It is also a tale of two cities, Tokyo and Philadelphia, where in

It is also a tale of two cities, Tokyo and Philadelphia, where investigators kept asking “why?” until understanding was achieved. ALT, alanine aminotransferase (also SGPT); AST, aspartate aminotransferase (also SGOT); Au, Australia antigen; HUP, Hospital of the University of Pennsylvania; ICR, Institute for Cancer Research; NIH, National Institutes

of Health; PGH, Philadelphia General Hospital. Homologous serum hepatitis was a great problem during World War II where large numbers of wounded combatants were infected by pooled plasma administered to save lives threatened by blood loss. Serum selleck products hepatitis after transfusion of blood or plasma was thought in the 1950s to be distinct from the more general worldwide infectious hepatitis that was believed to be transmitted by fecally-contaminated water. The two forms of hepatitis were also designated3 more simply as hepatitis B and hepatitis A. Studies in World War II and later in the Korean War4, 5 on epidemic Deforolimus solubility dmso catarrhal jaundice and homologous serum hepatitis led to advances in understanding,6 but many questions were left unresolved. In 1959, during his gastrointestinal research fellowships in the laboratories of Dr. Kurt Isselbacher at the Massachusetts General Hospital, a trainee from Japan, Dr. Yoshitaka Shimizu, fascinated another trainee (Senior) with accounts of his recent clinical studies in five Tokyo hospitals. By using serum transaminase activity

measurements biweekly, he had found that almost 65% of patients undergoing thoracic or gastrointestinal procedures, for which they received transfusions, had delayed post-operative elevations in serum enzyme activities. About 9%-10% of the patients with hepatitis became jaundiced, as subsequently MCE公司 published7 by Dr. Shimizu in April 1963 after his return to Japan. Senior had returned to the University of Pennsylvania to start a new laboratory for gastrointestinal clinical research at the Philadelphia General Hospital (PGH). While awaiting delivery of laboratory equipment in

the second half of 1962, seeking to confirm or contrast the Tokyo findings, he and two medical residents observed patients transfused during gynecologic procedures, then followed them biweekly for post-operative serum enzyme activity elevations. The clinical laboratories of the adjacent Hospital of the University of Pennsylvania (HUP) were used to measure activities of serum glutamic-oxalacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), and isocitric dehydrogenase (ICD). They found in 1963 that 10 of 56 (18%) patients followed at PGH developed post-transfusion enzyme elevations 4 to 14 weeks later, but none were obviously jaundiced and four were asymptomatic. Six consented to liver biopsy, which showed diffuse interlobular inflammation, nuclear pleomorphism, eosinophilic degeneration, and hepatocellular pyknosis, as reported in 1964.

It is also a tale of two cities, Tokyo and Philadelphia, where in

It is also a tale of two cities, Tokyo and Philadelphia, where investigators kept asking “why?” until understanding was achieved. ALT, alanine aminotransferase (also SGPT); AST, aspartate aminotransferase (also SGOT); Au, Australia antigen; HUP, Hospital of the University of Pennsylvania; ICR, Institute for Cancer Research; NIH, National Institutes

of Health; PGH, Philadelphia General Hospital. Homologous serum hepatitis was a great problem during World War II where large numbers of wounded combatants were infected by pooled plasma administered to save lives threatened by blood loss. Serum http://www.selleckchem.com/products/R788(Fostamatinib-disodium).html hepatitis after transfusion of blood or plasma was thought in the 1950s to be distinct from the more general worldwide infectious hepatitis that was believed to be transmitted by fecally-contaminated water. The two forms of hepatitis were also designated3 more simply as hepatitis B and hepatitis A. Studies in World War II and later in the Korean War4, 5 on epidemic C646 cell line catarrhal jaundice and homologous serum hepatitis led to advances in understanding,6 but many questions were left unresolved. In 1959, during his gastrointestinal research fellowships in the laboratories of Dr. Kurt Isselbacher at the Massachusetts General Hospital, a trainee from Japan, Dr. Yoshitaka Shimizu, fascinated another trainee (Senior) with accounts of his recent clinical studies in five Tokyo hospitals. By using serum transaminase activity

