S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial

Background: S‐adenosyl‐L‐methionine (SAM) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione, the main cellular antioxidant. Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases (ALDs). The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24‐week trial. The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores, and the secondary endpoints were changes in serum levels of methionine metabolites. Methods: We randomized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily. Subjects were required to remain abstinent from alcohol drinking. A baseline liver biopsy was performed in 24 subjects, and a posttreatment liver biopsy was performed in 14 subjects. Results: Fasting serum SAM levels were increased over timed intervals in the SAM treatment group. The entire cohort showed an overall improvement of AST, ALT, and bilirubin levels after 24 weeks of treatment, but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra‐ or intergroup differences or changes in liver histopathology scores for steatosis, inflammation, fibrosis, and Mallory‐Denk hyaline bodies. Conclusions: Whereas abstinence improved liver function, 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD.     

A simple and inexpensive point‐of‐care test for hepatitis B surface antigen detection: serological and molecular evaluation

Early identification of chronic hepatitis B is important for optimal disease management and prevention of transmission. Cost and lack of access to commercial hepatitis B surface antigen (HBsAg) immunoassays can compromise the effectiveness of HBV screening in resource‐limited settings and among marginalized populations. High‐quality point‐of‐care (POC) testing may improve HBV diagnosis in these situations. Currently available POC HBsAg assays are often limited in sensitivity. We evaluated the NanoSign^® HBs POC chromatographic immunoassay for its ability to detect HBsAg of different genotypes and with substitutions in the ‘a’ determinant. Thirty‐seven serum samples from patients with HBV infection, covering HBV genotypes A–G, were assessed for HBsAg titre with the Roche Elecsys HBsAg II quantification assay and with the POC assay. The POC assay reliably detected HBsAg at a concentration of at least 50 IU/mL for all genotypes, and at lower concentrations for some genotypes. Eight samples with substitutions in the HBV ‘a’ determinant were reliably detected after a 1/100 dilution. The POC strips were used to screen serum samples from 297 individuals at risk for HBV in local clinical settings (health fairs and outreach events) in parallel with commercial laboratory HBsAg testing (Quest Diagnostics EIA). POC testing was 73.7% sensitive and 97.8% specific for detection of HBsAg. Although the POC test demonstrated high sensitivity over a range of genotypes, false negatives were frequent in a clinical setting. Nevertheless, the POC assay offers advantages for testing in both developed and resource‐limited countries due to its low cost (0.50$) and immediately available results.     

Single‐nucleotide substitution of Hepatitis B virus in intrauterine infection

The relationship between hepatitis B virus (HBV) gene polymorphism and intrauterine infection has not been completely illuminated. Six pairs of mother and infant from intrauterine infection group and six mothers from nonintrauterine infection group in the previous study were randomly selected and separately divided into group M (Mother group), group N (Neonate group) and group NM (Negative‐mother group) in this study. We found that age, gestational weeks, HBsAg titre, HBeAg titre and HBV DNA level of mothers from group M and group NM were not significantly different. Pre‐S1/S2 and S regions in HBV genome were amplified, inserted into pUC19 plasmid and sequenced. It was found that all clone sequences clustered into genotype C ( AY123041 ) through the Genotyping tool in NCBI and phylogenetic trees. Compared with AY123041 , there were 20 (11 plus 9) mutations significantly different in the three groups. Most of the mutations were synonymous in pre‐S1/S2/S region, while mutations of C2990T, T3205A, A167G, C407A, A667T and A680C resulted in amino acid substitution of A90V, S162T, T47A, P127T, L213F and I218L, respectively. In addition, most of the 20 mutations caused amino acid substitution in polymerase region for the tight structure of HBV genome. The occurrence and location of mutations indicated that mutation of C2990T only existing in group NM may serve as an index for nonintrauterine infection. In contrast, the incidence of intrauterine HBV infection from mothers with mutation of T3205A was lower. Then, mutations of G403A, T670G, A673G, A167G, C407A, A667T and A680C may be closely related to intrauterine HBV infection.     

