Effects of genetic and nutritional factors on bone mineral density in young adults

To estimate the genetic and dietary factors influencing bone mineral density (BMD) in young adults, a total of 53 healthy volunteers (HV) (age 20.89+/-1.34), from whom informed consent was obtained, answered a questionnaire on dietary factors and had DNA from peripheral blood mononuclear cells analyzed for single nucleotide polymorphisms (SNPs) for vitamin (Vit) D receptor (VDR), estrogen receptor alpha (ERalpha), interleukin 1 receptor antagonist (IL1RA), and apolipoprotein E (ApoE) genes. Daily intakes of Vit C, fiber, soybean and related foods, and green and yellow vegetables showed a correlation with % BMD. In addition, Vit B2 as well as Vit C, and vegetables were identified as important factors for BMD by Stepwise regression analysis. Among the SNPs analyzed, the B+ type of the VDR gene tended to be associated with a lower BMD, and pp type of the ER gene digested by the PvuII enzyme in females indicated a significantly lower BMD than that in males. In addition, these SNPs were also identified by factor analysis to be associated with BMD. These results suggested that a complex array of genetic factors, such as two or more SNPs or SNPs and gender, may be important to BMD.     

Induced reactivity of intestinal CD4(+) T cells with an epithelial cell lectin, galectin-4, contributes to exacerbation of intestinal inflammation

Inflammatory bowel disease is an immune-mediated intestinal inflammatory condition that is associated with an increase in autoantibodies that bind to epithelial cells. However, it is unknown whether the epithelial cell-derived products that are recognized by such autoantibodies are involved in the pathogenic process. Through a combined antigen-screening approach utilizing humoral and cellular immune responses, we identify herein an epithelial lectin, galectin-4, that specifically stimulates IL-6 production by CD4(+) T cells. Interestingly, the reactivity of CD4(+) T cells to galectin-4 is precisely elicited under intestinal inflammatory conditions. The galectin-4-mediated production of IL-6 is MHC class II independent and induced by PKCtheta-associated pathway through the immunological synapse. The galectin-4-mediated stimulation of CD4(+) T cells is shown to exacerbate chronic colitis and delay the recovery from acute intestinal injury. These studies identify the presence of an immunogenic, endogenous lectin in the intestine and dissect the biological role of lectin/CD4(+) T cell interactions under inflammatory conditions.     

Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats

The present study aims to investigate whether azithromycin reverses P-glycoprotein-dependent anticancer drug resistance in vitro and modifies the hepatobiliary excretion of doxorubicin, a substrate for P-glycoprotein in vivo. Azithromycin increased dose-dependently the intracellular accumulation of doxorubicin in adriamycin-resistant human myelogenous leukemia cells (K562/ADR) with no effect on the expression of P-glycoprotein in the cells. However, the inhibitory effect was much weaker than that of cyclosporin A and was comparable to that of erythromycin. When Sprague-Dawley (SD) rats, which have drug transporting P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) in the bile canalicular membrane of hepatocytes, received an infusion of doxorubicin, the steady-state biliary clearance of doxorubicin was significantly decreased for 40 min after a single intravenous injection of azithromycin. However, azithromycin did not increase the plasma concentration of doxorubicin. The biliary clearance of doxorubicin in Eisai hyperbilirubinemic rats (EHBRs), which have a hereditary deficiency in Mrp2, was significantly decreased compared with that in Sprague-Dawley rats, suggesting the involvement of Mrp2 in the biliary excretion of doxorubicin. The present findings suggest that azithromycin overcomes P-glycoprotein-dependent anticancer drug resistance of tumors by inhibiting the binding of doxorubicin to P-glycoprotein in K562/ADR cells and inhibits the hepatobiliary excretion of drugs that are substrates for P-glycoprotein and Mrp2.     

