[Organisational factors associated with the repetition of infections among children in Parisian day-care setting]. / Facteurs organisationnels associés à la répétition des épisodes infectieux des enfants accueillis en crèche à Paris.

OBJECTIVE: This study analyzes the organisational factors linked with episodes of infections in children attending child day-care setting in Paris. POPULATION AND METHODS: A sample of children who attended parisian municipal child day-care setting, stratified on the type and the size of the day-care setting, was achieved. This cohort was followed from September 2000 to June 2001. We compared the risk of repeated infections according to the type of day-care setting (family day-care or day-care centre), and for the day-care centre according to the size (< or =60 or >60 places) and the structure of groups (mixing age groups or not). The events studied were the occurrence of at least: 6 episodes of any infection, 2 otitis, 2 gastroenteritis, 2 conjunctivitis or 5 upper respiratory tract infections. RESULTS: Nine hundred and ninety-three children were included in this study. The 878 children attending a day-care centre had a significant higher risk of infections compare to children in family day-care (RR = 2.92[1.58-5.38]) except for gastroenteritis and conjunctivitis. This relationship between the type of day-care setting and the repeated infections was especially shown for children younger than 1 year. The mixing of ages only increased the risk of conjunctivitis (RR = 1.98[1.15-3.42]). No significant relationship between the size of the day care centre and the repetition of every studied infection was found. CONCLUSION: This study strengthens the orientation of the more vulnerable children towards the family day-care centers.

[How are personal child health records completed? A multicentric evaluation study]. / Le carnet de santé de l'enfant est-il informatif? Evaluation dans différentes structures de prévention et de soins.

OBJECTIVE: To evaluate the completeness of personal child health record in France. PATIENTS AND METHODS: Cross-sectional multicentric study, based on child health records analysed and parents' interviews; 1685 children were included: 863 infants aged from 12 to 18 month and 822 children aged from three and a half to four and a half years. RESULTS: One Apgar score was recorded in 96% of cases; the sitting position's acquisition was registered in 91%; the age of walk in 81%. Growth curves were plotted in 64% of cases for weight and in 62% for height in infant's records and 22% of cases for both in older children's records. Ten per cent of the last visit to a physician were not recorded in infants health records, 19% in those of children; as well an hospitalisation for respectively 1,5% and 3,3% and a performed operation for 1,8% and 5,1% respectively. Immunization batches were exhaustively indicated in 68% and 50% of the records. CONCLUSION: Many important data for medical follow-up are missing in the child health records, especially for the oldest children. Physicians and parents should be incited to a better use of the personal record.

[Medical gas delivery systems. Activity report of the local commission for surveillance of gas delivery at the University Hospital of Nancy]. / Réseaux de distribution des gaz médicaux. Bilan d'activité de la commission locale de surveillance de cette distribution au CHR de Nancy.

Local commissions for the surveillance of medical gas supply systems were made compulsory in France in 1985. This article analyses the activity of the local commission of the University hospital of Nancy. Main anomalies which occurred in the pipeline network, especially tightness problems, are discussed. Difficulties concerning the planning and the course of the visits of the gas supply systems by the commission are analysed. Finally, the actual power and responsibility of the commission members are considered.

Subchronic toxicity studies with the leukotriene D4 antagonist RG 12525.

Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.

Histopathologic approaches to chemical toxicity using primary cultures of dissociated neural cells grown in chamber slides.

Morphologic lesions have received only limited attention as in vitro endpoints of toxicity. In the present work, "tissue" and cell morphology of control and toxicant-treated primary dissociated cerebrocortical cell cultures from fetal mice were examined using phase-contrast and bright-field microscopy. In untreated control cultures, a reproducible sequence of developmental events included cellular reaggregation, intercolony bridging with cell migration, and neuronal apoptosis, with maturation yielding confluent monolayers containing both neurons and glia. Because even mature cultures had regions of varying differentiation, an understanding of the normal developmental sequence was essential when assessing toxicant-treated cultures for damage. Chemicals induced neuronotoxic, gliotoxic, and cytotoxic (i.e., nonspecific) patterns of morphologic damage in growing (< 6 day old) or mature (6-15 day old) cultures in both a concentration-dependent and cell type-specific manner. In addition, exposure to some toxicants consistently reduced the staining intensity for glial fibrillary acidic protein in the astrocyte carpet prior to the appearance of structural damage. These data indicate that histopathologic endpoints, including methods for neural-specific markers, represent potentially valuable criteria for in vitro assessments of neurotoxicity.

