Density functional theory study of Rh(n)S(0,±) and Rh(n+1)(0,±) (n = 1-9).

A basin-hopping search strategy has been used to determine likely candidates for low-energy Rh(n)S(0,±) (n = 1-9) cluster structures. Cluster structures were optimized at the density functional level of theory using the PBE and PBE0 functionals. Ionization energies, electron detachment energies, HOMO-LUMO gap energies, UV-visible spectra, low-lying fragmentation channels and energies, cluster structures, spin multiplicities, and vibrational spectra are predicted for Rh(n)S(0,±) and Rh(n+1)(0,±) (n = 1-9). Donation from valence sulfur atomic p orbitals to valence rhodium atomic d orbitals and back-donation to valence sulfur atomic d orbitals leads to electron density delocalization and metal-like behavior for rhodium sulfide clusters.

Ministry of Health clinical practice guidelines: Chronic Hepatitis B Infection.

The Ministry of Health (MOH) publishes clinical practice guidelines on Chronic Hepatitis B Infection to provide doctors and patients in Singapore with evidence-based guidance on managing important medical conditions. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Chronic Hepatitis B Infection, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website (http://www.moh.gov.sg/mohcorp/publications.aspx?id=26108). The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

5-(Dimethylamino)-N-(4-ethynylphenyl)-1-naphthalenesulfonamide as a novel bifunctional antitumor agent and two-photon induced bio-imaging probe.

A novel compound, (5-(dimethylamino)-N-(4-ethynylphenyl)-1-naphthalenesulfonamide), was prepared and characterized; it shows dual functional roles as an effective antitumor and a two-photon induced bio-imaging agent.

Minimal hepatic encephalopathy runs a fluctuating course: results from a three-year prospective cohort follow-up study.

INTRODUCTION: Minimal hepatic encephalopathy (mHE) has been reported in up to 84 percent of cirrhotics. The natural history of mHE has not been well-described. We designed a three-year prospective cohort study to determine the prevalence and natural history of mHE among cirrhotic patients. METHODS: The patient cohort comprising 62 consecutive outpatients with cirrhosis were assessed at baseline and followed-up with a repeat assessment three years later. The assessments include: (1) Neuropsychometric analysis (digit-symbol substitution test, block-design test, number-connection test A); (2) Clinical, biochemical assessment; and (3) Quality of life (QOL) assessment (abbreviated sickness impact profile). RESULTS: Baseline characteristics were: age 52.9 +/- 11.0 years; Child's A:B:C was 46:14:2. mHE was detected in 33.9 percent of the cohort. Older age, a higher Child-Pugh score and female gender were independently associated with mHE. mHE was associated with a poorer QOL. Follow-up assessment three years later showed that seven patients had died, while six were lost to follow-up; these patients had significantly higher baseline Child's scores. Of the remaining patients, 36/49 (73 percent) agreed to a repeat evaluation. In this group, none had mHE. QOL remained impaired despite the resolution of mHE. CONCLUSION: It has been shown for the first time that mHE can revert to a normal state in a significant proportion of patients with well-compensated cirrhosis.

Prospective evaluation of transient elastography for the diagnosis of hepatic fibrosis in Asians: comparison with liver biopsy and aspartate transaminase platelet ratio index.

BACKGROUND: Transient elastography (TE) is a reliable non-invasive predictor of hepatic fibrosis, but data on TE in Asians are limited. AIM: To evaluate prospectively the accuracy of TE for diagnosis of hepatic fibrosis in Asians compared with APRI (aspartate transaminase to platelet ratio index). METHODS: One hundred and twenty consecutive patients who underwent liver biopsy were enrolled. TE (Fibroscan) was performed by two independent operators. Fibrosis was graded by two independent pathologists using the METAVIR classification. Area under receiver operating curves (AUROC) were used to evaluate the accuracy of TE and APRI in diagnosing significant fibrosis (F >or= 2) and cirrhosis (F4). RESULTS: Predominant aetiologies were hepatitis B (48%), non-alcoholic steatohepatitis (14%) and hepatitis C (8%). TE was unsuccessful in five patients (4.2%) because of small inter-costal space (three patients), obesity and ascites. There was good correlation between TE and fibrosis (r = 0.606). AUROC for diagnosis of significant fibrosis was 0.856 (95% CI 0.779-0.932) for TE and 0.673 (95% CI 0.568-0.777) for APRI. AUROC for diagnosis of cirrhosis was 0.924 (95% CI 0.857-0.990) for TE and 0.626 (95% CI 0.437-0.815) for APRI. Optimal TE value was 9.0 kPa for diagnosis of significant fibrosis and 16.0 kPa for cirrhosis with specificity/sensitivity/PPV/NPV/accuracy of 82.6%/85.2%/80.9%/86.7%/84.1% and 88.9%/82.7%/32.0%/98.8%/83.2%, respectively. CONCLUSIONS: Transient elastography is a reliable predictor of hepatic fibrosis in Asians. Failure of TE in Asians is commonly because of small inter-costal space. TE is superior to APRI for non-invasive diagnosis of hepatic fibrosis and cirrhosis.

