Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b: a randomized controlled trial.

Chronic HCV-infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG-IFN/RBV. Eighty-four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG-IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG-IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG-IFN/RBV in HCV genotype 1b-infected patients.

Long-term prognosis of patients undergoing transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: comparison of cisplatin lipiodol suspension and doxorubicin hydrochloride emulsion.

PURPOSE: To evaluate long-term prognosis of transcatheter arterial chemoembolization (TACE) with use of cisplatin (CDDP) lipiodol (LPD) suspension (CDDP/LPD) compared with that with use of doxorubicin hydrochloride (ADM) LPD emulsion (ADM/LPD) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: One hundred eight patients were treated with use of CDDP/LPD and 26 were treated with use of ADM/LPD. Survival rates and frequency of side effects and complications in the CDDP/LPD group were compared with those in the ADM/LPD group. RESULTS: CDDP/LPD was given at a dose of 15-70 mg (mean dose, 41 mg), whereas ADM/LPD was given at a dose of 20-100 mg (mean dose, 57 mg) throughout the study period. The survival rates in the CDDP/LPD group were 81% at 1 year, 41% at 3 years, 19% at 5 years, and 13% at 7 years, whereas those in the ADM/LPD group were 67% at 1 year, 18% at 3 years, and 0% at 5 years. The CDDP/LPD group showed significantly better survival than the ADM/LPD group (P <.05). In the CDDP/LPD group, there was a significant prolongation of survival in patients with monofocal HCC (P <.05) and patients with HCC assessed as an almost complete LPD accumulation (P <.05). There were no significant differences in survival rates in the ADM/LPD group according to tumor size and number of tumors. Hepatic failure was observed in 8% of all procedures and was not different between the two therapeutic groups. Renal dysfunction was observed in 2% of all treatments involving CDDP/LPD, and it resolved spontaneously with appropriate medications. CONCLUSIONS: TACE with use of low-dose CDDP was efficacious for unresectable HCC and had few complications. TACE with use of CDDP may contribute to prolongation of the life span of patients with HCC versus TACE with use of ADM.

Identification of new melanoma epitopes on melanosomal proteins recognized by tumor infiltrating T lymphocytes restricted by HLA-A1, -A2, and -A3 alleles.

To isolate melanoma Ags recognized by T cells, cDNA libraries made from melanoma cell lines were screened with four CTLs derived from tumor infiltrating lymphocytes (TIL) that were able to recognize melanoma cells in a HLA-A1, -A2, or -A3 restricted manner. Although cDNAs encoding the previously identified melanoma Ags, tyrosinase and gp100, were isolated, these TIL were found to recognize previously unidentified peptides. An HLA-A1-restricted CTL, TIL1388, was found to recognize a tyrosinase peptide (SSDYVIPIGTY), and an HLA-A3-restricted CTL, TIL1351, recognized a gp100 peptide (LIYRRRLMK). CTL clones isolated from the HLA-A2-restricted TIL1383 recognized a gp100 peptide (RLMKQDFSV). HLA-A2-restricted CTL, TIL1200, recognized a gp100 peptide (RLPRIFCSC). Replacement of either cysteine residue with alpha-amino butyric acid in the gp100 peptide, RLPRIFCSC, enhanced CTL recognition, suggesting that the peptide epitope naturally presented on the tumor cell surface may contain reduced cysteine residues. Oxidation of these cysteines might have occurred during the course of the synthesis or pulsing of the peptide in culture. These modifications may have important implications for the development of efficient peptide-based vaccines. These newly identified peptide epitopes can extend the ability to perform immunotherapy using synthetic peptides to a broader population of patients, especially those expressing HLA-A1 or HLA-A3 for whom only a few melanoma epitopes have previously been identified.

Repeated mazindol and methamphetamine administration produces cross-sensitization to stereotyped behavior induced by these agents in rats.

