revealed both kidneys with numerous cysts of different sizes scattered throughout the parenchyma . the total kidney volume measured by mri was 3053 ml ( right kidney 1530 ml and left kidney 1523 ml ) . moreover , the sacral radicular cysts had a fluid content with homogenous high signal intensity on t2-weighted sequences similar to the signal of cerebrospinal fluid ( csf ) . coronal t2-weighted mri of spine showing radicular cysts ( arrows ) at the sacral level . most of the cases of meningeal cysts occur in patient with neurofibromatosis , marfan syndrome , ehlers danlos syndrome and lehman syndrome [ 810 ] . a primary defect in the organization of collagen , with the decrease in its tensile strength , leads to dural weakness to such an extent that it becomes ectatic . these abnormalities , also called arachnoid cysts , meningoceles or meningeal diverticula , are abnormal outpouching of the common dural sac , the spinal arachnoids or the nerve root sheath . these cysts may have thin walls and contain csf , so they may sometimes be detected only by the mass effect they exert . mri is the diagnostic procedure of choice because of its ability to demonstrate the exact location , extent and relationship of the arachnoid cyst with the adjacent brain or spinal cord . myelography and ct myelography remain of diagnostic value , especially for cases that are not definitive on mri . clinical features result from nerve root or spinal cord compression and vary with the location of the cyst . bowel or bladder dysfunction may also occur in individuals with sacral cysts . although arachnoid cyst has been associated with adpkd [ 15 ] , thus , spinal meningeal cyst has only been described in four adult patients with adpkd . the cysts were found at the thoracic level in three of them and the lumbar level in the fourth one . although the aetiology of spinal meningeal cysts is unknown , it is likely that an underlying weakness of the meninges is involved . some of these patients had a history of postural headaches caused by spontaneous intracranial hypotension . however , the association of sacral radicular cysts with adpkd has never been previously reported . in our patient , our patient exhibited no features of neurofibromatosis , marfan syndrome , ehlers danlos syndrome or lehman syndrome . in this case , mri provided sufficiently clear anatomical information and demonstration of the pathological entity . in summary , we believe that the association between spinal meningeal cysts and adpkd is not fortuitous . cysts arising from arachnoid or spinal meningeal sac should be considered one of the manifestations of a more widespread connective tissue disorder associated with adpkd . however , in other published cases meningeal cysts were complicated by postural headaches , cranial nerve palsies , visual blurring , upper or lower limb pain , weakness or numbness . such signs and symptoms occurring without a clear explanation in a patient with adpkd should lead the physician to perform an mri of the spinal chord .

this is the first report of a case of sacral radicular cysts in a patient with autosomal dominant polycystic kidney disease ( adpkd ) . a 46-year - old woman with adpkd was found to have bilateral sacral radicular cysts discovered incidentally by magnetic resonance imaging ( mri ) . cysts arising from arachnoid or spinal meningeal sac should be considered one of the manifestations of a more widespread connective tissue disorder associated with adpkd .

pneumocystis jirovecii is an opportunistic pathogen , and is a major cause of serious pneumonia in immunocompromised conditions , including congenital immunodeficiency , organ transplantation , or acquired immune deficiency syndrome ( aids ) . the standard regimen of treatment or prophylaxis for pneumonia caused by p. jirovecii is cotrimoxazole which contains sulfamethoxazole ( smx ) and trimethoprim ( tmp ) . however , a few studies have reported therapeutic failure of the regimens used to treat pneumonia caused by p. jirovecii [ 3 - 10 ] , and no reports occurred in korea . here , we describe a case in which tmp - smx , in sufficient dose and duration , had failed to treat pneumonia caused by p. jirovecii which was then successfully treated with clindamycin - primaquine thereafter . a 50-year - old male visited the outpatient clinic and complained of fever , poor oral intake , and weight loss ( 6 kg loss in 2 months ) . complete blood counts revealed mild leucopenia ( wbc 3,720/l ) , mild anemia ( hb 11.2 g / dl ) , and mild eosinophilia ( 830/l ) , however , a normal platelet level ( 246,000/ ) was observed . liver function tests showed elevated liver enzymes ( ast 61 iu / l , alt 74 iu / l , and ggt 215 iu / l ) , and serologic studies for hepatitis b virus , hepatitis c virus , human immunodeficiency virus ( hiv ) , and syphilis were negative . a routine chest x - ray yielded streaky and fibrotic lesions in both lungs ( fig . 