Association between combinations of glutathione‐S‐transferase M1, T1 and P1 genotypes and non‐alcoholic fatty liver disease

Background/Aims: Glutathione‐S‐transferases (GSTs) play a crucial role in antioxidant defence mechanisms, by detoxifying xenobiotics and by inactivating endogenous byproducts of oxidative stress. Functional failure, as a sequel of an altered GST genotype, may thus aggravate non‐alcoholic fatty liver disease (NAFLD). This study investigated whether the GSTs genotypes could affect the risk for NAFLD. Methods: A cross‐sectional case–control analysis included 253 Japanese participants in a health screening programme. The GSTM1 null, GSTT1 null and GSTP1 Ile105Val variant genotypes were determined as putative high‐risk genotypes. Results: The incidence of NAFLD was 27.3%. The frequency of the GSTM1 null genotype was higher in NAFLD than in the control [adjusted odds ratio (OR), 2.00; 95% confidence intervals (CI), 1.01–3.95]. Moreover, any combination of two putative high‐risk genotypes exhibited a higher risk for NAFLD with an adjusted OR from 3.52 (95% CI, 1.08–11.43)–4.01 (95% CI, 1.28–12.56). However, the significance for the combination of GSTM1 null and GSTT1 null genotypes only remained after Bonferroni's correction. In addition, the risk for NAFLD increased as the number of high‐risk genotypes, and the OR among three high‐risk genotypes carriers was 9.67 (95% CI: 1.61–58.26). Conclusion: This is the first report to show the impact of the GSTs genotypes on the development of NAFLD. This finding, which should be confirmed in further studies in larger populations, may help to develop a more targeted prevention programme at an early stage for subjects with an increased risk for NAFLD.     

Concurrent chemoradiotherapy with S‐1 and cisplatin in advanced esophageal cancer

How best to manage advanced esophageal cancer remains unresolved, especially in palliative care. Here, in a pilot study, we evaluated the efficacy and safety of concurrent chemoradiotherapy with S‐1 and cisplatin in advanced esophageal cancer. Patients with locally advanced or metastatic squamous cell carcinoma of the esophagus received S‐1 and cisplatin at doses of 70 mg/m²/day for 14 days and 70 mg/m² on day 1, respectively, every 3 weeks. Concurrently, radiotherapy was started at a dose of 200 cGy/day, up to a total of 5400 cGy. After concurrent chemoradiotherapy, additive chemotherapy was repeated up to six cycles. Thirty patients were enrolled in this study; of the 27 in whom efficacy could be evaluated, an objective response rate was seen in 20 (74.1%), including five (18.5%) complete pathologic responses in primary lesions. Improvement of dysphagia was seen in 21 (76%) patients. In patients with stage II or III esophageal cancer, the median progression‐free survival and overall survival were 10.6 ± 0.6 months (95% CI: 9.4–11.8) and 23.0 ± 5.1 months (95% CI: 13.0–32.9), respectively. In patients with stage IV esophageal cancer, the median progression‐free survival and overall survival were 5.4 ± 1.6 months (95% CI: 2.2–8.6) and 11.6 ± 1.6 months (95% CI: 8.4–14.8), respectively. The main hematological toxicity was neutropenia, but no neutropenic fever was observed. The major non‐hematological toxicities were asthenia and vomiting, mostly of grades 1 and 2. Thus, concurrent chemoradiotherapy with S‐1 and cisplatin may be a promising nonsurgical treatment in advanced esophageal cancer.     

