Some intermediate hepatocytes at portal tract/parenchyma interface were positive for MMP-2 and revealed intercellular junctions with HPCs. A closely spatial association between HPCs and singly vimentin-positive cells in DRs was recognized, although the cells with co-expression Selleckchem Sorafenib of vimentin and NCAM were not identified. Cells with epithelial phenotype were negative for αSMA while some fibroblast-like cells expressing αSMA were present around DRs. CD4 and TGFβ positive Cells surrounding

DRs increased parallel with the severity of inflammation and fibrosis. Neither HPCs nor cells with EMT in the control group were found. Conclusion: HPCs occur from cholangiocytes in DRs and contribute to hepatic

fibrosis via EMT in hepatitis B virus-related liver diseases. To mesenchymal or to hepatocytic differentiation of HPCs depends on, at least in part, the adjustment of microenvironment TGFβ, presenting by infiltrating CD4+ T-cells responding to HBV infection. Key Word(s): 1. HBV; 2. progenitor cell; 3. EMT; 4. liver; Presenting Author: YONGWEI LI Additional Authors: MINGFEN ZHU, GANG LI Corresponding Author: YONGWEI LI Affiliations: the Third Affiliated Hospital of Sun Yat-sen University; the Sixth Hospital of Shanghai Jiao Tong University; the Third see more Affiliated Hospital of Sun Yat-sen University Objective: Hepatitis B virus (HBV) uses heparan sulfate proteoglycans (HSPG) for its initial attachment to hepatocytes[1], but little is known about proteoglycans in HBV infection. Methods: Full-length HBV genomes from four patients with chronic HBV infection were cloned as our prior methods [2]. HBV genomes were transfected to HepG2 cells with

Lipofectamine™ 2000. An integrative genomic analysis was performed in HepG2 cells respectively transfected with the four HBV genomes, HepG2.215 cells and HepG2 cells using Affymetrix Human Genome U133 Plus 2.0 Array (HG-U133_Plus_2). Differentially expressed genes were identified by relative quantitative PCR. Results: Of 47,000 transcripts and variants on the gene chip, serglycin was one of the most significantly altered genes. The levels of serglycin were significantly upregulated in the HepG2 cells Selleckchem Sirolimus transfected with HBV genomes, but downregulated in HepG2.215 cells. Conclusion: Different HBV infection status results in profound changes in global gene transcription patterns. Serglycin, a proteoglycan, implied a different expression pattern between transient and chronic HBV infection. The shedding of serglycin maybe for immune evasion or other mechanisms in HepG2.215 cells with chronic HBV infection. Further study about serglycin is needed to perform in HBV infection. Key Word(s): 1. Serglycin; 2. HepG2; 3. Proteoglycans; 4.

Caucasians were the predominant ethnic population in this study (n = 1443) with the frequency of the good responder IFN-λ3 rs12979860 CC and rs8099917 TT genotypes being 32% and 52%, respectively. These results were very similar to that found in Caucasians from the pivotal GWAS from North America and Australia-Europe see more reporting on the IFN-λ3 rs12979860 and rs8099917 SNPs, respectively.[1, 2] Asian subjects, in contrast, had a higher prevalence of good

responder genotypes, and both SNP responder alleles were of similar prevalence. The overall frequency of the IFN-λ3 rs12979860 CC was 80%, while the rs8099917 TT genotype frequency was 86%. These findings were similar to that reported in other Asian cohorts with HCV Gt1 infection, including those from Taiwan (rs12979860 CC 90%, rs8099917 TT 90%),[11] China (rs12979860 CC 88%, rs8099917 TT 85%),[12, 13] and Korea (rs8099917 TT 85%).[14] Reports from Japan have been mixed, however, with the prevalence of the rs8099917 TT genotype in HCV Gt1 varying from 71% to 86%.[3, 15] The high prevalence of good responder IFN-λ3 polymorphisms along with recent data linking favorable IFN-λ3 genotype

to improved viral clearance and kinetics[16, 17] among Asians explains much of why Asian subjects have high response rates to PEG-IFN plus RBV. To our knowledge, this study is the first to report the distribution of IFN-λ3 polymorphisms among Australian INCB024360 nmr (or non-Australian) Aboriginals with CHC. Interestingly, we found that the prevalence of favorable IFN-λ3 genotypes among the 33 Aboriginals tested was similar to that of Caucasians with the frequency of the IFN-λ3 rs12979860 CC and rs8099917 TT genotypes being 33% and 63%, respectively. Limited data exists, however, on the outcomes of PEG-IFN and RBV therapy in Aboriginal Australians with CHC to determine whether our findings have a clinical corollary. Indeed, the only relevant study of note evaluating this issue involved Aboriginal Canadians who had similar response rates to PEG-IFN plus RBV therapy compared with non-Aboriginal

