Local modulation of steroid action: rapid control of enzymatic activity.

peer reviewedEstrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17beta-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues

Association between endocrine disruptor contamination and thyroid hormone homeostasis in Belgian type 1 diabetic children.

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Impact of exposure to diesel exhaust during pregnancy on mammary gland development and milk composition in the rabbit

Exposure to fine-particulate air pollution is a major global health concern because it is associated with reduced birth weight and an increased risk of cardiovascular disease. Here we have investigated the potential for exposure to diesel exhaust during pregnancy to influence mammary gland development and milk composition. Female rabbits were therefore exposed by nose-only inhalation to either diluted diesel exhaust fumes (1 mg/m3) or clean air for 2h/day, 5 days/week, from the 3rd to the 27th days of pregnancy. On Day 28 of pregnancy, mammary glands were collected from twelve females (six controls and six diesel-exposed) and assessed for morphological and functional alterations. Milk samples were collected from eighteen dams (nine controls and nine diesel-exposed) during early (days 2 to 4) and established (days 13 to 16) lactation to verify the composition of fatty acids and major proteins and leptin levels. The mammary alveolar lumina contained numerous fat globules, and stearoyl CoA reductase expression was higher in mammary epithelia from diesel exhaust-exposed rabbits, which together suggested increased mammary lipid biosynthesis. Gas chromatography analysis of the composition of milk fatty acids revealed a sharp rise in the total fatty acid content, mainly due to monounsaturated fatty acids. Liquid chromatography-mass spectrometry analysis of milk samples enabled identification and quantification of the main rabbit milk proteins and their main phosphorylated isoforms, and revealed important changes to individual casein and whey protein contents and to their most phosphorylated isoforms during early lactation. Taken together, these findings suggest that repeated daily exposure to diesel exhaust fumes during pregnancy at urban pollution levels can influence lipid metabolism in the mammary gland and the lipid and protein composition of milk. As milk may contribute to metabolic programming, such alterations affecting milk composition should be taken into account from a public health perspective

Population pharmacokinetics of cefazolin in maternal and umbilical cord plasma, and simulated exposure in term neonates

Background:Intra-partum cefazolin is used to prevent group BStreptococcus(GBS) vertical transmission inmothers allergic to penicillin without a history of anaphylaxis.Objectives:To investigate the maternal cefazolin dose–exposure relationship and subsequent maternal andneonatal target attainment at delivery.Methods:Data were obtained from 24 healthy, GBS-colonized pregnant women (20–41 years), undergoing vagi-nal delivery (gestational age 37 weeks). During labour, all women received a 2 g cefazolin IV infusion. Eighthours later, eight women received another 1 g in the event of delayed (>8 h) delivery. Next to maternal plasmaconcentrations (up to 10 per dosing interval, until delivery), venous and arterial umbilical cord concentrationswere determined at delivery. Target attainment in maternal/neonatal plasma was set at 1 mg/L for 60% of thedosing interval (unbound cefazolin, worst-case clinical breakpoint). A population pharmacokinetic (popPK) modelwas built (NONMEM 7.4). ClinicalTrials.gov Identifier: NCT01295606.Results:At delivery, maternal blood and arterial umbilical cord unbound cefazolin concentrations were >1 mg/Lin 23/24 (95.8%) and 11/12 (91.7%), respectively. The popPK of cefazolin in pregnant women was described by atwo-compartment model with first-order elimination. Two additional compartments described the venous andarterial umbilical cord concentration data. Cefazolin target attainment was adequate in the studied cohort,where delivery occurred no later than 6.5 h after either the first or the second dose. PopPK simulations showedadequate maternal and umbilical cord exposure for 12 h following the first dose.Conclusions:PopPK simulations showed that standard pre-delivery maternal cefazolin dosing providedadequate target attainment up to the time of delivery

