Case-control study of nonfatal myocardial infarction in relation to selected foods in Japanese men and women

Most studies of diet and coronary heart disease (CHD) have focused on constituents rather than on whole foods. The present study examined the relationship of selected foods to nonfatal acute myocardial infarction (AMI) in Japan, with special reference to vegetables, fruits, fish, and tofu. A total of 660 cases with their first episode of AMI aged 40-79 years living in Fukuoka City or adjacent areas and 1,277 controls matched for age, sex, and residence were surveyed on lifestyle, including dietary factors. Participation rates were 87% of cases and 52% of controls. Consumption frequencies of 19 food/beverages items and daily amounts of 4 items were ascertained by interview. The final analysis was done with 632 cases and 1,214 controls. Although consumption of vegetables showed no clear association with the risk of AMI, fruit consumption appeared to reduce the risk of AMI in both men and women. The results also suggested that fish consumption was related to a decreased risk of AMI in men, although the trend was not statistically significant. In women only, tofu consumption was inversely related to the risk of AMI; relative risks for eating tofu <2, 2-3, and 4+ times per week were 1.0, 0.8, and 0.5, respectively, after adjustment for non-dietary factors (p for trend = 0.01). Further adjustment for consumption of fruit, fish and tofu did not alter the findings generally. The findings suggest that, in women at least, tofu consumption may be protective against the risk of AMI. Further studies are needed to corroborate the relationship of consumption of fish and fruit to AMI risk in Japanese men and women.     

A case of hepatitis C-associated osteosclerosis that was improved with the combination therapy of peginterferon alfa-2b and ribavirin

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in skeletal mass in patients who are infected with hepatitis C virus (HCV). The clinical presentation is an acquired deep bone pain with increased serum alkaline phosphatase (ALP) activity. We present a case of a patient with HCAO who was treated with antiviral therapy. A 42-year-old Japanese man presented with severe, stabbing pain in his lower limbs. He was diagnosed with hepatitis C secondary to intravenous drug use 20 years earlier. Serum biochemical studies revealed markedly elevated ALP activity and osteocalcin levels. Skeletal radiographs showed diffuse bony sclerosis with marked cortical thickening in the long bones. The bony findings and clinical symptoms were attributed to HCAO. The HCV RNA viral load was high and the genotype was 2a. The patient was treated with peginterferon alfa-2b and ribavirin for 24 weeks. After 24 weeks of the combination therapy, the patient had a sustained virological response and clinical remission of bone pain and a decrease in the level of serum ALP. In conclusion, HCAO was improved by the combination therapy of peginterferon alfa-2b and ribavirin when the patient achieved sustained virological response. It was confirmed that HCAO was one of the extrahepatic manifestations of HCV.     

Immune suppression gene on HLA-Bw54-DR4-DRw53 haplotype controls nonresponsiveness in humans to hepatitis B surface antigen via CD8+ suppressor T cells

The development of antiviral vaccines has been accelerated using monoclonal antibody and/or recombinant DNA techniques, the objective being to prevent grave viral infectious diseases, such as acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia (ATL), and hepatitis B virus (HBV)-associated liver diseases. Certain proportions of individuals in the human population do not have any appreciable immune response to foreign antigens, either in cases of natural exposure or a planned immunization. Here we report that in the nonresponders to HB vaccine, there is an HLA-linked immune suppression gene for hepatitis B surface antigen (Is-HBsAg) controlling the nonresponsiveness to HBsAg through HBsAg-specific suppressor T cells. The Is-HBsAg is in strong linkage disequilibrium with the HLA-Bw54-DR4-DRw53 haplotype.     

Calcineurin inhibitors suppress acute graft-versus-host disease via NFAT-independent inhibition of T cell receptor signaling

Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of gene expression dependent on nuclear factor of activated T cells (NFAT) is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of Lck^S59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express Lck^S59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either Lck^WT or Lck^S59A, it was ineffective in treating disease when the T cells expressed Lck^S59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in Lck^S59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8⁺ T cells and antigen-specific T/DC adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.     

Ciliatamides A-C, bioactive lipopeptides from the deep-sea sponge Aaptos ciliata

Three lipopeptides, ciliatamides A-C ( 1- 3), were isolated from the deep-sea sponge Aaptos ciliata, and their structures were elucidated on the basis of spectroscopic and chemical methods. Ciliatamides A ( 1) and B ( 2) were found to be antileishmanial, while 2 also exhibited marginal cytotoxicity to HeLa cells.     

Cadmium exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity

Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl(2)) markedly decreased the activity of an enzyme (acetohexamide reductase) catalysing the ketone-reduction of acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on acetohexamide reductase activity in liver cytosol of male rats.     

Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.     

Cigarette smoking and subsequent risk of lung cancer by histologic type in middle-aged Japanese men and women: the JPHC study

In order to update the findings of relative risk associated with cigarette smoking for lung cancer by histologic type in Japan, the data from a population-based cohort study of 91,738 men and women were analyzed. During 1990-1999, 422 lung cancer incident cases were identified. The relative risk for all incident cases associated with current smokers versus non-smokers was 4.5 [95% confidence interval (CI): 3.0-6.8] and 4.2 (95% CI: 2.4-7.2), for men and women, respectively. When divided by histologic type, relative risk for squamous cell carcinoma and small cell carcinoma was 12.7 (95% CI: 4.7-34.7) and 17.5 (95% CI: 4.9-62.1), while for adenocarcinoma it was 2.8 (95% CI: 1.6-4.9) and 2.0 (95% CI: 0.8-5.0) for men and women, respectively. We confirmed that the lung cancer risk in men rose with increasing cigarette smoking, especially the duration of smoking among current smokers and decreased after the cessation of smoking among former smokers. Unlike the US or European countries, the relative risk did not increase in this updated study, compared with previous studies in 1960s to 1990s in Japan either for all incident cases or for specific histologic types and the magnitude of relative risks was substantially lower than that observed in the US or European countries, especially for adenocarcinoma.