Canadians.[18] Further studies are therefore needed to address the issue of the relationship of IFN-λ3 genotype and IFN responsiveness among this important ethnic Fludarabine chemical structure group. Our study is also the first to describe the distribution of IFN-λ3 polymorphisms in native New Zealanders and Pacific Islanders. Although subject numbers were small (n = 17), Maoris and Pacific Islanders both had a relatively high prevalence of good responder genotypes, with the frequency of IFN-λ3 rs12979860 CC being 75% and 78%, and rs8099917 TT genotype 88% and 89%, respectively. Thus, the IFN-λ3 distribution of both ethnic groups appears to resemble far more closely that of Asians rather than indigenous Australians.

We have known for a long time that HRS represented a spectrum of pathology and pathophysiology, and this culminated in the publication in 1996 of the new criteria for the definition of HRS by the International Ascites Club of type 1 HRS and type 2 HRS.1 Without going into the definitions,

in essence type 1 HRS is the rapid onset of renal failure that occurs in patients with rapid decompensation of cirrhosis due to either alcoholic hepatitis, or acute on chronic liver failure, or acute liver failure. Type 2 HRS is the type of renal impairment observed in patients with refractory ascites, with renal function fluctuating over a relatively long period of time. This definition was born out of necessity, mainly to facilitate research Dabrafenib concentration in the area since, prior to this date, patients tended to be clumped together when it was clear that clinically and presumably their underlying pathophysiology were different. see more While these definitions have helped us move on in terms of identifying mechanisms, the definitions have by virtue of their criteria probably held us back, by identifying patients late, and with relatively advanced renal

failure. Thus, the definitions involve absolute serum creatinine values which we now know are inappropriate. Thus, a serum creatinine in a heavily built black muscular man are treated the same as an emaciated white female with advanced alcoholic liver disease. This definition bit us back when two clinical trials of terlipressin in HRS showed a response rate to treatment of 34%-40%,2, 3 probably because patients were randomized too late for true efficacy. We are now seeing articles that state predictability of response to terlipressin is determined by serum creatinine.4 Another way of putting this is that patients with early HRS respond better to treatment than patients

with advanced kidney failure. In many ways this is “kind of obvious,” so we need new criteria that can be adapted to individual patients. This was also recognized in the working party report of Wong et al.5 The development of HRS is due to four main factors. These are: (1) altered systemic hemodynamics with vasodilatation and lowering of arterial pressure; (2) activation of the sympathetic nervous system, Pregnenolone which alters renal autoregulation such that renal blood flow becomes more dependent on arterial pressure; (3) a terminal decline in cardiac function due to cirrhotic cardiomyopathy, which renders patients unable to maintain an adequate cardiac output as they decompensate; and (4) increased circulating or intrarenal vasoactive mediators, the role of which remain unknown. Importantly, the role of each of these factors probably varies from patient to patient. The advent of the new definition of acute kidney injury (AKI) by the AKI network has led to a reevaluation and proposed new definitions for HRS.5 What is well recognized by all is that current criteria for HRS recognize and treat patients too late.