The effects of fexofenadine on eosinophilia and systemic anaphylaxis in mice infected with Trichinella spiralis

BACKGROUND: The effects of the non-impairing, H(1)-receptor antagonist fexofenadine were investigated in in vivo mouse models of eosinophilia and systemic anaphylaxis. METHODS: Eosinophilia was investigated in C57BL/6 mice (n=5 per group) infected with Trichinella spiralis, with and without administration of fexofenadine HCl (5, 10 and 20 mg/kg/day). Eosinophilia was also studied, with and without fexofenadine administration, in mice with a congenital mast-cell deficiency (W/W(v)) and controls (+/+). The effect of fexofenadine HCl (20 mg/kg/day) on IL-5 and eotaxin blood levels was also investigated in C57BL/6 mice. In a separate model, systemic anaphylaxis was induced in C57BL/6 mice using T. spiralis antigen. Fexofenadine HCl (5, 10 and 20 mg/kg) or vehicle was administered 20 min before antigen challenge (n=5 per group). The effect of fexofenadine on systemic anaphylaxis caused by IgE and anti-IgE was also examined in CBF1 mice injected with serum from NC/Nga mice with high IgE levels. Rectal temperature was measured as an indicator of anaphylaxis. RESULTS: In C57BL/6 mice, repetitive oral administration of fexofenadine HCl (5, 10 and 20 mg/kg/day) resulted in dose-dependent suppression of eosinophilia (p<0.05-0.0001). No suppression was observed in mast-cell deficient W/W(v) mice. In addition, single oral administration of fexofenadine HCl (10 and 20 mg/kg) significantly suppressed the decrease in rectal temperature (p<0.01), a marker for systemic anaphylaxis, in C57BL/6 mice. In CBF1 mice injected with serum from NC/Nga mice with high IgE levels, the decrease in rectal temperature was suppressed by single administration of fexofenadine HCl (10 and 20 mg/kg; p<0.01 and p<0.001, respectively). Fexofenadine had no effect on peripheral IL-5 and eotaxin levels. CONCLUSION: These results indicate that fexofenadine suppresses both eosinophilia and systemic anaphylaxis, both of which are fundamental reactions in allergic diseases.     

Methylenetetrahydrofolate reductase polymorphism, alcohol intake, and risks of colon and rectal cancers in Korea

Several, but not all, studies have reported that a variant genotype of the polymorphism (C677T) of 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, is associated with a decreased risk of colorectal cancer. A case-control study was conducted to investigate the association of MTHFR polymorphism and heavy alcohol intake to colon and rectal cancer in Korean. Cases were a consecutive series of patients with histologically confirmed, incident colorectal cancer who were admitted to two university hospitals in Seoul, Korea between 1998 and 2000, and controls were selected at the same hospitals. A total of 243 cases (colon 111, rectum 132) and 225 controls were enrolled. While the genotype of MTHFR was not associated with the overall risk of colorectal cancer, increased colon cancer risk was found to be associated with the CT and TT genotypes combined (multivariate odds ratio [OR] 2.01, 95% confidence interval [CI] 1.14-3.53) compared with the wild type. The risk of rectal cancer was found to be, though statistically non-significant, lower in those with the CT and TT genotypes combined (multivariate OR 0.67, 95% CI: 0.43-1.07). Those consuming two or more drinks per day (30 g+/day) had nearly twice the colorectal cancer risk (multivariate OR 1.94, 95% CI 1.03-3.68) of light or non-drinkers (<5 g/day). The present study did not find a reduced risk of colorectal or rectal cancer among those with a variant genotype of the MTHFR polymorphism, but observed rather an increased risk of colon cancer, suggesting that the effects of the MTHFR genotype may differ in populations with different levels of folate intake.     

A rare case of primary hyperparathyroidism with clear cell adenoma

We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 x 2.8 x 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.     

Randomized controlled study on the effectiveness of community pharmacists' advice for smoking cessation by Nicorette--evaluation at three months after initiation

