The combination of each individual’s coagulation factors (outside

The combination of each individual’s coagulation factors (outside of fVIII) determine each individual’s baseline thrombin potential and may affect bleeding risk. “
“The purpose of this study was to evaluate the efficacy and safety of postoperative wound drain salvage and autotransfusion system in haemophilic patients undergoing elective total knee arthroplasty (TKA). No literature exists on reinfusing drained blood in patient with haemophilia undergoing

TKA. Eighty-eight knees of 66 patients received cemented TKA due to end-stage haemophilic arthropathy (group I; with autotransfusion in 59 knees, group II; without autotransfusion in 29 knees). In group I, the postoperative shed blood was transfused within 6 h after surgery. The amount of blood drainage and reinfused blood, rate and amount of allogenic transfusion, postoperative selleck chemicals change of haemoglobin level, prothrombin time (PT) and activated partial thromboplastin time were analysed. The mean postoperative blood drainage was 932 ± 479 mL in group I and 830 ± 492 mL in group II (P > 0.05). The mean volume of blood reinfused was 530 ± 265 mL in group I. Allogenic transfusion was needed in six knees (10.2%) of group I and eight knees (27.6%) of group II (P = 0.036). The mean volume of allogenic transfusion was

480 ± 49 mL in group I and 1041 ± 691 mL in group II (P > 0.05). Changes of all the laboratory results before and after TKA showed no statistically

significant difference except PT was prolonged in group I (P = 0.008) at postoperative day 1. Moreover, there was no significant complication related to Y-27632 nmr oxyclozanide either reinfusion or allogenic transfusion in both groups. This study showed that reinfusion of drained blood is a simple, safe and efficacious method in patients with haemophilia undergoing TKA. “
“Summary.  Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web-based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.

For biomarker discovery, the latter was chosen as a control group

For biomarker discovery, the latter was chosen as a control group because the risk of postprocedural pancreatitis or cholangitis ethically bans ERC from application in healthy subjects. However, as the control group consists of patients with choledocholithiasis, proteomic analysis may reflect the difference between a relatively normal GSK-3 assay biliary tree and liver, and an inflamed, cholestatic liver, which can be expected in patients with PSC and patients with a dominant stenosis due to CC. The PSC/CC model was able to distinguish CC and PSC from nonmalignant lesions with an AUC of 0.93 (P = 0.0001), a sensitivity of 93%, and a specificity of

86% as validated in an independent cohort. These findings are of clinical significance,

as in patients with suspected CC or PSC endoscopic procedures will be performed and thus bile becomes accessible. Furthermore, even in the presence of large masses suspicious of CC, a definite diagnosis often cannot be made. The surveillance of patients with PSC is of crucial importance, as those patients have an increased risk to develop CC and curative treatment such as liver transplantation or radical resection can be performed only at an early stage. Therefore, our aim was to distinguish PSC from CC in a second model. This model was established using a training Metformin molecular weight set consisting of 18 patients with PSC and 16 with CC. Applied to an independent validation set (18 PSC, 25 CC) it showed an AUC of 0.87, a specificity Amylase of 78%, and a high sensitivity of 84%. Our findings indicate a possible role of proteomic analysis for surveillance in patients with PSC. Nevertheless, PSC-associated CC may be of different origin than sporadic cholangiocarcinoma. Ten patients within the CC group developed CC in addition to PSC. Eight of those patients were identified positive for CC by proteomic analysis. This proteomic model

reaches a high sensitivity compared to single biochemical markers. Direct comparison with the widely used CA 19-9 tumor marker is impossible, because previous studies used different cutoff values in various study populations, leading to enormous range of sensitivity (53%-92%) and specificity (50%-98%).44 Our proposed model may be of clinical relevance in diagnosing CC in patients with PSC especially if supplementary to other diagnostic methods, as a higher accuracy can be reached by a combination of different diagnostic tools.45 All in all, proteomic analysis of bile as a diagnostic tool for surveillance of patients with PSC alone or in combination with other methods may provide an early and reliable diagnosis of CC. In summary, our data indicate a possible role of proteomic analysis of bile to differentiate CC from PSC and benign lesions.