1a ) , which led to further evaluation using contrast chest computed tomography ( ct ) . the chest ct revealed multifocal peribronchial patchy ground - glass opacities in both lungs with septated cystic lesions in the left upper lobe , and the right lower lobe ( fig . cell counts in bal revealed a lymphocyte - dominant leukocytosis ( white cells 342/l , neutrophils 9% , lymphocytes 37% , eosinophils 5% , and macrophages 49% ) . further analysis of lymphocyte subsets showed a predominance of cytotoxic t cells ( cytotoxic t cells 98.3% , t helper cells 1.7% , natural killer cells 3% , and b cells 0.1% ) . cytologic studies , acid - fast bacillus stain , and pcr for tuberculosis and non - tuberculotic mycobacteria in the bal fluid exhibited negative results . a tuberculin skin test and interferon- release assay ( quantiferon ; carnegie , victoria , australia ) a video - assisted wedge resection of the left upper lobe was performed . upon histological examination , hematoxylin and eosin ( h&e ) staining revealed eosinophilic frothy exudates in alveolar spaces accompanied by mild interstitial inflammation , and grocott - gomori s methenamine silver ( gms ) stains , performed during the histological examination , revealed many cystic- and trophic - form organisms ( arrows ) in the alveolar exudate , consistent with p. jirovecii infection ( fig . trimethoprim - sulfamethoxazole ( tmp - smx ) was administered orally ( 2 double strength tmp - smx tablets every 8 hr ) . the patient s fever subsided within 3 days ( from 38.5c to 37.0c ) , and the streaky and fibrotic lesions observed in both lungs on the chest x - ray were also markedly improved ( fig . 1b ) after 12 days of tmp - smx administration , which enabled the patient to be discharged . tmp - smx treatment continued to be administrated for additional 17 days following the patient s discharge from the hospital . however , the patient complained of cough again , and a follow - up chest x - ray showed aggravation of the streaky and fibrotic lesions in both lungs ( fig . a follow - up chest ct revealed an aggravation of multifocal peribronchial ground - glass opacity and septated cystic lesions in both upper lungs , and a newly appeared consolidation in the left lower lobe ( fig . 2c , p. jirovecii was clinically suspected to be resistant to tmp - smx , and molecular studies carried out using pcr with primers dp15 ( 5-tctgaattttataaagcgcctacac-3 ) and dp800 ( 5-atttcataaacatcatgaacccg-3 ) demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase ( dhps ) gene as a previous report . primaquine ( 4 mg / kg / day intravenous once daily ) and clindamycin ( 600 mg intravenous every 8 hr ) were administrated for 3 weeks in place of the tmp - smx . consequently , the cough was resolved , and a follow - up chest x - ray showed improvement of the streaky and fibrotic lesions in both lungs ( fig . we strongly suspected that hiv infection was an underlying condition , and rechecked the hiv immunoassay , which was determined to be positive . further evaluation of hiv infection was performed ; the titer of hcv rna was determined to be 110,000 copies / ml , and the number of t helper cells in the peripheral blood was only 3/l . antiviral treatment regimen targeting the hiv was initiated , including lopinavir ( 800 mg / day ) , ritonavir ( 200 mg / day ) , lamivudine ( 300 mg / day ) , and zidovudine ( 600 mg / day ) , and the patient was discharged . p. jirovecii pneumonia ( pcp ) should be strongly suspected in hiv - infected patients that have a cd4 + t cell count less than 200 cells/l , 1 - 3--d - glucan levels greater than 80 pg / ml ( if available ) , and signs and symptoms that are typical of the infection ; especially dyspnea , cough , and diffuse , bilateral , interstitial , or alveolar infiltrates present on a chest x - ray or chest ct . a confirmatory diagnosis of pcp requires the identification of cystic or trophic forms in appropriate specimens , both of which can be visualized using gms , cresyl violet , gram - weigert , toluidine blue , wright - giemsa , and diff - quick staining . pathologic confirmation is especially important when other infections or co - infections are suspected or need to be excluded [ 14 - 16 ] . cotrimoxazole , namely tmp - smx , is the most common drug used for prophylaxis and treatment of pcp , and has been utilized as an effective treatment option for many years . in addition to tmp - smx , tmp - dapsone or clindamycin - primaquine can be used as an alternative regimen . in patients that do not exhibit any improvement after 4 to 8 days of therapy , treatment failure must be considered . a previously published multicenter study randomly assigned 181 patients with mild to moderate pcp to therapy with tmp - smx , tmp - dapsone , or clindamycinprimaquine for 21 days , and no differences were observed in the therapeutic failure rate ( approximately 5% at day 7 , and 10% at day 21 ) among the treatment groups . another randomized trial comparing tmp - smx with tmp - dapsone in 60 