Imatinib mesylate-related fatal acute hepatic failure in a patient with chronic myeloid leukaemia and chronic hepatitis B infection.

Imatinib mesylate (Gleevec) is widely-used in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour. Up to four percent of patients treated with imatinib may develop hepatotoxicity, which usually resolves with discontinuation of the drug. We report a 45-year-old Chinese man with CML and chronic hepatitis B virus infection, on imatinib treatment, presenting with herpetic rash and acute liver failure. This case illustrates the diagnostic challenges in the management of such a patient, as well as the need for greater vigilance in the monitoring of liver function tests for patients treated with imatinib. A short review on imatinib-related hepatotoxicity is also presented.

Significant non-alcoholic fatty liver disease is found in non-diabetic, pre-obese Chinese in Singapore.

INTRODUCTION: To characterise the anthropometrical and metabolic parameters of a group of non-diabetic and non-obese patients who had histologically-proven nonalcoholic steatohepatitis (NASH). METHODS: During September 1997 to November 1999, consent for liver biopsies were sought from a consecutive series of patients, whose body mass index (BMI) were equal to or less than 30 kg per square metres, and who had persistently elevated serum alanine transaminase (more than 2.5 times upper limit of normal for more than six months), with no associated viral hepatitis, alcohol or drug-induced liver disease, hereditary liver disease and diabetes mellitus. Patients who were found to have steatohepatitis histologically were further studied. Their body weight, height, waist and hip circumferences were taken, and fasting serum lipid and glucose measured. Serum insulin was measured in six patients and insulin resistance (IR) was calculated by homeostasis model assessment. Oral glucose tolerance tests were done if fasting glucose levels were greater than 6 mmol/L. All liver biopsies were reviewed by a single histopathologist. Three age- and sex-matched controls were randomly selected for each patient. RESULTS: 11 of 12 patients who underwent liver biopsies were found to have NASH. All 11 were Chinese: eight males and three females. 73 percent of them had hepatic fibrosis. Overall, compared to controls, they had significantly higher body weight, BMI, IR and triglyceridaemia. The female patients also had a higher waist-hip ratio than controls. None had diabetes mellitus, and one had impaired glucose tolerance/fasting glycaemia. Nine out of 11 had BMI between 25 and 30 kg per square metres. CONCLUSION: Significant histological changes of NASH with hepatic fibrosis were found in Singaporean Chinese non-diabetic patients with BMI of less than 30 kg per square metres.

Nimesulide-induced hepatotoxicity and fatal hepatic failure.

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (cox-2) inhibitors are structurally heterogeneous drugs that share similar therapeutic actions and adverse effects. Hepatotoxicity, although a relatively rare adverse effect of this class of drugs, can be severe. This has led to the withdrawal of some NSAIDs from the market. Nimesulide is an NSAID, with cox-2 preference, which has been reported to cause death from hepatic failure. However, most reports have been from European countries. Asian reports include that from Israel and India. We report three patients who presented with acute hepatitis after being prescribed nimesulide, one of whom died from fulminant hepatic failure.

A study into the characteristics and outcome of variceal bleeding in a tertiary hospital in Southeast Asia.

This retrospective study evaluated patients admitted to the Department of Gastroenterology, Singapore General Hospital for variceal bleeding in the year 2004. Improvement in outcome of variceal bleeding has been reported in the West. There is no regional data on this condition. This study aims to determine the characteristics and outcome of variceal bleeding in a tertiary hospital in Southeast Asia. Twenty-two patients were eligible. The main aetiologies of liver cirrhosis were chronic hepatitis B (38%) and alcohol (33%). Child's A, B and C were 29%, 48% and 24% respectively. Nineteen patients (86%) had bleeding oesophageal varices (band ligation performed). The remaining three patients (14%) had bleeding gastric varices (N-butyl-2-cyanoacrylate injection performed). Detailed description of certain endoscopic findings was absent in up to 18 patients (82%). All patients received antibiotics and vasoactive drug. In-hospital mortality and rebleeding were 9% and 18% respectively. We conclude that the relatively low in-hospital mortality and rebleeding rates in our series are most probably due to the smaller proportion of patients with severe liver dysfunction and management which adhered to recommendations. Documentation of endoscopic findings needs to be improved to facilitate the continuation of care.

