Organic carbon, and major and trace element dynamic and fate in a large river subjected to poorly-regulated urban and industrial pressures (Sebou River, Morocco).

An annual-basis study of the impacts of the anthropogenic inputs from Fez urban area on the water geochemistry of the Sebou and Fez Rivers was conducted mostly focusing on base flow conditions, in addition to the sampling of industrial wastewater characteristic of the various pressures in the studied environment. The measured trace metals dissolved/particulate partitioning was compared to the ones predicted using the WHAM-VII chemical speciation code. The Sebou River, upstream from Fez city, showed a weakly polluted status. Contrarily, high levels of major ions, organic carbon and trace metals were encountered in the Fez River and the Sebou River downstream the Fez inputs, due to the discharge of urban and industrial untreated and hugely polluted wastewaters. Trace metals were especially enriched in particles with levels even exceeding those recorded in surface sediments. The first group of elements (Al, Fe, Mn, Ti, U and V) showed strong inter-relationships, impoverishment in Fez particles/sediments and stable partition coefficient (Kd), linked to their lithogenic origin from Sebou watershed erosion. Conversely, most of the studied trace metals/metalloids, originated from anthropogenic sources, underwent significant changes of Kd and behaved non-conservatively in the Sebou/Fez water mixing. Dissolved/particulate partitioning was correctly assessed by WHAM-VII modeling for Cu, Pb and Zn, depicting significant differences in chemical speciation in the Fez River when compared to that in the Sebou River. The results of this study demonstrated that a lack of compliance in environmental regulations certainly explained this poor status.

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital.

PURPOSE: The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database "Programme de Médicalisation des Systèmes d'Information" (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre. METHODS: The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture-recapture method was applied to estimate the incidence of ADRs. RESULTS: During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of "serious" ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p < 0.0001). The most frequent ADRs reported were musculoskeletal (12.4 %) and central (11.3 %) ADRs in PMSI database versus cutaneous (22.4 %) and general (17.5 %) ADRs in FPVDB. The most frequently suspected drugs were antineoplastic drugs (31.1 %) in PMSI database versus anti-infectives (38.2 %) in FPVDB. The estimated number of ADRs was 717 [95 % confidence interval (CI) 513, 921], and the incidence of ADRs among admissions was 0.6 % (95 % CI 0.4, 0.8). CONCLUSIONS: Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.

Impact of rapid urbanisation and industrialisation on river sediment metal contamination.

This study aimed at evidencing contaminant inputs from a rapidly growing population and the accompanying anthropogenic activities to river sediments. The Fez metropolitan area and its impacts on the Sebou's sediments (the main Moroccan river) were chosen as a case study. The Fez agglomeration is surrounded by the river Fez, receiving the wastewaters of this developing city and then flowing into the Sebou. The sediment cores from the Fez and Sebou Rivers were extracted and analysed for major elements, butyltins and toxic metals. Normalised enrichment factors and geoaccumulation index were calculated. Toxicity risk was assessed by two sets of sediment quality guideline (SQG) indices. A moderate level of contamination by butyltins was observed, with monobutyltin being the dominant species across all sites and depths. The lowest level of metal pollution was identified in the Sebou's sediments in upstream of Fez city, whilst the Fez' sediments were heavily polluted and exhibited bottom-up accumulation trends, which is a clear signature of recent inputs from the untreated wastewaters of Fez city. Consequently, the sediments of Fez and Sebou at the downstream of the confluence were found to be potentially toxic, according to the SQG levels. This finding is concerned with aquatic organisms, as well as to the riverside population, which is certainly exposed to these pollutants through the daily use of water. This study suggests that although Morocco has adopted environmental regulations aiming at restricting pollutant discharges into the natural ecosystems, such regulations are neither well respected by the main polluters nor efficiently enforced by the authorities.

Dynamics and fates of trace metals chronically input in a Mediterranean coastal zone impacted by a large urban area.

Quantification and characterization of chronic inputs of trace metals and organic carbon in a coastal Mediterranean area (the city of Marseille) during the dry season was carried out. The 625 km(2) watershed includes two small coastal rivers whose waters are mixed with treated wastewater (TWW) just before their outlet into the sea. Dissolved and particulate Cu, Pb, Cd, Zn, Co, Ni and organic carbon concentrations in the rivers were comparable to those in other Mediterranean coastal areas, whereas at the outlet, 2- to 18-fold higher concentrations reflected the impact of the TWW. A non-conservative behavior observed for most of the studied metals in the mixing zone was validated by a remobilization experiment performed in the laboratory. The results showed that sorption/desorption processes could occur with slow kinetics with respect to the mixing time in the plume, indicating non-equilibrium in the dissolved/particulate metal distribution. Thus, a sample filtration immediately after sampling is strictly required.