Oxidative Stress Status and its correlation with Redox Status as Measured By An Electrochemical (PAOT®) Methodology: A Pilot Study in Critical COVID-19 Pneumonia Survivors

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A Pilot Study on Oxidative Stress during the Recovery Phase in Critical COVID-19 Patients in a Rehabilitation Facility: Potential Utility of the PAOT ® Technology for Assessing Total Anti-Oxidative Capacity

peer reviewedBackground: Oxidative stress (OS) could cause various COVID-19 complications. Recently, we have developed the Pouvoir AntiOxydant Total (PAOT®) technology for reflecting the total antioxidant capacity (TAC) of biological samples. We aimed to investigate systemic oxidative stress status (OSS) and to evaluate the utility of PAOT®for assessing TAC during the recovery phase in critical COVID-19 patients in a rehabilitation facility. Materials and Methods: In a total of 12 critical COVID-19 patients in rehabilitation, 19 plasma OSS biomarkers were measured: antioxidants, TAC, trace elements, oxidative damage to lipids, and inflammatory biomarkers. TAC level was measured in plasma, saliva, skin, and urine, using PAOT and expressed as PAOT-Plasma, -Saliva, -Skin, and -Urine scores, respectively. Plasma OSS biomarker levels were compared with levels from previous studies on hospitalized COVID-19 patients and with the reference population. Correlations between four PAOT scores and plasma OSS biomarker levels were analyzed. Results: During the recovery phase, plasma levels in antioxidants ( -tocopherol,  -carotene, total glutathione, vitamin C and thiol proteins) were significantly lower than reference intervals, whereas total hydroperoxides and myeloperoxidase (a marker of inflammation) were significantly higher. Copper negatively correlated with total hydroperoxides (r = 0.95, p = 0.001). A similar, deeply modified OSS was already observed in COVID-19 patients hospitalized in an intensive care unit. TAC evaluated in saliva, urine, and skin correlated negatively with copper and with plasma total hydroperoxides. To conclude, the systemic OSS, determined using a large number of biomarkers, was always significantly increased in cured COVID-19 patients during their recovery phase. The less costly evaluation of TAC using an electrochemical method could potentially represent a good alternative to the individual analysis of biomarkers linked to pro-oxidants

Variation de la sensibilité de la transferrine désialylée (Etude chez 192 patients alcoolodépendants en phase active)

La CDT (carbohydrate deficient transferrin) est une forme hypoglycosylée de la transferrine, synthétisée sous l'influence de l'alcool. Ce marqueur d'alcoolisation est plus spécifique que la GGT et le VGM classiquement utilisés. Par contre, sa sensibilité est très variable selon les études. Le but de notre étude clinique transversale est d'étudier la variabilité de la CDT dans une population de patients alcoolodépendants en fonction de la vulnérabilité au développement de l'alcoolodépendance (rapidité d'installation des dommages). Parallèlement, la sensibilité de la CDT a été comparée à celles de la GGT et du VGM. Les résultats de l'étude montrent que la CDT varie en fonction du type d'alcoolodépendance. En effet, elle est plus performante type Cloninger II qui sont particulièrement vulnérables au développement précoce de l'alcoolodépendance. La sensibilité de la CDT s'élève à 84.4 % dans ce groupe alors qu'elle est de 77.4 % dans le groupe de type Cloninger I (ayant une dépendance d'installation tardive). Par ailleurs, la CDT a montré sa supériorité par rapport à la GGT et au VGM, en terme de sensibilité, et ce plus particulièrement dans le groupe de type Cloninger II. Il semble donc que la CDT soit un marqueur intéressant pour le suivi de patients alcoolodépendants et qu'il soit nécessaire de pendre en compte dans l'interprétation des résultats un certain nombre de critères cliniques permettant de distinguer les types d'alcoolodépendance. Des études ultérieures permettraient cependant de mieux préciser encore la place de ce marqueur dans la prise en charge des maladies liées à l'alcool.PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF