Aromatic DNA adducts in foundry workers in relation to exposure, life style and CYP1A1 and glutathione transferase M1 genotype

Levels of aromatic DNA adducts in foundry workers and controls were followed at four annual samplings. During this time exposure to polycyclic aromatic hydrocarbons (PAH) decreased and the level of DNA adducts decreased accordingly. In the total group exposure was related to the level of adducts. Adduct levels correlated with urinary 1- hydroxypyrene (LOGU1OH), air benzo[a]pyrene, weekly working hours and daily cigarette consumption. In a multivariate model 1-hydroxypyrene had a consistent effect. Neither glutathione transferase M1 (GSTM1) nor cytochrome P450 1A1 (CYP1A1) genotypes had clear effects. Yet the individuals lacking GSTM1 had a stronger effect of LOGU1OH and some effect by other sources of PAH, such as charcoal broiled food, although all these variables were not significant in the multivariate model. The rare individuals with a CYP1A1 polymorphism MspI containing an amino acid change at isoleucine had an increased level of adducts. The results showed that the postlabelling method used was able to detect an increase in aromatic DNA adducts in leukocytes when exposure to benzo[a]pyrene in air was approximately 5 ng/m3. At such low levels smoking and charcoal broiled food may be important contributors to adducts.      

Gastric interposition following transhiatal esophagectomy: CT evaluation

Transhiatal esophagectomy without thoracotomy (THE) but with gastric interposition results in less morbidity and mortality than standard transpleural esophagectomy with thoracotomy. Barium examination has been the primary radiographic study following THE for detecting postoperative complications. We reviewed computed tomography (CT) scans of 21 patients who had undergone THE and correlated CT appearance with clinical status and with findings of the barium studies. Local mediastinal recurrent neoplasm was detected by CT in seven patients; barium study within 2 weeks of the CT scan failed to detect tumor recurrence in three of these patients. A mediastinal abscess well delineated by CT was percutaneously drained under CT guidance. Water-soluble contrast medium/barium study is preferable for the evaluation of certain postoperative complications such as anastomotic leak. However, CT is the modality of choice for detecting locally recurrent neoplasm and distant metastases following THE and may also be helpful in patients with postoperative mediastinal abscess. Normal mediastinal CT anatomy after esophagectomy is reviewed in order to warn against pitfalls in scan interpretation.     

治疗生殖道感染推荐用药的研究——79家五倍可利胶囊用户的调查报告

目的:评估五倍可利胶囊对常见女性生殖道感染(包括念珠菌性、滴虫性、细菌性阴道病以及复合感染)的治疗效果,以及相关的综合性能,为生殖道感染干预工程筛选推荐用药。方法:按照安全性、疗效广谱、药价相对低廉、难以替代4项标准,采用函调方式,在全国24个省份所涉79个县级计划生育服务站中进行。结果:认为五倍可利临床使用安全或比较安全的合计为100％;认为临床很有效及有明显疗效的合计83.5％,无效的为0;平均使用五倍可利治疗过3种以上阴道炎(病)的占100％;认为不可替代的为63.3％。结论:五倍可利胶囊具有较高的安全性、较高的疗效和相对广谱的特点,特别在实施生殖道感染干预工程的农村地区具有肯定的推广价值,可鼓励推广应用。     

16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5

The cytochrome P450 (P450) enzymes that catalyse metabolism of the estrogen, estrone (E1), to the putative carcinogen 16alpha-hydroxy E1 (16alpha-OHE1) in humans were determined. The potential of the most abundant circulating form of estrogen, estrone 3-sulfate (E1S), to be the substrate was also investigated. Human liver microsomal sulfatases convert E1S to E1, an essential prerequisite for formation of 16alpha- OHE1 from added E1S in this system. E1 metabolism to 16alpha-OHE1 in a panel of 15 human liver microsomal preparations correlated with total P450 concentrations (r2 = 0.63) and with activities associated with P450 forms CYP3A4 and 3A5 (r2 = 0.72). E1 16alpha-hydroxylase activity in human liver microsomes was inhibited by 75% by monoclonal anti human CYP3A4/5 antibodies at 4 mg antibody/nmol total P450, and by troleandomycin, a specific CYP3A4/5 inhibitor. Rates of E1 metabolism to 16alpha-OHE1 were 1.6-fold higher when E1 was generated in situ from E1S than when E1 was added. Microsomal preparations of cDNA expressed CYP3A4 or 3A5, with NADPH-P450-reductase co-expressed, both metabolized E1 to 16alpha-OHE1, and added cytochrome b5 increased the rates 5.1- and 7.5-fold, respectively. In these systems rates of E1 metabolism to 16alpha-OHE1 were 2.8-fold higher when E1 was generated in situ from E1S than when E1 was added. Kinetic values for E1 metabolism to 16alpha- OHE1 by human liver microsomes and for the expressed CYP3A4 system were Km 154 and 172 microM, respectively, and Vmax 238 pmol/min/nmol total P450 and 1050 pmol/min/nmol CYP3A4, respectively. Thus, formation of the putative carcinogen 16alpha-OHE1 is catalysed by CYP3A4 and 3A5 and stimulated by cytochrome b5. E1S is not a substrate but formation of E1 from E1S in situ stimulates formation of 16alpha-OHE1, possibly because E1S is more water soluble and in situ generation of E1 provides for facilitated exposure of E1 to the P450 substrate binding sites. Blocking of the pathway of E1 to 16alpha-OHE1 could provide a therapeutic approach for diminishing the risk of estrogen dependent breast cancer.      