Probabilistic distribution coefficients (K(d)s) in freshwater for radioisotopes of Ag, Am, Ba, Be, Ce, Co, Cs, I, Mn, Pu, Ra, Ru, Sb, Sr and Th: implications for uncertainty analysis of models simulating the transport of radionuclides in rivers.

The objective of this study was to provide operational probability density functions (PDFs) for distribution coefficients (K(d)s) in freshwater, representing the partition of radionuclides between the particulate and the dissolved phases respectively. Accordingly, the K(d) variability should be considered in uncertainty analysis of transport and risk assessment models. The construction of PDFs for 8 elements (Ag, Am, Co, Cs, I, Mn, Pu and Sr) was established according to the procedure already tested in Durrieu et al. [2006. A weighted bootstrap method for the determination of probability density functions of freshwater distribution coefficients (K(d)s) of Co, Cs, Sr and I radioisotopes. Chemosphere 65 (8), 1308-1320]: (i) construction of a comprehensive database where K(d)s values obtained under various environments and parametric conditions were collected; (ii) scoring procedure to account for the 'quality' of each datapoint (according to several criteria such as the presentation of data (e.g. raw data vs mean with or without replicates), contact time, pH, solid-to-liquid ratio, expert judgement) in the construction of the PDF; (iii) weighted bootstrapping procedure to build the PDFs, in order to give more importance to the most relevant datapoints. Two types of PDFs were constructed: (i) non-conditional, usable when no knowledge about the site of concern is available; (ii) conditional PDFs corresponding to a limited range of parameters such as pH or contact time; conditional PDFs can thus be used when some parametric information is known on the site under study. For 7 other radionuclides (Ba, Be, Ce, Ra, Ru, Sb and Th), a simplified procedure was adopted because of the scarcity of data: only non-conditional PDFs were built, without incorporating a scoring procedure.

Long-term survey of heavy-metal pollution, biofilm contamination and diatom community structure in the Riou Mort watershed, South-West France.

In a metal-polluted stream in the Riou Mort watershed in SW France, periphytic biofilm was analyzed for diatom cell densities and taxonomic composition, dry weight and metal bio-accumulation (cadmium and zinc). Periphytic diatom communities were affected by the metal but displayed induced tolerance, seen through structural impact (dominance of small, adnate species) as well as morphological abnormalities particularly in the genera Ulnaria and Fragilaria. Species assemblages were characterized by taxa known to occur in metal-polluted environments, and shifts in the community structure expressed seasonal patterns: high numbers of Eolimna minima, Nitzschia palea and Pinnularia parvulissima were recorded in Summer and Autumn, whereas the species Surirella brebissonii, Achnanthidium minutissimum, Navicula lanceolata and Surirella angusta were dominant in Winter and Spring. Commonly used indices such as the Shannon diversity index and Specific Pollution Sensitivity Index reflected the level of pollution and suggest seasonal periodicity, the lowest diversities being observed in Summer.

Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance database.

Nefopam is widely used for the relief of moderate acute pain. Its safety profile remains to be specified. The objective of the study was to review adverse reactions to nefopam spontaneously reported to the French Pharmacovigilance system. All cases of adverse drug reactions (ADRs) associated with nefopam, registered in the French Pharmacovigilance database from January 1, 1995 to December 31, 2004, were reviewed. For each reported ADR, information about patient (age, gender, medical history), drug exposure (suspected and concomitantly used drugs), characteristics of ADRs (imputability score, time of onset, seriousness, outcome) were collected. A total of 114 ADRs with an imputability rated from 'plausible' (I2) to 'likely' (I3) and 'very likely' (I4) was analysed. The most frequent ADRs included 'expected' ADRs such as sweating, nausea, tachycardia, malaise or vomiting; 61 ADRs were 'unexpected. No overdose was reported; 26 ADRs (23%) were considered as 'serious'. Most of them were 'unexpected', including neuropsychiatric (hallucinations, convulsions) or cutaneous (pruritus, erythema, urticaria) ADRs. Six cases of anaphylactic ADRs (two angioedema and four anaphylactic shocks) were reported, all occurring shortly after use of nefopam during the post-operative period. Physicians should be aware of the possible occurrence of some serious ADRs when using nefopam such as convulsions and anaphylactic shocks, especially when the drug is used in special medical conditions, like post-operative periods.

