Whereas malonyl-CoA produced by ACC1 could be used for DNL, malonyl-CoA generated by ACC2 could specifically serve as a CPT1 inhibitor.125 Experimental and clinical investigations showed increased hepatic mtDNA levels during fatty liver,73,79,126,127 although other studies showed reduced mtDNA content (Table 1).123,128,129 Hepatic mtDNA levels could depend on the severity of lipid overload123 and/or oxidative stress.128,129Discrepancies also exist regarding MRC activity (i.e., electron transfer), mitochondrial

respiration (i.e., oxygen consumption), and OXPHOS efficiency (Table 1). For instance, COX activity was either increased,130 normal,82,88,127,131 or moderately reduced.86,132 Oxygen consumption in isolated liver mitochondria with adenosine diphosphate (ADP) (i.e., state 3 respiration) and different substrates was either augmented,53 unchanged,82,88,131,133,134 Protein Tyrosine Kinase inhibitor or significantly reduced (but H 89 molecular weight with mild to moderate decreased respiration).73,76,77,86,127,135 OXPHOS efficiency and the mitochondrial membrane potential

ΔΨm were either increased,64,76,86,88 unchanged,131,133 or decreased,136 which could reflect OXPHOS uncoupling. Increased OXPHOS efficiency could be an adaptive mechanism to produce more ATP that is needed to promote DNL and gluconeogenesis.64 Finally, hepatic ATP levels were either unchanged,130,137 or moderately decreased.132,138,139 The noninvasive functional test with ketoisocaproic acid (KICA) has been used to assess mitochondrial function in patients with Methocarbamol NAFLD. KICA is a leucine catabolite which enters mitochondria to be fully degraded into H2O and CO2.140 In one study, 13C-KICA decarboxylation was unchanged in patients with simple steatosis but it was significantly impaired in NASH.141 In another study, 13C-KICA decarboxylation was unaffected in patients with nonalcoholic fatty liver, while it was significantly reduced in patients with alcoholic steatosis.142 Altogether, these data suggest that some, but not all, of the mitochondrial metabolic pathways are able to adapt to fat overload in liver. The discrepancies between the above-mentioned

studies regarding mtDNA levels, MRC activity, OXPHOS efficiency, and ATP levels could be due to differences in the severity of fatty liver and oxidative stress. Accordingly, reduced mtDNA levels and impairment of MRC and OXPHOS seem to be more consistently observed in fatty liver induced by a choline-deficient (CD) diet, which is associated with overt oxidative stress.128,134,143-146 Since numerous investigations have been performed in genetic leptin-deficient ob/ob mice and leptin-resistant db/db mice, a specific section is dedicated to these murine models of mild to moderate steatohepatitis. Indeed, liver lesions in these mice are characterized by moderate hepatic necroinflammation and mild fibrosis,147-150 in addition to steatosis, which is more severe in the ob/ob genotype.

All patients underwent

endoscopic biopsies from Vater’s ampulla and the common bile duct. Biopsied specimens were histologically examined using immunostaining for IgG4. Results:  For the ampullary and bile duct biopsies, the IgG4-SC samples had a significantly greater number RGFP966 order of IgG4-positive plasma cells than the PSC or pancreatobiliary carcinoma specimens. In addition, bile duct biopsies from five patients (17%) with IgG4-SC showed diffuse inflammatory cell infiltration with irregular fibrosis corresponding to the histological features of lymphoplasmacytic sclerosing pancreatocholangitis. Based on the threshold of 10 IgG4-positive plasma cells per high power field, the diagnostic rates of the ampullar and bile duct biopsies were both 52% (15/29 cases). Twenty-one patients (72%) had more than 10 IgG4-positive plasma cells in at least one biopsy. The bile duct biopsy was significantly valuable for IgG4-SC patients with swelling of the pancreatic head. Conclusion:  The present study suggested that ampullar and bile duct biopsies are useful for diagnosing IgG4-SC. Autoimmune pancreatitis (AIP) is characterized by swelling

of the pancreas, irregular stenosis of the pancreatic duct, high serum immunoglobulin (Ig) G4 concentrations and steroid sensitivity.1,2 IgG4-related diseases including AIP have characteristic pathological features, such as diffuse lymphoplasmacytic infiltration, irregular fibrosis, occasional eosinophil infiltration, obliterative phlebitis and many IgG4-positive plasma cells.3–5 AIP is commonly associated with sclerosing cholangitis, which is also called IgG4-related sclerosing cholangitis selleck products or IgG4-associated cholangitis.6,7 Much attention has focused on discriminating between AIP with cholangitis and primary sclerosing cholangitis (PSC) or pancreatobiliary malignancies, from both clinical and academic aspects.8–10 Distinguishing between