The cross-sensitization to stereotyped behavior between mazindol (MZD) and methamphetamine (MAP) was investigated in rats. MZD (5 and 10 mg/kg/day, p.o.), MAP (5 and 10 mg/kg/day, p.o.) and saline (1 ml/kg, p.o.) were administered once daily for a week. Challenge with MZD (10 mg/kg, p.o.) on the 8th day caused markedly stereotyped behavior in MAP-pretreated group compared with the saline-pretreated control group. MAP (10 mg/kg, p.o.)-induced stereotyped behavior on the 8th day was also greater in MZD-pretreated group rather than the saline-pretreated control group. These results suggest that repeated MZD and MAP administration cross-sensitizes to their stereotype-producing effects.

Effects of tea infusions of various varieties or different manufacturing types on inhibition of mouse mast cell activation.

We investigated effects of various tea infusions on mast cell activation using mouse mast cells. Among various tea extracts, infusions from cultivar 'Benihomare' and Taiwan lineage strongly inhibited histamine release after Fc epsilon RI cross-linking. Among three types of tea (from cultivar 'Benihomare'), extract from oolong tea or black tea inhibited histamine release more strongly than green tea extract. Furthermore, 'Benihomare' oolong tea extract suppressed tyrosine phosphorylation of cellular proteins after Fc epsilon RI cross-linking, but polyvinyl polypyrrolidone treatment of the extract to remove phenolic compounds, weakened the suppressive effect.

Relationship between muscle fiber pennation and force generation capability in Olympic athletes.

The thickness (TBmt) and fiber pennation angle (TBpen) of triceps brachii as well as isokinetic force developed during elbow extension were measured in Olympic athletes to investigate the relationship between muscle fiber pennation and force generation capability. The subjects were male members of the 1996 Japanese Olympic team who competed in seven different events; 9 wrestlers, 16 soccer players, 11 sprinters, 5 judo athletes, 7 gymnasts, 9 rowers and 18 baseball players. The TBmt and TBpen, measured by a B-mode ultrasound, ranged between 29 mm and 50 mm and between 11 degrees and 30 degrees, respectively, and on average were larger in the judo athletes, wrestlers and gymnasts compared to the other groups. A significant correlation (r=0.580, p < 0.05) was found between TPpen and TBmt per unit of the upper arm length, and so the observed event-related differences in TBpen tended to reflect the differences in TBmt. The isokinetic forces relative to the cross-sectional area (CSA) estimated from TBmt, measured at two constant velocities of 1.05 rad/s (F1.05/CSA) and 3.14 rad/s (F3.14/ CSA), were negatively correlated to the CSA; r=-0.617 (p < 0.05) for F1.05/CSA and r=-0.635 (p < 0.05) for F3.14/CSA. In addition, low but significant negative correlations existed between TBpen and both F1.05/CSA (r=-0.365, p < 0.05) and F3.14/ CSA (r=-0.336, p <0.05). Even when the effect of TBpen was statistically normalized, the F1.05/CSA and F3.14/CSA were still negatively correlated to the CSA, r=-0.530 (p < 0.05) for F1.05/ CSA and r=-0.561 (p < 0.05) for F3.14/CSA. Therefore, at least in the Olympic athletes tested in this study, the magnitude of the pennation angles reflects muscle size, but it does not seem to be a factor that explains extensively the lower F/CSA in athletes with large muscle size.

Interaction of drugs for eradication therapy against antibiotic-resistant strains of Helicobacter pylori.

To clarify the interactions of drugs for combination therapy of Helicobacter pylori infection, especially due to antibiotic-resistant strains, we have evaluated the in vitro effect of combining different drugs. Using a modified time-kill assay, we tested the effect of combining 2 drugs from 4 agents; amoxicillin (AMPC), clarithromycin (CAM), metronidazole (MTZ) and lansoprazole (a proton pump inhibitor). The H. pylori in the study consisted of 4 strains sensitive to the all drugs, 2 strains resistant only to CAM, 2 strains resistant only to MTZ, and 2 strains resistant to both CAM and MTZ. From the 6 different drug combinations, synergism was observed for 5 of the combinations, among which the combination of AMPC and CAM revealed such effects most frequently. However, all of the strains which showed synergism were sensitive to both of the drugs. In the case of the strains resistant to CAM and/or MTZ, no synergism was demonstrated in any of the combinations including CAM and/or MTZ. When a strain was resistant to one drug from a combination, no synergism was detected. Thus, the administration of a drug to which the strains are resistant may have no advantage in the eradication therapy of H. pylori. For a more effective and safer therapy, susceptibility testing should be performed before treatment.