Twenty-one patients with a history of failed PD were prospectively recruited as the case group, and 30 patients with no history of prior treatment for achalasia were included as the control group. Outcome of

POEM procedures buy FG-4592 was evaluated through esophageal manometry, timed barium esophagogram and short form 36 (SF-36) questionnaires, which were performed before surgery, at 5 days after surgery and at the last follow-up, respectively. Relief of patients’ symptoms was considered as the primary outcome. Secondary outcomes included lower esophageal sphincter pressure, esophageal emptying, quality of life of the patient, and procedure-related complications. The two groups were matched in terms of age, gender, body mass index, and results of preoperative examinations. For patients with failed PD, it was observed that Eckardt score, lower esophageal sphincter pressure, and height of the barium column were significantly

decreased after POEM surgery. Besides, the mean physical component summary and mental component summary of patients at the final follow were significantly higher than those before surgery. Complications that occurred during the surgery included three cases of subcutaneous emphysema (14.3%) and one case of pneumothorax (4.8%). Patients with failed PD were found to have the significantly longer operation time than the control group. There was no significant difference between the two groups in terms of surgical outcome learn more at the final follow-up. POEM is a promising

therapeutic modality for achalasia patients who have failed to respond to PD therapy. Previous dilation procedures might have no obvious influence on the efficacy of POEM surgery. “
“Egypt has the highest hepatitis C virus (HCV) prevalence in the world (14.7%). The drivers of the HCV epidemic in Egypt are not well understood, but the mass parenteral antischistosomal therapy (PAT) campaigns in the second half of the 20th century are believed to be the determinant of the high prevalence. We studied HCV exposure in Egypt at a microscale through spatial mapping and epidemiological description of HCV clustering. The source of data was the 2008 Egypt Demographic and Health IMP dehydrogenase Survey. We identified clusters with high and low HCV prevalence and high and low PAT exposure using Kulldorff spatial scan statistics. Correlations across clusters were estimated, and each cluster age-specific HCV prevalence was described. We identified six clusters of high HCV prevalence, three clusters of low HCV prevalence, five clusters of high PAT exposure, and four clusters of low PAT exposure. HCV prevalence and PAT exposure were not significantly associated across clusters (Pearson correlation coefficient [PCC] = 0.36; 95% confidence interval [CI] −0.12 to 0.71).

Therefore, our aim was to test whether this pathway underlies PA-induced lipotoxicity in hepatocytes. Methods: primary cultured mouse hepatocytes (PMH) from adeno-shlacZ controls and adeno-shSab treated mice and Huh7 human hepatoma cells were exposed for various times to PA in albumin (constant ratio) over a concentration (0.05-4.0mM) for up to 24 hours. Western blots of cell extracts were performed for JNK, P-JNK, ER stress markers. Oxygen consumption rate (OCR; oxidative phosphorylation, proton leak, maximum and reserve respiratory capacity) was measured of over time in a Seahorse XF

analyzer. Cell death was determined using Sytox Green uptake and activated caspase 3 staining. Results: In PMH, PA dose dependently up to

1mM stimulated OCR due to mitochondrial β-oxidation, an effect that was blocked by CPT-1 inhibition by etomoxir. At ≥1.5mM, PA reduced AZD0530 mw OCR, followed by PA- induced cell death. Inhibition of JNK by SP600125, caspases by Z-VAD, or antioxidant BHA protected PMH against PA-induced cell death. Antagonism Lapatinib in vivo of Sab by genetic knockdown or by a membrane permeable Sab blocking peptide prevented PA-induced mitochondrial impairment and cell death. Similar results were seen in Huh7 cells but at lower PA concentrations (0.8mM). PA increased P-PERK and downstream target CHOP, in PMH but failed to activate the IRE-1 a arm of the UPR, as reflected by the lack of spliced

XBP-1. However, Sab silencing did not affect PA- induced PERK activation. Conversely, specific inhibition of PERK by GSK2606414 prevented JNK activation and cell death, indicating a major role in upstream JNK activation. The protection against PA-induced cell death by Sab knockdown was not further increased by pan-caspase inhibitor or antioxidant, indicating that Sab is essential for caspase activation and ROS generation by PA. Conclusions: Our studies demonstrate that mitochondria play a key role in PA- mediated lipotoxicity. The toxicity of PA in hepatocytes is mediated by the interplay of JNK with mitochondrial Sab, which leads to impaired respiration, ROS production, and apoptosis. Disclosures: Neil Kaplowitz – Consulting: GlaxoSmithKline, JNJ, Merck, Novartis, Hepregen, Takeda, Aspartate Otsuka, Pfizer, Geron, Daiichi-Sanyo; Independent Contractor: Acetaminophen Litigation The following people have nothing to disclose: Sanda Win, Tin A. Than, Carmen García-Ruiz, Jose Fernandez-Checa Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising in the last decades and non-alcoholic fatty liver (NAFL) as well as non-alcoholic steatohepatitis (NASH) are now endemic in Western countries. The current hypothesis about the pathogenesis is a two hit theory, i.e. first steatosis due to e.g.