these two conditions is important because their therapeutic strategies are completely different.11 In clinical situations, imaging and serological examinations, such as testing serum IgG4 levels, are carried out to discriminate these two conditions. However, in some cases, a pathological diagnosis is necessary for a definitive diagnosis. The needle biopsy is one tool that can be used to pathologically L-gulonolactone oxidase examine the pancreas. However, interpreting the results is sometimes difficult as a result of the small specimen size and the heterogeneous distribution of inflammation in AIP.12,13 Recently, several groups reported that IgG4 immunostaining of endoscopic biopsies from Vater’s ampulla is useful for diagnosing AIP.14,15 The number of IgG4-positive plasma cells in ampullar biopsies for AIP was significantly higher than those for PSC or pancreatobiliary malignancies. Sepehr et al. also suggested that ampullary biopsies might be useful for assessing IgG4-positive plasma cells based on pathological examinations of surgically resected specimens.

Halting the intra-articular accumulation of blood is essential to abbreviate these processes, and standard therapy for a joint haemorrhage is to replace clotting factor until evidence of ongoing bleeding has stopped. Nevertheless, achieving haemostasis cannot be expected to arrest inflammation once initiated. Iron deposition, inflammation and neoangiogenesis likely continue for prolonged periods after the cessation of haemorrhage and contribute to increased

risk of recurrent haemorrhage. There is limited data evaluating whether adjunctive therapy with anti-inflammatory agents Maraviroc supplier can augment replacement clotting factor concentrates to improve joint outcomes. To our knowledge, the only prospective, randomized controlled studies in humans with haemophilia that have examined the addition of anti-inflammatory

agents to clotting factor in the treatment of haemarthrosis have used short courses of oral corticosteroids. This approach led to lower amounts of factor replacement needed to achieve return Everolimus ic50 of joint function in one report in which 5 days of prednisolone treatment was used [24]. Another report using only 2 days of oral prednisolone, and conducted exclusively in inhibitor patients, failed to demonstrate a benefit [25]. Several non-controlled series report partial amelioration of chronic synovitis using intra-articular corticosteroids [26–28]. Like corticosteroids, non-steroidal anti-inflammatory agents (NSAIDs) are important in the chronic management of rheumatoid arthritis, which is the archetypal inflammatory arthritis. Bleeding due to NSAID-related platelet dysfunction limits the use of NSAIDs for most individuals with haemophilia to the cyclooxygenase 2 (COX-2) inhibitors. Uncontrolled series report that COX-2 inhibitors

improve patient-reported and subjective symptoms in chronic synovitis [4,29,30]. Our group has examined the addition of a short-course of a TNF-α receptor antagonist (etanercept, given as a course of 10 doses) to factor replacement in both haemophilia A and haemophilia B mice with induced recurrent knee bleeding using a joint capsular puncture model. In each of Tryptophan synthase these haemophilic strains, if the TNF-α antagonist is begun early in the course of developing synovitis, the presence of joint pathology examined 3–4 weeks after the induced haemorrhages was strikingly better than control mice receiving only clotting factor replacement at the time of haemorrhage or clotting factor with dexamethasone [3]. In further proof-of-concept experiments, we investigated combining MR16-1, a rat IgG-blocking antibody directed against mouse IL-6 receptor (anti IL-6R), with factor VIII (FVIII) replacement to protect against inflammatory sequelae of haemarthrosis in haemophilia A mice.

The divergent findings between the two studies may be secondary to differences in what constituted a nutritionally deprived

cell-culture medium. The findings from this study elevate the importance of the lysosome in autophagy from a passive dumping site for autophagosomal contents to an actively regulated component of the autophagic process. Coordinated Anti-infection Compound Library up-regulation of both lysosomes and autophagosomes might prevent the problem of generating too many cargo-filled autophagosomes that overwhelm the degradative capacity of lysosomes. A mismatch between the numbers of autophagosomes and lysosomes could have dire consequences for the cell. The study emphasizes the need to focus more on whether defects in autophagy are secondary to lysosomal problems and, possibly, TFEB. Steatosis inhibits autophagic function in hepatocytes, 10 and this decrease in autophagy has been attributed to both defects in autophagosome/lysosome fusion 11 and

decreased expression of ATGs. 12 It is possible that defects in TFEB regulation contribute to a multifactorial impairment in autophagic function in fatty liver disease. The study by Settembre et al. 7 also delineates another critical Tamoxifen purchase function for MAPK signaling. Studies in nonhepatic cells have shown that the MAPK c-Jun N-terminal kinase (JNK) up-regulates autophagy through phosphorylation of Bcl-2 family members, 13 although the existence of this pathway in hepatocytes, which lack Bcl-2, remains unproven. ERK1/2 and JNK, which are frequently activated in tandem by cellular stresses, may counterbalance each other’s effect on autophagy. That