Risk factors for human immunodeficiency virus (HIV) infections in homosexual men.

To clarify risk factors for infection with the human immunodeficiency virus (HIV) we selected at random 785 homosexual men who had participated in studies of hepatitis B in San Francisco in 1978-80 for a follow-up study of the acquired immunodeficiency syndrome. Although most had not been contacted in over five years, 492 (63 per cent) were located and enrolled. The 240 (67 per cent) who had developed antibodies to HIV, as measured by an enzyme-linked immunosorbent assay (ELISA), were compared with 119 who had remained seronegative. In multivariate analyses, receptive anal intercourse with ejaculation by nonsteady sexual partners, many sexual partners per month, and other indicators of high levels of sexual activity were highly associated with seroconversions. None of the sexual practices that we studied appeared to offer protection against HIV infection.     

Ultrasound prediction of fetal lung maturity

Amniocentesis for determination of fetal lung maturity and ultrasonographic (US) evaluation of the biparietal diameter (BPD) and placental grade were performed simultaneously in 261 nondiabetic pregnant women. A BPD of at least 9.3 cm and a grade 3 placenta were evaluated as predictors of fetal lung maturity using amniotic fluid phospholipids as indicators of a mature lung profile. The ability of the sonographic parameters to predict fetal lung maturity was closely related to menstrual age. Before 37 weeks, the false-positive prediction rate using a grade 3 placenta was 100%, and the false-positive prediction using the BPD was 85.6%. After 37 weeks, the false-positive rate using a grade 3 placenta was 5.9%, and the false-positive rate using the BPD was 9.5%. Thus menstrual age, and not these two US parameters, dictated fetal lung maturity. The authors conclude that the best use of US for predicting fetal lung maturity is in establishing menstrual age early in pregnancy.     

Pallidal stimulation for segmental dystonia: Long term follow up of 11 consecutive patients

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6‐12‐24‐36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective. © 2009 Movement Disorder Society     

Inhibition of anti-IgE mediated human mast cell activation by NO donors is dependent on their NO release kinetics

Background and purpose:

Although the mast cell is a source of nitric oxide (NO), the effect of NO on human mast cells has not been defined. This study investigated if exogenous NO could affect human mast cell activation.

Experimental approach:

Effects of different NO donors on immunoglobulin E (IgE)-dependent activation of human-cultured mast cells (HCMC) derived from precursors in buffy coat were investigated by measuring histamine release. Intracellular NO in HCMC was monitored with confocal microscopy using the fluorescent NO indicator 4-amino-5-methylamino-2′, 7′-difluorofluorescein.

Key results:

Diethylamine NONOate (DEA/NO) and MAHMA NONOate (NOC-9), both have rapid NO release rates, only inhibited anti-IgE-induced histamine release when added to HCMC at the time of activation. NO donors with slower NO release kinetics were ineffective even after 30 min incubation. Confocal microscopy revealed that the effectiveness of NO donors was dependent on the availability of adequate NO inside HCMC during activation. The inhibitory action of DEA/NO was diminished by the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl but potentiated by the anti-oxidant, N-acetylcysteine (NAC). Furthermore, co-incubation with NAC allowed previously ineffective NO donors to suppress HCMC activation and thus suggested that NAC could increase the availability of NO from NO donors.

Conclusions and implications:

Our results demonstrated that NO was able to modulate human mast cell activation but only when enough NO was present at the time of cell activation. Our findings explain the controversy over the effectiveness of NO on mast cell degranulation and supports the possibility that NO donors could be beneficial for treating allergic inflammation.