Randomized trial of peginterferon α-2a plus ribavirin versus peginterferon α-2b plus ribavirin for chronic hepatitis C in Japanese patients

Background

Pegylated interferon (PegIFN) plus ribavirin is the standard therapy for patients with chronic hepatitis C genotype 1. Although several randomized clinical trials have compared PegIFNα-2a with PegIFNα-2b, these 2 regimens have not been directly compared in Asian patients. We, therefore, compared the safety and antiviral efficacy of these agents in Japanese patients.

Methods

A total of 201 PegIFN-na?ve, chronic hepatitis C patients were randomly assigned to once-weekly PegIFNα-2a (180?μg) or PegIFNα-2b (60–150?μg) plus ribavirin. We compared the sustained virological response (SVR) rates between the 2 regimens and analyzed their effects in relation to baseline characteristics, including single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene (rs8099917).

Results

PegIFNα-2a was associated with a higher SVR rate than PegIFNα-2b (65.3 vs. 51.0%, P?=?0.039). PegIFNα-2a and SNPs near IL28B independently predicted SVR (odds ratio 2.36; 95% confidence interval [CI] 1.19–15.50, and odds ratio 7.31; 95% CI 3.45–4.68, respectively) in logistic regression analysis. PegIFNα-2a was more effective than PegIFNα-2b (81.8 vs. 62.7%, P?=?0.014) in IL28B TT genotype patients, despite similarly low SVR rates in patients with TG or GG genotypes (36.4 vs. 35.9%). Patients weighing <60?kg, women, and patients aged >60?years had significantly higher SVR rates with PegIFNα-2a than with PegIFNα-2b (63.9, 61.3, and 67.3% vs. 43.8, 43.3,and 39.2%, respectively).

Conclusions

PegIFNα-2a plus ribavirin resulted in higher SVR rates than PegIFNα-2b plus ribavirin in Japanese patients. PegIFNα-2a-based treatment should therefore be the preferred choice for women, older or low-weight patients, and those with the IL28B TT genotype.     

Rapid integration of young newborn dentate gyrus granule cells in the adult hippocampal circuitry

Newborn dentate gyrus granule cells (DGCs) are integrated into the hippocampal circuitry and contribute to the cognitive functions of learning and memory. The dendritic maturation of newborn DGCs in adult mice occurs by the first 3–4 weeks, but DGCs seem to receive a variety of neural inputs at both their dendrites and soma even shortly after their birth. However, few studies on the axonal maturation of newborn DGCs have focused on synaptic structure. Here, we investigated the potentiality of output and input in newborn DGCs, especially in the early period after terminal mitosis. We labeled nestin-positive progenitor cells by injecting GFP Cre-reporter adenovirus into Nestin-Cre mice, enabling us to trace the development of progenitor cells by their GFP expression. In addition to GABAergic input from interneurons, we observed that the young DGCs received axosomatic input from the medial septum as early as postinfection day 7 (PID 7). To evaluate the axonal maturation of the newborn DGCs compared with mature DCGs, we performed confocal and electron microscopic analyses. We observed that newborn DGCs projected their mossy fibers to the CA3 region, forming small terminals on hilar or CA3 interneurons and large boutons on CA3 pyramidal cells. These terminals expressed vesicular glutamate transporter 1, indicating they were glutamatergic terminals. Intriguingly, the terminals at PID 7 had already formed asymmetric synapses, similar to those of mature DGCs. Together, our findings suggest that newborn DGCs may form excitatory synapses on both interneurons and CA3 pyramidal cells within 7 days of their terminal mitosis.     

Case report: periodical infliximab administration enabled closure of colostomy in fistulating perianal Crohn's disease]

A 29-year old woman with Crohn's disease was performed colostomy due to severe perianal abscess. Her disease had been easy to recur and she was admitted to hospital for intestinal bleeding caused by acute exacerbation in Crohn's disease on October 2006. The bleeding was stopped rapidly and clinical remission was maintained with bimonthly administration of infliximab. Finally, her colostomy was closed after 5 years 8 months. Periodical treatment of infliximab not only prevented recurrence but also enabled closure of colostomy in fistulating perianal Crohn's disease.     