ERK1/2 down-regulates autophagy contradicts the concept Bacterial neuraminidase of ERK1/2 signaling as cytoprotective, because autophagy generally promotes survival. Interestingly, although oxidant stress is considered a major inducer of autophagy, hepatocyte oxidant stress associated with ERK1/2 activation failed to increase levels of autophagy. 14 The effects of JNK and ERK1/2 on autophagic function specifically in hepatocytes need to be examined. The study does not provide direct evidence that endogenous TFEB regulates hepatocyte autophagy in vivo; however, this is likely given the strong evidence of TFEB function and TFEB’s high expression in liver. 15 However, hepatocyte knockout/knockdown studies of TFEB need to be performed. Whether TFEB mediates increases in autophagy to stimuli other than starvation also needs to be examined. Recently, a chemical stimulator of autophagy has been shown to be an effective treatment for murine α1-antitrypsin deficiency. 16 A number of other hepatic diseases, including nonalcoholic and alcoholic fatty liver disease, viral hepatitis, and liver cancer, may benefit from autophagy-directed therapies. 1 By establishing a central role for TFEB in the regulation of autophagy, this study identifies this protein as a potential therapeutic target.

Comparison of Wilate to a previous VWF-containing concentrate revealed similar VWF activity profiles. However, there were differences. Higher peak factor VIII levels were observed

(as expected given the higher dose of FVIII in Wilate) and there was some variation in FVIII elimination curves. Factor VIII in the historical VWF concentrate showed an initial plateau phase prior to the decay curve – a phenomenon not seen in the pharmacokinetic studies using Wilate. From their pharmacokinetic studies Austin et al. were able to individualize a patient’s treatment regimen and to optimize therapy for planned prophylaxis or surgery. They observed that optimal levels of VWF and factor VIII could generally be attained with Wilate using a dose of 20–60 IU kg−1 in steady state. Most importantly their results indicate a relevant interindividual variability of pharmacokinetic find more parameters in the VWD population and enabled them click here to remove some of the unpredictability associated with effective dosing. It is clear that pharmacokinetic studies provide valuable information for dosing and dosing frequency of VWF concentrate, and are useful in the familiarization phase of using newer VWF concentrates in the VWD patient population. In a prospective,

randomized crossover study, Kessler et al. observed significant pharmacokinetic diversity of FVIII in VWD patients treated with

two different von Willebrand (VWF)/factor VIII (FVIII) concentrates [62]. Possible underlying mechanisms for the different FVIII kinetics were discussed, but remained unclear. Based on the fact that a main difference between the evaluated VWF/FVIII concentrates was their VWF:RCo/FVIII:C-ratio, the hypothesis of VWF-dependent FVIII clearance was evaluated in detail. The main clearance mechanism of FVIII is still largely unclear Resveratrol although clearance via the LRP receptor, asialo GP receptor and by protease cleavage has been suggested [71]. At least the latter is restricted to free FVIII, i.e. the very low amount of less than 5% VWF-unbound FVIII circulating in plasma. The major fraction of circulating FVIII, above 90%, is bound to VWF with very high affinity of around KD 0.2 nm. Although not evaluated in detail, there are no data implying that the VWF-bound FVIII dissociates from VWF before or during the clearance event of VWF, which is strongly suggestive of co-clearance of VWF-bound FVIII. With regard to VWF clearance, van Schooten et al. [72] demonstrated that VWF uptake by macrophages in the liver contributes to VWF clearance in vivo. VWF clearance has been shown to take place independent of multimeric size [73] and proteolytic cleavage by ADAMTS13 seems not to contribute to VWF clearance [74].