measurements biweekly, he had found that almost 65% of patients undergoing thoracic or gastrointestinal procedures, for which they received transfusions, had delayed post-operative elevations in serum enzyme activities. About 9%-10% of the patients with hepatitis became jaundiced, as subsequently MCE published7 by Dr. Shimizu in April 1963 after his return to Japan. Senior had returned to the University of Pennsylvania to start a new laboratory for gastrointestinal clinical research at the Philadelphia General Hospital (PGH). While awaiting delivery of laboratory equipment in

the second half of 1962, seeking to confirm or contrast the Tokyo findings, he and two medical residents observed patients transfused during gynecologic procedures, then followed them biweekly for post-operative serum enzyme activity elevations. The clinical laboratories of the adjacent Hospital of the University of Pennsylvania (HUP) were used to measure activities of serum glutamic-oxalacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), and isocitric dehydrogenase (ICD). They found in 1963 that 10 of 56 (18%) patients followed at PGH developed post-transfusion enzyme elevations 4 to 14 weeks later, but none were obviously jaundiced and four were asymptomatic. Six consented to liver biopsy, which showed diffuse interlobular inflammation, nuclear pleomorphism, eosinophilic degeneration, and hepatocellular pyknosis, as reported in 1964.

The yield of neuroimaging studies was higher in the group with in

The yield of neuroimaging studies was higher in the group with indeterminate headache (3.7%) than in the migraine (0.4%) or tension-type headache (0.8%) groups. The study does not provide information on white matter abnormalities in migraineurs. MRI performed in 119 patients with normal CT revealed significant lesions in 2 cases: a small meningioma and an acoustic neurinoma. No saccular aneurysms were detected; MR angiography was not obtained. However, the studies do not give information about the detection of paranasal sinus selleck compound disease,

which may be the cause of some headaches. For example, sphenoid sinusitis may cause a severe, intractable, new-onset headache that interferes with sleep and is not relieved by simple analgesics. The headache may increase in severity with no specific location.

There may be associated pain or paresthesias in the facial distribution of the fifth nerve and photophobia or eye tearing with or without fever or nasal drainage. The headache may mimic other causes such as migraine or meningitis.24 Wang et al25 retrospectively reviewed the medical records and MRI images of 402 adult patients (286 women and 116 men) who had been evaluated by the neurology service with a primary complaint of chronic headache (a duration of 3 months or more) and no other neurologic symptoms or findings. Major abnormalities (a mass, click here caused mass effect, or was believed to be the likely cause of the patient’s MCE headache) were found in 15 patients (3.7%) including a glioma, meningioma, metastases, subdural hematoma, arteriovenous malformation, 3 with hydrocephalus, and 2 Chiari I malformations. They were found in 0.6% of patients with migraine, 1.4% of those with tension headaches, 14.1% of those with atypical headaches, and 3.8% of those with other types of headaches. Finally, Lewis and Dorbad26 retrospectively reviewed records of children aged 6-18 years with migraine and chronic daily headache with normal examinations.

Of 54 patients with migraine who underwent either CT (42) or MRI (12) scans, the yield of abnormalities was 3.7%, none clinically relevant. Of 25 patients with chronic daily headache who underwent either CT (17) or MRI (8) scans, the yield of abnormalities was 16%, none clinically relevant. Secondary Headaches (NDPH Mimics).— Spontaneous intracranial hypotension (SIH) syndrome often presents with a headache that is present when a patient is upright but is relieved by lying down, or by an orthostatic headache. However, as SIH syndrome persists, a chronic daily headache may be present without orthostatic features. SIH syndrome may also present with other types of headaches, including exertional or cough without any orthostatic features, acute thunderclap onset, paradoxical orthostatic headaches (present in recumbency and relieved when upright), intermittent headaches due to intermittent leaks, and the acephalgic form with no headaches at all.

The yield of neuroimaging studies was higher in the group with in

The yield of neuroimaging studies was higher in the group with indeterminate headache (3.7%) than in the migraine (0.4%) or tension-type headache (0.8%) groups. The study does not provide information on white matter abnormalities in migraineurs. MRI performed in 119 patients with normal CT revealed significant lesions in 2 cases: a small meningioma and an acoustic neurinoma. No saccular aneurysms were detected; MR angiography was not obtained. However, the studies do not give information about the detection of paranasal sinus Ceritinib nmr disease,

which may be the cause of some headaches. For example, sphenoid sinusitis may cause a severe, intractable, new-onset headache that interferes with sleep and is not relieved by simple analgesics. The headache may increase in severity with no specific location.