Susceptibility of Helicobacter pylori isolates against agents commonly administered for eradication therapy and the efficacy of chemotherapy.

Although chemotherapy has been documented to be effective in the treatment of Helicobacter pylori-associated gastritis and gastroduodenal ulcers, some cases are known to have been unsuccessful in the attempt to eradicate this species. In this study, we examined the relation between the susceptibility of H. pylori isolates and the efficacy of chemotherapy. We utilized the modified agar plate dilution method to determine the minimum inhibitory concentrations (MICs) of 63 H. pylori strains isolated before treatment with several drugs routinely used during eradication chemotherapy. Among the drugs tested, amoxicillin (AMPC) and clarithromycin (CAM) demonstrated high degrees of activity with MIC99, 0.39 and 0.2 micrograms/ml, respectively. No highly resistant strain against AMPC was detected among the strains examined, while for CAM and metronidazole (MTZ), 9.5% and 7.9% of the strains, respectively, were resistant before treatment. It should be noted that all of the MICs of the strains from patients with successful therapy were lower than those from patients with unsuccessful therapy. These findings indicate that susceptibility tests should be carried out prior to the commencement of drug administration in order to provide safer and more effective chemotherapy.

Induction of long-lasting potentiation in the secondary somatosensory cortex by thalamic stimulation requires cortico-cortical pathways from the primary somatosensory cortex.

We have investigated the role of cortico-cortical inputs from the primary somatosensory cortex in the induction of long-lasting potentiation in the secondary somatosensory cortex. Long-lasting potentiation of evoked potentials in the feline secondary somatosensory cortex is induced by high frequency stimulation of the ventral posterolateral thalamic nucleus. The secondary somatosensory cortex receives two projections from the ventral posterolateral thalamic nucleus; a direct pathway from the ventral posterolateral thalamic nucleus and a cortico-cortical pathway via the primary somatosensory cortex. The present study was designed to examine dominance of these pathways in the induction of long-lasting potentiation in the secondary somatosensory cortex. Long-lasting potentiation was evaluated by changes in the amplitude of field potentials and current source densities elicited by ventral posterolateral thalamic nucleus test stimulation (0.1 Hz) following conditioning stimulation. The conditioning stimulation, consisting of 20 trains of 200 Hz bursts, was delivered to the ventral posterolateral thalamic nucleus or the primary somatosensory cortex. Field potentials in the secondary somatosensory cortex were simultaneously recorded at 16 points placed vertically at 150 microns intervals from the cortical surface and current source density was computed using these field potentials. First, we blocked inputs from the primary somatosensory cortex to the secondary somatosensory cortex by intracortical injection of lidocaine into the primary somatosensory cortex. The amplitudes of the field potentials recorded in the secondary somatosensory cortex diminished within 5 min after lidocaine injection. Current source density analysis showed a marked decrease in the sink currents in layers II/III (at depths of 450-600 microns).(ABSTRACT TRUNCATED AT 250 WORDS)

Disturbed lipid metabolism in patients with subclinical hypothyroidism: effect of L-thyroxine therapy.

To evaluate whether patients with subclinical hypothyroidism have a disturbance in lipid metabolism, and whether supplemental L-thyroxine (L-T4) therapy would improve their lipid parameters, we measured serum levels of thyroid hormones, TSH and lipid parameters in 34 patients with subclinical hypothyroidism before and 2 months after treatment with L-T4. Before treatment, patients with subclinical hypothyroidism had elevated serum low density lipoprotein cholesterol (LDL-C) concentrations compared with control subjects (P < 0.05). Overall, L-T4 therapy significantly decreased the serum level of TSH (P < 0.01), total cholesterol (TC; P < 0.02), high density lipoprotein cholesterol (P < 0.02), LDL-C (P < 0.05), and the ratio of apolipoprotein B to apolipoprotein A1 (P < 0.05). Lipid values in patients with basal serum TSH levels below 10 mU/l were not affected by L-T4 therapy, whereas serum levels of TC and LDL-C decreases significantly (P < 0.01) in patients with serum TSH levels above 10 mU/l. Thus, the L-T4 treatment appears to have a preventive effect on the disturbance of lipid metabolism in patients with subclinical hypothyroidism, especially in patients with serum TSH levels above 10 mU/l.