Perception of risk of adverse drug reactions by medical students: influence of a 1 year pharmacological course.

AIMS: To investigate how adverse drug reactions (ADRs) to several classes of drugs are perceived by young medical students before and after a 1 year pharmacology course. METHODS: The whole cohort of 92 medical students (63 females and 29 males) was questioned during their third year. A visual analogue scale was used to define a score (ranging from 0 to 10) of perceived risk of ADRs associated with each drug class before and at the end of the pharmacological training period. RESULTS: Before the pharmacology course, hypnotics were ranked as the most dangerous drugs by the medical students, followed by antidepressants and anticoagulants. Contraceptive pills were listed in the last position. After pharmacological training, antidepressants moved into the first position, followed by anticoagulants and hypnotics. When all different drug classes were taken as a whole, the mean (+/-SD) of median scores of the perceived risk were 4.8 (+/-1.3) before and 5.8 (+/-1.5) at the end of the pharmacology course (P < 0.0001). Except for antidiabetics, antihypertensive drugs, tranquillizers, corticosteroids and hypnotics, the perceived risk significantly increased after the pharmacology course for the other drugs. The highest increases were observed for contraceptive pills (+104%, P < 0.01), NSAIDs (+86%, P < 0.01) and aspirin (+56%, P < 0.01). CONCLUSIONS: Pharmacological training allows young medical students to be aware of potentially serious ADRs associated with drugs, in particular with drugs considered relatively safe (such as NSAIDs and aspirin) by nonhealth professionals.

A weighted bootstrap method for the determination of probability density functions of freshwater distribution coefficients (Kds) of Co, Cs, Sr and I radioisotopes.

The objective of the study was to provide global probability density functions (PDFs) representing the uncertainty of distribution coefficients (Kds) in freshwater for radioisotopes of Co, Cs, Sr and I. A comprehensive database containing Kd values referenced in 61 articles was first built and quality scores were affected to each data point according to various criteria (e.g. presentation of data, contact times, pH, solid-to-liquid ratio, expert judgement). A weighted bootstrapping procedure was then set up in order to build PDFs, in such a way that more importance is given to the most relevant data points (i.e. those corresponding to typical natural environments). However, it was also assessed that the relevance and the robustness of the PDFs determined by our procedure depended on the number of Kd values in the database. Owing to the large database, conditional PDFs were also proposed, for site studies where some parametric information is known (e.g. pH, contact time between radionuclides and particles, solid-to-liquid ratio). Such conditional PDFs reduce the uncertainty on the Kd values. These global and conditional PDFs are useful for end-users of dose models because the uncertainty and sensitivity of Kd values are taking into account.

COX-2 inhibitors and arterial hypertension: an analysis of spontaneous case reports in the Pharmacovigilance database.

OBJECTIVE: To evaluate the main characteristics of case reports of arterial hypertension (AH) related to COX-2 inhibitor (coxib) use in real-life practice. METHODS: This study was based on spontaneous reports of adverse drug reactions (ADRs) submitted to the French Pharmacovigilance system. Associations between AH and the different groups of those using non-steroidal anti-inflammatory drugs (NSAIDs: rofecoxib, celecoxib and non-selective NSAIDs) were compared using calculation of the odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: In France, between 1 April 2000 and 30 November 2003, 34 AH cases related to coxibs were reported. Case reports include predominantly patients older than 65 years, with a previous story of essential AH. Most AH (60%) occurred during the first 15 days of treatment. The AH was reported significantly more frequently for rofecoxib than celecoxib. The OR for development of AH with rofecoxib versus celecoxib was 3.3 (1.6-6.9). The AH was also reported more frequently with coxib (2.8%) than with non-selective NSAID (0.5%) use, OR = 5.9 (3.8-9.0). CONCLUSION: This study shows that coxibs are associated with a risk of AH in real-life practice. More spontaneous reports of AH to the French Pharmacovigilance system concern rofecoxib than celecoxib (and coxibs than non-selective NSAIDs). This ADR is of special epidemiological importance due to both the risks of AH and the large use of coxibs.

Fertility and outcomes of pregnancy after chemotherapy in a sample of childbearing aged women.