Effect of methyl bromide on regional brain glutathione, glutathione-S-transferases, monoamines, and amino acids in F344 rats.

Both metabolic and neurotransmitter changes have been implicated in the pathogenesis of monohalomethane neurotoxicity in rodents. This study in male and female F344 rats examined the effects of methyl bromide (MeBr) on regional brain glutathione-S-transferase (GST) activities and concentrations of glutathione (GSH), monoamines, and amino acid. Inhalation exposure to 150 ppm MeBr (6 hr/day x 5 days) yielded no histologic evidence of brain lesions but resulted in a number of biochemical changes. GSH depletion and GST inhibition were detected in the frontal cortex, caudate nucleus, hippocampus (examined for GSH only), brain stem, and cerebellum from animals of both sexes. Differences between sexes were detected for GSH depletion. Simultaneous treatment of rats with the inhibitor of monohalomethane toxicity, BW 755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline; 10 mg/kg bw ip, 1 hr pre- and 1 hr postexposure) completely protected against GST inhibition in all brain regions of both sexes. Partial protection by BW 755C against GSH depletion was observed in the cerebral cortex and in the cerebellum only. In males, MeBr exposure had no effect on the regional concentrations of the monoamines dopamine and serotonin and the amino acids glutamate, glutamine, taurine, and gamma-aminobutyric acid. Regional increases of brain aspartate and glycine levels were observed after exposure of males to MeBr but BW 755C had no effect on these changes induced by MeBr. Thus, of all the parameters studied, only GST, and in some brain areas GSH, correlated with inhibition of toxicity. It is concluded that, in contrast to the monoamines and the amino acids, GST and GSH are sensitive and potentially relevant indicators of MeBr neurotoxicity which could explain sex and regional differences in response to the monohalomethanes.

Mitochondrial glutathione and methyl iodide-induced neurotoxicity in primary neural cell cultures.

The status of both cytosolic and mitochondrial glutathione was studied in primary cultured cerebrocortical cells from fetal mice using the selective membrane-solubilizing properties of digitonin and after exposure to the monohalomethane methyl iodide. A correlation was found between cell injury (assessed by lactate dehydrogenase leakage 24 hr after exposure) and early loss of mitochondrial glutathione (2 hr after exposure), while cell death did not appear directly dependent on cytosolic glutathione depletion. The antioxidants BW 755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline) and DPPD (N,N'-diphenyl-p-phenylenediamine), and the glutathione precursor N-acetyl-L-cysteine were used to modify cellular responses to methyl iodide. Prevention of cell injury by these reagents was obtained only under conditions where at least 50% of the normal level of mitochondrial glutathione was preserved after methyl iodide exposure. Mitochondrial metabolic activity (reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, MTT) was affected by exposure to methyl iodide and correlated with mitochondrial glutathione depletion and cytotoxicity. These findings indicate that the mitochondrial glutathione pool and mitochondrial functions may be the most significant intracellular targets of methyl iodide in neural cultures. Moreover, the present work exemplifies the dependence of neural cell viability on the status of mitochondrial functions and suggests that, as in the liver, mitochondrial glutathione is an important component of cellular homeostasis in nervous tissue.

In vitro neurotoxicity of methyl iodide.

