Shotgun Ecotoxicoproteomics of Daphnia pulex: Biochemical Effects of the Anticancer Drug Tamoxifen.

Among pollutants released into the environment by human activities, residues of pharmaceuticals are an increasing matter of concern because of their potential impact on ecosystems. The aim of this study was to analyze differences of protein expression resulting from acute (2 days) and middle-term (7 days) exposure of aquatic microcrustacean Daphnia pulex to the anticancer drug tamoxifen. Using a liquid chromatography-mass spectrometry shotgun approach, about 4000 proteins could be identified, providing the largest proteomics data set of D. pulex published up to now. Considering both time points and tested concentrations, 189 proteins showed a significant fold change. The identity of regulated proteins suggested a decrease in translation, an increase in protein degradation and changes in carbohydrate and lipid metabolism as the major effects of the drug. Besides these impacted processes, which reflect a general stress response of the organism, some other regulated proteins play a role in Daphnia reproduction. These latter results are in accordance with our previous observations of the impact of tamoxifen on D. pulex reproduction and illustrate the potential of ecotoxicoproteomics to unravel links between xenobiotic effects at the biochemical and organismal levels. Data are available via ProteomeXchange with identifier PXD001257.

Estimation de la fonction rénale par l'equation MDRD: intérêt et limites pour l'adaptation des doses de médicaments [Renal function estimation by MDRD equation: interest and limitations for drug dosing].

The MDRD (Modification of diet in renal disease) equation enables glomerular filtration rate (GFR) estimation from serum creatinine only. Thus, the laboratory can report an estimated GFR (eGFR) with each serum creatinine assessment, increasing therefore the recognition of renal failure. Predictive performance of MDRD equation is better for GFR < 60 ml/min/1,73 m2. A normal or near-normal renal function is often underestimated by this equation. Overall, MDRD provides more reliable estimations of renal function than the Cockcroft-Gault (C-G) formula, but both lack precision. MDRD is not superior to C-G for drug dosing. Being adjusted to 1,73 m2, MDRD eGFR has to be back adjusted to the patient's body surface area for drug dosing. Besides, C-G has the advantage of a greater simplicity and a longer use.

Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period.

In 10 moderately obese women, 24-h energy expenditure (24EE) was measured in a respiration chamber under four conditions: 1) before weight loss (body weight = 77.9 kg), 2) during weight loss (63.9 kg), 3) after realimentation (62.5 kg), and 4) 6-15 mo after the study diet with ad libitum diet (67.7 kg). The 14 +/- 8 kg (mean +/- SD) weight loss produced a decrease in 24EE of 1498 +/- 1138 kJ/d (P < 0.001), ie, a decrease of weight of 107 kJ.kg body wt-1.d-1. The subsequent 24EE (conditions 3 and 4) remained lower than the value before weight loss. A significant correlation was found between changes before and after weight regain in basal respiratory quotient (RQ) and the spontaneous rate of body-weight gain after cessation of the period of low energy intake (r = 0.89, P < 0.01); this suggests that the value of the postabsorptive RQ may be a predictor of relapse of weight gain. After discontinuation of the low energy diet, an elevated postabsorptive RQ shows that the endogenous lipid oxidation is low, a condition favoring weight gain.

Traitement pharmacologique de l'état de mal réfractaire [Drug treatment of refractory status epilepticus]

Status epilepticus (SE) refractory to benzodiazepines and other antiepileptic agents is managed with intravenous anesthetic compounds, such as thiopental, propofol or midazolam. These drugs display quite different pharmacodynamic and pharmacokinetic properties, but have not been prospectively compared to date. Their use is clearly advocated for the treatment of generalized convulsive SE, whereas partial-complex, or absence SE are generally managed less aggressively, in consideration of their better prognosis. The most important aspect seems to be related to the correct use of these anesthetics in the right context, rather than the choice of one specific compound. An electroencephalographic burst-suppression should be targeted for about 24hour, before progressive weaning of the dosage under EEG monitoring. If this approach proves unsuccessful, the use of other drugs, including inhalational anesthetics, has been described.

The biochemistry of drug metabolism-an introduction: part 7. Intra-individual factors affecting drug metabolism.

