Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes.

To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 5.3% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of HLA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general.     

Durch Stichverletzung erzeugtes Aneurysma arterio-venosum zwischen der Vena anonyma und der Art. subclavia sin. mit Vagusverletzung

Ohne Zusammenfassung (Aus dem kaiserl. Ottomanischen Lehrerkrankenhause Gülhane zu Konstantinopel, chirurg. Abteilung Prof. Dr. Wieting.)     

Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study.

Once-weekly alendronate 70 mg and once-weekly risedronate 35 mg are indicated for the treatment of postmenopausal osteoporosis. These two agents were compared in a 12-month head-to-head trial. Greater gains in BMD and greater reductions in markers of bone turnover were seen with alendronate compared with risedronate with similar tolerability. INTRODUCTION: The nitrogen-containing bisphosphonates, alendronate and risedronate, are available in once-weekly (OW) formulations for the treatment of postmenopausal osteoporosis. A 12-month, head-to-head study was performed to compare these agents in the treatment of postmenopausal women with low BMD. MATERIALS AND METHODS: A total of 1053 patients from 78 U.S. sites were randomized to OW alendronate 70 mg (N = 520) or risedronate 35 mg (N = 533), taken in the morning after fasting. Endpoints included BMD changes over 6 and 12 months at the hip trochanter, total hip, femoral neck, and lumbar spine (LS); percent of patients with predefined levels of change in trochanter and LS BMD at 12 months; and change in biochemical markers of bone turnover at 3, 6, and 12 months. Tolerability was evaluated by adverse experience (AE) reporting. RESULTS: Significantly greater increases in hip trochanter BMD were seen with alendronate (3.4%) than risedronate (2.1%) at 12 months (treatment difference, 1.4%; p < 0.001) as well as 6 months (treatment difference, 1.3%; p < 0.001). Significantly greater gains in BMD were seen with alendronate at all BMD sites measured (12-month difference: total hip, 1.0%; femoral neck, 0.7%; LS, 1.2%). Significant differences were seen as early as 6 months at all sites. A greater percentage of patients had > or =0% (p < 0.001) and > or =3% (p < 0.01) gain in trochanter and spine BMD at 12 months with alendronate than risedronate. Significantly greater (p < 0.001) reductions in all biochemical markers of bone turnover occurred with alendronate compared with risedronate by 3 months. No significant differences were seen between treatment groups in the incidence of upper gastrointestinal AEs or AEs causing discontinuation. CONCLUSIONS: In this 12-month, head-to-head trial of alendronate and risedronate, given in accordance with the approved OW regimens for treatment of osteoporosis in postmenopausal women, alendronate produced greater gains in BMD and greater reductions in markers of bone turnover than risedronate. The greater antiresorptive effect of alendronate was seen as early as 3 months, and the tolerability profiles were similar.     

Studies on the multiple-drug induction immunosuppressive therapies with cyclosporine after renal transplantation

Our induction immunosuppressive therapies were carried out on patients split into three groups. The first group of 25 recipients were treated with regimen I [cyclosporin (CsA); 12 mg/kg/day and prednisolone (Pred)]. The second group of 16 recipients were treated with regimen II [CsA; 6 mg/kg/day, Pred and mizoribine (MIZ) or azathioprine (AZA)]. The third group of 14 recipients were treated with regimen III [CsA; 10 mg/kg/day, Pred and MIZ or AZA]. There was no significant difference among the three groups in renal function three months after renal transplantation. The frequency and grade of rejection were significantly higher in Group II than in the other groups. One of group I had CsA nephrotoxicity and none of group III had liver dysfunction three months after renal transplantation. Group I had a higher incidence of posttransplant hypertension. Hypertension of group I was very severe. We concluded that the triple-drug therapy on group III was the best induction immunosuppressive therapy after renal transplantation of the above three.     

In vitro susceptibilities of BRL 25000 (clavulanic acid-amoxicillin) against causative organisms in the field of obstetrics and gynecology

The in vitro susceptibilities of various causative organisms recently isolated from patients with genital infections to BRL 25000 (a formulation with 2 parts of amoxicillin and 1 part of potassium clavulanate), amoxicillin (AMPC), cefaclor (CCL), cephalexin (CEX), cefadroxil (CDX) and cefroxadine (CXD) were determined. beta-Lactamase-producing strains were detected by the nitrocefin disc method. Frequencies of isolation of beta-lactamase producing strains of E. coli, K. pneumoniae and B. fragilis were 36%, 96% and 100%, respectively. The activity of BRL 25000 against S. agalactiae and anaerobic GPC (anaerobic Streptococci, Peptostreptococcus spp.) was slightly less than that of AMPC but was 2- to 4-fold higher than CCL and 8- to 16-fold higher than CEX, CDX and CXD. Against E. coli and K. pneumoniae, the activity of BRL 25000 was superior to that of AMPC and approximately equal to CEX, CDX and CXD but 2-fold less than CCL. Against the B. fragilis group, BRL 25000 was much more active than AMPC or any of the cephalosporins tested, clearly demonstrating the beta-lactamase inhibitory properties of the clavulanic acid in BRL 25000. At inocula of 10(6) CFU/ml, MIC values of BRL 25000 were 12.5-50 micrograms/ml against some strains of E. coli, K. pneumoniae and B. fragilis. A mechanism of resistance other than beta-lactamase production is obviously prevalent in these strains. It is speculated that the resistance may be due to a low affinity of the drug to target proteins. Mixed infections of B. fragilis and E. coli or K. pneumoniae are commonly found in the obstetric and gynecological patients. BRL 25000 shows activity against these strains and also against both aerobic and anaerobic GPC. Therefore, BRL 25000 is considered useful for the treatment of genital infections.     

Effect of trazodone (KB-831) and its metabolites on brain monoamines in rat

The effects of trazodone (KB-831) and its metabolites on the uptake, turnover and contents of monoamines in rats were studied in comparison with those of imipramine and mianserin. Trazodone exhibited a more potent inhibitory effect on the uptake of [3H] 5-hydroxytryptamine (5-HT) into brain synaptosomes than on the uptake of [3H]norepinephrine (NE). Trazodone at 10-30 mg/kg, p.o., also inhibited the p-chloramphetamine-induced depletion of 5-HT in rat brain, but not the 6-hydroxydopamine-induced NE depletion in rat heart. Trazodone was the most selective 5-HT uptake inhibitor among the drugs tested in vitro. Its metabolite, m-chlorophenyl-piperazine (m-CPP), inhibited 5-HT and NE uptake in vitro, but not in vivo. Trazodone (100 mg/kg) and imipramine (30-100 mg/kg) inhibited the depletion of NE induced by alpha-methyl-p-tyrosine, whereas mianserin (100 mg/kg) facilitated it. At 1 hr after a single administration of each drug, an increase in 5-HT content and a decrease in 5-hydroxyindole-3-acetic acid (5-HIAA) content were observed when 30 mg/kg trazodone was used. At 100 mg/kg, trazodone increased the levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the NE content. m-CPP (10-30 mg/kg) produced similar effects on monoamine contents to those of trazodone. Imipramine and mianserin had no effect on monoamine contents even at a dose of 100 mg/kg. After 3 weeks of successive administration, an increase in 5-HT and a decrease in 5-HIAA were induced by trazodone and m-CPP at 1 hr, but not at 17 hr, after the final administration. Imipramine decreased the contents of NE and 5-HIAA, and its effects lasted for 17 hr. These results suggest that trazodone is a selective 5-HT uptake inhibitor and that its neurochemical profile is different from those of imipramine and mianserin.