CD4 binding facilitates viral attachment and mediates conformatio

CD4 binding facilitates viral attachment and mediates conformational changes in gp120 that allow a high-affinity click here interaction with the respective chemokine receptor.

HSCs express both functional CXCR49 and CCR5.8 Therefore, we examined whether HSCs express CD4. FACS analysis revealed that 4% of passage #3 HSCs express CD4 (data not shown). Because CD4 receptors can be disrupted by trypsinization, immunofluorescent staining for CD4 on primary HSCs was performed (Fig. 3A). Although a subset of primary HSCs expressed CD4, the expression level was low. To determine whether HIV entry into HSCs is CD4- and/or CXCR4-dependent, primary HSCs were preincubated with anti-CD4, anti-CXCR4, or isotype control, challenged with HIV-IIIB (X4-tropic), and ELISA for p24 performed on culture supernatants (Fig. 3B). Neither blocking antibody inhibited HIV infection of HSCs. Efficacy of blocking antibodies was simultaneously confirmed in

primary CD4 cells where HIV infection was inhibited by both antibodies (Fig. 3C). As additional confirmation, HSCs were incubated with anti-CD4 and anti-CXCR4 prior to challenge with HIV-GFP and FACS analysis (Fig. 3D). Similar to p24 results, GFP expression was not significantly blocked by anti-CXCR4 or anti-CD4 antibodies. Whereas baseline efficiency of viral entry by R5-tropic virus (HIV-BaL) into HSCs was low, infection was not blocked using CCR5 blocking antibodies (data not shown). Taken together, these results indicate that the major pathway of viral entry into HSCs is independent of CD4 and chemokine Etofibrate coreceptor binding. Although alternative HIV receptors such as C-type lectins have been shown to mediate HIV entry into dendritic cells (DCs)14 and astrocytes,15

this mechanism of entry will have to be further explored for HSCs. To determine whether HSCs can produce infectious virus, culture supernatants from HSCs previously infected with HIV-IIIB were incubated with primary CD4 lymphocytes and TZM cells. There was no detectable p24 in culture supernatant from CD4 cells (Fig. 4A) or luciferase activity in TZM cells (Fig. 4B) exposed to culture supernatants from HIV-infected HSCs, respectively. In contrast, both purified HIV as well as culture supernatants derived from primary CD4 lymphocytes previously infected with HIV led to infection of both CD4 cells as indicated by p24 ELISA and luciferase activity for TZM cells (Fig. 4A). These findings indicate that most of the viral particles released into culture supernatants from HSCs are noninfectious. Transmission of HIV through points of cell contact has been demonstrated between DCs and T cells16 as well as between T cells.17 Because HSCs share features with DCs,18, 19 we examined whether HSCs could transfer infectious virus to lymphocytes in a coculture system.

These results suggest that chaetocin has therapeutic potential fo

These results suggest that chaetocin has therapeutic potential for the control of solid tumors, including hepatoma. Furthermore, our findings suggest that HIF-1α pre-mRNA splicing should also be viewed as a therapeutic Ensartinib order target. The thiodioxopiperazine moiety of chaetocin has chirality opposite to that of chetomin. Chetomin has been reported to directly

inhibit the interaction between HIF-1α and p300 and, thus, to repress HIF-1-driven gene expression.21 A recent report demonstrated that despite structural differences, three thiodioxopiperazines commonly inhibit the p300 binding in vitro and reduce VEGF secretion in HCT116 cells.22 However, as HIF-1α expression had not been determined, we examined whether chetomin, like chaetocin, down-regulates HIF-1α. Although chetomin selleckchem repressed the transcriptional activity of HIF-1α, it had no effect on HIF-1α expression or pre-mRNA splicing (Supporting Information Fig. 7). These results indicate that chaetocin and chetomin inhibit HIF-1α in different ways. Indeed, we could not check the effect of chaetocin on p300-HIF-1α binding because HIF-1α disappeared. Nevertheless, because HIF-1α synthesis precedes p300-HIF-1α binding, the anticancer effect of chaetocin might be primarily