pcp patients demonstrated no differences in the response to therapy ; however , more tmp - smx treated patients exhibited adverse reactions to the therapy . the current case was not initially diagnosed as having hiv infection as an underlying condition . the patient complained of fever , poor oral intake , and weight loss , and multifocal , peribronchial patchy ground - glass opacities in both lungs with septated cystic lesions were observed in chest ct . bronchoscopy performed with bal did not yield a confirmative diagnosis , so we could not but carry out a video - assisted wedge resection of the left upper lobe . in histological examinations , gms staining of the specimen showed many cystic and trophic forms , which finally led to the diagnosis of pcp . we retrospectively suspected the presence of hiv infection as an underlying condition , and reassessed the hiv immunoassay , which turned out to be positive , and the hiv rna titer was determined to be 110,000 copies / ml . the initial negative and subsequent positive hiv immunoassay and a positive virologic test , led us to suspect that the patient was in the initial stages of hiv infection , since the approximate time from infection to a positive immunoassay and viral load test is 15 to 45 days and 5 to 15 days , respectively [ 17 - 19 ] . to treat the pcp , high - dose tmp - smx was orally administered , and the patient s symptoms and radiologic findings were markedly improved within several days the pcp was suspected to be resistant to tmp - smx , and molecular studies confirmed mutations at codons 55 and 57 of the dhps gene that are known to be associated with sulfaresistance of p. jirovecii . intravenous tmp - smx , or pentamidine , is primarily recommended when oral tmp - smx treatment failure is suspected , as demonstrated in a previous case report . however , these 2 drugs were unavailable in our hospital , so primaquine and clindamycin were substituted for tmp - smx , which resulted in an improvement of pcp . cotrimoxazole consists of tmp and smx , and tmp seems to be inactive against pneumocystis . a common second - line agent is dapsone , which , like sulfamethoxazole , inhibits the enzyme dhps . these 2 dhps inhibitors have been used as a prophylaxis or treatment for pcp in hundreds of thousands of patients over the past 2 decades , and the development of sulfa - resistant strains of p. jirovecii was inevitable . mutations in the p. jirovecii dhps gene have been described in 2 case reports , and a small cohort study that contained 27 patients . however , those studies did not demonstrate that the mutations caused the drug resistance , since human strains of p. jirovecii can not be cultured in vitro . instead , helwig - larsen et al . found an association between the occurrence of dhps mutations and the failure of pcp treatment with sulfa drugs in a large study . more importantly , dhps mutations were linked to a higher risk of death within 3 months of the diagnosis , most likely due to inadequate responses to therapy . in a japanese study , dhps mutations were identified at amino acid positions 55 and/or 57 in isolates from 6 ( 25.0% ) of 24 patients with p. jirovecii pneumonia , and cotrimoxazole treatment failed more frequently in patients whose isolates had dhps mutations than in those whose isolates had wild - type dhps . suggested that theses dhps mutations were significantly more common in patients exposed to sulfa drugs than in those not exposed to sulfa drugs in their study of 70 bronchoalveolar lavage ( bal ) specimens with positive pcr for p. jirovecii . these phenomena were also confirmed in a study by nahimana et al . who conducted bal in 13 aids patients who had 2 separate episodes of pneumonia . while p. jirovecii can not be cultivated , subsequent in vitro studies used saccharomyces cerevisiae and escherichia coli to further elucidate the association between dhps polymorphisms and sulfa resistance , and suggested that mutations in dhps correlate with sulfa drug resistance [ 9,10,25 - 27 ] . in the current case report in addition to dhps , a recent study demonstrated the association of dihydrofolate reductase ( dhfr ) variants and resistance to trimethoprim in clinical isolates of p. jirovecii . in summary , tmp - smx however , treatment failure was eventually detected in a follow - up chest x - ray and chest ct , and molecular analysis suggested mutations at codons 55 and 57 of the dhps gene , which has been shown to confer sulfa resistance to p. jirovecii . primaquine and clindamycin were substituted for tmp - smx , which finally improved the pcp . the current case report indicates that pcp patients must be carefully monitored during treatment , and molecular analysis of dhps mutations should be performed . additionally , appropriate changes of anti - pcp drugs should be considered when a drugresistant p. jirovecii infection is suspected . to our knowledge , this is the first case of tmp - smx - resistant pcp reported in korea .