CCP has been associated with a variety of disease, including solitary rectal ulcer syndrome, rectal prolapse, inflammatory bowel disease, diverticulitis, radiation, and infectious colitis. In addition, CCPs accompanied by colonic adenoma or adenocarcinoma have been reported. It is possible that the mucin pool within the stalk stump in this case DAPT cost could have resulted from deeper-placed epithelial glands being forced into the submucosa. A possible mechanism is trauma from torsion of pedunculated polyps, resulting in a mechanical disruption at the base of the adenoma. However, the exact etiology of CCP is

still unknown. In the present case, there were no complications, such as delayed bleeding or perforation. Follow-up selleck colonoscopy revealed no remarkable findings six months after the polypectomy. “
“We read with interest the article by Komuta et al.1 showing large differences in clinical-pathological features of intrahepatic cholangiocarcinomas (ICCs) arising from columnar mucin-producing cholangiocytes lining large bile ducts versus ones arising from cuboidal non mucin-producing cholangiocytes located in or near canals of Hering, comprised of human hepatic stem cells (hHpSCs) that are lineage-restricted to hepatocytes and cholangiocytes. These results are

in keeping with previous studies dealing with the pathological, epidemiological, and clinical heterogeneity of cholangiocarcinomas (CCs)2, 3 and with the biological mechanisms underlying this heterogeneity.4 Indeed, Komuta et al. demonstrated that multiple cells of origin determine CC clinical-pathological differences and suggested that mixed-ICC and cholangiolocarcinoma (CLC) are completely

separate entities with respect to the pure mucin-producing ICC (muc-ICC). Recently, Nakanuma and Sato5 provided evidence that peribiliary glands (PBGs) could be involved in the origin of intraductal papillary neoplasms GNAT2 of the bile duct, a preneoplastic lesion of muc-ICC. This confirms that human biliary tree stem cells (hBTSCs), residing in PBGs,6 are probable cells of origin of muc-ICCs. The results by Komuta et al.,1 together with advances with respect to stem cell biology,6, 7 and the relationship between tumor types and their normal stem cell counterparts,4 enable a CCs classification based on cells of origin. Hypothetically, the mixed-ICCs originate from cells from hHpSC-derived lineages,7 whereas pure mucin-producing CCs (intra- and extrahepatic) originate from hBTSC-derived lineages. Based on the grade of maturation of the cell of origin within the two lineages, CCs can be reclassified as: CCs with focal hepatocytic differentiation from hHpSC-derived lineages: combined hepatocellular-cholangiocarcinoma, mixed-CC, and CCL. Pure mucin-producing CCs from hBTSC-derived lineages in PBGs or from epithelium of intra- or extrahepatic large bile ducts: hilar CC and muc-ICC.

Unfortunately, routine imaging of the head at birth is not a standard practice. A single institution study reported ICH in 3/20 Selleck Adriamycin (15%) newborns, detected on radiological screening obtained immediately following diagnosis; all were delivered by instrumental delivery and had no family history of haemophilia [29]. The Hemophilia

Growth and Development study found abnormal MRIs in 20% of children with haemophilia and 50% silent ICH [30]. In the UDC data, 22/633 newborns (3.47%) had an ICH associated with delivery. The most common sites were subdural (68.2%), intracerebral (13.6%), cerebellar (9%) and 4.6% each of subarachnoid and ventricular. Nineteen were diagnosed by CT imaging and only one by an ultrasound of the head. Table 3 shows the relationship between family history, maternal carrier status, mode of delivery and ICH in 612 newborns with haemophilia with complete

delivery information. Among the three groups, there was no statistically significant difference in the occurrence of ICH based on the method of delivery. However, Table 4 shows that when the newborns were grouped by presence or absence of family history, ICH occurred more in vaginal births than C-S births. While most subdural haemorrhages in non-haemophilic newborns resolve by 4 weeks [23], the natural history of check details delivery-associated ICH and the long-term consequences and recurrence rates in haemophilic newborns are not known. In the UDC data, two (9%) of the 22 newborns with ICH had long-term neurological effects including focal deficits and seizure disorders. Eyster et al. [31] reported a 26% rate of rebleeding in ICH (all ages). ICH related mortality rates in newborns have ranged from 27% to 30% [31,32]. Recombinant products were the most common product (398/633) used. In addition, 20 infants were administered fresh frozen plasma, packed cells or whole blood. Of these, three also received cryoprecipitates.

Inhibitors, while rare, have been reported to occur in the newborn period. Risk factors included haemophilia severity, intron 22 inversions and intensity of factor tuclazepam exposure [33,34]. There are little data regarding inhibitor development and risk factors in newborns with haemophilia B. Among the 633 newborns in UDC, five infants developed an inhibitor in the newborn period (four were FVIII deficiency); three were low and two were high titre and three began immune tolerance before 1 month of age. In summary, the UDC data highlights the fact that while the diagnosis of haemophilia is being made at an early age, bleeding events still predominate as the diagnostic trigger in newborns. Prospective studies are needed to: (i) determine optimal mode of delivery of carrier mothers and those with a family history of haemophilia, (ii) identify asymptomatic and symptomatic ICH preferably using bedside screening MRIs, and (iii) determine risks and benefits of instituting long-term prophylaxis at birth.