due to HIF-1α suppression. VEGF acts in a paracrine manner on endothelial cells to increase numbers of blood and lymphatic vessels, and also in an autocrine manner activates the VEGF receptor-mediated survival pathway. Therefore, antibodies

and peptides that antagonize VEGF or its receptors have been developed as anticancer therapies.23, 24 We found that chaetocin inhibits VEGF production in hepatoma cells and grafts, and that vessels were poorly developed in chaetocin-treated tumors. These results suggest that the VEGF suppression underlies the antiangiogenic and anticancer action of chaetocin. To correct ATP depletion and subsequent acidosis in hypoxia, HIF-1α facilitates ATP generation by up-regulating PDK4 a number of glycolytic enzymes, but it inhibits oxidative phosphorylation by inducing PDK1, which blocks the trichloroacetic acid (TCA) cycle.25 HIF-1α also corrects acidosis by inducing CA9, which generates HCO.26 Accordingly, suppression of these metabolic genes by chaetocin may contribute to its cytotoxicity to hepatoma cells cultured under severe hypoxic conditions. Many small molecules that inhibit HIF-1 have been reported in the literature. Some functionally inhibit HIF-1α by blocking its binding to p300 or DNA,21, 27 and others down-regulate HIF-1α by destabilizing it or by inhibiting its translation.28, 29 However, to the best of our knowledge, no agent has been previously reported to inhibit HIF-1α at the mRNA splicing level. Then, how does chaetocin inhibit HIF-1α pre-mRNA splicing? Spliceosome consists of small nuclear ribonucleoproteins and a host of associated proteins.

PET/CT and DWI could play different roles in diagnosing pancreati

PET/CT and DWI could play different roles in diagnosing pancreatic carcinoma. Enhanced PET/CT seems to be superior to unenhanced PET/CT. Further larger prospective studies are needed to establish its value for diagnosis in pancreatic cancer. Pancreatic cancer is one of the leading causes of cancer death in Western countries with an increasing incidence. The overall survival for patients with pancreatic find more cancer is very poor, with a 5-year survival of 1% to 4%.1 Given its incidence and high mortality, substantially increased research efforts are clearly warranted to understand, detect, and control the disease. In spite of the development of

imaging modalities, the preoperative diagnostics of pancreatic tumors has remained suboptimal, thus restricting the treatment planning of these malignancies. The discrimination between inflammatory processes and malignancies of the pancreas and the assessment of local resectability and distant metastases of the pancreatic cancer remains challenging with different imaging modalities. Over the years, integrated positron emission tomography/computed tomography (PET/CT), in which a full-ring detector clinical see more PET scanner

and multidetector row helical CT (MDCT) scanner are combined, has made it possible to acquire both metabolic and anatomic imaging data using a single device in a single diagnostic session and provides precise anatomic localization of suspicious areas of increased fluorodeoxyglucose (FDG) uptake and

rules out false-positive PET findings.2,3 Tang et al.4 did a meta-analysis about the detection of pancreatic malignancy with PET/CT. They found that the pooled sensitivity and specificity estimate for PET/CT were 90.1% and 80.1%. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique based old on the imaging of the molecular mobility of water. During recent years, DWI of diseases of pelvic, for example, prostate,5 urinary bladder,6 uterus7 and rectum,8 has presented promising results. DWI of the upper abdomen has been a technical challenge due to respiration, bowel peristalsis, blood flow and long acquisition times. The implementation of ultrafast imaging techniques, such as parallel imaging, has made DWI of the upper abdomen a feasible option and has been found to be useful in differentiation of malignant from benign liver lesions.9,10 Recently, studies have reported the diagnostic performance of DWI in discrimination of pancreatic lesions, but the diagnostic value of DWI for pancreas has not yet been defined. Since PET/CT is highly sensitive and DWI is highly specific, it implies PET/CT and DWI could play different roles during different conditions in diagnosing pancreatic cancer.

