Entecavir safety and effectiveness in a national cohort of treatment-naïve chronic hepatitis B patients in the US - the ENUMERATE study.

BACKGROUND: Entecavir (ETV) has been shown to be safe and efficacious in randomised controlled trials in highly selected patients with hepatitis B virus (HBV) infection. AIM: To determine the safety and effectiveness of ETV in 'real-world' HBV patients in the United States (US). METHODS: Treatment-naïve HBV patients ≥18 years old who received ETV for ≥12 months between 2005 and 2013 were included in a retrospective, cohort study. Rates of ALT normalisation, undetectable HBV DNA, HBeAg and HBsAg loss/seroconversion, adverse events (AE) and clinical outcomes were evaluated. RESULTS: Of 841 patients, 658 [65% male, 83% Asian; median age 47 years] met the inclusion criteria. 36% were HBeAg+ and 9.3% cirrhotic. 89% had abnormal ALT. Baseline median HBV DNA was 5.8 log 10 IU/mL. Median duration of ETV treatment was 4 years. Rates of ALT normalisation at 1, 3 and 5 years were 37.2%, 48.7% and 56.2% in HBeAg+ and 39.6%, 46.8% and 55.6% in HBeAg- patients. HBV DNA was undetectable at 1, 3 and 5 years in 34.6%, 64.7% and 84.6% in HBeAg+ patients, and 81.9%, 90.3% and 96.2% in HBeAg patients. Five-year cumulative probability of HBeAg loss and seroconversion was 46% and 33.7% and HBsAg loss was 4.6%. ETV was discontinued due to adverse events in 1.2% of patients. Hepatic decompensation occurred in 0.8%, liver cancer in 2.7% and death in 0.6%. CONCLUSION: Entecavir treatment was safe in a large cohort of US patients, but ALT normalisation and hepatitis B virus DNA suppression rates were lower than previously reported in clinical trials.

Ukaipo niho: the place of nurturing for oral health.

OBJECTIVES: To report on oral-health-related characteristics, beliefs, and behaviours among participants in a randomised control trial of an intervention to prevent early childhood caries (ECC) among Maori children, and to determine whether there were any systematic differences between the intervention and control groups at baseline. DESIGN: Baseline measurements from a randomised control trial (involving 222 pregnant Maori women allocated randomly to either Intervention or Delayed groups) which is currently underway. SETTING: The rohe (tribal area) of Waikato-Tainui. METHODS: Self-report information collected on sociodemographic characteristics, pregnancy details, self-reported general and oral health and health-related behaviours, and oral health beliefs. RESULTS: Other than those in the Delayed group being slightly older, on average, there were no significant differences between the two groups. Some 37.0% were expecting their first child. Most reported good health; 43.6% were current smokers, and 26.4% had never smoked. Only 8.2% were current users of alcohol. Almost all were dentate, and 57.7% described their oral health as fair or poor. One in six had had toothache in the previous year; 33.8% reported being uncomfortable about the appearance of their teeth, and 27.7% reported difficulty in eating. Dental service-use was relatively low and symptom-related; 78.9% needed to see a dentist. Overall, most of the sample believed that it was important to avoid sweet foods, visit dentists and to brush the teeth, while about half thought that using fluoride toothpaste and using floss were important. Some 38.2% felt that drinking fluoridated water was important. Oral-health-related fatalism was apparent, with 74.2% believing that most people usually get dental problems, 58.6% believing that most people will need extractions at some stage, and that most children eventually get dental caries. CONCLUSIONS: Mothers' important role in nurturing the well-being of the young child includes the protection and maintenance of the growing child's oral health (or ukaipo niho). The findings provide important insights into Maori mothers' oral health knowledge, beliefs and practices.

Antibody-mediated rejection in ABO compatible husband to wife living donor liver transplant and review of the literature.

Role of donor specific antibodies (DSAs) in liver allograft function has not been fully defined. We report an ABO compatible orthotopic liver transplant case with DSAs to donor HLA, where the patient developed immediate antibody-mediated rejection (AMR).The patient, a 43-year-old female with cirrhosis, underwent ABO-compatible living-donor liver transplant from her husband. On post-operative day (POD)1, serum transaminases were sharply elevated. Retrospective testing of pre-transplant serum demonstrated presence of strong class I and class II anti-HLA antibodies and positive T- and B-cell flow-cytometric crossmatches (FCXM). Transaminase levels improved with plasmapheresis and thymoglobulin. On POD7, her liver enzymes became elevated again and allograft biopsy stained positive for C4d. Patient was treated with intravenous immunoglobulin and rituximab and recovered over time. Pre-transplant sera of patient were retrospectively tested by C1q assay to determine the cytotoxic function of DSAs; DSAs were positive for C1q binding. Our results suggest that pre-liver transplant antibody testing may be helpful in identifying patients at risk for development of AMR.

Reducing disease burden and health inequalities arising from chronic disease among indigenous children: an early childhood caries intervention in Aotearoa/New Zealand.

BACKGROUND: Maaori are the Indigenous people of New Zealand and do not enjoy the same oral health status as the non-Indigenous majority. To overcome oral health disparities, the life course approach affords a valid foundation on which to develop a process that will contribute to the protection of the oral health of young infants. The key to this process is the support that could be provided to the parents or care givers of Maaori infants during the pregnancy of the mother and the early years of the child. This study seeks to determine whether implementing a kaupapa Maaori (Maaori philosophical viewpoint) in an early childhood caries (ECC) intervention reduces dental disease burden among Maaori children. The intervention consists of four approaches to prevent early childhood caries: dental care provided during pregnancy, fluoride varnish application to the teeth of children, motivational interviewing, and anticipatory guidance. METHODS/DESIGN: The participants are Maaori women who are expecting a child and who reside within the Maaori tribal area of Waikato-Tainui.This randomised-control trial will be undertaken utilising the principles of kaupapa Maaori research, which encompasses Maaori leadership, Maaori relationships, Maaori customary practices, etiquette and protocol. Participants will be monitored through clinical and self-reported information collected throughout the ECC intervention. Self-report information will be collected in a baseline questionnaire during pregnancy and when children are aged 24 and 36 months. Clinical oral health data will be collected during standardised examinations at ages 24 and 36 months by calibrated dental professionals. All participants receive the ECC intervention benefits, with the intervention delayed by 24 months for participants who are randomised to the control-delayed arm. DISCUSSION: The development and evaluation of oral health interventions may produce evidence that supports the application of the principles of kaupapa Maaori research in the research processes. This study will assess an ECC intervention which could provide a meaningful approach for Maaori for the protection and maintenance of oral health for Maaori children and their family, thus reducing oral health disparities. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000111976.

Hepatitis E virus infection in a liver transplant recipient in the United States: a case report.

BACKGROUND: Chronic infection with hepatitis E virus (HEV) has recently been recognized in immunocompromised or immunosuppressed individuals. CASE REPORT: We report a case of concurrent HEV and human herpes virus-6 (HHV-6) infection, documented by serum HEV RNA and HHV-6 DNA, in an orthotopic liver transplant (OLT) recipient in the United States, where HEV genotype 3 infection, although prevalent, is considered to be self-limited and almost always asymptomatic. The coinfection was accompanied by elevated serum aminotransaminases, liver biopsies demonstrating chronic hepatitis, and the presence of HEV RNA in the tissue. After lowering of immunosuppressive therapy and 2 courses of valganciclovir, sequential clearance of the viruses and normalization of the serum aminotransaminases were observed. CONCLUSIONS: HEV infection can lead to chronic hepatitis in OLT recipients, and evaluation of this virus should be considered in immunosuppressed individuals with unexplained liver test abnormalities.

Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Comparison of hepatitis C histological recurrence rates and patient survival between split and deceased donor liver transplantation.

INTRODUCTION: Controversy exists as to whether there is an increased severity or frequency of recurrent hepatitis C viral (HCV) infection in recipients of adult living donor liver transplantation (LDLT) grafts. We sought to examine the time to histological recurrence and survival in HCV (+) patients who underwent split liver transplantation (SLT), which is technically similar to what occurs in the LDLT procedure. METHODS: Twenty four HCV (+) adult recipients were identified through the UNOS database as having had SLT procedures at three centers: Mount Sinai Medical Center, University of Chicago, and University of California at Los Angeles. Of these, 17 patients with comprehensive data were matched to 32 HCV (+) patients who underwent whole deceased donor liver transplantation (DDLT) during the same time period. Outcome and time to initial HCV recurrence as documented by liver biopsy were assessed. Liver biopsy was performed when clinically indicated. RESULTS: Patients who had SLT were significantly older (P=.01). There was no difference in number of rejection episodes (P=.40). Fifteen of 17 SLT (88%) versus 24/32 DDLT (75%) patients had documented HCV recurrence by biopsy (P=.46). The time to median cumulative incidence of recurrence of HCV post-liver transplantation was 12.6 months (SLT) versus 39.8 months (DDLT) patients. There was no difference in survival between SLT and DDLT patients (47 vs 70 months, P=.62) nor in cumulative incidence of histological HCV recurrence at 1, 2, and 3 years (P=.198, .919, and .806, respectively). CONCLUSION: There is no difference in the cumulative incidence of histological recurrence of HCV post-liver transplant or in survival between recipients of deceased donor and split liver transplants.

Beaklike SnO2 nanorods with strong photoluminescent and field-emission properties.

Beaklike SnO2 nanorods were synthesized by a vapor-liquid-solid approach using Au as a catalyst. The nanorods grow along the [10 1] direction and the beak is formed by switching the growth direction to [1 12] through controlling the growth conditions at the end of the synthesis. The photoluminescence (PL) spectrum of the nanorods exhibits visible light emission with a peak at 602 nm. The field-emission (FE) properties of the nanorods have been measured to exhibit a turn-on field of 5.8 V microm(-1). A comparative study of FE measurements between SnO2 nanorods with uniform diameters and these beaklike nanorods suggests that the shape and curved tips are important factors in determining the FE properties.

Nonlinear cortical modulation of muscle fatigue: a functional MRI study.

Muscle fatigue has been studied for over a century, but almost no data are available to indicate how the brain perceives fatigue and modulates its signals to the fatiguing muscle. In this study, brain activation was measured by functional magnetic resonance imaging (fMRI) during a sustained (2-min) maximal-effort handgrip contraction while handgrip force and finger muscle electromyographic (EMG) data were recorded simultaneously by a magnetic resonance environment-adapted force-EMG measurement system. The results showed decoupled progresses in brain and muscle activities when muscle was fatigued and correlated behaviors among the cortical areas being analyzed. While handgrip force and EMG signals declined in parallel during the course of muscle fatigue, fMRI-measured brain activities first substantially increased and then decreased. This similar signal modulation occurred not only in the primary sensorimotor areas but also in the secondary and association cortices (supplementary motor, prefrontal, and cingulate areas). The nonlinear changes of brain signal may reflect an early adjustment to strengthen the descending command for force-loss compensation and subsequent inhibition by sensory feedback as fatigue became more severe. The close association in the activation pattern in many cortical regions may reflect integrated processing of information in the brain.

Results of steroid-based therapy for the hepatitis C-autoimmune hepatitis overlap syndrome.

OBJECTIVE: Overlap syndromes in which persons manifest clinical, histological, or immunological features of both hepatitis C infection and autoimmune hepatitis are well described. The discordant forms of treatment for hepatitis C and autoimmune hepatitis have made medical management of these patients difficult. We report our experience in using corticosteroids as first line therapy for the hepatitis C-autoimmune hepatitis overlap syndrome. METHODS: Seven patients with this overlap syndrome (diagnosis based on the presence of serum hepatitis C antibody by RIBA and serum hepatitis C RNA by polymerase chain reaction, and serum hypergammaglobulinemia, elevated ANA or ASMA titers, or histological findings consistent with autoimmune hepatitis) were treated with prednisone with or without azathioprine or cyclosporine, and followed for a median duration of 44.5 months. RESULTS: Five patients (71%) showed improvement of median serum ALT level from 162 U/L to 38 U/L (p = 0.04) and median serum gamma-globulin from 2.1 g/dl to 1.4 g/dl (p = 0.04) by 6 months of therapy. The mean modified histological activity index score also decreased from 11.4 +/- 2.5 to 6.6 +/- 2.6 (p = 0.04) by at least 1 yr of therapy. One patient discontinued prednisone while taking azathioprine and experienced a rebound elevation of serum ALT that did not respond to retreatment with prednisone. Antiviral therapy was subsequently administered and resulted in biochemical and virologic response. Hepatitis C virus RNA remained detectable in all other patients. CONCLUSION: Corticosteroids are beneficial as a first line therapy for some patients with the hepatitis C-autoimmune overlap syndrome, resulting in appreciable biochemical and histological response but without viral eradication.

Open cardiotomy for removal of migrating transjugular intrahepatic portosystemic shunt stent combined with liver transplantation.

BACKGROUND: Transjugular intrahepatic shunts are widely used for the management of variceal bleeding. Complications such as stent misplacement or migration may occur. METHODS: We describe the management of a transjugular intrahepatic shunts stent that migrated across the tricuspid valve in a patient with Child-Pugh category C cirrhosis. RESULTS: An attempt at percutaneous retrieval of the stent was unsuccessful. Due to the unacceptably high risk for mortality from open heart surgery with cardiopulmonary bypass in the setting of cirrhosis, stent removal was deferred until the time of orthotopic liver transplantation. The procedures were performed successfully, and the patient made a good recovery. CONCLUSION: Surgical stent extraction and valve repair can be performed safely along with orthotopic liver transplantation in carefully selected patients with end-stage liver disease.

Characterization and quality control of recombinant adenovirus vectors for gene therapy.

Highly purified recombinant adenovirus undergoes routine quality controls for identity, potency and purity prior to its use as a gene therapy vector. Quantitative characterization of infectivity is measurable by the expression of the DNA binding protein, an early adenoviral protein, in an immunofluorescence bioassay on permissive cells as a potency determinant. The specific particle count, a key quality indicator, is the total number of intact particles present compared to the number of infectious units. Electron microscopic analysis using negative staining gives a qualitative biophysical analysis of the particles eluted from anion-exchange HPLC. One purity assessment is accomplished via the documented presence and relative ratios of component adenoviral proteins as well as potential contaminants by reversed-phase HPLC of the intact virus followed by protein peak identification using MALDI-TOF mass spectrometry and subsequent data mining. Verification of the viral genome is performed and expression of the transgene is evaluated in in vitro systems for identity. Production lots are also evaluated for replication-competent adenovirus prior to human use. For adenovirus carrying the human IL-2 transgene, quantitative IL-2 expression is demonstrated by ELISA and cytokine potency by cytotoxic T lymphocyte assay following infection of permissive cells. Both quantitative and qualitative analyses show good batch to batch reproducibility under routine test conditions using validated methods.

[Induction of callus of Hypericum perforatum L. and qualitative identification of active constituents of its callus].

OBJECTIVE: To induce the callus of H. perforatum and identify hypericin and pseudohypericin of its callus. METHOD: The callus was induced in different culture conditions, and active constituents were determined by HPLC. RESULT AND CONCLUSION: The inductions of callus from different parts were discussed, the induction rate of the leaf axil being the highest. The MS basic medium with 4 micrograms.L-1 2,4-D and 0.2 microgram.L-1 6-BA was the best of all screened media. Hypericin in the callus is determined by HPLC.

Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease.

OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients.

Donor liver uridine diphosphate (UDP)-glucuronosyltransferase-1A1 deficiency causing Gilbert's syndrome in liver transplant recipients.

BACKGROUND: Uridine diphosphate-glucuronosyltransferase-1A1 deficiency, causing Gilbert's syndrome, has been attributed to two extra (TA) bases in the TATAA-box of the promoter region of its gene, where the A(TA)6TAA allele corresponds to the normal gene and A(TA)7TAA corresponds to a gene with reduced expression. Our aim was to determine whether isolated hyperbilirubinemia in liver transplant recipients was due to Gilbert's syndrome acquired through the liver allograft. METHODS: From 305 patients followed in our Liver Transplant Clinic, five patients with isolated unconjugated hyperbilirubinemia in the absence of hemolysis, recurrent viral hepatitis, and biliary tract pathology were identified; 10 other post-orthotopic liver transplantion patients with normal liver chemistry tests were randomly selected as a control group. DNA was extracted from paraffin-embedded liver allograft tissue and peripheral lymphocytes and was genotyped for the TA repeat at the uridine diphosphate glucononosyltransferase-lA1 promoter region by polymerase chain reaction and acrylamide gel electrophoresis. Homozygosity for the (TA)7 allele was considered diagnostic of Gilbert's syndrome. RESULTS: The mean serum total bilirubin level of the study patients was 2.28 mg/dl (range 1.8-3.0), consisting predominantly of the unconjugated form; that of the control patients was 0.76 mg/dl (range 0.4-1.1). The liver tissue from all five patients in the study group possessed the homozygous A(TA)7TAA genotype that was not observed in their lymphocytes. None of the liver tissue from the control patients demonstrated homozygosity for the A(TA)7TAA allele. CONCLUSION: Uridine diphosphate-glucuronosyltransferase-1A1 deficiency, causing Gilbert's syndrome, may be carried by the donor liver and present with isolated unconjugated hyperbilirubinemia in liver transplant recipients.

Fulminant hepatic failure secondary to malignant melanoma: case report and review of the literature.

Malignant melanoma has a propensity to metastasize widely to many organs, involving the liver in up to one-third of cases. Fulminant hepatic failure is an unusual presentation of hepatic neoplasms, whether primary or metastatic. We describe a case of malignant melanoma with liver metastases that rapidly progressed to fulminant hepatic failure and death. Striking elevations of liver tests, particularly lactate dehydrogenase, were seen. Liver biopsy showed diffuse intrasinusoidal infiltration with melanoma cells. In patients with malignant melanoma, raised serum lactate dehydrogenase levels may suggest hepatic involvement, with extreme elevations possibly predictive of liver failure.

Intrahepatic cholestasis following liver transplantation.

Intrahepatic cholestasis following liver transplantation commonly occurs after liver transplantation and may be caused by infections, drugs such as cyclosporine and sulfonamides, and acute or chronic rejection. Less common causes such as fibrosing cholestatic hepatitis or recurrent primary biliary cirrhosis or primary sclerosing cholangitis may also be encountered. Biliary strictures may also be present. Although some disorders may be managed medically, others often require repeat liver transplantation. Prompt recognition and specific treatment can improve the outcome for liver transplant recipients.

Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis.

A patient presented with pruritus and recent elevation of aminotransferases. The case fulfilled most of the criteria for the diagnosis of autoimmune hepatitis and achieved clinical and complete biochemical response to steroid therapy. However, the liver biopsy specimen revealed an unusual histological pattern consisting of severe centrilobular necrosis demarcated by a thin rim of hepatitic reaction. In contrast, the portal tracts appeared almost normal. This histological appearance has not been associated with autoimmune hepatitis. This presentation and the histology may represent an early pattern of autoimmune injury to the liver.