Bisphenol A (BPA), a widespread man-made chemical classified as an endocrine disruptor, is increasingly considered as a major cause of concern for human health. Chlorine present in drinking water may react with BPA to form chlorinated derivatives (ClxBPA), which have demonstrated a heightened level of estrogenic activity. If many epidemiological studies report that more than 90% of people have detectable BPA levels in their urine, then no such study has been undertaken regarding ClxBPA. The purpose of this work is to propose a highly sensitive and accurate analytical method adapted to large-scale biomonitoring studies aimed at assessing exposure to BPA and ClxBPA through the use of human urine. To achieve this, we have comprehensively validated a method using salting-out assisted liquid/liquid extraction (SALLE) coupled to UPLC-MS/MS and isotope dilution quantification, to measure unconjugated BPA and ClxBPA in human urine according to the accepted guidelines. Deutered BPA as well as deutered 2,2'-DCBPA was used as internal standards. The matrix calibration curve ranged from 0.05 to 1.60 ng mL(-1) and from 0.5 to 16.0 ng mL(-1) for ClxBPA and BPA respectively, and provided good linearity (r²>0.99). This method was precise (the intra- and inter-day coefficients of variation were <20% at three different concentrations: 0.05 ng mL(-1), 0.2 ng mL(-1), 0.8 ng mL(-1) and 0.5 ng mL(-1), 2 ng mL(-1), 8 ng mL(-1) for ClxBPA and BPA, respectively) and accurate (bias ranged from -13% to +12%). The limit of quantification, validated at 0.05 ng mL(-1) and 0.5 ng mL(-1) for ClxBPA and BPA respectively when using 300 µL of urine, was found to be suitable for the concentration existing in real samples. The matrix effect and the BPA cross-contamination were also investigated in this study. The analytical method developed in this study is in accordance with the requirements applicable to biomonitoring of BPA and ClxBPA in human urine.

The objective of this study was to implement a semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of ciprofloxacin against Pseudomonas aeruginosa in vitro. Time-kill curves were generated with an initial inoculum close to 5 ؋ 10 6 CFU/ml of P. aeruginosa PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 g/ml (corresponding to 0.5؋ and 16؋ MIC). To support the model, phenotypic experiments were conducted with the PAO7H mutant strain, which overexpresses the MexEF OprN efflux pump and phenyl arginine ␤-naphthylamide (PA␤N), a known efflux inhibitor of main Mex multidrug efflux systems. A population approach was used for parameter estimation. At subinhibitory ciprofloxacin concentrations (0.12 and 0.25 g/ml), an initial CFU decay followed by regrowth was observed, attesting to rapid emergence of bacteria with increased but moderate resistance (8-fold increase of MIC). This phenomenon was mainly due to an overexpression of the Mex protein efflux pumps, as shown by a 16-fold diminution of the MIC in the presence of PA␤N in these strains with low-level resistance. A PK-PD model with adaptation development was successfully used to describe these data. However, additional experiments are required to validate the robustness of this model after longer exposure periods and multiple dosing regimens, as well as in vivo.Pseudomonas aeruginosa is one of the leading pathogens involved in nosocomial pneumonia. Infections with P. aeruginosa are associated with significant morbidity and mortality. The increasing frequency of multidrug-resistant P. aeruginosa strains is a concern since effective antimicrobial options are severely limited (27). Fluoroquinolones (FQs) such as ciprofloxacin, which target the bacterial enzymes DNA gyrase and topoisomerase IV, which are essential for maintenance of the appropriate DNA topological state for replication and transcription may represent an effective therapy against P. aeruginosa (8). However, P. aeruginosa also becomes resistant to FQs through two well-documented and separate mechanisms: (i) expression of drug efflux pumps that reduce the accumulation of antibiotics in the cell and (ii) point mutations in the genes of the quinolone target enzymes, topoisomerase and gyrase (9,12,18,29,38).Because amplification of a resistant subpopulation is dependent on the antibiotic dosing regimen (14), optimization of dosing regimens should allow the limiting of these phenomena. Time-kill studies are commonly used to address these issues by exploring the changes of bacteria counts in the presence of different concentrations of antibiotics in vitro, and pharmacokinetic-pharmacodynamic (PK-PD) indexes derived from the MIC are used to quantify the activity of antibiotics against bacteria (22). However, although very popular, these approaches present several limits when attempting to select the best dosing regimens, especially when bacterial regrowth is observed after an initial decay, as occasionally observed (7,24,25). A more complex but also more powerf...