395; 95% CI, 0180-0896; P = 0021) Age of onset below 18 was a

395; 95% CI, 0.180-0.896; P = 0.021). Age of onset below 18 was a significant risk factor (HR, 1.963; 95% CI, 1.21-3.20; P = 0.007) for the use of immunosuppressants in CD. Extent of disease was a significant factor associated with surgical resection (p = 0.012) in univariate analysis but not in multivariate analysis. Extensive disease in UC was a significant risk factor in multivariate

cox model (HR, 3.558; 95% CI, 1.32-9.58; P = 0.012) for primary use of immunosuppressants. Conclusion: In CD, colonic disease were associated with decreased risk while stricturing and penetrating behavior were associated with increased risk of surgical resection. In UC, extensive disease was associated with the need for immunosuppressants. Key Word(s): 1. inflammatory bowel disease; 2. bowel resection Presenting Author: GOVIND K MAKHARIA Additional Authors: GOVIND K MAKHARIA, selleck ABHISHEK AGNIHOTRI,

Palbociclib research buy SUDIPTO CHAUDHARY, UC GHOSHAL, MANISH K PATHAK, ASHA MISHRA, SIDDHARTHA DATTA GUPTA, RAJU SHARMA, RM PANDEY, VINEET AHUJA, SK SHARMA, BS RAMAKRISHNA Corresponding Author: GOVIND K MAKHARIA Affiliations: All India Institute of Medical Sciences, All India Institute of Medical Sciences, Christian Medical College, Sanjay Gandhi Postgraduate Institute of Medical Sc, All India Institute of Medical Sciences, All India Institute of Medical Sciences, All India Institute of Medical Sciences, All India Institute of Medical Sciences, All India Institute of Medical Sciences,All India Institute of Medical Y-27632 2HCl Sciences, All India Institute of Medical Sciences, SRM Institute of Medical Sciences Objective: Whether patients with abdominal tuberculosis

(both gastrointestinal and peritoneal) should be treated with six months or nine months is a debatable. There is also a lack of data on the efficacy of short course intermittent therapy in treatment of abdominal tuberculosis. We conducted a multicenter single blinded randomized controlled trial to assess the efficacy of 6 months and 9 months of anti-tuberculous therapy (ATT) in abdominal tuberculosis using Directly Observed Therapy Short Course (DOTS). Methods: Of 499 patients screened, 197 patients with abdominal tuberculosis (gastrointestinal-154, peritoneal-40, mixed-3) were randomized to receive 6-mo (Group A, n = 104) and 9-mo (Group B, n = 93) of ATT using DOTS strategy. All patients were evaluated for primary end point (complete clinical response, partial clinical response, no response, or death) and secondary end point (mucosal healing). Patients were followed up further for one year after completion of treatment to assess recurrence. Results: Both groups had similar baseline characteristics, clinical manifestations, site of disease, proportion of definitive or presumptive diagnosis of tuberculosis. Per protocol analysis showed no difference in complete clinical response (91.5% vs 90.8%, P = 0.882) between group A and group B.

5, 6 Several recent studies have suggested that HBx is also invol

5, 6 Several recent studies have suggested that HBx is also involved in epigenetic regulation during hepatocarcinogenesis.7, 8

Recent reports have emphasized that selleck chemicals llc epigenetic modifications, especially DNA hypermethylation, might play crucial roles in the initiation of cancer. Methylation changes to the epigenome are controlled by DNA methyltransferases (DNMTs). Three catalytically active DNMTs have been identified in mammals: DNMT1, DNMT3A, and DNMT3B. Although the mechanisms leading to aberrant DNA hypermethylation remain to be fully elucidated, increased levels of DNMT1, DNMT3A, and DNMT3B have been observed in various malignancies, including leukemia, lung, colorectal, and breast tumors.9-12 It was reported that the average levels of messenger RNA (mRNA) for DNMT1 and DNMT3A were significantly higher in noncancerous liver tissues showing chronic hepatitis or cirrhosis versus