There may be associated pain or paresthesias in the facial distribution of the fifth nerve and photophobia or eye tearing with or without fever or nasal drainage. The headache may mimic other causes such as migraine or meningitis.24 Wang et al25 retrospectively reviewed the medical records and MRI images of 402 adult patients (286 women and 116 men) who had been evaluated by the neurology service with a primary complaint of chronic headache (a duration of 3 months or more) and no other neurologic symptoms or findings. Major abnormalities (a mass, HSP inhibitor cancer caused mass effect, or was believed to be the likely cause of the patient’s MCE headache) were found in 15 patients (3.7%) including a glioma, meningioma, metastases, subdural hematoma, arteriovenous malformation, 3 with hydrocephalus, and 2 Chiari I malformations. They were found in 0.6% of patients with migraine, 1.4% of those with tension headaches, 14.1% of those with atypical headaches, and 3.8% of those with other types of headaches. Finally, Lewis and Dorbad26 retrospectively reviewed records of children aged 6-18 years with migraine and chronic daily headache with normal examinations.

Of 54 patients with migraine who underwent either CT (42) or MRI (12) scans, the yield of abnormalities was 3.7%, none clinically relevant. Of 25 patients with chronic daily headache who underwent either CT (17) or MRI (8) scans, the yield of abnormalities was 16%, none clinically relevant. Secondary Headaches (NDPH Mimics).— Spontaneous intracranial hypotension (SIH) syndrome often presents with a headache that is present when a patient is upright but is relieved by lying down, or by an orthostatic headache. However, as SIH syndrome persists, a chronic daily headache may be present without orthostatic features. SIH syndrome may also present with other types of headaches, including exertional or cough without any orthostatic features, acute thunderclap onset, paradoxical orthostatic headaches (present in recumbency and relieved when upright), intermittent headaches due to intermittent leaks, and the acephalgic form with no headaches at all.

This accounted for 172 of the pregnancies in 21 of the studies O

This accounted for 172 of the pregnancies in 21 of the studies. Of these 172 pregnancies

that received DDAVP prophylaxis there were no significant bleeding complications in 167 deliveries. Adverse bleeding events were reported in five pregnancies – postpartum haemorrhage (four cases) and sub-cutaneous haematoma (one case). The underlying bleeding disorder for patients who developed bleeding complications despite prophylactic treatment with DDAVP were two cases of Hermansky–Pudlak Syndrome (HPS) and a single case each of storage pool disorder, Ehlers–Danlos syndrome (EDS) and VWD [5,7,21–23]. DDAVP was used as a treatment for established bleeding complications in six cases of postpartum haemorrhage and two cases of postpartum soft tissue haemorrhage [9,16,17,25–28]. Clinical

see more improvement was seen in five of six cases of postpartum haemorrhage and in both cases of soft tissue haemorrhage that received DDAVP as part of their treatment. Other therapies were used in conjunction with DDAVP in 11 studies for both prophylaxis and treatment of bleeding complications associated with delivery. These additional therapies included oxytocin, cryoprecipitate, fresh frozen plasma, tranexamic acid, platelet transfusion and red cell transfusion. Two pregnancies that developed the most severe postpartum haemorrhage required internal pudendal artery embolization in one case and hysterectomy in the second case were in patients with acquired factor VIII inhibitor and storage pool disorder respectively [5,28]. Serious adverse ABT-737 manufacturer maternal events were reported in one case study after use of DDAVP in the perinatal period. One patient with severe type 1 von Willebrand‘s disease was reported to have a seizure after receiving DDAVP infusions at a dose of 0.3 μg kg−1 every 18 h during the postpartum period. The indication was to prevent bleeding complications following an emergency

Caesarean section. The patient developed a grand mal seizure secondary to severe hyponatraemia. A second patient with von Willebrand’s disease developed premature labour after a trial infusion of DDAVP at a dose of 0.4 μg kg−1 intended to establish response to DDAVP during the last month of pregnancy. Both complications were thought by the author of this article 上海皓元医药股份有限公司 to be due to water intoxication as a result of treatment with DDAVP [10]. One further study recorded a mild increase in uterine contractility with relatively high dose of 20 μg DDAVP intravenously and was observed 30 min after discontinuation of an oxytocin infusion. There was no adverse effect on the pregnancy or delivery in this case [32]. In total there were 109 vaginal deliveries recorded and 62 Caesarean sections. The mode of delivery was not recorded in 31 of the pregnancies. Foetal outcomes were recorded in 10 studies and all recorded no adverse effects for the foetus after delivery [3,7,8,11,15,21,22,29–31].