a 50-year - old male visited the outpatient clinic and complained of fever , poor oral intake , and weight loss . a chest x - ray demonstrated streaky and fibrotic lesions in both lungs , and chest ct revealed multifocal peribronchial patchy ground - glass opacities with septated cystic lesions in both lungs . cell counts in the bronchoalveolar lavage fluid revealed lymphocyte - dominant leukocytosis , and further analysis of lymphocyte subsets showed a predominance of cytotoxic t cells and few t helper cells . video - assisted wedge resection of the left upper lobe was performed , and the histologic examination was indicative of a pneumocystis jirovecii infection . trimethoprim - sulfamethoxazole ( tmp - smx ) was orally administered for 3 weeks ; however , the patient complained of cough , and the pneumonia was aggravated in the follow - up chest x - ray and chest ct . molecular studies demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase ( dhps ) gene , which is associated with the resistance to tmp - smx . clindamycin - primaquine was subsequently administered for 3 weeks replacing the tmp - smx . a follow - up chest x - ray showed that the pneumonia was resolving , and the cough was also alleviated . a positive result of hiv immunoassay and elevated titer of hcv rna indicated hiv infection as an underlying condition . this case highlights the importance of careful monitoring of patients with p. jirovecii pneumonia ( pcp ) during the course of treatment , and the molecular study of dhps mutations . additionally , altering the anti - pcp drug utilized as treatment must be considered when infection with drug - resistant p. jirovecii is suspected . to the best of our knowledge , this is the first case of tmp - smx - resistant pcp described in korea .

gastrointestinal stromal tumors ( gists ) are well recognized nonepithelial neoplasms of the gastrointestinal tract ( gi ) . after decades of ultra structural , immunohistochemical , and genetic studies , it is now evident that most gists are believed to differentiate from cajal ( iccs ) pacemaker cells . the cajal pacemaker cells are involved in gastrointestinal tract mobility and regulation of autonomous neuronal transmission . other common sites include the jejunum and ileum ( 30% ) , duodenum ( 5% ) , colon and rectum ( 5% ) , and the esophagus ( 5% ) . only seven gallbladder gists have ever been reported , and of these , four were malignant [ 39 ] . these malignant gallbladder gists were all positive for cd 117 ( c - kit ) and cd34 or cd117 alone [ 47 ] . we report a unique gallbladder gist which is negative for cd 117 and cd 34 but positive for platelet - derived growth factor receptor alpha ( pdgfra ) . apart from the extremely rare site of occurrence , gist of the gallbladder remains a challenging topic and needs to be examined on the basis of histologic findings , clinical history , and molecular profile with the later having significant impact on the treatment strategy . a 72-year - old woman was admitted to the first department of surgery , university of athens with symptoms suggestive of obstructive jaundice : fever and chills , dark urine , intermittent right upper quadrant ( ruq ) abdominal pain , and jaundice . initial investigations showed a white cell count ( wcc ) of 11,556 cells / mm , total bilirubin / direct bilirubin ( tbil / dbil ) of 4.80/3.60 mg / dl , alkaline phosphatase ( alp ) 440 iu / l , and -glutamyl transpeptidase ( -gtp ) 210 iu / l . ultrasound demonstrated a thickened gallbladder wall , bile stones , and moderate common bile duct ( cbd ) dilatation . bile duct lithiasis was suspected and an endoscopic retrograde cholangiopancreatography ( ercp ) was performed . this demonstrated an almost complete obstruction at the level of the cystic duct and common hepatic duct confluence . however , the underlying pathology could not be identified , and an exploratory laparotomy was decided . the mass was adherent to the duodenum involving the confluence of the cystic duct with the common hepatic duct and the retroduodenal part of the common bile duct . the common bile duct and common hepatic were excised en bloc with the specimen ensuring free surgical margins along the extrahepatic billiary tree . lymph node dissection was performed of the hepatoduodenal ligament , the hepatic artery lymph nodes , and the retropancreatic lymph nodes . the enteric - billiary continuity was established through a