Are adverse events of nevirapine and efavirenz related to plasma concentrations?

OBJECTIVE: The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study. METHODS: Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics. RESULTS: In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified. CONCLUSIONS: Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.     

细胞色素P450 2C19单碱基突变位点CYP2C19m1的分析

目的:CYP2C19ml是引起CYP2C19酶活性缺陷的主要等位基因,有83％左右的慢代谢者含有CYP2C19ml等位基因,本文试图建立一步PCR测定CYP2C19ml等位基因的方法。方法:根据等位基因特异扩增(ASA)原理设计两对分别特异扩增野生型等位基因和突变型等位基因的引物,建立了一步PCR测定CYP2C19ml等位基因的方法。结果:对39位随机受试者进行了基因分型研究,发现3位CYP2C19ml纯合子、18位CYP2C19ml杂合子,其余18位为野生型纯合子。结论:说明效法能够用于测定CYP2C19ml等住基因,并且证明该法具有简便、快速和污染少的优点。     

Early osteonecrosis of the femoral head: detection in high-risk patients with MR imaging

To determine whether magnetic resonance (MR) imaging can demonstrate the early stages of osteonecrosis that are not detectable radiographically, the authors compared radiologic findings with histologic results in seven patients at high risk for osteonecrosis of the femoral head. Radiography and MR imaging were performed, and proximal femoral intramedullary pressures were measured in all patients, even if results from imaging studies were normal. If the pressures were elevated, core decompression with biopsy was performed. Seven patients had elevated pressures in 11 hips. Of 11 hips from which biopsy specimens were taken, all had histologic evidence of osteonecrosis. However, in only five were the MR imaging findings consistent with osteonecrosis. In the remaining six hips with osteonecrosis, MR imaging findings were normal. Sensitivity of MR imaging in detection of osteonecrosis was 46%. The authors conclude that normal MR imaging results in high-risk patients do not rule out the presence of osteonecrosis.     

The human autosomal gene DAZLA: testis specificity and a candidate for male infertility

The DAZ (Deleted in AZoospermia) and DAZLA (DAZ-like autosomal) genes may be determinants of male infertility. The DAZ gene on the long arm of the human Y chromosome is a strong candidate for the 'azoospermia factor' (AZF). Its role in spermatogenesis is supported by its exclusive expression in testis, its deletion in a high percentage of males with azoospermia or severe oligospermia, and its homology with a Drosophila male infertility gene boule. No DAZ homologous sequences have been found on the mouse Y chromosome. Instead, a Dazla gene was isolated from mouse chromosome 17 and has been considered to be a murine homologue of DAZ. However, the homology between human DAZ and mouse Dazla is not strong, and Dazla contains only one of the seven DAZ repeats found in DAZ. We report the isolation of the human DAZLA gene by screening a human testis cDNA library with a DAZ cDNA clone. DAZLA encodes only one DAZ repeat and shares high homology with the mouse Dazla, indicating that these two genes are homologues. Using a panel of rodent-human somatic cell lines and fluorescence in situ hybridization, the DAZLA gene was mapped to 3p24, a region not known to share homology with mouse chromosome 17. The DAZLA gene may be involved in some familial cases of autosomal recessive male infertility.      

Fragile X premutation screening in women with premature ovarian failure

We have screened 132 women with premature ovarian failure for fragile X (FRAXA) premutations. Three out of 23 (13%) pedigrees with the familial premature ovarian failure and 3/106 (3%) of women with the sporadic form of premature ovarian failure have FRAXA premutations compared with an expected prevalence of 1:590 (P=0.02). The mechanism of the association between FRAXA premutations and premature ovarian failure is unknown but as a genetic marker, FRAXA screening will be particularly valuable in predicting premature ovarian failure in some pedigrees and in the identification of families at risk of transmitting fragile X syndrome.      

通信兵智力水平与专业水平的关系

0　引言　智力在很大程度上决定着个体的作业绩效水平 [1 - 3] ,同时也是预测个体职业成就的一个重要指标 .因此 ,我们试图通过对通信兵智力的测量与分析 ,揭示通信兵智力与专业技术水平的关系以及通信兵重要岗位人员智力与专业技术水平的关系 ,为最终科学地建立通信兵职业适宜性测评体系奠定必要的工作基础 .1　对象和方法1.1　对象　某集团军通信团在岗专业技术人员 ,其中技术难度高的报、话务专业人员 6 3名 ,载波、接力等仅对仪器进行操作的专业人员 5 1名 ,外线、架设等一般专业人员 43名 ,共 15 7名 .工作 1a以上 ,年龄在 18～ 32岁之…     

The combined contraceptive vaginal device (NuvaRing®): A comprehensive review

Objectives?The aim of this study is to review the development of NuvaRing® over the past decade to illustrate its use-effectiveness and acceptance as an alternative contraceptive option for women.

Methods?The data were extracted from the literature using computerised MEDLINE system. NuvaRing® is a new combined hormonal contraceptive vaginal ring made of ethylene-vinyl-acetate copolymer, releasing 120?μg etonorgestrel and 15?μg ethinyloestradiol per day. This ring is inserted on any day from day 1 to day 5 of a menstrual cycle for 21 days, thereafter removed for 7 days ring-free period and discarded.

Results?Complete inhibition of ovulation is observed during treatment with this device. Clinical exposure to NuvaRing® for 1786 women-years has resulted in 21 pregnancies, giving a Pearl Index of 1.18. Withdrawal bleeding (4.7–5.3 days) is regular (97–99% of cycles) with rare incidence of irregular bleeding (2.6–6.4%). The cycle control is good with the use of this combined contraceptive vaginal ring. NuvaRing® is well tolerated and accepted by women as compared to oral pill.

Conclusions?NuvaRing® is an effective vaginal contraceptive option for women. However, further study is needed for monitoring its long-term effectiveness and impact on patient's quality of life since the NuvaRing^R is marketed in many countries.