The aim of the study was to review the characteristics and outcomes of pregnancies occurring in women of childbearing age after chemotherapy for malignant disease. Between November 1998 and October 1999, a total of 16 patients who were treated for ovary (three), mole (one), vaginal (one), breast (four), Hodgkin's disease (four), lung (one), melanoma (one) and osteosarcoma (one) carcinoma were identified and retrospectively questioned about their fertility status. All the 16 women included in this study received at least one alkylating agent. Five patients (31%) experienced anomalies of hormonal cycle during and after the treatment. All of them recovered normal cycle without consequence of fertility. Caesarean section was performed in seven of 20 (35%) pregnancies with known outcomes. No obstetrical events were reported. The 16 women had 21 pregnancies resulting in 18 normal infants, one newborn with a minor abnormality (tallus foot), one spontaneous abortion and one lost of follow-up to 6 months of pregnancy. The present survey suggests that cytotoxic drug exposure had no deleterious effects on subsequent pregnancies. A prospective and systemic survey would be the only means able to clarify the actual cancer therapy on reproductive outcome and to investigate the long-term effects in the progeny.

Statistical analysis of mitochondrial pathologies in childhood: identification of deficiencies using principal component analysis.

Mitochondrial pathologies are a heterogeneous group of metabolic disorders that are frequently characterized by anomalies of oxidative phosphorylation, especially in the respiratory chain. The identification of these anomalies may involve many investigations, and biochemistry is a main tool. However, considering the whole set of biochemical data, the interpretation of the results by the traditionally used statistical methods remains complex and does not always lead to an unequivocal conclusion about the presence or absence of a respiratory chain defect. This arises from three main problems: (a) the absence of an a priori-defined control population, because the determination of the control values are derived from the whole set of investigated patients, (b) the small size of the population studied, (c) the large number of variables collected, each of which creates a wide variability. To cope with these problems, the principal component analysis (PCA) has been applied to the biochemical data obtained from 35 muscle biopsies of children suspected of having a mitochondrial disease. This analysis makes it possible for each respiratory chain complex to distinguish between different subsets within the whole population (normal, deficient, and, in between, borderline subgroups of patients) and to detect the most discriminating variables. PCA of the data of all complexes together showed that mitochondrial diseases in this population were mainly caused by multiple deficits in respiratory chain complexes. This analysis allows the definition of a new subgroup of newborns, which have high respiratory chain complex activity values. Our results show that the PCA method, which simultaneously takes into account all of the concerned variables, allows the separation of patients into subgroups, which may help clinicians make their diagnoses.

Detection of quantitative trait loci associated with alcohol-dependence: use of model-free sib-pair method and combined segregation-linkage analysis based on regressive models.

Two linkage methods were used to detect loci underlying neurophysiological measures associated with alcohol dependence 1) the Haseman-Elston (H-E) sib pair method for genome-wide search, and 2) the combined segregation-linkage (CSL), based on regressive models, to confirm positive linkages found by the genome screening. Among 14 linkage results that were significant at the 0.5% level using H-E, the CSL method leads to similar p-values in only three cases but to higher p-values in all others. Investigation of these discrepancies shows that assumptions (normality and homoscedasticity of the error term) of H-E least-squares regression method are not verified. A robust estimator of slope parameters without assuming any distribution function for the linear model error terms increases the p-values and reduces the difference between H-E and CSL results. Alternatively, the CSL approach may lack power when multiple genes with small effects are involved.

[Phylogeny of fungi responsible for smut of plants based on ITS sequence analysis]. / Phylogénie de champignons responsables des charbons des végétaux à partir de l'analyse des séquences ITS.

Phylogenetic relationships among fungi belonging to the family of Ustilaginaceae (genera Microbotryum, Spacelotheca, Ustilago, Sporisorium) are inferred from a parsimony analysis using the ITS sequences of nuclear ribosomal genes. The introduction in the phylogeny of sequences from species of Suillus, Puccinia and Taphrina as outgroup shows the polyphyletism of this family. These results support the division of this taxon into two groups: Ustilaginaceae s. str. formed only by the pathogens of Poaceae, and Microbotryaceae constituted by the pathogens of Dicotyledons. Furthermore, we proposed to extend the host plant spectrum of Ustilaginaceae s. str. to all the Monocotyledons. Several discriminating characteristics are listed to support this distinction.

Clinical pharmacology of befloxatone: a brief review.