This review on intra-individual factors affecting drug metabolism completes our series on the biochemistry of drug metabolism. The article presents the molecular mechanisms causing intra-individual differences in enzyme expression and activity. They include enzyme induction by transcriptional activation and enzyme inhibition on the protein level. The influencing factors are of physiological, pathological, or external origin. Tissue characteristics and developmental age strongly influence enzyme-expression patterns. Further influencing factors are pregnancy, disease, or biological rhythms. Xenobiotics, drugs, constituents of herbal remedies, food constituents, ethanol, and tobacco can all influence enzyme expression or activity and, hence, affect drug metabolism.

Estimating national-level syringe availability to injecting drug users and injection coverage: Switzerland, 1996-2006.

BACKGROUND: Measuring syringe availability and coverage is essential in the assessment of HIV/AIDS risk reduction policies. Estimates of syringe availability and coverage were produced for the years 1996 and 2006, based on all relevant available national-level aggregated data from published sources. METHODS: We defined availability as the total monthly number of syringes provided by harm reduction system divided by the estimated number of injecting drug users (IDU), and defined coverage as the proportion of injections performed with a new syringe, at national level (total supply over total demand). Estimates of supply of syringes were derived from the national monitoring system, including needle and syringe programmes (NSP), pharmacies, and medically prescribed heroin programmes. Estimates of syringe demand were based on the number of injections performed by IDU derived from surveys of low threshold facilities for drug users (LTF) with NSP combined with the number of IDU. This number was estimated by two methods combining estimates of heroin users (multiple estimation method) and (a) the number of IDU in methadone treatment (MT) (non-injectors) or (b) the proportion of injectors amongst LTF attendees. Central estimates and ranges were obtained for availability and coverage. RESULTS: The estimated number of IDU decreased markedly according to both methods. The MT-based method (from 14,818 to 4809) showed a much greater decrease and smaller size of the IDU population compared to the LTF-based method (from 24,510 to 12,320). Availability and coverage estimates are higher with the MT-based method. For 1996, central estimates of syringe availability were 30.5 and 18.4 per IDU per month; for 2006, they were 76.5 and 29.9. There were 4 central estimates of coverage. For 1996 they ranged from 24.3% to 43.3%, and for 2006, from 50.5% to 134.3%. CONCLUSION: Although 2006 estimates overlap 1996 estimates, the results suggest a shift to improved syringe availability and coverage over time.

Administration intra-vitréenne de liposomes pour la vectorisation de principes actifs [The use of liposomes as intravitreal drug delivery system].

Liposomes are vesicular lipidic systems allowing encapsulation of drugs. This article reviews the relevant issues in liposome structure (composition and size), and their influence on intravitreal pharmacokinetics. Liposome-mediated drug delivery to the posterior segment of the eye via intravitreal administration has been addressed by several authors and remains experimental. Liposomes have been used for intravitreal delivery of antibiotics, antivirals, antifungal drugs, antimetabolites, and cyclosporin. Encapsulation of these drugs within liposomes markedly increased their intravitreal half-life, and reduced their retinal toxicity. Liposomes have also shown an attractive potential for retinal gene transfer by intravitreal delivery of plasmids or oligonucleotides.

Fish oil after abdominal aorta aneurysm surgery

OBJECTIVE: Fish oil (FO) may attenuate the inflammatory response after major surgery such as abdominal aortic aneurysm (AAA) surgery. We aimed at evaluating the clinical impact and safety aspects of a FO containing parenteral nutrition (PN) after AAA surgery. METHODS: Intervention consisted in 4 days of either standard (STD: Lipofundin medium-chain triglyceride (MCT): long-chain triglyceride (LCT)50%-MCT50%) or FO containing PN (FO: Lipoplus: LCT40%-MCT50%-FO10%). Energy target were set at 1.3 times the preoperative resting energy expenditure by indirect calorimetry. Blood sampling on days 0, 2, 3 and 4. Glucose turnover by the (2)H(2)-glucose method. Muscle microdialysis. Clinical data: maximal daily T degrees, intensive care unit (ICU) and hospital stay. RESULTS: Both solutions were clinically well tolerated, without any differences in laboratory safety parameters, inflammatory, metabolic data, or in organ failures. Plasma tocopherol increased similarly; with FO, docosahexaenoic and eicosapentaenoic acid increased significantly by day 4 versus baseline or STD. To increased postoperatively, with a trend to lower values in FO group (P=0.09). After FO, a trend toward shorter ICU stay (1.6+/-0.4 versus 2.3+/-0.4), and hospital stay (9.9+/-2.4 versus 11.3+/-2.7 days: P=0.19) was observed. CONCLUSIONS: Both lipid emulsions were well tolerated. FO-PN enhanced the plasma n-3 polyunsaturated fatty acid content, and was associated with trends to lower body temperature and shorter length of stay.

