Risks associated with the microbiological quality of bodies of fresh and marine water used for recreational purposes: summary estimates based on published epidemiological studies

The current European standards for microbiological quality of bathing water (i.e., all running or still fresh waters or parts thereof and/or sea water [with the exception of water intended for therapeutic purposes and water used in swimming pools]) were issued in 1976 and are currently undergoing revision. In this article, the authors propose parameters for select microorganism indicators to assist in the establishment of public-health-based objectives for fresh and marine water quality. A type-II meta-analysis of the results of 18 published epidemiological studies was implemented in an attempt to characterize the relationship(s) between concentrations of bacterial indicators and rates of acute gastrointestinal diseases among bathers who had used fresh or marine water for recreational purposes. The authors fit multiple linear-regression models, which allowed for random effects across studies, to derive dose-response curves. Several confounders and effect modifiers were controlled for in the analyses. Risks were then estimated for a hypothetical individual who would bathe 20 times/yr in water that contained a given concentration of microorganisms. For fresh-water-associated highly credible gastrointestinal illnesses, a level of 10 fecal coliforms/100 ml water yielded an attributable risk of 0.2 cases/1,000 person-years; a risk of 2 cases/1,000 person-years was found for fecal streptococci. The corresponding yearly attributable risks were 1 and 13 cases/1,000 person-years, respectively, for 100 bacteria/100 ml fresh water. Risks associated with fecal coliforms were found to be lower in marine water than in fresh water. Irrespective of the type of water examined, total coliforms were related only weakly with acute digestive morbidity. Developers of future bathing-water standards should state the level of risk deemed acceptable for public health. The authors of this study maintain that levels of fecal coliforms and fecal streptococci should be used as criteria for infectious risk management associated with bodies of marine and fresh water used for recreational purposes.     

Melanoma: role of ultraviolet radiation: from physiology to pathology

EPIDEMIOLOGIC DATA: The frequency of malignant melanoma, by far the most fatal skin cancer, has increased by a factor of approximately 15 in the past 60 years. The factors underlying this rapid increase are incompletely understood, although ultraviolet radiations are likely strongly implicated. Epidemiologic studies demonstrate the role of altered patterns of sun exposure, and overexposition to UVA radiation, as confirmed by experimental data on animal models. BIOLOGICAL ASPECTS: Melanin produced by melanocytes has a photoprotective function in the skin, whereas UVB-induced DNA damage enhance the repair capacity of these cells. However, this photoprotective effect is not induced by intense intermittent sun exposure. In addition, melanocytes demonstrate resistance to UVB-induced apoptosis and are thus at high risk for incorporating UV-induced mutations. MOLECULAR ASPECTS: Different mutations in susceptibility genes (CDKN2A, INK4), or in genes implicated in control of cell cycle or maintenance of cell integrity (DNA repair) are involved in initiation and promotion steps of melanocarcinogenesis. Moreover, tumor progression is stimulated by UVB through the activation of different target genes that are implicated in control of melanoma environment (immune surveillance, angiogenesis, growth factors...).     

Population pharmacokinetics of fluconazole given for secondary prevention of oropharyngeal candidiasis in HIV-positive patients

OBJECTIVES: To determine fluconazole population pharmacokinetics and explore the relationships between fluconazole average concentration and treatment effectiveness or microbiological resistance induction during a study aimed at evaluating the efficacy, tolerability and resistance induction after secondary prevention with fluconazole (150 mg weekly) versus placebo in human immunodeficiency virus-positive (HIV+) patients with oropharyngeal candidiasis. METHODS: Population pharmacokinetic parameters of fluconazole determined from 458 serum drug concentration measurements obtained over 37 months in 132 HIV + patients not receiving highly active antiretroviral therapy. Mean estimates and variabilities were generated using non-linear regression analysis. Logistic and linear regression analyses were used to explore the relationships between the estimated average concentration of fluconazole and candidiasis relapse or fungal resistance towards fluconazole. RESULTS: Fluconazole kinetics were best described by a one-compartment model with first-order oral absorp tion from the gastrointestinal tract. The pharmacokinetics were influenced only by body weight. No effect was observed for gender, age, height or lymphocyte CD4 counts. The mean apparent population clearance was 0.79 l/h, the volume of distribution 571 and the absorption constant (ka) 0.93 h(-1). Inter-occasion variability in clearance (45%) was large relative to intersubject variability (21%). Taking into account the average fluconazole concentration or the time above the minimal inhibitory concentrations did not clinically improve the prediction of the occurrence of oropharyngeal relapse or microbiological resistance. CONCLUSION: The relationship between fluconazole concentrations and preventive effectiveness was poor. Together with the rather large inter-occasion variability in fluconazole clearance, this suggests no role of therapeutic drug monitoring in optimising fluconazole treatment for secondary prevention.     