31)8 were synthesized in the

Medicinal Chemistry Laboratory of the Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences, with a purity over 99.0%. The compound structure was confirmed with 1H-NMR and MS spectra. Interferon-α-2b (Intron A) was from Schering Plough (Brinny) (Kenilworth, NJ). BILN2061, a known NS3-4A protease inhibitor, was provided by Shanghai Lechen International Trading (Shanghai, China). Plasmid pcDNA3.1-Vif coding for HIV-1 full-length Vif was created by insertion of Vif (amplified Gefitinib molecular weight by polymerase chain reaction [PCR] from HIV-1 plasmid SVC21.BH10) into pcDNA3.1; the plasmids hA2, hA3B, hA3C, hA3F, and hA3G that express wildtype forms of hA2, hA3B, hA3C, hA3F, and hA3G, respectively, possess a fused HA tag at the C-terminus. The above-mentioned plasmids were gifts from Dr. Shan Cen at the Lady Davis Institute for Medical Research and McGill University AIDS Centre. The plasmid pFL-J6/JFH/JC1 containing the full-length chimeric

HCV cDNA was kindly provided by Vertex Pharmaceuticals (Boston, MA). Production of infectious HCV in hepatocytes was done as described.14 The plasmid pFL-J6/JFH/JC1 was restricted with XbaI and treated with Mung Bean nuclease (New England Biolabs) to generate the according HCV cDNA with T7 promotor. The cDNAs were purified and used as templates for RNA synthesis. HCV RNA was synthesized Cediranib (AZD2171) in vitro using a MEGAscript T7 kit (Ambion). The synthesized RNA was treated

with DNase I (New England Biolabs) and purified with Wizard RAD001 research buy SV Gel and PCR Clean-Up System (Promega). The synthesized HCV RNA was used to transfect naïve Huh7.5 cells with the addition of Lipofectamine 2000 (Invitrogen). The culture medium was collected and cleaned with centrifugation at 3,000 rpm for 10 minutes. The supernatants were stored at −70°C as HCV viral stock and quantified with the Diagnostic Kit for Quantification of Hepatitis C Virus RNA (Shanghai Kehua Bio-Engineering). Huh7.5 cells 24 hours after HCV infection with viral stock (45 IU per cell) were transfected with different concentrations of APOBEC- or Vif-containing plasmids in the FuGENE HD Transfection Reagent (Roche), with pcDNA3.1 as plasmid control. Then, 72 hours later the culture medium was removed and total intracellular proteins were extracted using CytoBuster Protein Extraction Reagent (Novagen) with 1 mM protease inhibitor cocktail (Roche Applied Science). HCV Core, NS3, and hA3G protein (or APOBEC proteins with HA tag) was detected with western blot. A similar procedure was used for the experiment using GS4.3 cells, except the infection step. Huh7.5 cells were planted into the 6-well plate with 3 × 105 cells per well in the complete growth medium and infected with HCV viral stock (45 IU per cell).

In conclusion, our data reported here propose a novel molecular mechanism to explain the stepwise decrease of HBsAg expression during HBV tumorigenesis. The negative regulation of HBsAg by mTOR signal raises a serious issue regarding the clinical

significance of decreased levels of HBV DNA and surface antigens in patients with chronic HBV infection, especially at the advanced stage of diseases. Our current attempt on targeted therapy using mTOR inhibitors may carry a potential risk to activate HBV replication and result in untoward clinical consequences. Additional Supporting Information may be found in the online version of this article. “
“The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim BMS-907351 nmr of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis. The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated. Of the 45 subjects, 24 (53.3%) were

CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2–5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001, 139.36 ± 77.43 Volasertib order vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). The percentage of

patients achieving the optimal trough level on days 2–5 was significantly higher in the Non-Exp group than in the Exp group (40.0% vs 4.3%, P = 0.01). This trend was also observed on days 7–10. On multivariate analysis, factors associated with achievement of the optimal trough level were food non-intake and Non-Exp of CYP3A5. The remission rate was significantly higher in the Non-Exp group than in the Exp group (47.6% vs 16.7%, P = 0.046). CYP3A5 genetic polymorphisms affected the pharmacokinetics Metalloexopeptidase of Tac, so that the short-term clinical remission rate was different between Exp and Non-Exp of CYP3A5. In recent years, the calcineurin inhibitor tacrolimus (Tac) has been widely used internationally as an immunosuppressant in organ transplantation patients.[1] In a double-blind trial in Japan, Tac was also shown to be safe and effective in ulcerative colitis (UC) patients with moderate-to-severe activity.[2] In Japan, Tac has been used as remission induction therapy in UC patients since 2009. One characteristic of Tac is that its effect is trough level-dependent.[2, 3] Tac metabolism is affected by various factors, including food intake/non-intake, drug metabolism enzymes, and transporters.

In conclusion, our data reported here propose a novel molecular mechanism to explain the stepwise decrease of HBsAg expression during HBV tumorigenesis. The negative regulation of HBsAg by mTOR signal raises a serious issue regarding the clinical

significance of decreased levels of HBV DNA and surface antigens in patients with chronic HBV infection, especially at the advanced stage of diseases. Our current attempt on targeted therapy using mTOR inhibitors may carry a potential risk to activate HBV replication and result in untoward clinical consequences. Additional Supporting Information may be found in the online version of this article. “
“The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim Idasanutlin nmr of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis. The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated. Of the 45 subjects, 24 (53.3%) were

CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2–5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001, 139.36 ± 77.43 www.selleckchem.com/products/icg-001.html vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). The percentage of

patients achieving the optimal trough level on days 2–5 was significantly higher in the Non-Exp group than in the Exp group (40.0% vs 4.3%, P = 0.01). This trend was also observed on days 7–10. On multivariate analysis, factors associated with achievement of the optimal trough level were food non-intake and Non-Exp of CYP3A5. The remission rate was significantly higher in the Non-Exp group than in the Exp group (47.6% vs 16.7%, P = 0.046). CYP3A5 genetic polymorphisms affected the pharmacokinetics Gemcitabine nmr of Tac, so that the short-term clinical remission rate was different between Exp and Non-Exp of CYP3A5. In recent years, the calcineurin inhibitor tacrolimus (Tac) has been widely used internationally as an immunosuppressant in organ transplantation patients.[1] In a double-blind trial in Japan, Tac was also shown to be safe and effective in ulcerative colitis (UC) patients with moderate-to-severe activity.[2] In Japan, Tac has been used as remission induction therapy in UC patients since 2009. One characteristic of Tac is that its effect is trough level-dependent.[2, 3] Tac metabolism is affected by various factors, including food intake/non-intake, drug metabolism enzymes, and transporters.

5A (magnification 200×). Kidneys from the wildtype mice subjected to liver IR demonstrated multifocal acute tubular injury including

S3 segment proximal tubule necrosis, cortical tubular simplification, cytoplasmic vacuolization, and dilated lumina as well as focal granular bile/heme casts (Fig. 5A). The summary of renal injury scores for percent renal tubular hypereosinophilia, percent peritubular leukocyte margination, and percent cortical vacuolization are shown in Fig. 5B. Neutralization of IL-17A (200 μg antibody), deficiency in IL-17A receptor or IL-17A significantly reduced kidney injury. Consistent with plasma creatinine, IL-17A-deficient mice transfused LEE011 purchase with IL-17A wildtype splenocytes were still protected against kidney injury after liver IR. Hepatic IR injury also caused severe small intestinal injury (Fig. 6). Small intestine histology assessed 24 hours after 60 minutes hepatic IR in H&E-stained sections demonstrated villous endothelial cell apoptosis (Fig. 6B, magnified insert), villous epithelial cell necrosis, and the development of a necrotic epithelial pannus over the mucosal surface. Neutralization of IL-17A (200 μg antibody, Fig. 6C), deficiency in IL-17A (Fig. 6D) or IL-17A receptor (Fig. 6E) significantly reduced small intestine injury 24 hours after 60 minutes hepatic IR. In addition,