Free-living energy expenditure assessed by two different methods in rural Gambian men.

OBJECTIVE: To assess total free-living energy expenditure (EE) in Gambian farmers with two independent methods, and to determine the most realistic free-living EE and physical activity in order to establish energy requirements for rural populations in developing countries. DESIGN: In this cross-sectional study two methods were applied at the same time. SETTING: Three rural villages and Dunn Nutrition Centre Keneba, MRC, The Gambia. SUBJECTS: Eight healthy, male subjects were recruited from three rural Gambian villages in the sub-Sahelian area (age: 25 +/- 4y; weight: 61.2 +/- 10.1 kg; height: 169.5 +/- 6.5 cm, body mass index: 21.2 +/- 2.5 kg/m2). INTERVENTION: We assessed free-living EE with two inconspicuous and independent methods: the first one used doubly labeled water (DLW) (2H2 18O) over a period of 12 days, whereas the second one was based on continuous heart rate (HR) measurements on two to three days using individual regression lines (HR vs EE) established by indirect calorimetry in a respiration chamber. Isotopic dilution of deuterium (2H2O) was also used to assess total body water and hence fat-free mass (FFM). RESULTS: EE assessed by DLW was found to be 3880 +/- 994 kcal/day (16.2 +/- 4.2 MJ/day). Expressed per unit body weight the EE averaged 64.2 +/- 9.3 kcal/kg/d (269 +/- 38 kJ/kg/d). These results were consistent with the EE results assessed by HR: 3847 +/- 605 kcal/d (16.1 +/- 2.5 MJ/d) or 63.4 +/- 8.2 kcal/kg/d (265 +/- 34kJ/kg/d). Physical activity index, expressed as a multiple of basal metabolic rate (BMR), averaged 2.40 +/- 0.41 (DLW) or 2.40 +/- 0.28 (HR). CONCLUSIONS: These findings suggest an extremely high level of physical activity in Gambian men during intense agricultural work (wet season). This contrasts with the relative food shortage, previously reported during the harvesting period. We conclude that the assessment of EE during the agricultural season in non-industrialized countries needs further investigations in order to obtain information on the energy requirement of these populations. For this purpose the use of the DLW and HR methods have been shown to be useful and complementary.

Energy expenditure during walking and running in obese and nonobese prepubertal children.

We measured body composition and energy expenditure during walking and running on a treadmill in 40 prepubertal children: 23 obese children (9.3 +/- 1.1 years of age; 46 +/- 10 kg (mean +/- SD)) and 17 nonobese matched control children (9.2 +/- 0.6 years of age; 30 +/- 5 kg). Energy expenditure was assessed by indirect calorimetry with a standard open-circuit method. At the same speed of exercise, the energy expenditure was significantly (p < 0.01) greater in obese than in control children, in both boys and girls. Expressed per kilogram of body weight or per kilogram of fat-free mass, the energy expenditure was comparable in the two groups. Obese children had a significantly (p < 0.01) larger pulmonary ventilatory response to exercise than did control children. Heart rate was comparable in boys and girls combined but significantly higher (p < 0.05) in obese subjects, if boys and girls were analyzed separately. These data indicate that walking and running are energetically more expensive for obese children than for children of normal body weight. The knowledge of these energy costs could be useful in devising a physical activity program to be used in the treatment of obese children.

Measurement of glomerular filtration rate in obese patients: pitfalls and potential consequences on drug therapy.

Epidemiological studies have shown that obesity is associated with chronic kidney disease and end stage renal disease. These studies have used creatinine derived equations to estimate glomerular filtration rate (GFR) and have indexed GFR to body surface area (BSA). However, the use of equations using creatinine as a surrogate marker of glomerular filtration and the indexation of GFR for BSA can be questioned in the obese population. First, these equations lack precision when they are compared to gold standard GFR measurements such as inulin clearances; secondly, the indexation of GFR for 1.73 m(2) of BSA leads to a systematic underestimation of GFR compared to absolute GFR in obese patients who have BSA that usually exceed 1.73 m(2). Obesity is also associated with pathophysiological changes that can affect the pharmacokinetics of drugs. The effect of obesity on both renal function and drug pharmacokinetics raises the issue of correct drug dosage in obese individuals. This may be particularly relevant for drugs known to have a narrow therapeutic range or excreted by the kidney.