Prevalence of hepatitis G virus infection in patients with liver diseases in Singapore.

The prevalence of hepatitis G virus (HGV) infection in patients with liver diseases in Singapore and its pathogenic role in these patients was studied. One hundred and forty-eight patients who had chronic hepatitis or acute non A-E hepatitis were studied. Presence of HGV RNA was determined by nested polymerase chain reaction of the 5'non-coding region of the virus in all the patients. Hepatitis G IgG antibody to the envelope (E2) antigen was tested with an enzyme immunoassay (Boehringer Mannheim, Singapore) in 76 of them. Most patients (93%) were ethnically Chinese, predominantly males (74%) and chronic hepatitis B (72%) patients. Others had chronic hepatitis C (19%) or cryptogenic cirrhosis (6%). Four patients had acute non A-E hepatitis. HGV RNA and anti-HGenv were present in 3.5% and 8.3% of those with chronic liver disease. HGV infection did not account for any of the acute non A-E hepatitis and most of the cryptogenic cirrhosis.

Hepatitis C: retreatment and treatment of patients with renal failure.

This paper addresses two difficult issues in the treatment of hepatitis C: patients who fail to achieve a sustained response after the first course of treatment, and those who simultaneously suffer from chronic renal failure. With the recent improvements in firstline treatment, retreatment is mainly applicable to those who have previously received 6-month of interferon monotherapy at 3 MU thrice weekly. For those who had an end-of-treatment response but relapsed, there is a choice between interferon monotherapy at increased dose and/or duration of treatment, or a 6-month course of combination therapy. Retreatment of non-responders is generally unsuccessful, but some patients may respond to interferon-alpha 3 MU and ribavirin 1.0-1.2 g/day. For patients with chronic renal failure and hepatitis C, combination treatment is not possible because ribavirin is contraindicated. Interferon given at a dose of 1.5 MU thrice weekly was reported to be fairly well tolerated by patients who were on dialysis and resulted in end-of-treatment and sustained biochemical and virological response in some cases. Interferon given in the usual doses may be associated with severe adverse effects in patients with renal failure, and can precipitate allograft rejection in patients who have undergone renal transplantation.

Acute myeloid leukemia relapsing as gynecomastia.

Granulocytic sarcoma (GS) is an increasingly common relapse feature of acute myeloid leukemia (AML), late in the disease course or post bone marrow transplantation (BMT). Any solid organ can be affected, and there have been a number of reports of GS in breast tissue in female patients. We present a unique case of GS in a male AML patient, presenting as painless gynecomastia immediately before BMT at advanced disease. Aberrant expression of CD56 was found in the relapsed GS tissue but not in the original AML clone. Twelve months after allogeneic BMT, leukemia relapsed again in the same breast, with normal marrow morphology and full donor chimerism. The lesion failed to respond to donor lymphocyte infusion, chemotherapy and radiotherapy, and disseminated to other subcutaneous tissues.

Antibodies to Ro/La, Cenp-B, and snRNPs antigens in autoimmune hepatitis of North America versus Asia: patterns of immunofluorescence, ELISA reactivities, and HLA association.

To assess whether demography is one of the important factors determining antibody response to nuclear antigens [ANA: SSA-Ro (52K and 60K), SSB-La, snRNPs (A, 70K, B'/B), and Cenp-B], we investigated 95 and 47 sera of autoimmune hepatitis (AIH) from North America and Asia, respectively, by immunofluorescent (IF) and recombinant ELISA. Correlations among nuclear IF patterns, ELISA, and disease indices were analyzed. The frequency and titer of individual antibodies differed significantly between the groups. Patients with speckled patterns were younger in both regions and had higher aspartate aminotransferase levels only in North America. HLA-A1, B8, DQ2, and DR4 or DR3 or both in North America, and A2, B61, DQ7, and DR4 in Asia were predominant. In Asia, B61 correlated with anti-70K, and DQ7 correlated with antibodies to 52K, Cenp-B, and B'/B. In North America, A1, B8, DR3 haplotype, and DQ2 correlated with antibodies to A and 70K. Anti-B'/B and DR4 in North America, and A2 in Asia, were associated with concurrent immunologic disorder. Individual ANA clusters correlated with individual HLA in the demography, and different HLA alleles might determine disease expression as well as different ANA being produced in AIH.

Re-treatment with interferon alfa of patients with chronic hepatitis C.