infusion of wildtype splenocytes into IL-17A-deficient mice did not reverse the intestinal protection in these mice (Fig. 6F). We assessed this website tissue inflammation by detecting neutrophil infiltration and by measuring proinflammatory mRNA up-regulation. Sixty minutes of hepatic ischemia resulted in significant recruitment of neutrophils into the liver, kidney, and intestine in IL-17A wildtype mice (Supporting Fig. selleck 2A-C). Neutrophil infiltration coincided with areas of liver necrosis. Neutralization of IL-17A, deficiency in IL-17A receptor or IL-17A significantly reduced neutrophil infiltration in all three organs. We also measured the expression of proinflammatory

cytokine mRNAs in the liver, kidney, and intestine 24 hours after liver IR with semiquantitative RT-PCR. Hepatic IR significantly increased proinflammatory mRNA expression (ICAM-1, KC, MCP-1, and MIP-2) in all three organs compared to the sham-operated mice (Supporting Fig. 3A-C). However, neutralization of IL-17A, deficiency in IL-17A receptor or IL-17A significantly reduced proinflammatory mRNA expression in all three organs. We were able to detect IL-17A mRNA expression in all tissues (data not shown) of IL-17A-deficient mice transfused with IL-17A wildtype splenocytes. Furthermore, wildtype IL-17A splenocyte transfused IL-17A-deficient mice showed significantly attenuated proinflammatory mRNA expression in the liver, kidney, and small intestine (data not shown). We used three separate indices to detect apoptosis: (1) TUNEL staining (Supporting Fig. 4), (2) DNA laddering (Supporting Fig.

By contrast, HBeAg-positive patients with baseline ALT levels 1.3 to 2 times ULN who received entecavir had significantly lower rates of all responses at week 48 in comparison with those with baseline ALT levels > 2 times ULN: 62% histological improvement versus 75% (P = 0.001), 48% HBV DNA suppression versus 73% (P < 0.001), 55% ALT normalization versus 73%

(P = 0.001), and 8% HBeAg seroconversion http://www.selleckchem.com/products/ldk378.html versus 26% (P < 0.001). These data extend the results of previous studies showing that both interferon and nucleos(t)ide analogues are less efficacious in patients who are in the immune-tolerant phase13 and support the recommendations that HBeAg-positive patients with ALT levels 1 to 2 times ULN should be monitored and that those with ALT levels persistently in this range should undergo liver selleck products biopsy to guide treatment decisions. Although Wu et al.12 showed

that antiviral therapy can result in viral suppression and histological improvement, responses were assessed at week 48 while the patients were undergoing treatment. Long-term (multiyear and possibly lifelong) treatment will be necessary for many of these patients to maintain the responses. Therefore, until data supporting a benefit of antiviral therapy for clinical outcomes become available, initiating every chronic hepatitis B patient with mildly elevated ALT levels is not warranted. Some of these patients will turn out to have mild liver disease on biopsy, and others, notably young HBeAg-positive patients, may undergo spontaneous HBeAg seroconversion and enter into remission (at least temporarily) during the next few years. As our knowledge about the natural history of chronic HBV infection improves and new and better treatments become available, it is appropriate to regularly review the indications for treatment. The Hepatitis B Research Network, sponsored by the National Institute of Diabetes and Digestive and Kidney 6-phosphogluconolactonase Diseases, will be conducting clinical trials in patients with mild liver disease. Until data from these trials become available,

the decision to initiate treatment in chronic hepatitis B patients with mildly elevated ALT levels should be individualized. “
“Common and rarer causes of diarrhoea lasting more than four weeks are explored. This includes functional bowel disorders (toddler diarrhoea and irritable bowel syndrome), coeliac disease and inflammatory bowel disease. Assessment and management of Crohn’s disease and ulcerative colitis are reviewed. “
“Children with cystic fibrosis (CF) have several reasons to require close nutritional management such as: (i) increased resting energy expenditure (REE) from chronic inflammation and recurrent chest infections; (ii) anorexia; and (iii) fat malabsorption secondary to pancreatic exocrine insufficiency. There needs to be close nutritional monitoring in infancy where growth is rapid.