Methyl iodide (MeI) and two other commonly used monohalomethanes, methyl bromide and methyl chloride, are potent human neurotoxicants. In the present study neural cell cultures were used to investigate MeI neurotoxicity in vitro. In primary, dispersed mixed (neurons and glia) neural cultures from mouse embryos, MeI produced severe morphological alterations and leakage of lactate dehydrogenase into the medium (LC(50), 5-6 mm). These effects showed steep concentration-response curves. Both glial and neuronal cells from both the cerebral cortex and the cerebellum were affected. The dual cyclooxygenase-lipoxygenase inhibitor, 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW755C) protected against monohalomethane toxicity (EC(50) 100 mum). All of these observations reflected those previously reported to occur in vivo after exposure to other monohalomethanes. They indicated that MeI shared similar mechanisms of toxicity with other monohalomethanes and supported the validity of the in vitro model to study these mechanisms. Another lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was also effective in protecting neural cultures against the effects of MeI (EC(50) 3 mum). The use of BW755C/NDGA and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) as specific inhibitors of MeI and glutamate neurotoxicity, respectively, demonstrated that MeI toxicity is not mediated by glutamate, a potential by-product of glutathione-mediated metabolism of MeI. When BW755C and NDGA were compared with other modifiers of arachidonic acid metabolism for their protection against MeI toxicity, their mechanisms of action appeared to be unrelated to inhibition of the oxygenases. Their mechanism of action could be related to their antioxidant effect. Results from this work show the value of primary neural cultures to demonstrate and study monohalomethane neurotoxicity.

Toxic and neoplastic responses in the nasal passages: future research needs.

It is evident that much remains to be learned about the nasal passages and their responses to toxic materials. For the nose of both laboratory animals and humans, information is needed in the areas of anatomy, physiology, biochemistry, neurobiology, physiopathology, and oncology. This article briefly discussed toxic and neoplastic responses of the nasal passages, and identified a number of issues and questions that provide potentially valuable areas for further research. It was stated that: (1) Histopathologic examination of the nose could profit from the development of a good all-purpose fixative. (2) A consistent and appropriate classification of nasal passageways, epithelia, and other structures is needed to avoid further confusion. (3) A workable scheme for lesion mapping is needed for routine description of lesion distribution in the nasal passages in rodent toxicology studies. (4) Quantitative data are needed concerning regional substrate specificities and kinetics of nasal enzymes in animals and humans for a wide range of enzymes responsible for metabolism of xenobiotics. Moreover, the following questions should be addressed in the future: (1) What is the nature of the progenitor cells in the olfactory epithelium, basal cells alone, or basal and ductular cells? (2) What determines the resistance of regenerated rat olfactory epithelium to subsequent methyl bromide exposure? (3) Can this resistance phenomenon be demonstrated with other olfactory toxicants and in other species? (4) What influence do cage contaminant gases have on olfactory research in laboratories using rodents? The authors also believe that, despite the fact that nasal airflow has been a subject of investigation for many years, much remains to be learned about this complex process. It is expected that the application of computer technology to mathematical modeling of nasal airflow and regional gas uptake will yield significant new information for the understanding of mechanisms responsible for the distribution of upper respiratory tract lesions in animals and humans. The combination of models of regional uptake, wall flux rates, critical biochemical events, nasal blood flow, and other features of nasal physiology, and integration of these models with lower respiratory tract models, will provide valuable tools for investigations of nasal pathology and toxicology. It was also stressed that the effects of toxicants on olfactory function in humans deserve more attention since, in some past studies, it was suggested that the protection afforded by current TLVs against olfactory toxicity may be marginal. A simple and sensitive olfactometric test of general application for toxicology testing in animals remains to be validated.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxic interactions in the rat nose: pollutants from soiled bedding and methyl bromide.