A pharmacokinetic study of intramuscular (i.m.) parecoxib sodium in normal subjects

A single-center, double-blind, placebo-controlled, randomized study was conducted to determine the pharmacokinetics, safety, and tolerability of single, rising intramuscular (i.m.) doses and the single maximum tolerated dose of parecoxib sodium, a prodrug of the novel COX-2 selective anti-inflammatory analgesic drug valdecoxib, in 56 healthy male volunteers, ages 18 to 45 years inclusive. Cohorts of up to 6 subjects in each dose schedule were administered either parecoxib sodium (1 mg, 2 mg, 5 mg, 10 mg, 20 mg, or 40 mg) or matching placebo. Following i.m. administration, serial blood samples for measurement of plasma concentrations of parecoxib, valdecoxib, and valdecoxib metabolite (M1) were collected at predetermined intervals (from 15 minutes prior to dose and through 96 hours postdose). Urine collections were obtained for drug assay (from -12 to 0 hours, 0 to 12 hours, and 12 to 24 hours postdose). After i.m. administration, peak plasma concentrations of parecoxib were reached within 15 minutes and then declined rapidly as prodrug was converted to the active moiety, valdecoxib. Change in plasma concentrations of valdecoxib, which declined more slowly (t(1/2) = 5.4-9.9 hours), reflected transformation to several metabolites, one of which was the minor active metabolite M1. As measured by the AUC(0-infinity), Cmax, and XU(0-24) of valdecoxib, parecoxib sodium demonstrated dose proportionality when administered in the range of 1 mg to 40 mg of parecoxib. All single i.m. doses up to the maximum of 40 mg of parecoxib, as well as concentrations of up to 20 mg/ml, were well tolerated.     

Evidence against a major role of plasmalogens in the resistance of astrocytes in lactic acid-induced oxidative stress in vitro

Astrocytes are known to play a key role in buffering extracellular pH variations and, in addition, they are particularly resistant to oxidative stress and subsequent lipid peroxidation. This great resistance may be ascribed to the presence of high concentrations of certain antioxidants, but another explanation may be the presence of a high quantity of plasmalogens, which are a special group of glycerophospholipids characterized by a vinyl ether bond instead of an ester bond in the sn-1 position of the glycerol backbone. Plasmalogens are sensitive to free radical attack and acidity, and numerous works have supported the hypothesis that they may be antioxidant molecules that protect cells from oxidative stress. The aim of this work was to investigate, on astrocytes in lactic acid-induced oxidative stress (pH 5.5), the behavior of phospholipids and, in particular, plasmalogens. Two main techniques, based on the susceptibility of the vinyl ether bond to hydrolysis, were employed in this study to measure plasmalogen levels. In both cases, the sn-1 vinyl ether linkage was cleaved using mercuric chloride, producing a lysophospholipid that was assessed by phosphorus measurement or using HCl treatment, producing a long-chain fatty aldehyde assayed by gas chromatography/mass spectrometry. On astrocytes in culture, only plasmenylethanolamine (PlmEtn) was evidenced, representing 40% of glycerophosphoethanolamine lipids. When astrocytes were incubated with lactic acid, no modification in the amount of PlmEtn was seen. Furthermore, free aldehydes and aldehydes corresponding to the quantity of intact plasmalogens were similar to those observed on controls. In addition, the constancy of two lipid peroxidation markers, thiobarbituric acid reactive substances and polyunsaturated fatty acids, was clear evidence of the resistance of these cells in lactic acid conditions. In conclusion, our results fail to demonstrate a major role of plasmalogens in the resistance of astrocytes in lactic acid-induced oxidative stress.     

No evidence for linkage between COMT and schizophrenia in a French population

Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings.     

Monitoring of tinzaparin in a ten day treatment dose in elderly patients

PURPOSE: Renal impairment, which is frequently observed in elderly patients, raises the question of low molecular weight heparins treatment dose adjustment in this population. Thus, we conducted a prospective study to determine whether tinzaparin, administered subcutaneously at treatment dose (175 anti-Xa IU/kg) once daily for 10 days, does accumulate in patients older than 70 years of age. METHODS: Accumulation criteria were an increase of plasma anti-Xa and anti-IIa levels determined prior to the first injection and on days 2, 5, 7 and 10. The characteristics of the 30 consecutive included patients receiving tinzaparin at treatment dose (six men, 24 women) were: age 87.0 +/- 5.9 years (range: 71-96 years), body weight: 62.7 +/- 14.6 kg (range: 38-90 kg) and creatinine clearance 40.6 +/- 15.3 mL/min (range: 20-72 mL/min). RESULTS: None of the patients required a dose adjustment of tinzaparin over the 10-day treatment period. Anti-Xa and anti-IIa activity levels on day 2 were 0.66 +/- 0.20 IU/mL (range: 0.26-1.04 IU/mL) and 0.33 +/- 0.10 IU/mL (range: 0.18-0.55 IU/mL), respectively. These levels did not significantly change over the 10 days. These results favor the absence of the accumulation effect of tinzaparin. There was no correlation between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. Concerning the side-effects, only one minor hematoma at the injection site was reported. CONCLUSION: Tinzaparin may thus be administered in older patients with renal impairment, at a treatment dose (175 anti-Xa IU/kg/d) for a 10-day treatment period, without accumulation effect nor hemorrhagic side-effect in patients with creatinine clearance greater than 20 mL/min.     

Severe fetal cytomegalic inclusion disease after documented maternal reactivation of cytomegalovirus infection during pregnancy

Recurrent cytomegalovirus infection during pregnancy is considered less dangerous for the fetus than primary infection. We present a case of severe fetal cytomegalic inclusion disease after maternal reactivation of cytomegalovirus during the first trimester of pregnancy. The possibility of such fetal injury is an argument for prenatal diagnosis in seropositive pregnant women when ultrasonographic findings suggest cytomegalovirus infection.