alpha-Glucosidase inhibitor reduces the progression of carotid intima-media thickness

OBJECTIVE: An open randomized prospective study was performed to elucidate the effect of an alpha-glucosidase inhibitor, voglibose, on the progression of atherosclerosis in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Voglibose at a dose of 0.4-0.6 mg/day was added on 51 subjects out of 101 type 2 diabetic patients being treated with diet, sulphonylurea (SU) or insulin injections, and the average (AveIMT) and maximum intima-media thickness (MaxIMT) of their carotid arteries were examined for 3 years. RESULTS: Irrespective of the differences in treatments, addition of voglibose reduced the progression of AveIMT and MaxIMT to -0.024 +/- 0.047 (+/-S.D.) and -0.021 +/- 0.144 mm/year, respectively. Without voglibose, diabetic patients showed significant (P < 0.0001) progression of AveIMT and MaxIMT (0.056 +/- 0.046 and 0.098 +/- 0.122 mm/year, respectively). The administration of voglibose resulted in a significant reduction of hemoglobin A1c (HbA1c), total cholesterol and triglyceride concentrations, as well as an increase in HDL cholesterol concentration. Multivariate regression analysis showed that administration of voglibose independently reduced the progression of AveIMT by 0.069 mm/year (P < 0.0001). CONCLUSIONS: These results suggest that voglibose reduces the progression of IMT and may be a candidate for an anti-atherosclerotic drug for type 2 diabetic patients.     

Gene mutations responsible for overexpression of AmpC beta-lactamase in some clinical isolates of Enterobacter cloacae

AmpC regulatory genes in 21 ceftazidime-resistant clinical isolates of Enterobacter cloacae (MICs of > or = 16 microg/ml) were characterized. All isolates exhibited AmpC overproduction due to AmpD mutation. Additionally, we found two AmpR mutants among the isolates. This is the first report of chromosomal ampR mutation in clinical isolates of E. cloacae.     

Oxidative stress and the JNK pathway in diabetes

Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in deterioration of pancreatic beta-cell function found in diabetes. Oxidative stress and/or activation of the JNK pathway suppress insulin gene expression, accompanied by reduction of PDX-1 DNA binding activity. Treatment with antioxidants and/or suppression of the JNK pathway protect beta-cells from some of the toxic effects of hyperglycemia. The JNK pathway is also involved in the progression of insulin resistance; suppression of the JNK pathway in obese diabetic mice markedly improves insulin resistance and ameliorates glucose tolerance. The phosphorylation state of key molecules for insulin signaling is altered upon modification of the JNK pathway. Taken together, the JNK pathway plays a crucial role in progression of insulin resistance as well as beta-cell dysfunction found in diabetes and thus could be a potential therapeutic target for diabetes.     

A comparison of the microbiological characteristics of Neisseria gonorrhoeae isolated from male and female patients with gonorrhea

BACKGROUND: A trend towards a decrease in gonorrhea in Japan was observed until the mid-1990s, but soon after that period, an increased incidence of gonorrhea was reported. METHODS: Antimicrobial susceptibility, auxotype and the type of gyrA and parC mutations were compared between 200 and 132 Neisseria gonorrhoeae isolates from male and female patients with gonorrhea, respectively. RESULTS AND CONCLUSION: The isolation frequency of ciprofloxacin-resistant isolates from male patients was higher than that from female patients (19.5 and 13.6%, respectively). All ciprofloxacin-resistant isolates had single to triple mutations in gyrA and/or parC genes. N. gonorrhoeae isolates showed a predominance of Pro-requiring auxotypes (46.5 and 46.2% of the isolates from male and female patients, respectively). Of the Pro-requiring isolates, the incidence of ciprofloxacin-resistant isolates was higher in the isolates from male patients than in the isolates from female patients.     

A case of psoas abscess caused by Candida albicans

We report a rare case of psoas abscess caused by Candida albicans. A 59-year-old man with diabetes mellitis presented with right flank mass. Computed tomography (CT) showed a psoas abscess. Needle aspiration of the right flank mass revealed pus which was proved to be C. albicans by culture. The literature is briefly reviewed.     

Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling

Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. It was reported that TNF-alpha could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-alpha-induced apoptosis. Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. Using reduced MitoTracker Red probe, we confirmed that TNF-alpha increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). TNF-alpha significantly activated ASK1, increased serine phosphorylation of insulin receptor substrate (IRS)-1, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, and all of these effects were inhibited by overexpression of either UCP-1 or MnSOD. Similar to TNF-alpha, overexpression of wild-type ASK1 increased serine phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation of IRS-1, whereas overexpression of dominant-negative ASK1 ameliorated these TNF-alpha-induced events. In addition, TNF-alpha activated c-jun NH(2)-terminal kinases (JNKs), and this observation was partially inhibited by overexpression of UCP-1, MnSOD, or dominant-negative ASK1. These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling.     

(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an orally potent and peripherally selective nonsteroidal androgen receptor antagonist

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.     

Choroid Plexus Carcinoma in Infants: Report of Two Cases and Review of the Literature

Summary  Choroid plexus carcinoma (CPC) is a rare malignant brain tumour which occurs predominantly in childhood. We present the cases of two infants with CPC. One, a 6-month-old boy with the tumour in the right lateral ventricle, who died of a postoperative intracranial haemorrhage and severe gastrointestinal bleeding, and the other, a 9-month-old boy with the tumour in the fourth ventricle, who has been well without recurrence for 12 months after total removal in combination with chemotherapy using cisplatin and VP-16 and local radiotherapy. In the 54 CPC cases in children under 2 years of age including our 2 cases in which the clinical results were described in the literature since 1983, tumour location (lateral ventricle, p=0.0225), surgery (gross total resection, p=0.0447), and chemotherapy (yes, p=0.0010) were revealed to be significant positive prognostic factors by the univariate analysis using the log rank test, and surgery (gross total removal, p=0.0259) and chemotherapy (yes, p=0.0016) were independent, significant positive prognostic factors in the multivariate analysis using the Cox proportional hazard regression model. Although there is a risk in doing a statistical analysis of other people's reports, these results suggest that, at present, the gross total removal of the tumour with intensive chemotherapy is the best choice of initial treatment for young children with CPC, and that radiotherapy should be considered for patients after 24 months of age and/or should be performed locally.     

Mechanism of action of habekacin, a novel amino acid-containing aminoglycoside antibiotic.

The molecular basis for activity of habekacin was studied by using Escherichia coli Q-13. Electron microscopic studies revealed that numerous blebs, derived from the outer membrane, were formed on cells treated with habekacin. Cytoplasmic contents leaked into the lumina of blebs, and the membrane of some enlarged blebs was disrupted. In a cell-free system, habekacin interfered with polypeptide synthesis, caused codon misreading, and inhibited translocation of N-acetylphenylalanyl-tRNA from the acceptor site to the donor site on ribosomes. [3H]habekacin bound to both 50S and 30S ribosomal subunits. The current experiments indicated that the mechanism of action of habekacin is similar to that of 2-deoxystreptamine-containing aminoglycoside antibiotics such as dibekacin, kanamycin, gentamicin, and related substances. The relationship of membrane damage to inhibition of ribosomal functions remains to be determined.