Clinical pharmacology studies of befloxatone, a new selective reversible inhibitor of monoamine oxidase-A (MAO-A), have addressed safety, with special emphasis on tyramine interactions, and have also investigated pharmacokinetics (PK) and pharmacodynamics in terms of both MAO-A inhibition (using 3,4-dihydroxyphenylglycol, DHPG, as a pharmacological activity marker) and effects on psychomotor and cognitive function, in young and elderly healthy volunteers. Clinical and laboratory safety data were satisfactory in healthy volunteers given single doses of up to 160 mg or repeated doses of up to 80 mg/day for 7 days. Tyramine interaction studies showed that the expected potentiation of the tyramine pressor effect occurred with a safety margin that was so wide as to make dietary restrictions unnecessary with dosages of up to 20 mg once daily in clinical settings. Absorption was rapid (tmax = 2 h), terminal halflife was about 11 h, and PK parameters increased linearly with the dose. Befloxatone induced a dose-dependent decrease in plasma DHPG levels from 2.5 mg upwards, and a 10-mg dose provided sub-maximal activity (80% DHPG decrease) of 24 h duration. No sedative or stimulant effects were detected using several batteries of psychometric tests. Befloxatone was devoid of deleterious effects on memory in young volunteers, and exhibited the EEG profile of a non-sedative antidepressant. In summary, available clinical pharmacology studies confirm that befloxatone is a safe and potent RIMA with no potential for inducing deleterious CNS effects.

Identification of mitochondrial deficiency using principal component analysis.

The mitochondrial pathologies are a heterogeneous group of metabolic disorders that are characterized by anomalies of oxidative phosphorylation, especially in the respiratory chain. The diagnosis of these pathologies involves many investigations among which biochemical study is at present the main tool. However, the analysis of the results obtained during such study remains complex and often does not make it possible to conclude clearly if a patient is affected or not by a biochemical and/or bioenergetic deficiency. This arises from two main problems: 1. The determination of control values from the whole set of variable values (affected and unaffected people). 2. The small size of the population studied and the large number of variables collected which present a rather large variability. To cope with these problems, the principal component analysis method is applied to the results obtained during our biochemical studies. This analysis makes it possible for each respiratory chain complex, to distinguish clearly two subsets of the whole population (affected and unaffected people) as well as to detect the variables which are the most discriminative.

A study of dopaminergic sensitivity in Parkinson's disease: comparison in "de novo" and levodopa-treated patients.

The present study investigates dopaminergic sensitivity in Parkinson's disease (PD) through the measurement of neuroendocrine (growth hormone: GH, prolactin: PRL) and cardiovascular (blood pressure: BP, heart rate: HR) responses to low doses of apomorphine (5 micrograms/kg s.c.) in three groups of subjects: 13 normal volunteers (controls), 19 "de novo" never-treated PD patients, and 14 levodopa-treated PD patients. Apomorphine did not change BP and HR but significantly decreased PRL plasma levels in controls as well as in the two groups of PD patients. GH plasma levels significantly increased after apomorphine. There was no significant difference in the changes in neuroendocrine (GH, PRL) parameters in the two groups of PD patients in comparison with controls. However, "de novo" patients exhibited a significantly higher number of apomorphine-induced orthostatic symptoms (7 of 19) than did controls (0 of 13) or treated PD patients (2 of 14). These results show that hypothalamic dopaminergic sensitivity (studied through GH and PRL responses to apomorphine) is normal in PD. In contrast, because apomorphine-induced orthostatic hypotension is mainly due to the stimulation of peripheral dopaminergic receptors, our study suggests a peripheral dopaminergic hypersensitivity in some "de novo" never treated (but not in treated) PD patients.

Effects of befloxatone, a reversible selective monoamine oxidase-A inhibitor, on psychomotor function and memory in healthy subjects.

Befloxatone is a new reversible and selective monoamine oxidase (MAO-A) inhibitor that has been shown to have antidepressant activity in various animal models. To assess the effects of single oral doses of befloxatone (5, 10, and 20 mg) on psychomotor performance and memory, a randomized, double-blind, five-way, crossover study with both placebo and amitriptyline (50 mg) was carried out in 15 healthy male volunteers. Psychomotor and cognitive functions were evaluated using both objective measures, including Critical Flicker Frequency (CFF), Choice Reaction Time (CRT), Digit Symbol Substitution Test (DSST), and a picture memory test and subjective measures, including Visual Analog Scales (VAS) and Addiction Research Center Inventory (ARCI), before and 2, 4, and 8 hours after administration. Pupil diameter was recorded by videopupillography. Single doses of befloxatone from 5 to 20 mg did not result in any detrimental effects on skilled performance and memory. In contrast, amitriptyline significantly impaired arousal (CFF), speed of reaction (CRT), information processing (DSST) and long-term memory (delayed free recall of pictures) and produced subjective sedation from 2 to 8 hours after administration. At the doses studied amitriptyline induced miosis but befloxatone did not modify pupil diameter. There was no evidence in this study to suggest that befloxatone, at the doses studied, has any sedative or amnesic effects in healthy subjects.