retrocolic roux - en - y hepatico - jejunostomy . the postoperative course was uneventful , and the patient was discharged ten days after operation . in the pathological review , the gallbladder was dilated and measured 7.5 cm 3.5 cm in size . within the gallbladder , there was a wide mass covering the entire wall , neck , and body , while the remainder of the mucosal layer was ulcerated . microscopically , tumor cells infiltrated the muscle layer were spindle shaped in nature , arranged in a short fascicle pattern and immunopositive for pdgfra ( figures 1(a ) and 1(b ) ) . the cells demonstrated hypercromatic nuclei , severe pleomorphism and an increased mitotic rate of up to 50 mitosis/50 high power field ( hpf ) . genomic dna isolationten m sections were cut from the paraffin - embedded tissue block and treated with xylene / ethanol . the samples were digested overnight at 37c using proteinase k. dna was extracted with phenol - chloroform , precipitated in ice - cold ethanol , redissolved in distilled water , and quantitated using a picodrop microliter spectrophotometer . ten m sections were cut from the paraffin - embedded tissue block and treated with xylene / ethanol . the samples were digested overnight at 37c using proteinase k. dna was extracted with phenol - chloroform , precipitated in ice - cold ethanol , redissolved in distilled water , and quantitated using a picodrop microliter spectrophotometer . high - resolution melting analysisfor the detection of c - kit exon 9 , 11 , 13 , and 17 mutations as well as pdgfra mutations in exons 12 and 18 , a real - time polymerase chain reaction approach followed by high - resolution melting curve analysis has proved to be a rapid , highly sensitive , and efficient screening method . pcr and hrm were consecutively performed on a lightcycler 480 ( roche diagnostics , gmbh , germany ) in one single run , and all reactions were repeated twice . each reaction consisted of 20 ng of dna , 200 nmol / l of each primer , 10 l of lightcycler lc480 high resolution melting master ( roche ) , 3.5 mm mgcl2 and pcr - grade water adjusted to a total volume of 20 l . for the detection of c - kit exon 9 , 11 , 13 , and 17 mutations as well as pdgfra mutations in exons 12 and 18 , a real - time polymerase chain reaction approach followed by high - resolution melting curve analysis pcr and hrm were consecutively performed on a lightcycler 480 ( roche diagnostics , gmbh , germany ) in one single run , and all reactions were repeated twice . each reaction consisted of 20 ng of dna , 200 nmol / l of each primer , 10 l of lightcycler lc480 high resolution melting master ( roche ) , 3.5 mm mgcl2 and pcr - grade water adjusted to a total volume of 20 l . sequencingpcr products with an abnormal hrm pattern were sequenced using the big dye terminator cycle sequencing kit ( applied biosystems , california , usa ) . the sequencing products were analysed on an abi prism 310 genetic analyzer ( applied biosystems ) . pcr products with an abnormal hrm pattern were sequenced using the big dye terminator cycle sequencing kit ( applied biosystems , california , usa ) . the sequencing products were analysed on an abi prism 310 genetic analyzer ( applied biosystems ) . the specimen was analysed for the presence of activating mutations in exons 9 , 11 , 13 , and 17 of c - kit gene as well as exons 12 and 18 of pdgfra gene by performing high resolution melting analysis and sequencing . a mutation at codon 824 coding for valine in exon 18 of pdgfra gene was detected by high - resolution melting analysis ( hrm ) and was further confirmed by sequencing as c. 2472 c > this silent mutation has previously been described in 2 tumors from the central nervous system ( gliosarcomas ) as well as in soft - tissue tumors ( gists ) . results were verified by a second independent pcr reaction and hrm analysis followed by sequencing . an estimated five - to - six thousand new cases of gist are diagnosed annually with 10% to 30% of these being malignant . most tumors are sporadic , affecting individuals in their 5th or 6th decade with some evidence indicating a male predominance . gists can also present earlier and this is often seen in one of the rare gist syndromes , which include neurofibromatosis type 1 ( nf1 ) , the carney - stratakis dyad and familial gist syndrome . these tumors may occur anywhere in the gastrointestinal tract but most commonly present in the stomach and small