Clinical,autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study)

OBJECTIVE: To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies. RESEARCH DESIGN AND METHODS: GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab(+)) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load. RESULTS: GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non-insulin deficient, and 19 (10.1%) were unclassified. The GADab(+) insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA(1c). The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab(+) insulin-deficient patients were significantly higher than those in the GADab(+) non-insulin-deficient patients (P < 0.05). GADab(+) patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab(+) non-insulin-deficient patients. Of note is the fact that the GADab(+) non-insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab(+) patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies. CONCLUSIONS: We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.     

Effects of prostaglandin E1 infusion in the pre-operative management of critical congenital heart disease

Prostaglandin E1 (PGE1) was administered to 27 infants in whom pulmonary or systemic blood flow was entirely or significantly dependent upon the patency of the ductus arteriosus. In 12 patients with pulmonary atresia or severe pulmonary stenosis, PGE1 infusion was followed by an improvement in hypoxemia and acidemia (group I). In 2 patients with left ventricular outflow-tract obstruction, PGE1 infusion was followed by an improvement in arterial blood pressure, peripheral perfusion and urine output (group II). In 5 patients with d-transposition of the great arteries and intact ventricular septum who had persistent severe hypoxemia after creation of an interatrial communication, PGE1 infusion improved the arterial oxygenation with dilatation of the ductus arteriosus (group III). Seven patients (3 of group I, 2 of group II and 2 of group III) failed to respond to PGE1. There were no fatal side effects. It is concluded that PGE1 therapy is highly effective in stabilizing pre-operative conditions of infants with ductus-dependent congenital heart disease.     

Serum concentrations of trace elements in patients with Crohn's disease receiving enteral nutrition

We investigated the trace element status in Crohn's disease (CD) patients receiving enteral nutrition, and evaluated the effects of trace element-rich supplementation. Thirty-one patients with CD were enrolled in this study. All patients were placed on an enteral nutrition regimen with Elental(R) (Ajinomoto pharmaceutical. Ltd., Tokyo, Japan). Serum selenium, zinc and copper concentrations were determined by atomic absorption spectroscopy. Serum selenoprotein P levels were determined by an ELISA system. Average serum levels of albumin, selenium, zinc and copper were 4.1 +/- 0.4 g/dl, 11.2 +/- 2.8 microg/dl, 71.0 +/- 14.8 microg/dl, and 112.0 +/- 25.6 microg/dl, respectively. In 9 patients of 31 CD patients, serum albumin levels were lower than the lower limit of the normal range. Serum selenium, zinc and copper levels were lower than lower limits in 12 patients, 9 patients and 1 patient, respectively. Serum selenium levels significantly correlated with both serum selenoprotein P levels and glutathione peroxidase activity. Supplementation of selenium (100 microg/day) and zinc (10 mg/day) for 2 months significantly improved the trace element status in CD patients. In conclusion, serum selenium and zinc levels are lower in many CD patients on long-term enteral nutrition. In these patients, supplementation of selenium and zinc was effective in improving the trace element status.     

Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: role of interleukin-17

Background. Subepithelial myofibroblasts (SEMFs) play a role in extracellular matrix (ECM) metabolism in the colon. In this study, we investigated the effects of interleukin (IL)-17, IL-1β, and tumor necrosis factor (TNF)-α on matrix metalloproteinase (MMP)-3 secretion in colonic SEMFs. Methods. MMP-3 secretion and MMP-3 mRNA expression were determined by Western and Northern blotting, respectively. The secretion of tissue inhibitor of matrix metalloproteinase (TIMP)-1 was determined by enzyme-linked immunosorbent assay (ELISA). Results. In human colonic SEMFs, MMP-3 secretion and MMP-3 mRNA expression were induced by IL-17, IL-1β, and TNF-α. The effect of IL-17 was observed, but this was weak as compared with those induced by IL-1β or TNF-α. A c-Jun/activating protein-1 (AP-1) inhibitor, curcumin, reduced the IL-17-, IL-1β-, and TNF-α-induced MMP-3 mRNA expression, and mitogen-activated protein (MAP) kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. There findings indicate a role for AP-1 and MAP kinases in cytokine-induced MMP-3 secretion. Furthermore, costimulation by IL-17 + IL-1β and by IL-17 + TNF-α induced a marked increase in MMP-3 secretion. The costimulatory effects of these combinations were also observed for TIMP-1 mRNA expression and TIMP-1 secretion. Conclusions. Colonic SEMFs actively secreted MMP-3 in response to IL-17, IL-1β, and TNF-α. This was coupled with TIMP-1 secretion. Colonic SEMFs may play an important role in ECM turnover via MMP secretion. Received: July 2, 2002 / Accepted: December 18, 2002 RID="*" ID="*" Reprint requests to: A. Andoh     

Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines.

Aim: The cross-talk pathway between angiotensin II (AngII) and the epidermal growth factor receptor (EGFR) mediated by epidermal growth factor (EGF)-like ligands cleaved by a disintegrin and metalloprotease (ADAM) has been elucidated in several cell types. Even though the liver is a representative angiotensinogen-producing organ, such cross-talk has never been elucidated in hepatocellular carcinomas (HCCs). We investigated whether AngII exerted a mitogenic effect on HCC cell lines through the AngII-EGFR cross-talk pathway. Methods: We determined the expression and/or phosphorylation status of AngII receptor type 1 (AGTR1), ADAM9, ADAM17, ERK1/2, STAT3, AKT and EGFR in five HCC cell lines using Western blotting. Proliferation and invasion activities were measured by ATP and Matrigel invasion assays, respectively. Results: AGTR1 was expressed ubiquitously in HCC cell lines. EGFR expression in HepG2 was relatively weaker than that in the remaining HCC cell lines. The phosphorylation status of EGFR, ERK1/2, STAT3 and AKT was upregulated by AngII treatment in two EGFR-overexpressing cell lines (Huh7 and PLC/PRF/5), but not in HepG2 (showing weak EGFR expression). AngII stimulation significantly accelerated proliferation and invasion activities in Huh7 and PLC/PRF/5, and was inhibited by pretreatment with an ADAM inhibitor. A selective AGTR1 blocker significantly repressed proliferation activity in both cell lines, but did not significantly repress the invasion activity. Both chemical agents and neutralizing antibodies against ADAMs (ADAM9 and ADAM17) and EGF-like ligands suppressed EGFR transactivation and/or subsequent phosphorylation of ERK1/2, STAT3 and AKT. Conclusion: These results suggest that AngII-EGFR cross-talk signaling mediated by ADAMs is involved in the proliferation and invasion activities of several HCC cell lines.     

Effects of adipocytes on the proliferation and differentiation of prostate cancer cells in a 3‐D culture model

Objective: To investigate how the mechanism of adipocyte–prostate cancer cell interaction affects the proliferation and differentiation of prostate cancer cells. Methods: An androgen‐dependent cell line (LNCaP), two androgen‐independent cell lines (PC‐3, DU145), and mature adipocytes harvested from male Wistar rats were used. Cancer cells were co‐cultured with the isolated mature adipocytes in 3‐D collagen gel matrix culture. The morphology and proliferative ability of the prostate cancer cells were examined. With regard to the activation of the phosphatidylinositol 3‐kinase (PI3K) pathway, the expression of phosphatase and tensin homologue deleted on chromosome ten (PTEN), Akt and Bad were determined by immunohistochemistry. Results: LNCaP cells co‐cultured with adipocytes formed larger clusters than those of the control. PC‐3 cells co‐cultured with adipocytes did not form larger clusters, but formed spherical and spindle‐shaped cells. The phosphorylation of Akt in PC‐3 cells was greater in the co‐cultured group compared with the controls, but there were no significant differences in the phosphorylation of Akt with regard to LNCaP and DU145 cells. Conclusions: Adipocytes could modulate the proliferation and differentiation of prostate cancer cell lines. Activation of the PI3K pathway might be involved in the prostate cancer cell–adipocyte interaction.