Patients receiving lamivudine prophylaxis should be monitored wit

Patients receiving lamivudine prophylaxis should be monitored with serial HBV DNA assays, and formal testing for lamivudine resistance should be performed if there is a 1 log increase in HBV DNA.86 Once resistance is confirmed, patients should be given adefovir in addition to lamivudine

or changed to tenofovir if this is available. Patients receiving intensive chemotherapy who are positive for HBcAb but HBsAg negative should have a sensitive HBV DNA assay performed to determine whether they have occult HBV infection. If HBV DNA is detected, these patients should be treated as for positive-HBsAg patients. Patients with undetectable CH5424802 molecular weight HBV DNA should be monitored regularly during chemotherapy for evidence of HBV reactivation.

The optimal monitoring schedule for these patients has not yet been ascertained. However it seems logical to perform regular measurement of HBsAb, HBsAg titers and HBV DNA after each cycle of chemotherapy since changes in these parameters are likely to precede changes in ALT and the development of clinically important hepatitis; this would allow antiviral treatment to be commenced in a timely fashion. Recipients of hematopoietic stem cell transplants selleck chemical positive for HBcAb are likely to undergo seroreversion; they are then at risk of HBV reactivation. These patients should probably be treated with prophylactic lamivudine, as for the HBsAg-positive patients. Chemotherapy-induced reactivation of hepatitis B may result in severe liver injury and prevent completion of life-saving treatment of the underlying malignancy. This potentially fatal complication can be effectively prevented by the use of oral antiviral medication prior to commencing

chemotherapy. It is therefore paramount that all patients receiving intensive chemotherapy be screened for HBV. Most of the experience with antivirals in this setting has centered on lamivudine. Although drug resistance is a problem with long-term use of this drug, it has proven to 上海皓元 be safe, well tolerated and highly effective in preventing HBV reactivation. All those involved in the use of immunosuppressive chemotherapy should be aware of the risk of HBV reactivation and understand the principles of prevention or management of this condition. Finally, it is very likely that alternative antiviral agents such as entecavir and tenofovir, will prove at least as effective as lamivudine however, they are currently more expensive and there is a need for further research to confirm their cost-efficacy in this setting. “
“The hemodynamics of patients with portal hypertension within 4 h after a single injection of terlipressin has been studied. However, the hemodynamics in a longer phase under different infusion styles is unknown.

Patients receiving lamivudine prophylaxis should be monitored wit

Patients receiving lamivudine prophylaxis should be monitored with serial HBV DNA assays, and formal testing for lamivudine resistance should be performed if there is a 1 log increase in HBV DNA.86 Once resistance is confirmed, patients should be given adefovir in addition to lamivudine

or changed to tenofovir if this is available. Patients receiving intensive chemotherapy who are positive for HBcAb but HBsAg negative should have a sensitive HBV DNA assay performed to determine whether they have occult HBV infection. If HBV DNA is detected, these patients should be treated as for positive-HBsAg patients. Patients with undetectable ABT-263 concentration HBV DNA should be monitored regularly during chemotherapy for evidence of HBV reactivation.

The optimal monitoring schedule for these patients has not yet been ascertained. However it seems logical to perform regular measurement of HBsAb, HBsAg titers and HBV DNA after each cycle of chemotherapy since changes in these parameters are likely to precede changes in ALT and the development of clinically important hepatitis; this would allow antiviral treatment to be commenced in a timely fashion. Recipients of hematopoietic stem cell transplants Caspase inhibition positive for HBcAb are likely to undergo seroreversion; they are then at risk of HBV reactivation. These patients should probably be treated with prophylactic lamivudine, as for the HBsAg-positive patients. Chemotherapy-induced reactivation of hepatitis B may result in severe liver injury and prevent completion of life-saving treatment of the underlying malignancy. This potentially fatal complication can be effectively prevented by the use of oral antiviral medication prior to commencing