Polyclonal human T-cell activation by silicate in vitro.

Silica (SiO2) or related substances such as silicone ([-R2Si-O-]n), which is used in plastic surgery, or asbestos (e.g. chrysotile; 3MgO.2SiO2.H2O) have 'adjuvant effects'. In a study of scleroderma patients in Germany more than 78% had experienced exposure to silicate dust. T-cell receptor (TcR) V beta gene analysis on CD4- CD8- double-negative alpha beta T cells from scleroderma patients, using polymerase chain reaction (PCR), showed that certain V beta genes, V beta 5, V beta 7 and V beta 17, were predominantly expressed in the cells. We found that certain V beta repertoires, V beta 5.3 and V beta 6.7, were predominantly expressed on fractionated T cells with a high Ca2+ level that had been stimulated by chrysotile in vitro. The intracellular Ca2+ level in human peripheral blood mononuclear cells (PBMC) increased after incubation with silica or chrysotile. Interleukin-2 (IL-2) release from PMBC also rose significantly with chrysotile stimulation, but no change was observed when major histocompatibility complex (MHC) class II DP/DR positive cells were depleted. Therefore, our results support the possibility that silicate acts as a superantigen.

[Studies on the mechanism of protective effect of selenium on nephrotoxicity of cis-diamminedichloroplatinum (CDDP) in mice].

The mechanism of protective effect of sodium selenite (Se) on the nephrotoxicity of cis-diamminedichloroplatinum (CDDP) was studied with mice. CDDP and Se concentrations in the plasma, blood cell, kidney and liver were measured in mice given CDDP alone and those given both CDDP and Se. The nephrotoxicity of CDDP was observed in mice fed Se deficient diet (SDD). The activities of glutathione peroxidase (G-Px) in the plasma, blood cells, kidney and liver were measured in mice mentioned above. Co-administration of Se did not influence on the concentration of CDDP in the blood, kidney and liver. In mice fed SDD, the nephrotoxicity of CDDP increased and G-Px activities of the blood and kidney decreased. In mice given Se, G-Px activities was not increased. These results suggest that interaction between CDDP and Se differs from that between mercury and Se, or between cadmium and Se (formation of compound). Intake of Se is related to the appearance of the nephrotoxicity of CDDP. G-Px may be related partially to the protective effect of Se on the nephrotoxicity of CDDP.

Serum selenium and vitamin E concentrations in families of lung cancer patients.

Whether or not serum selenium and vitamin E (alpha-tocopherol) concentrations were changed was examined among healthy families of lung cancer patients. Family members as a whole (115 sons and daughters of 55 patients with primary lung cancer) were found to have a trend to lower serum selenium levels (0.116 +/- SD 0.024 microgram/ml, 0.05 less than P less than 0.1). Particularly among families of adenocarcinoma patients, the mean level was significantly lower (0.111 +/- 0.019 microgram/ml, P less than 0.05) than that (0.122 +/- 0.014 microgram/ml) in age-ratio matched controls who did not have cancer patients among their second-degree relatives. Serum vitamin E levels (11.85 +/- 2.85 micrograms/ml) were significantly lower among family members of adenocarcinoma patients than the controls (14.1 +/- 3.1 micrograms/ml, P less than 0.01). Serum selenium and vitamin E levels were significantly lower in lung cancer patients (n = 37, mean age, 63.9 +/- 11.2 yr) than in the controls (P less than 0.001). These data suggest that there are familial factors in serum selenium and vitamin E levels among families of lung cancer patients.