Interactions between test chemicals and pollutants can confound toxicology studies. To test the sensitivity of the regenerating olfactory epithelium to additional challenge with the olfactory epithelial toxicant methyl bromide (MeBr), Fischer 344 (F344) rats received 2 6-hr inhalation exposures (separated by a 28-day recovery period) to either 0 or 175 ppm MeBr. The regenerating epithelium was resistant to the second MeBr exposure. In addition, histopathologic examination revealed squamous epithelial hyperplasia in the vestibule; inflammation, epithelial necrosis, mucosal erosions, and squamous metaplasia of the respiratory epithelium in the anterior nose; and olfactory sensory cell loss in the dorsal medial meatus. These changes could not be attributed to MeBr, but they were correlated with housing in filter-capped cages between MeBr exposures and were presumably caused by volatile pollutants from soiled bedding. Moreover, olfactory sensory cell loss in the dorsal medial meatus was associated with local resistance to MeBr-induced damage in rats with pollutant-induced changes. Analysis of cage air revealed a progressive increase in ammonia levels between bedding changes (up to 50 ppm), but exposure to 300 ppm ammonia in an additional experiment reproduced only the anterior nasal lesions and not olfactory sensory cell loss. This study demonstrates that 1) regenerating olfactory epithelium is refractory to further MeBr toxicity; 2) pollutants from soiled bedding (in addition to ammonia) produce nasal lesions; and 3) pollutant-induced changes modify the nasal response to inhaled MeBr.

Metabolism and toxicity of methyl iodide in primary dissociated neural cell cultures.

The metabolism and the toxicity of methyl iodide (Mel) has been studied in primary dissociated neuronal and glial murine cell cultures to further characterize the mechanisms of monohalomethane neurotoxicity. Measurement of intracellular glutathione (GSH) concentrations in cerebellar and cerebral cultures revealed GSH levels (21.6 +/- 1.9 and 29.1 +/- 1.9 nmol/mg protein, respectively) close to brain GSH levels measured in vivo. A GSH-depleting effect of Mel was demonstrated, with an ED50 for a 5 min exposure of 0.2 and 0.5 mM for glial and mixed (neurons + glia) cultures, respectively. Mel-induced GSH depletion was correlated with its neurotoxicity as the two powerful protective agents of monohalomethane toxicity, 3-amino-1-[m-(trifluoromethyl) phenyl]-2-pyrazoline (BW 755C, 1 mM) and nordihydroguaiaretic acid (NDGA, 10 microM) provided a 20-fold protection against depletion of GSH levels following Mel exposure. When glia and neurons from cerebral cultures were exposed in suspension to increasing concentrations of Mel for 30 min at 37 degrees C, a concentration-dependent increase in the production of formaldehyde resulted. Formaldehyde appeared to be an indicator of Mel metabolism as its production was decreased by sulfasalazine, a compound which was shown to be an inhibitor of the glutathione-S-transferases in this culture system. Since BW 755C and NDGA had no effect on formaldehyde production, while sulfasalazine as well as semicarbazide, a protective agent against formaldehyde-producing toxicants, failed to protect the cells against Mel toxicity, mechanism(s) of Mel neurotoxicity appeared independent of the GSH-mediated metabolism of this compound. It is concluded that GSH-mediated metabolic biotransformation is not necessary for the neurotoxicity of the monohalomethanes, that GSH depletion may act as a starting point in the chain of events leading to neural cell death, and that glia may be more sensitive than neurons to this primary effect. Moreover, these results demonstrate the value of primary dissociated neuronal cell cultures for studies of biochemical mechanisms of neurotoxicity.

[Effects of sporidesmin on liver zinc, metallothionein and cytochromes in vivo]. / Effets de la sporidesmine sur le zinc, la métallothionéine et les cytochromes hépatiques in vivo.

In vitro studies have suggested that sporidesmin hepatotoxicity may be related to thiol oxidation and generation of cytotoxic oxygen species. After a single i.p. injection of 2.8 mg/kg bw sporidesmin in guinea-pigs, hepatic and plasma zinc, hepatic metallothionein, cytochromes P-450 and b5, total glutathione and proteins (total, microsomal and cytosolic) were monitored for 21 days. The only variations observed were significant increases in liver concentrations of zinc (cytosolic and total), metallothionein, and cytochromes, which peaked on day 8 after the sporidesmin challenge (+45, 55, 50, 376 and 413%, respectively) and, except for cytochrome b5, went back to control levels before the 21st day. These results suggest that cytochromes P-450 and b5 may be involved in sporidesmin cellular damage.

Ecotoxinogenesis of Pithomyces chartarum.