chemotherapy. It is therefore paramount that all patients receiving intensive chemotherapy be screened for HBV. Most of the experience with antivirals in this setting has centered on lamivudine. Although drug resistance is a problem with long-term use of this drug, it has proven to medchemexpress be safe, well tolerated and highly effective in preventing HBV reactivation. All those involved in the use of immunosuppressive chemotherapy should be aware of the risk of HBV reactivation and understand the principles of prevention or management of this condition. Finally, it is very likely that alternative antiviral agents such as entecavir and tenofovir, will prove at least as effective as lamivudine however, they are currently more expensive and there is a need for further research to confirm their cost-efficacy in this setting. “
“The hemodynamics of patients with portal hypertension within 4 h after a single injection of terlipressin has been studied. However, the hemodynamics in a longer phase under different infusion styles is unknown.

S31) Moreover, the decline

in annual survival rate afte

S3.1). Moreover, the decline

in annual survival rate after 2004 in the year model was not statistically significant, though in the age model, decline after age 17 was. In males, however, the year model produced a better fit to data than the age model (Fig. S3.2). Nevertheless, the survival-year model added information, because it revealed fluctuations in young Cell Cycle inhibitor animals not evident in the age model (Appendix S3). Survival was high in 1986, low in 1987, then increased until 1989 before settling on a long plateau (Fig. S3.3). The 1986–1986 variation was a cohort effect: first-year survival was high for the 1985 cohort relative to the 1986 and 1987 cohorts in both males and females. The cohort difference, however, did not persist in older

animals (Fig. S3.1, Fig. S3.2). The age model produced an intermediate estimate for first-year survival, averaging the three cohorts. Annual survival of adult females was high from age BGB324 5 to 16, averaging 86%/yr, but then declined abruptly. This is a higher rate and a longer duration of prime survival than we expected and the first evidence for senescence in survival rates of northern elephant seals. Our earlier work did not detect the decline in female survival because there were no data on females older than 15 yr (Le Boeuf and Reiter 1988, Reiter and Le Boeuf 1991). Schwarz et al. (2012) found limited power in estimating survival beyond age 15 due to the small number of animals retaining tags. Average male survival was <72%/yr at all ages and lower than female survival after age 3, as reported in earlier studies (Clinton and Le Boeuf 1993). Neither our MCE current analysis nor the earlier work detected senescence in male survival, but high mortality throughout life meant few males were still living at age 12 when senescence would be most likely. On the other hand, our earlier study did detect declining competitive ability in males past age 12 (Clinton and Le Boeuf 1993). Juvenile survivorship in the current study was 31% from weaning to

age 3 and similar in the two sexes, a rate close to the average reported across several previous cohorts (Le Boeuf and Reiter 1988, Le Boeuf et al. 1994). This average masked variation, however, and low survival in 1986–1987 may have been due to poor foraging conditions associated with an El Niño event (Trenberth and Stepaniak 2001, Crocker et al. 2006). Our earlier study of juvenile survival also described substantial year-to-year fluctuations (Le Boeuf et al. 1994). These rates of survivorship, though, began at weaning and omit pup mortality, and 10% of pups in the Año Nuevo mainland colony died before weaning in 1985–1987 (Le Boeuf et al. 2011). In population modeling, the relevant rate of juvenile survivorship (from birth) was thus 28%, not 31%. Dispersal of branded animals to nearby colonies—“prospecting” for alternative breeding sites—also confirms earlier observations (Le Boeuf et al. 1974, 2011).

7C,F) As noted in the whole livers, the mRNA expression levels o

7C,F). As noted in the whole livers, the mRNA expression levels of collagen 1α1, collagen 1α2, and α smooth muscle actin (αSMA) were significantly increased in HSCs from the MCD and HF diet-fed groups compared with the corresponding control diet-fed groups. These increases were significantly enhanced by the increased intake of cholesterol (Fig. 1A,D). The mRNA expression levels of PPARγ1 in HSCs were significantly lower in the MCD and HF diet-fed groups than in the corresponding control diet-fed groups. In addition,

these decreases were significantly enhanced by the increased intake of cholesterol (Fig. 1A,D). Contrarily, the mRNA expression levels of SREBP2 were significantly higher in HSCs learn more from the MCD and HF diet-fed groups than in those from the corresponding control diet-fed groups, and these increases were significantly enhanced by the increased intake of cholesterol (Fig. 1A,D).