Efficacy and tolerability of initial high vs low doses of S‐(‐)‐amlodipine in hypertension

In an 8‐week randomized trial of patients with mild or moderate hypertension, the authors investigated the efficacy and tolerability of initial high (5.0 mg/d) vs low (2.5 mg/d) doses of S‐(‐)‐amlodipine (equivalent to 5 and 10 mg of racemic amlodipine, respectively). In the S‐(‐)‐amlodipine 2.5‐mg group (n=263), 24‐hour ambulatory systolic/diastolic blood pressure (±standard deviation) decreased from 131.5±15.0/82.1±10.7 mm Hg at baseline to 126.0±13.5/78.5±9.5 mm Hg at 8 weeks of follow‐up by a least square mean (±standard error) change of 6.0±0.6/3.8±0.4 mm Hg. In the S‐(‐)‐amlodipine 5‐mg group (n=260), the corresponding changes were from 133.6±13.7/83.1±9.9 mm Hg to 125.0±12.0/78.2±8.9 mm Hg by 8.1±0.6/4.7±0.4 mm Hg, respectively. The between‐group differences in changes in 24‐hour systolic/diastolic blood pressure were 2.1/0.9 (P=.02/.17) mm Hg. Similar trends were observed for daytime and nighttime ambulatory and clinic blood pressure. The incidence rate was similar for all adverse events. An initial high dose of S‐(‐)‐amlodipine improved ambulatory blood pressure control with similar tolerability as an initial low dose in hypertension.     

Null genotype of glutathione S-transferase Tl contributes to colorectal cancer risk in the Asian population: a meta-analysis

Background and Aim: Previous studies investigating the association between the glutathione S‐transferase Tl (GSTT1) null genotype and colorectal cancer (CRC) risk in the Asian population have reported controversial results. Thus, a meta‐analysis was performed to clarify the effect of the GSTT1 null genotype on CRC risk in the Asian population. Methods: A comprehensive study was conducted, and 12 case‐control studies were finally included, involving a total of 4517 CRC cases and 6607 controls. Subgroup analyses were performed by the sample size. Results: A meta‐analysis of all 12 studies showed that the GSTT1 null genotype was significantly associated with an increased CRC risk in the Asian population (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.02–1.19, the P‐value of the OR [P_OR] = 0.02, the value of the heterogeneity analysis [I²] = 42%). A more obvious association was observed after the heterogeneity was eliminated by excluding one study (OR = 1.15, 95% CI: 1.06–1.25, P_OR = 0.001, I² = 0%). This association was further identified by both subgroup analyses and a sensitivity analysis. Conclusions: This meta‐analysis suggests that the GSTT1 null genotype contributes to an increased colorectal cancer risk in the Asian population.     

Clinical characteristics and outcome of complicated pneumococcal pneumonia in a pediatric population

The incidence of complicated pneumonia caused by S. pneumoniae is reported to be increasing. This increase may be related to host susceptibility and/or pathogen virulence. The objective of this study was to evaluate clinical and laboratory characteristics associated with complicated pneumococcal pneumonia, and to identify risk factors associated with prolonged fever and hospitalization. The study involved reviewing the records of all children who were hospitalized in four major hospitals in Jerusalem with a confirmed diagnosis of pneumococcal pneumonia during a 12-year period (1986-1997). Demographic, clinical, laboratory, and outcome variables were compared between those with uncomplicated and complicated pneumonia. One hundred and eleven children (median age, 2.2 years) were hospitalized with pneumococcal pneumonia during the study period. Forty-four (39%) of them had complicated pneumonia, characterized by pleural effusion, empyema, pneumothorax, pneumatocele, and/or atelectasis. There was no correlation between the isolation of penicillin-resistant S. pneumonia (16% of cases) and complicated pneumonia. Factors that were significantly associated with complicated pneumonia included weight 相似文献   

Use of suture-mediated vascular closure devices for the management of femoral vein access after transcatheter procedures.