histologically normal liver tissues. The levels were even higher in HCCs, and DNMT3B was significantly overexpressed in HCCs in comparison with the corresponding noncancerous liver tissues.13, 14 Increased protein expression of DNMT1 has been significantly Tamoxifen research buy correlated with the malignant potential and poor prognosis of human HCC.15 Moreover, the overexpression of HBx in vitro can increase total DNMT activity by the up-regulation of DNMT1 and DNMT3A.7 This suggests that DNMT overexpression contributes to gene promoter hypermethylation and in turn to HCC. However, the mechanism by which HBx activates DNMTs expression remains unknown. MicroRNAs (miRNAs) are noncoding RNAs, 19 to 25 nucleotides long, that regulate gene expression by targeting mRNAs through base pairing at partially or fully complementary sites for cleavage or translational repression.16 Deviations from normal miRNA expression patterns play roles in human diseases, including cancers.17, 18 Some miRNAs may function as oncogenes or tumor suppressor genes (TSGs).19 Growing evidence supports a role Nintedanib (BIBF 1120) for miRNAs as both targets and effectors in aberrant mechanisms of DNA hypermethylation.

Some miRNAs have been reported to be inactivated in human tumors by the aberrant hypermethylation of CpG islands encompassing miRNA genes or located nearby.20, 21 It has also been reported that miRNAs are involved in the control of DNA methylation machinery. Fabbri et al.22, 23 recently demonstrated that miRNA-29b can target DNMT3s and induce aberrant DNA methylation in lung cancer and acute myeloid leukemia. We wondered if similar DNA methylation mechanisms occur in HCC and if there are some HBx-related miRNAs that can regulate DNMTs and then promote the aberrant DNA methylation. We found that the expression of microRNA-152 (miR-152) was down-regulated in the livers of HBx transgenic mice in comparison with the livers of wild-type (WT) mice by miRNA microarray and real-time polymerase chain reaction (PCR) in our previous studies (see the supporting information in ref. 24).

09) to 50% (28 – 59%;

p<00001) This demonstrates a norm

09) to 50% (28 – 59%;

p<0.0001). This demonstrates a normal uptake of 11C-CSar from blood to hepatocytes, combined with a significant backflux of 11C-CSar from hepatocyte AZD3965 to blood in patients with cholestasis, and essentially no backflux in healthy subjects. Median fractional biliary excretion (time point 50 min) of 11C-CSar was 73% (55 – 80%) in healthy subjects and 38% (17 – 70%) in patients with cholestasis (p<0.001). This demonstrates reduced secretion of 11C-CSar from hepatocyte to bile in patients with cholestasis. Conclusions: 11C-CSar PET/ CT enables quantitation of the hepatobiliary excretion of conjugated bile acids. In patients with cholestasis, hepatic uptake of 11C-CSar from blood was

normal while there was backflux of 11C-CSar to blood and the secretion from liver to bile was reduced. These results show potential for investigation of the hepatobiliary function using 11C-CSar PET/CT. Disclosures: The following people have nothing to disclose: Nikolaj W. Ørntoft, Kim Frisch, Peter Ott, Susanne Keiding, Michael Sørensen “
“Multiple inhibitory receptors may play a role in the weak or absent CD8+ T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. Ivacaftor solubility dmso In the present study, we investigated Interleukin-3 receptor the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chronically infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was analyzed in virus-specific CD8+ T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus

(EBV), or influenza virus (Flu). In chronic HBV infection, virus-specific CD8+ T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-specific CD8+ T-cells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-specific proliferation and cytotoxicity as measured by the expression of CD107a, interferon-γ, and tumor necrosis factor-α in CD8+ T-cells. Conclusion: CD244 and PD-1 are highly coexpressed on virus-specific CD8+ T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway.


is beyond the scope of these guidelines to elaborate o


is beyond the scope of these guidelines to elaborate on the theories of pathogenesis of HE, as well as the management of encephalopathy resulting from acute liver failure (ALF), which has been published as guidelines recently. Rather, its aim is to present standardized terminology and recommendations to all health care workers who have patients with HE, regardless of their medical discipline, and focus on adult patients with chronic liver disease (CLD), which is, by far, the most frequent scenario. As these guidelines on HE were created, the authors found a limited amount of high-quality evidence to extract from the existing literature. There are many reasons for this; the elusive character of HE is among them, as well as the lack of generally accepted and