Unfortunately, routine imaging of the head at birth is not a standard practice. A single institution study reported ICH in 3/20 selleck compound (15%) newborns, detected on radiological screening obtained immediately following diagnosis; all were delivered by instrumental delivery and had no family history of haemophilia [29]. The Hemophilia

Growth and Development study found abnormal MRIs in 20% of children with haemophilia and 50% silent ICH [30]. In the UDC data, 22/633 newborns (3.47%) had an ICH associated with delivery. The most common sites were subdural (68.2%), intracerebral (13.6%), cerebellar (9%) and 4.6% each of subarachnoid and ventricular. Nineteen were diagnosed by CT imaging and only one by an ultrasound of the head. Table 3 shows the relationship between family history, maternal carrier status, mode of delivery and ICH in 612 newborns with haemophilia with complete

delivery information. Among the three groups, there was no statistically significant difference in the occurrence of ICH based on the method of delivery. However, Table 4 shows that when the newborns were grouped by presence or absence of family history, ICH occurred more in vaginal births than C-S births. While most subdural haemorrhages in non-haemophilic newborns resolve by 4 weeks [23], the natural history of LY2157299 delivery-associated ICH and the long-term consequences and recurrence rates in haemophilic newborns are not known. In the UDC data, two (9%) of the 22 newborns with ICH had long-term neurological effects including focal deficits and seizure disorders. Eyster et al. [31] reported a 26% rate of rebleeding in ICH (all ages). ICH related mortality rates in newborns have ranged from 27% to 30% [31,32]. Recombinant products were the most common product (398/633) used. In addition, 20 infants were administered fresh frozen plasma, packed cells or whole blood. Of these, three also received cryoprecipitates.

Inhibitors, while rare, have been reported to occur in the newborn period. Risk factors included haemophilia severity, intron 22 inversions and intensity of factor PDK4 exposure [33,34]. There are little data regarding inhibitor development and risk factors in newborns with haemophilia B. Among the 633 newborns in UDC, five infants developed an inhibitor in the newborn period (four were FVIII deficiency); three were low and two were high titre and three began immune tolerance before 1 month of age. In summary, the UDC data highlights the fact that while the diagnosis of haemophilia is being made at an early age, bleeding events still predominate as the diagnostic trigger in newborns. Prospective studies are needed to: (i) determine optimal mode of delivery of carrier mothers and those with a family history of haemophilia, (ii) identify asymptomatic and symptomatic ICH preferably using bedside screening MRIs, and (iii) determine risks and benefits of instituting long-term prophylaxis at birth.

We mimicked dietary exposures of obese children, utilizing a Westernized diet (WD) that was both high in dietary fat and contained high-fructose corn syrup (HFCS), to generate diet-induced obesity combined with a VitD depleted condition (WD+VDD). Our central hypothesis was that VDD contributes to IR, hepatic necroinflammation, and may result in NASH in diet-induced obesity. ALK, alkaline phosphatase; Z-VAD-FMK solubility dmso GTT, glucose tolerance test; HFCS, high-fructose corn syrup; H&E, hematoxylin-eosin; HO-1, heme oxygenase-1;

IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor α; IKKB, inhibitor of kappa B kinase; IL, interleukin; IR, insulin resistance; ITT, insulin tolerance test; JNK, c-Jun-N-terminal kinase; LFD, low-fat diet; LPS, lipopolysaccharide; LBP, LPS binding protein; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD Activity Score; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor kappa B; PPARγ, peroxisome proliferator activated receptor γ; SOCS3, suppression of cytokine signaling 3; TIRAP, Toll/interleukin-1 receptor adaptor protein; T2DM, type 2 diabetes mellitus; TLR, Toll-like receptor; TNFα, tumor necrosis factor α; VDD, vitamin D deficiency;