intestine . they can also occur in the surrounding structures such as the peritoneum , omentum , liver , pancreas , ovaries , and uterus . many gists are asymptomatic and are discovered incidentally ; however , over half of gastric gists present with signs of gi bleeding and anaemia with a smaller proportion presenting with abdominal pain or as an abdominal mass . histology can often be varied , but gists are broadly divided into spindle , epithelioid , or mixed cell types . in general , the risk of malignancy is greater in epithelioid tumors than in spindle - celled neoplasms [ 11 , 12 ] . with the advent of immunohistology , previously , sarcomas , undifferentiated carcinomas , and melanomas would have featured heavily in the differential diagnosis ; however , these can largely be excluded with identification or absence of specific immunohistochemical markers . the three most well - described immunohistochemical markers in gists are cd117 ( c - kit ) , pdgfra , and cd34 [ 13 , 14 ] . kit is positive in over 95% of gists and only 58% of tumors are kit negative and pdgfra positive . cd34 is a less sensitve marker for gists but is reported in up to 6070% of the tumors . miettinen and lasota who have carried out the largest ever studies on gists define these tumors as generally kit - positive and kit or pdgfra mutation - driven mesenchymal tumors of the gi tract with a set of characteristic histologic features including spindle cell , epithelioid , and rarely pleomorphic morphology . we present the case of a malignant gist of the gallbladder which demonstrated spindle cell morphology and was pdgfra positive and kit negative . there have been a small number of gallbladder gists described in the literature , of which only four were malignant and all were kit positive . to our knowledge the significance of the kit negative genotype has implications on the response to further management . the identification of specific cellular markers has led to the development of effective targeted agents , namely , tyrosine kinase inhibitor ( tki ) therapy ( e.g. , imatinib ) . most kit positive tumors are sensitive to imatinib ; however , the majority ( 80% ) of pdgfra mutations are resistant to treatment . primary gists , as in the case here , have the potential for curative treatment with surgical resection . overall 5-year survival rates for resectable gists have been shown to range from 46% to 78.5% ; however , predicting the recurrence rate of primary resectable gists has been very challenging [ 17 , 18 ] . the survival rates from the reported gall bladder gists are mixed with only short - term followup noted in some of the cases . although the mutation status is important , the current most important prognostic factor for gists is tumor size , mitotic count , and tumor location . this scheme has evolved from studies initially outlined by the national institute of health ( nih ) and were greatly expanded on by the work of miettinen and lasota [ 13 , 14 ] . the patient in this case had a very large tumor , with 50 mitosis/50 hpf , and was located in the gallbladder . the first two findings alone place this gist in the high - risk group for recurrence . this is likely compounded by the kit negative immunohistology which would potentially reduce the benefit of tyrosine kinase inhibitors treatment . it is important to mention that the immunohistochemical examination does not provide information on the exon affected on the type of mutation both of which may be prognostically important . this paper , presents a very unique case of gist , located in the gallbladder , negative for kit , and positive for pdgfra . apart from this being a previously undocumented case , it highlights the challenges in establishing the diagnosis , prognosis , and most effective management for this unpredictable tumour .

gastrointestinal stromal tumors ( gists ) compose the largest category of well - recognized nonepithelial neoplasms of the gastrointestinal tract ( gi ) . gists of the gallbladder are extremely rare tumors . only four malignant , two benign and one gist - like tumor of the gall bladder have ever been described . the four malignant gists were all positive for cd 117 antigen ( c - kit ) . we present for the first time a malignant gastrointestinal stromal tumor of the gallbladder , immunoreactive for platelet - derived growth factor receptor alpha ( pdgfra ) and negative for cd 117 antigen ( c - kit ) .