The aim of the present study, a part of the Endocrine Disruptor Deux-Sèvres (EDDS) cohort study, was to estimate water-use habits of pregnant French women. The study population consisted of 132 pregnant women living in Deux-Sèvres (France) in 2012-2013, in areas where drinking water is exclusively produced by surface water. Drinking-water data included ingested water (tap, bottled and filtered) and ingestion place (home, work and elsewhere). Dermal contact with water included showering, bathing, swimming, spa use, hand-washing and other water activities. Data were collected through face-to-face interviews at second and third trimesters of pregnancy with a 1-day-recall questionnaire. Intertrimestral differences in water-use habits were assessed. Predictors of water ingestion and duration of dermal contact with water were assessed with multiple linear regressions. At the second trimester of pregnancy, the mean total drinking-water ingestion was 1.8±0.6 l per day (mean and SD), 71% of which was tap water. Total drinking-water ingestion was not different between both trimesters but ingestion place differed. Dermal contact with water estimate was 188±118 and 173±92 min/week at second and third trimesters, respectively. Smoking increased water ingestion 777 ml/day 95% CI (171-1384). Duration of dermal contact in spring was 30 min/week 95% CI (13-48) higher than in winter. Obese women spend 26 min/week 95% CI (2-50) more showering than women with recommended weight. Our estimates of pregnant French women's exposure to water will help researchers to better assess water pollutant risks.

No abstract

Bisphenol A (BPA) is a well-known endocrine disruptor. Chlorinated derivatives of BPA (ClxBPA) may be formed by reaction of chlorine with BPA present in drinking water. ClxBPA exhibit a higher level of estrogenic activity than BPA. While many studies have reported detectable BPA concentrations in urine, only very few studies were conducted in regards to ClxBPA. Since ClxBPA are potentially more toxic, it is important to assess large-scale exposure of the general population. Indeed, in the field of environment health, large studies are required to assess exposure to pollutants at ultratrace concentrations; therefore, analytical methods have to be rapid and sensitive. This work intends to validate a highly sensitive and rapid analytical method suitable to evaluate BPA and ClxBPA exposures during large-scale biomonitoring studies. For that purpose, a method based on online solid-phase extraction coupled with isotope dilution ultrahigh - performance liquid chromatography-tandem mass spectrometry was developed and validated according to accepted guidelines. The matrix-matched calibration curve ranged from 0.25 to 16.0 ng mL(-1) and from 0.025 to 1.60 ng mL(-1) for BPA and ClxBPA, respectively. This method was precise (the intra- and inter-day coefficients of variation of quality control were <16.4%) and accurate (bias ranged from -4.0 to 16.8%). The limit of quantification was validated at 0.25 and 0.025 ng mL(-1), for BPA and ClxBPA, respectively. The limit of detection was estimated for each experiment performed. Finally, this method is rapid and sensitive enough to be carried out during biomonitoring studies of BPA and ClxBPA in human urine.