utilized terms for description and categorization of HE. This makes a practice guideline all selleck chemicals llc the more necessary for future improvement of clinical studies and, subsequently, the quality of management of patients with HE. With the existing body of evidence, these guidelines encompass the authors’ best, carefully considered opinions. Although not all readers may necessarily agree selleck kinase inhibitor with all aspects of the guidelines, their creation and adherence to them is the best way forward, with future adjustments when there is emergence of new evidence. Advanced liver disease and portosystemic shunting (PSS), far from being an isolated disorder of the liver, have well-known consequences on the body and, notably, on brain functioning. The alterations of brain functioning, which can produce behavioral, cognitive, and motor effects, were termed portosystemic encephalopathy (PSE)[3] and later included in BCKDHA the term HE.[4] Unless the underlying liver disease is successfully treated, HE is associated with poor survival and a high risk of recurrence.[5, 6] Even in its mildest form, HE reduces health-related quality of life and is a risk factor for bouts of severe HE.[7-9] Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or PSS; it manifests as a wide spectrum

of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. This definition, in line with previous versions,[10, 11] is based on the concept that encephalopathies are “diffuse disturbances of brain function”[5] and that the adjective “hepatic” implies a causal connection to liver insufficiency and/or perihepatic vascular shunting.[6] The incidence and prevalence of HE are related to the severity of the underlying liver insufficiency and PSS.[12-15] In patients with cirrhosis, fully symptomatic overt HE (OHE) is an event that defines the decompensated phase of the disease, such as VB or ascites.[7] Overt hepatic encephalopathy is also reported in subjects without cirrhosis with extensive PSS.[8, 9] The manifestation of HE may not be an obvious clinical finding and there are multiple tools used for its detection, which influences the variation in the reported incidence and prevalence rates.

These criteria are now widely accepted1 For this reason, we refe

These criteria are now widely accepted.1 For this reason, we refer to all cases with the above-described criteria—either “definite” or “probable” as “cases.” We defined “symptomatic” patients as those with pruritus, persistent fatigue, or signs and symptoms of cirrhosis. Patients with none of these were regarded as “asymptomatic” of liver disease at diagnosis. The study included all cases incident between January 1, 1987 and December 31, 2003 and who were resident in an area of northeast

England (i.e., Northumberland, Sunderland, North Durham, South Durham, Newcastle upon Tyne, North Tyneside, South Tyneside, and Gateshead), defined by postal (ZIP) code. The total population of the area at the 2001 census was less than 2.05 million.12 The methods for case finding have been described previously.13 Briefly, they were as follows: 1 Requests were made to all gastroenterologists and hepatologists in the region to identify all cases of PBC under their care. Case selection Lumacaftor in vivo was approved by the local ethical committees. After initial identification, hospital records of all cases were reviewed. Date of diagnosis was defined as the earliest date at which the patient was found (by examination of clinical case records—hospital or primary care) to have fulfilled any two of the three diagnostic criteria. This was to avoid the need for different criteria for date of diagnosis

in the asymptomatic versus the symptomatic group of patients. It is emphasised, therefore, that date of diagnosis was not the date at which a diagnosis of PBC was first made and Cyclooxygenase (COX) entered in an individual’s clinical case records by the attending doctors.11 Rather, date of diagnosis was determined after examination by the investigators of clinical records and depended upon the date at which the above diagnostic criteria were first fulfilled. The following etiological hypothesis was tested: A primary factor influencing temporal heterogeneity of PBC is related to exposure to a seasonally varying environmental agent occurring close to diagnosis or at similar times before diagnosis. Monthly expected (E) numbers of cases were calculated under an assumption

of a uniform distribution throughout the year. Observed counts (O) were compared with the expected numbers. A chi-squared test for heterogeneity was used to test for an overall seasonal effect in incidence. The test shows the presence of any departure from a uniform distribution throughout the year. Individual chi-squared tests for each month were used to test for the presence of specific excesses. Poisson analysis was used to determine the pattern of seasonality. A sinusoidal (i.e., harmonic) model was fitted to the data, using month of diagnosis as a covariate. The Poisson model used was of the following form: Statistical significance was taken to be P < 0.05, and marginal significance was taken as 0.05 ≤ P < 0.10. All statistical analyses were performed using STATA version 10 (StatCorp LP, College Station, TX).