Groin complications remain the most common complication of cardiac catheterization procedures. While the use of closure devices is increasing for arterial sheaths, venous sheaths tend to be removed and hemostasis achieved with manual compression. We report our experience using Perclose suture-mediated vascular closure device to achieve hemostasis and early mobility in patients who have had venous access as part of their procedure. There were a total of 42 patients (21 males; average age, 63.5 years) studied. The majority of the patients had 7 Fr sheaths (24), with access sites of sheaths up to 14 Fr being closed with this technique. Two patients developed complications at the access site: one patient requiring rehospitalization for intravenous antibiotics because of late access site infection, and one patient with deep venous thrombosis and pulmonary emboli. We conclude that the use of the Perclose suture-mediated closure device for closure of femoral venous access sites is feasible and should be considered especially in patients with larger venous sheaths and those at increased risk of groin complications.     

Therapeutic effect of photodynamic therapy using PAD‐S31 and diode laser on human liver cancer cells

Abstract: Background/aims: Photodynamic therapy (PDT) is an effective local cancer treatment which a photosensitizer is administered and the tumor is irradiated with light. We examined the effect of PDT using PAD‐S31 as the photosensitizer, and the 670 nm diode laser on human hepatocellular carcinomas (HCCs). Methods: Huh‐7, HepG2 and Hep3B cell lines were used in the all experiments. Cell viability was determined by a modified MTT assay. Two methods were used for the determination of apoptosis: terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP nick‐end labeling assay and detection of fragmented mono‐ and oligo‐nucleosomes by enzyme‐linked immunosorbent assay. The caspase activity was measured by fluorometric assay. Cytochrome c in cytosolic fraction was determined using a human cytochrome c immunoassay. Xenografts of human oral HCC cells were generated in KSN S1c nude mice. Results: In vitro PDT showed excellent cytotoxicity that was a function of laser energy, drug concentration and time to the hepatoma cell lines. The combined use of PAD‐S31 and laser irradiation showed excellent anti‐tumor activity without severe side‐effect against human hepatoma xenografts in nude mice. PDT‐mediated cell death occurred predominantly by apoptosis in vitro and in vivo. Furthermore, this treatment initiates early cytochrome c release, followed by late caspase‐3 and ‐9 activation. Conclusion: Our study demonstrates that PDT using PAD‐S31 and the diode laser induces apoptosis that is mediated by cytochrome c release and caspase activation in human liver cancer cell lines. It is expected that this therapy will be clinically useful for the treatment of patients with HCC.     

Effect of phorbol ester and platelet-derived growth factor on protein kinase C in rat hepatic stellate cells.

BACKGROUND/AIMS: Hepatic stellate cells (HSC) play a key role in hepatic fibrogenesis and thus, it is important to understand the intracellular signalling pathways that influence their behaviour. This study investigated the expression and regulation of protein kinase C (PKC) in HSC. RESULTS: Western blot analysis indicates that rat HSC express at least four PKC isoforms, PKC-alpha, PKC-delta, PKC-epsilon and PKC-zeta. PKC-alpha and PKC-zeta were located predominantly in the cytosol and were redistributed to the membrane by the PKC agonist, phorbol 12-myristate 13-acetate (PMA), while PKC-delta and PKC-epsilon were highly membrane-bound and did not undergo translocation by PMA. PKC-alpha, PKC-delta and PKC-zeta were rapidly downregulated by PMA. However, PKC-epsilon was resistant to downregulation. We also examined phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS), a specific substrate of PKC, as another approach to assess activation of PKC. Platelet-derived growth factor (PDGF) and PMA increased the phosphorylation of MARCKS, suggesting that PDGF can induce PKC activation. PDGF-induced stimulation of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase and p70-S6 kinase was not abrogated by downregulation of PKC-alpha, PKC-delta and PKC-zeta. Prolonged PKC inhibition did not inhibit the fibrogenic phenotype. CONCLUSION: Multiple PKC isoforms are expressed in rat HSC and are differentially regulated by PMA. PDGF activates certain mitogenic signalling pathways independent of PKC-alpha, PKC-delta and PKC-zeta. Specific PKC isoforms may modulate different cell functions in HSC.