The total and nuclear protein levels of PPARγ were lower in HSCs from the MCD and HF diet-fed groups than in those from the corresponding control diet-fed groups and these decreases were significantly enhanced by the increased intake of cholesterol (Fig. 1B,E). Meanwhile, the levels of the nuclear form of SREBP2 were significantly higher in HSCs from the MCD and HF diet-fed groups than in those from the corresponding control diet-fed groups. Furthermore, these increases were significantly enhanced by the increased intake of cholesterol (Fig. 1B,E). Similar to SREBP2 expression, the expression levels of LDLR and miR-33a in HSCs were significantly higher buy RXDX-106 in the MCD and HF diet-fed groups than in the corresponding control diet-fed groups. These increases were significantly enhanced by the increased intake of cholesterol (Fig. 1C,F). The total and nuclear forms of PPARγ were abundant in day 1 (quiescent) HSCs but declined in day 3 and 5 (activating) and day 7 (activated) HSCs (Fig. 2A). Meanwhile,

the nuclear form of SREBP2 was scarce in day 1 HSCs, and its expression increased 上海皓元 at days 3 and 5, and day 7 HSCs (Fig. 2A). Correspondingly, the PPARγ1 and SREBP2 mRNA expression levels were similar to the protein expression levels (Fig. 2A). Furthermore, the expression levels of LDLR and miR-33a in HSCs increased along with their activation (Fig. 2B). PPARγ-siRNA treatment significantly increased the expression levels of SREBP2, LDLR, and miR-33a in quiescent HSCs (Fig. 2C). Similarly, treatment with the PPARγ antagonist significantly increased the expression levels of SREBP2, LDLR, and miR-33a in quiescent HSCs in a dose-dependent manner (Fig. 2D). On the other hand, overexpression (O/E) of PPARγ1 significantly decreased the levels of SREBP2, LDLR, and miR-33a expression in activated HSCs (Fig. 2E). SREBP2-siRNA treatment significantly decreased the mRNA expression level of LDLR (Fig. 2F).

These recent discoveries will not only drive functional studies b

These recent discoveries will not only drive functional studies but will also hold the promise of developing novel this website disease-specific treatments. (HEPATOLOGY 2011;) Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by progressive destruction of small and medium size intrahepatic bile ducts, leading to cirrhosis and ultimately liver transplantation or death.1 PBC has an

estimated prevalence of 1 in 1000 in women over the age of 40, and ursodeoxycholic acid is the only approved therapy.2 The pathogenesis of PBC is clearly autoimmune,3 as indicated by specific serum- and cell-mediated responses against defined epitopes of self antigens, and by a striking female predominance (female-to-male ratio of approximately 10 to 1). In addition, epidemiological data indicate that family members of patients have an increased risk of developing PBC or another

autoimmune disorder. On the basis of these considerations, the current hypothesis on the etiopathogenesis of PBC implies that this disease is the result of a genetic predisposition that is PS-341 cost permissive for a still unknown environmental agent, possibly xenobiotic or infection.1 For decades, PBC has been considered to have a unique genetic background when compared to other autoimmune diseases because of the strong familial clustering but weak associations with genetic polymorphisms.4 Indeed, despite numerous candidate-gene association studies that were performed, no conclusive data on specific genes have been obtained. In addition,

it is worth noting that linkage analysis was poorly feasible in PBC based on the advanced age at diagnosis and the rarity of the disease. In contrast, recent evidences have strengthened the importance of genetic susceptibility in determining disease onset and severity, including a role for sex chromosome abnormalities in affected women5, MCE公司 6 and high concordance for disease in monozygotic twins.7 The human leukocyte antigen (HLA) loci, located in the major histocompatibility complex (MHC), are the most genetically diverse loci in the human genome8 (Fig. 1). HLA genes encode cell-surface molecules that by means of peptide presentation mediate key immunological events, such as definition of self-tolerance or cellular immune responses to tumors and pathogens.9, 10 Similar to other genetically complex diseases,11 HLA has been extensively studied in PBC, but for decades data have cumulatively suggested only a weak association with the class II HLA DRB1*08 allele.4 This was likely because early studies had several potential limitations: (1) insufficient statistical power due to inadequate sample sizes, (2) lack of careful matching between cases and controls, (3) earlier studies did not rely on molecular analysis, and (4) multiple replications have rarely been carried out.