VitD, vitamin D; WD, Westernized diet. Weanling (25 days old at start of diets) male Sprague-Dawley rats (Charles River selleck chemicals Laboratories, Wilmington, MA) were randomly assigned test groups and housed in pairs. Rats had a 12-hour light/dark cycle and provided ad libitum access to assigned diet and water. Additionally, WD (HFCS+HFD) groups had continuous access to a separate bottle with HFCS-55 (HFCS-55: 55% fructose, 45% glucose diluted with water to 12.5%, 0.375 kcal/mL solution). Custom rodent diets were purchased from Research Diets (New Brunswick, NJ), with 10% (LFD) or 45% (HFD) total kcal from fat (soybean oil and lard); similar amounts of maltodextrin, no sucrose, and 57% (LFD) or 22% (HFD) total kcal from cornstarch. Vitamin D3 content was either normal (1,000 IU Vitamin D3/4,057 kcal) or depleted

(25 IU Vitamin D3/4,057 kcal) adjusting the latter to approximately 30% of controls 3-mercaptopyruvate sulfurtransferase to mimic VDD in children without reaching levels that may create rickets.12-14 In VDD groups the ultraviolet section of light (290-315 nm) was filtered from the room. This strategy produced a reduction of 25(OH)D levels to 26% of normal after 14 days and reached 29% of normal at 70 days in VDD animals (95% confidence interval [CI]: 23%-36%, mean 25-(OH)D levels were 4.8 ± 1.3 ng/mL in VDD groups and 13.3 ± 0.6 ng/mL in controls (LFD) (see Supporting Fig. 1). Body weight and food intake measures were recorded daily. Blood was collected from trunk (final measures) following a 12-hour fast. After euthanizing the rats, livers and epididymal fat pads were quickly excised, weighed, and an aliquot was snap-frozen.

12 (0.07-0.21) and 0.90 (0.58-1.41). However, the significantly increased incidence rates BI 2536 solubility dmso were not observed for other subtypes. Women seropositive for HBsAg had relatively minor increases in the incidence rate of “small lymphocytic lymphoma and mantle cell lymphoma” and “mycosis fungoides

and Sezary’s disease” than HBsAg-seronegative women. On the contrary, the incidence rates of follicular lymphoma and peripheral T-cell lymphoma were higher among HBsAg-seronegative women compared with HBsAg-seropositive women. All eight cases of Burkitt lymphoma and the single case of NK/T-cell lymphoma were HBsAg-seronegative, whereas the single case of lymphoplasmacytic lymphoma was HBsAg-seropositive. Table 3 shows age-adjusted HR of ICC, NHL, and NHL subtypes comparing HBsAg-seropositive with HBsAg-seronegative parous women. The cumulative incidence of ICC, NHL overall, and diffuse large B-cell lymphoma are presented in Figs. 1, 2, and 3, respectively. Risks of these see more three cancers were higher in HBsAg-seropositive than in HBsAg-seronegative women throughout the period of follow-up. The risk for ICC among HBsAg-seropositive women was nearly 5-fold that among HBsAg-seronegative women (HR, 4.80; 95% CI, 1.88-12.20; Fig.

1). The risk for NHL was less strong but still more than double among HBV-infected women compared with HBV-uninfected women (HR, 2.63; 95% CI, 1.95-3.54; Fig. 2); stronger association was observed for diffuse large B-cell lymphoma (HR, 3.09; 95% CI, 2.06-4.64; Fig. 3) and other NHL (7.63; 3.70-15.74). On the contrary, the HBsAg serostatus was not associated with other major NHL subtypes, including follicular lymphoma, peripheral T-cell lymphoma, small lymphocytic lymphoma and mantle cell lymphoma, and mycosis Clomifene fungoides and Sezary’s disease. After considering both HBsAg and HBeAg serostatus, compared with noncarriers, the HRs of carriers with HBeAg-seropositivity were higher than the HRs

of those with HBeAg-seronegativity for ICC, NHL overall, and diffuse large B-cell lymphoma. The corresponding age-adjusted HRs (95% CI) were 9.58 (2.54-36.04) and 5.40 (1.79-16.25) for ICC; 3.46 (2.08-5.75) and 2.20 (1.45-3.33) for NHL overall; and 4.66 (2.44-8.88) and 2.29 (1.28-4.10) for diffuse large B-cell lymphoma. However, the differences in age-adjusted HRs between HBeAg-seropositive and HBeAg-seronegative women were not statistically significant. The main finding of this nationwide, population-based retrospective cohort study of parous women from Taiwan was the substantially increased risk for ICC and NHL associated with markers of chronic HBV infection. Furthermore, with the large number of NHL cases with subtype information identified in this large population, we were able to demonstrate that HBV infection was most strongly associated with an increased risk of diffuse large B-cell lymphoma, but not with other specific NHL subtypes.