We conducted a randomized, controlled study to evaluate whether pharmacists' advice on smoking cessation would result in a higher smoking cessation rate using Nicorette (nicotine gum preparation). Fourteen pharmacies in Tokyo, Kanagawa, and Nagano participated. Smokers who visited pharmacies to buy Nicorette from March 1, 2002, through August 31, 2002, were recruited and randomly assigned to two groups. For the intervention group (A), pharmacists provided both regular instructions on Nicorette use and smoking cessation advice at the first sale and then gave follow-up advice just before starting a cessation and 1, 3, and 8 weeks and 3 months thereafter. For the control group (B), pharmacists provided regular instructions alone. The primary outcome measure was the self-reported smoking cessation rate and the secondary outcome measure was the relationship between the smoker's egogram and effectiveness of intervention. Twenty-eight smokers were enrolled and randomized into group A (n=11) or group B (n=17). The absolute abstinence rate in groups A and B at 3 months was 45.5% and 31.2%, respectively. The odds ratio was 1.83, which was not statistically significant. There was no difference in egogram score between absolute abstinence subjects and nonabstinence subjects in group A. The egogram scores in Adapted Child of absolute abstinence subjects in group B were significantly higher than in nonabstinence subjects. In conclusion, instructions and advice given by pharmacists may improve the smoking cessation rate in smokers receiving nicotine replacement therapy.     

Potential risk factors aggravating airway allergy--aspects of involvement of airtight housing and passive smoking

OBJECTIVES: The involvement of tightly insulated housing conditions and passive smoking in atopic sensitization, a major risk factor for airway allergy, was examined with nonsmoking adult women and school-age children. SUBJECTS AND METHODS: The subjects were 382 nonsmoking healthy adult women (housewives) who underwent medical examinations for prevention of adult diseases conducted in a district of Osaka from 1995 to 1997, and 214 elementary school-children 9-12 years old living in an urban district of Osaka who underwent medical examinations at a health center in April, 2000 to prevent allergic diseases. We also examined the correlation between tightly insulated housing conditions and the amount of passive smoking based on family smoking habits with 170 children under 12 years old who had been under the care of a hospital pediatrics department between December, 1993 and May, 1994. A questionnaire was administered to all subjects to survey the housing structure (concrete/wooden housing), family smoking habits and visible mold proliferation in the kitchen in relation to airtight housing conditions, passive smoking and exposure to inhalant allergens. Atopic sensitization was assessed by positivity for serum house dust mite-specific IgE, and passive smoking was defined as a urinary cotinine level of more than 6 ng/mgCr. RESULTS: 1. Among the three factors, indoor mold proliferation and family smoking habits were positively and synergistically related with atopic sensitization to house dust mites. 2. Airtight conditions of concrete housing showed a promotional effect on passive smoking for housewives, but a suppressive effect for school-age children. 3. Taking into account the above results, the promotional effects of passive smoking on atopic sensitization appeared predominantly in the concrete housing-residence group of housewives and the wooden housing-residence group of school-age children. 4. Effects of visible mold proliferation in the kitchen on atopic sensitization appeared predominantly in wooden housing-residence group of housewives. CONCLUSIONS: The results suggest that involvement of the three factors in atopic sensitization is due to increased exposure to indoor inhalant allergens or enhanced IgE-antibody production (adjuvant effects of tobacco smoke) and the extent of their inpact varies depending on the individual life styles of the housewives and school-age children.     

Performance of an automated system for quantitation of hepatitis C virus core antigen

The performance of an automated system for the HCV core antigen assay using the Lumispot LS-2000 automated analyzer was evaluated against that of the COBAS AMPLICOR HCV MONITOR Test, version 2.0 (COBAS HCM-2) for the testing of sera from 155 chronic hepatitis C patients. The within-run coefficient of variations (CVs) and the between-day CVs were <9.6 and <8.4%, respectively. The analytical detection limit of the HCV core antigen assay was 5.0 fmol/l and it was linear up to at least 45000 fmol/l. No blood elements interfered with the assay. HCV core antigen levels were significantly correlated with HCV RNA levels in both serogroup 1 and serogroup 2 (r=0.829, P<0.001). It is estimated that 100 fmol/l of HCV core antigen level was equivalent to approximately 30000 IU/ml of HCV RNA level. Three sera had HCV core antigen levels below the detection limit of the assay and their HCV RNA levels as determined by COBAS HCM-2 assay were very low at 1000, 1100 and 1700 IU/ml, respectively. In six IFN responders among seven patients, HCV core antigen levels were in parallel with HCV RNA levels. In conclusion, since this assay demonstrated good reproducibility, a favorable dynamic range and adequate sensitivity, it may be useful as an alternative direct marker of viral level monitoring in patients with hepatitis C.