the two main sources of guidelines and practices for communicating during pandemics and infectious diseases outbreaks are the world health organization 's outbreak communications guidelines6 and the us centers for disease control and prevention crisis and emergency risk communication guidelines and training module ( 7 ) . these guidelines are very focussed on emergencies and outbreaks and the special challenges of communication during a period of uncertainty , confusion , and a sense of urgency ( 6 ) , and communicating effectively under nearly impossible time constraints ( 7). the focus on emergencies and crises arose out of specific needs : the experience of sars , the anthrax attacks in the united states , and the heightened focus on bioterrorism led to the creation of tools and guidelines for situations where health communicators would find themselves as part of a crisis and emergency response ( 8) . it begins as an outbreak when the new virus first emerges and starts causing disease at the community level . it then spreads globally over an extended period of time , causing different levels of disease at different places at different times . if the virus is unstable , then patterns of severity could also change with time and location , and changes in the virus could see a pandemic lasting for several years . the initial need was for clear communication on what the public needed to do to reduce transmission as well as advice on treatment . but as the pandemic progressed , this changed to more complex questions such as the necessity for vaccination and vaccine safety , the need for continued vigilance as well as questions about the quality of the public health response to the pandemic , and questions of accountability , cost , and so on . they were rather part of long - term health communication and health promotion , focusing on behavior change in areas such as cough etiquette , hand hygiene , and in wealthier societies on regular vaccination for influenza . although there are a variety of approaches to health communication , from the more traditional forms used in the western world , to more participatory , grassroots - based approaches that are often more effective in the developing world , these have never been integrated with risk and emergency communication . the who has its outbreak communication guidelines for emergencies , but it also has a communication for behavioral impact model for health communication and behavior change . this model has used to support leprosy control campaigns in india and mozambique , dengue prevention in malaysia , tb prevention in bangladesh , and kenya and in other places ( 9 ) . the united nations children 's emergency fund and the world bank have advocated similar social mobilization communication strategies ( 10 ) . other participatory communication programs for hiv / aids have also been described in the literature ( 11 ) . during the pandemic , a survey of the needs of developing countries conducted by the who and other un agencies showed many developing countries found communicating at the community level a problem and were requesting support for planning for behavior change communication at the community level ( 12 ) . there , therefore , appears to be merit in trying to combine the longer term , participatory health communication approaches with the more short - term communication principle for disease outbreaks and emergencies , into a broader framework for strategic communication for disease outbreaks . this was the first pandemic of the internet age , and it was clear that the web and web - based tools including social networking tools provided valuable channels for communicators to reach audiences . however , the internet is a challenging medium to use . the creation of blogs and other user - generated content has turned the internet into a conversation space in which everyone can participate , erasing the distinction between expert and lay person , and has created a space in which everyone can publish their opinions and views . unlike traditional top - down communication from expert to audience , the internet provides alternate lines of knowledge circulation, where websites and blogs also challenged assessments by experts and authorities ( 13 ) . through web sites and blogs , the internet has created a network of virtual communities based on shared interests and values , who communicate among themselves . for example , during the pandemic , environmental and sustainable development groups critical of factory farming created alternative narratives of the pandemic as a consequence of modern farming ( 14 ) . groups suspicious of modern businesses and their influence on politics created narratives in which the pharmaceutical industry influenced perceptions of the seriousness of the pandemic ( 15 ) . existing risk communication guidelines do not provide guidance or principles on the best way to use the internet , particularly social networking tools such as facebook and twitter during disease outbreaks as well as for longer health crises . the who and cdc emergency and outbreak communication guidelines are based on building a relationship of trust between communicator and audience . without this trust , but , it has been pointed out that public trust in policy makers and officials is declining , at least in western societies . the sociologist ragnar lofstedt described these societies as post - trust societies ( 4 ) . there is little literature on trust in government in developing societies , or societies with different social and political systems , but it is reasonable to assume that low trust in government and institutions is not a purely western phenomenon . a range of factors have been described in the literature as components of trust . renn and levine proposed competence , objectivity , fairness , consistency , and goodwill as making up trust ( 17 ) . peters , covello , and mccallum proposed knowledge and expertise , openness and honesty , and concern and care as the constituents of trust ( 18 ) . it is not clear how these various components are to be communicated to the public to build trust . risk and outbreak communication principles describe displaying empathy with the public and being open and transparent as factors to build trust . but are empathy and transparency sufficient to communicate the varied components of trust listed in the literature ? lack of trust can flow from a variety of factors : lack of belief in the competence and knowledge of authorities , lack of belief in their fairness , lack of belief in their honesty , and so on . it is possible to conceive of a situation where lack of trust is based on the perception that the authorities have knowledge and competence , but are not fair and another situation in which the authorities are perceived to be fair and honest , but lack competence . in addition to a general policy of openness and transparency , it is important that communication be addressed to the specific causes for low trust . establishing trust is a complex process that requires more than applying guidelines such as openness and transparency ( 19 ) . a research agenda for risk communication needs to understand the trust building process better and offer insights from the published literature in various disciplines , as well as suggest new areas for study . as has been noted earlier , infectious disease outbreaks and other health emergencies are highly charged political and social events ( 5 ) . communicating during such events is rarely a simple matter of communicating information clearly and transparently and winning public trust . more often than not , the issues are surrounded by political and economic overtones , requiring political decisions that can create controversy . to take an example , decisions over vaccine procurement , travel restrictions , and other public health measures , all have economic and political consequences , and therefore those who communicate about these issues find themselves confronting questions that are not essentially about health but about other aspects of society . therefore , health risk communicators need to draw insights from sociological and cultural studies of risk . the work of the german sociologist ulrich beck offers insights into the social and political basis of risk that can offer insights for the communication of risk . in his pioneering work on the risk society , beck described the distribution of technological and other risks produced through the process of modernization as a major preoccupation of modern governments and societies ( 20 ) . this distribution of risk is never equitable but follows the unequal distribution of power in national societies as well as global society . the struggles over the distribution of risks are a major reason for the differences in the scientific or expert views of risk and the views of different sections of society . to take an example , a farmer with an outbreak of h5n1 in his farm needs to cull his chicken and ducks if the outbreak is to be curtailed . from the farmer 's point of view , though , he is being asked to bear the cost of destroying his livelihood in order to reduce the risk to other members of society . he could well see himself as bearing a disproportionate level of risk , and his compliance with health messages would depend on the extent to which these messages also address the larger issues at the back of the farmer 's mind . in this case , the level of compensation for bearing this risk to his livelihood would be a key issue to address if there is to be compliance . therefore , what might seem a simple public health issue has complex roots in areas that lie outside health , and there is a need to develop tools and ideas that help to deal with these complexities . communication during a health emergency or crisis often gets bogged down in questions of blame . although communicators try to provide the public with information , the public , and very often the media , seem more interested in attributing blame . mary douglas cultural anthropological work has led her to describe risk in modern society as being part of a politicized blaming system. then , what action , which means what damages , what compensation , what restitution? risk thus becomes a stick for beating authority ( 21). based on this , it is necessary for health communication guidelines and principles to be broadened so that they equip communicators to address the underlying social and political questions about blame and risk distribution that are on the public mind during disease outbreaks and emergencies , and to have the tools to be able to respond to these queries . following from the earlier discussion , it is suggested that the tools and principles of risk communication be expanded in the following areas : the integration of communications tools and guidelines for long - term behavior change and social mobilization , especially in developing country settings , into the existing guidelines for outbreak communication.based on case studies of the experience of the pandemic as well as other disease outbreaks , guidance on how to use the internet , including social networking tools effectively to provide the public with health guidance.understanding how to build and maintain trust with the public before , during , and after disease outbreaks.guidance on how public health communicators can understand and negotiate the political and cultural complexities of pandemics and other disease events . the integration of communications tools and guidelines for long - term behavior change and social mobilization , especially in developing country settings , into the existing guidelines for outbreak communication . based on case studies of the experience of the pandemic as well as other disease outbreaks , guidance on how to use the internet , including social networking tools effectively to provide the public with health guidance . understanding how to build and maintain trust with the public before , during , and after disease outbreaks . guidance on how public health communicators can understand and negotiate the political and cultural complexities of pandemics and other disease events . the funding source had no involvement in the collection or interpretation of data , or the decision to submit this manuscript for publication .

the influenza pandemic of 2009 revealed shortcomings in the existing guidelines for risk and outbreak communication . concepts such as building trust proved hard to achieve in practice , whereas other issues such as communicating through the internet and coping with the political fallout of disease outbreaks are not dealt with in existing guidelines . this article surveys the current guidelines and makes recommendations for additional tools and guidelines to be developed in four areas : integrating long - term behavior change models with outbreak communications ; research to develop a better understanding of communicating through the internet ; research to understand how to use communications to build trust ; and developing guidelines and principles to understand the political nature of disease outbreaks .