Facial eczema is a hepatogenous photosensitivity mycotoxicosis resulting from sporidesmin ingestion. The morphological characters of toxigenic strains of P. chartarum are reported and the effect of temperature on growth and mycotoxin production are studied. The temperature range for which there is an actual risk of toxin accumulation (20-25 degrees C) is much narrower than for an appreciable growth (5-30 degrees C).

Clinical biochemistry of sporidesmin natural intoxication (facial eczema) of sheep.

The effects of facial eczema, i.e. intoxication by the mycotoxin sporidesmin, were investigated by extensive biochemical screening of serum in 100 controls (A), 31 clinically ill (B) and 219 apparently healthy (C) Manech ewes under field conditions. Dramatic increases of gamma-glutamyltransferase1), alkaline phosphatases, bilirubin, cholesterol, aspartate and alanine aminotransferases, and lactate dehydrogenase confirmed the severity of liver damage in group B, but they were also observed in slightly more than 50% of group C animals. This demonstrated the true extent of the disease, which could be best assessed by the measurement of serum gamma-glutamyltransferase; but since this enzyme was still elevated one year later, it cannot be used as a reliable prognostic parameter.

Liver enzyme changes in a guinea-pig model of facial eczema (sporidesmiotoxicosis).

Sporidesmin, a hepatotoxin from Pithomyces chartarum, is responsible for facial eczema in ruminants. In an attempt to clarify the biochemical processes supporting sporidesmin toxicity and response of the liver, haematology, plasma biochemistry and liver enzyme changes were monitored for 21 days in a model for facial eczema resulting from a single intraperitoneal injection of 2.8 mg/kg BW sporidesmin to guinea pigs. Most plasma disturbances were observed 8 days after administration and accounted for starvation, liver cytolysis, and cholestasis or liver enzyme induction. Alterations of hepatic enzyme activities were intense with a maximum increase on days 2 for alkaline phosphatases (ALP) and 8 for gamma-glutamyltransferase (GGT), and a maximum decrease on day 21 for aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). Comparison of liver and plasma enzyme changes indicates that GGT was the most reliable and significant plasma indicator of sporidesmin-associated liver alterations. Moreover, this study points out the validity of the one-dose intoxicated guinea-pig model for research on sporidesmin biochemical toxicity and pathobiology of facial eczema.

Effect of flunixin meglumine on the breakdown of the blood-aqueous barrier following paracentesis in the canine eye.

The protein and PGE2 metabolite content of the aqueous humor from untreated and flunixin meglumine pretreated dogs was determined prior to and after anterior chamber paracentesis. In the untreated dogs the concentrations of protein and PGE2 metabolite in aqueous humor were greatly elevated secondary to paracentesis. Intravenously administered flunixin meglumine (1.1 mg/kg or 2.2 mg/kg) significantly reduced these inflammatory parameters, confirming that prostaglandins are involved in the stability of the blood-aqueous barrier by paracentesis in the canine eye. The clinical implication of these results is that intravenous administration of flunixin meglumine before intraocular surgery should be considered as an adjunct therapy to reduce intraoperative and postoperative uveitis.

Effect of lysine-acetylsalicylate and phenylbutazone premedication on the protein content of secondary aqueous humour in the dog.

Inhibitory effects of the anti-inflammatory agents lysine-acetylsalicylate (LAS) and phenylbutazone (PBZ) on the breakdown of the blood-aqueous barrier by paracentesis were studied in canine eyes using protein determination of ocular fluid. In the untreated eyes the aqueous protein value was raised from 0.29 +/- 0.17 (mean +/- SD) g litre-1 at the initial paracentesis to 14.47 +/- 4.10 g litre-1 at the second paracentesis. Pretreatment with LAS or PBZ had no significant effect on the protein concentration of the primary aqueous humour. However the secondary aqueous protein concentration was only 10.05 +/- 7.00 g litre-1 with LAS and 5.80 +/- 3.83 g litre-1 with PBZ. With both drugs the maximum inhibitory effect was observed on the gammaglobulins and albumin. These results suggest that prostaglandins may be involved in the response of the canine eye to paracentesis and that premedication with LAS or PBZ may be of value in reducing postoperative ocular inflammation.