No abstract

While treatment of serious infectious diseases may require high-dose amoxicillin, continuous infusion may be limited by lack of knowledge regarding the chemical stability of the drug. Therefore, we have performed a comprehensive study so as to determine the chemical stability of high-dose amoxicillin solutions conducive to safe and effective continuous intravenous administration using portable elastomeric pumps. First, amoxicillin solubility in water was assessed within the range of 25 to 300 mg/mL. Then, amoxicillin solutions were prepared at different concentrations (25, 50, 125, 250 mg/mL) and stored in different conditions (5±2°C, 25±1°C, 30±1°C and 37±1°C) to investigate the influence of concentration and temperature on the chemical stability of amoxicillin. Finally, its stability was assessed under optimized conditions using a fully validated HPLC-UV stability-indicating method. Degradation products of amoxicillin were investigated by accurate mass determination using high-resolution mass spectrometry. Amoxicillin displayed limited water solubility requiring reconstitution at concentrations below or equal to 150 mg/mL. Amoxicillin degradation were time, temperature as well as concentration-dependent, resulting in short-term stability, in particular at high concentrations. Four degradation products of amoxicillin have been identified. Among them, amoxicilloic acid and diketopiperazine amoxicillin are at risk of allergic reaction and may accumulate in the patient. Optimized conditions allowing for continuous infusion of high-dose amoxicillin has been determined: amoxicillin should be reconstituted at 25 mg/mL and stored up to 12 hours at room temperature (22 ± 4°C) or up to 24 hours between 4 and 8°C.

Desde que el oftalmólogo inglês Marcus Gunn dió a conocer, en 1883 T el fenômeno que lleva su nombre (retracción dei párpado superior cuando se abre la boca o se desvia hacia un lado la mandíbula), se habrán descrito un centenar de casos típicos, puesto que el llamado síndrome de Marín-Amat (o fenômeno de Marcus Gunn invertido), también raro, representa una sincinesia facial de significación y de mecanismo dei todo diferentes. Wartenberg (1946Wartenberg ( y 1948 ha contribuído a precisar bien lo que son esos dos síndromes tan conexos. En los últimos anos --según los índices de "Excerpta Médica", de "Progress in Neurology and Psychiatry" y de la "Revue Neurologique", por ejemplo -tan sólo aparecen referencias de las citadas publicaciones de Wartenberg, de un caso de Wells, de otro de Halbertsma y de otro de Mortensen. Nosotros -en el transcurso de unos meses -hemos podido observar un autêntico o clásico fenômeno de Marcus Gunn y dos síndromes de Marín-Amat, tal como los definió el coJega oftalmólogo de Madrid y tal como los concibe e interpreta actualmente Wartenberg.Nos ocuparemos en el estúdio del primer caso, ya que los otros dos serán expuestos en un trabajo ulterior.M. R. M. M., de 5 anos de edad, natural y vecina de Barcelona. Açude por vez primera al Dispensario el 29 Marzo 51 (n 9 4015-D, de la Clínica de Neurologia I). Sus padres manifiestan que la nina presenta un detecto congênito en forma de asimetría facial (hendidura palpebral izquierda menor que la derecha). Antecedentes familiares: sin valor especial; un abuelo alcohólico; padre (41 anos) y madre (29 anos) sanos; hija única; no abortos. Antecedentes personales: Parto a término con aplicación de forceps (el tocólogo hubo de vencer una falta de encajamiento fetal en presentación cefálica y afirmo que pudo causar la lesion del 7* par craneal); sarampión y una intervención quirúrgica (adenoidectomía); desarrollo e inteligência normales. Exploration-Se nota, ya a la simple inspección, la asimetría facial mencionada, con discreta blefaroptosis izquierda y estrabismo divergente en el OJ. (desviación de la pupila, ligeramente, hacia fuera y hacia arriba). Pero la motilidad ocular extrínseca resulta con todo normal, como también la facial (auComunicación anunciada y no presentada a la "Seizième Réunion annuelle des Sociétés d'Oto-Neuro-Ophtalmologie de langue française", Marsella, mayo de 1951.Trabajo del Instituto Neurológico Municipal de Barcelona (Director: Prof.B. Rodríguez-Arias).