Treatment of patients with chronic hepatitis C has had limited success because of relapses and nonresponse to interferon alfa therapy (currently the only established therapeutic agent). A retrospective study was done to determine the efficacy of re-treatment with interferon and the predictors of response in patients who failed to achieve sustained response after one standard course of interferon therapy (3 million units three times a week for 24 weeks). One hundred and eleven patients (47 relapsers and 64 nonresponders), mean age 45 years, were included in the study. Eighteen relapsers and 13 nonresponders received a higher dose (5 MU), and 11 relapsers and 6 nonresponders received a longer duration (48 weeks) of interferon therapy. The remaining patients received the same regimen as the first treatment. Eighty-one percent and 23% of relapsers and nonresponders, respectively, had an end-of-treatment response, and 19% and 3% of the corresponding patient groups had a sustained response to re-treatment. Two patients with breakthrough during their first treatment were the only nonresponders with sustained response after re-treatment. Sustained response was observed only in patients who received an increased dose or duration of interferon therapy. No predictor of sustained response was found. In conclusion, sustained response to re-treatment with interferon was only observed with augmentation of dose or duration of therapy in some relapsers and patients who had breakthrough. Established predictors of response to interferon in naive patients, in particular serum hepatitis C virus RNA and genotype, were not associated with sustained response to re-treatment.

Acute viral hepatitis E: clinical and serologic studies in Singapore.

Seroprevalence of hepatitis E is now documented in many countries around the world, but studies of its clinical manifestations and serologic course have been confined to endemic areas. We have prospectively evaluated the occurrence, evolution, and outcome of acute hepatitis E in our patients. Fifteen patients (11 men, 4 women; median age: 41 years) were diagnosed to have acute, sporadic hepatitis E between July 1993 and January 1995; 10 of the 15 were followed up. Sera anti-hepatitis E virus (HEV) immunoglobulin (Ig)G and IgM antibodies and HEV ribonucleic acid in the blood and stool were tested at weeks 1 and 2; serial tests for hepatitis E antibodies and liver function were carried out at months 1, 3, 6, 9, 12, and 18. Coinfection with hepatitis A and superinfection on chronic hepatitis B were found in 3 and 2 patients, respectively. One patient had transient passage of virus in the stool, but none was viremic. Eighty-seven percent of patients lost their IgM antibodies within 3 months, but anti-HEV IgG, once present, persisted throughout follow-up. All patients but one had complete recovery. A higher than reported level of alanine transaminase (mean: 28.5 times normal) and the lack of viremia during acute infection in our patients may be due to increased immune-mediated viral clearance.

Hepatitis C, E and G virus--three new viruses identified by molecular biology technique in the last decade.

The development of molecular biology techniques has enabled us to clone the genetic sequence of three new hepatitis viruses, namely, hepatitis C virus, hepatitis E virus and hepatitis G, or GBV-C virus in the last decade. Hepatitis C virus (HCV) is now known to account for the majority of the parenterally transmitted non-A, non-B hepatitis and hepatitis E virus (HEV) is the major cause of the epidemics of enterally transmitted non-A, non-B hepatitis in the less developed countries, mainly through contaminated water supplies. While 80% of those who were infected with HCV will become chronic carriers, there is no known chronic carrier state for HEV. To date, 6 major genotypes of HCV were identified, with various variants of genotype 6 described in Southeast Asia. In Singapore, the majority of our chronic hepatitis C patients are infected with genotype 1. The seroprevalence rate of HEV is 10% to 14% in Singapore. This probably reflects our suboptimal sanitary condition in the past rather than a reflection of a currently high HEV infection rate in our population. However, local cases of acute hepatitis E have been reported. As for the most recently cloned hepatitis G virus, its aetiologic role in the remaining cases of non-A, non-B hepatitis is still unclear. Some preliminary evidence suggests that it may be just an innocent bystander with limited pathogenicity and it certainly cannot account for all the remaining cases of non A-E hepatitis. Hence, the search for yet another hepatitis virus continues.

Hepatitis E in Singapore--a seroprevalence study.

The seroprevalence of anti-HEV IgG was determined in a hospital-based population in a general medical unit. Patients who were otherwise well but admitted for acute, non-hepatological conditions represent the "healthy" general population, and those admitted primarily with liver disorders were studied. The seroprevalence of anti-HEV IgG was found to be 10.5% in the "healthy" population and 14.7% amongst those with liver diseases. The lack of travel history and past history of jaundice suggests presence of local cases and subclinical manifestation in some of the infected patients. There is an association between seroprevalence of hepatitis A and E, suggesting common predisposing factors for both infections. Anti-HAV IgG has a higher seroprevalence. Retesting of anti-HEV IgG in those who were initially positive found persistence of antibodies beyond twelve months. Both anti-HAV IgG and anti-HEV IgG were found more commonly in the older age groups.