Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

Hormonal regulation of the mouse adrenal melanocortinergic system.

Adrenocortical cells of several species have been reported to express significant levels of Agouti-related protein (Agrp) as well as melanocortin 4-receptor (MC4-R). In this study, we used the mouse tumoral adrenal cell line ATC7- L that secretes corticosterone in basal conditions with a 2- fold increase in response to ACTH treatment. We reported that these cells expressed functional MC4-R. They also expressed Agrp mRNA and secreted immunoreactive Agrp in the culture medium. Long-term treatment of ATC7-L with (Nle4,D-Phe7)-alpha MSH (NDP-alpha MSH) or forskolin as well as Agrp strongly reduced MC4-R level by more than 30%. On the contrary, leptin treatment did not modify this level although it significantly reduced MC2-R level. These results could be correlated to some data obtained in vivo on adrenal glands removed from diet-induced obese mice exhibiting a hyperleptinemia, where the level of both MC2-R and MC4-R appeared to be reduced as Agrp mRNA expression level was increased compared to Control mice. All these data would suggest the existence of a link between the metabolic status and the activation of the adrenal melanocortinergic system.

[Epidemiology and clinical characteristics of childhood parapneumonic empyemas]. / Epidémiologie et caractéristiques cliniques des complications suppuratives des pneumonies de l'enfant.

UNLABELLED: Several studies have reported an increasing incidence of childhood parapneumonic empyemas in various countries. AIM OF THE STUDY: The aim of our study was to estimate the annual incidence of complicated community-acquired pneumonias in children during a 9-year period in a French area and to describe the epidemiological and clinical characteristics of these complications. POPULATION AND METHODS: We have listed the children from 28 days to 15 years old, hospitalized in the 2 children hospitals of the Isere district for a community-acquired pneumonia complicated with a pleural empyema or a pulmonary abscess from 1995 to 2003. RESULTS: During the study period, 90 children were hospitalized for a complicated pneumonia including 83 pleural empyemas and 7 isolated lung abscess. The average number of cases was 4 per year from 1995 to 1998 then increased since 1999 to reach 34 cases in 2003, according to a linear model (P<0,001). The incidence of the complicated pneumonia, plotted to the paediatric population of the area has gone up from 0.5 per 100000 to 13 per 100000 children between 1995 and 2003. CONCLUSION: The incidence of the complicated pneumonias in children increased since 1999 in a French area. Additional investigations are necessary to identify the causes of this increase.

[Performance of the Breastfeeding Assessment Score for the prediction of early weaning in France]. / Intérêt du Breastfeeding Assessment Score pour la prédiction du sevrage précoce de l'allaitement maternel en France.

BACKGROUND: The Breastfeeding Assessment Score (BAS) was derived to help identify mothers at increased risk of early weaning in United States. Data are currently lacking on the accuracy of the BAS for French mother-infant pairs. OBJECTIVE: To assess the accuracy of the BAS in a French validation cohort. METHODS: We used the original data from a prospective cohort study of 488 mothers who were breastfeeding at discharge in 9 maternity wards in 2005. The outcome measures were assessed using structured follow-up telephone interviews at 4 and 26 weeks. RESULTS: The weaning rate was 3% at 14 days of infant age. The corresponding area under ROC curve was 0.73 [0.60-0.85] and was comparable to that observed in the derivation cohort (0.75). For a cut point of 8 recommended by the authors of the BAS, 43% of mother-infant pairs were categorized at high risk and the weaning rate in this subgroup was 5%. The mother-infant pairs with a score lower than 8 had a shorter median breastfeeding duration (18 versus 20 weeks, P=0.02), were more likely to report breastfeeding difficulties after discharge (63% versus 53%, P=0.03), and were less likely to be "very satisfied" with breastfeeding experience (66% versus 77%, P=0.007). CONCLUSION: The intrinsic properties of the BAS are robust. However, its use would be of limited interest in France because of the relatively low rate of early weaning. Randomized trials are needed before recommending routine use of BAS-based breastfeeding support intervention.

Expression of the human melanocortin-4 receptor gene is controlled by several members of the Sp transcription factor family.

The melanocortin-4 receptor (MC4-R) plays a key role in the hypothalamic control of food intake, lending importance to the understanding of the mechanisms that regulate its expression. To identify factors controlling the expression of the human (h) MC4-R gene, a fragment containing 1253 bp of the 5'-flanking region of the hMC4-R gene was isolated. A series of hMC4-R luciferase constructs were developed and used to transiently transfect HEK293 and GT1-7 cell lines, both expressing endogenous MC4-R mRNA. Deletion analysis of the 1253 bp fragment showed that the basal promoter activity is mainly restricted to the 179 bp upstream of the transcription start site in both cell types. Mutation of a putative Sp1-binding site located at position -76 bp resulted in a dramatic reduction of the luciferase activity in HEK293 and GT1-7 cells by 87 and 80% respectively. Both in vitro and in vivo studies (gel shift and chromatin immunoprecipitation analyses) revealed binding of both Sp1 and Sp3 to this site in HEK293 cells. Cotransfection with an Sp1 expression vector in Drosophila cells that do not express Sp1, in conjunction with treatment of HEK293 cells with mithramycin A, a specific inhibitor of Sp1, confirmed the role of Sp1. For the first time, we have demonstrated that the constitutive activity of the hMC4-R promoter is dependent upon Sp transcription factors.

[Future prospects in the management of cystic fibrosis]. / Perspectives d'avenir dans la prise en charge de la mucoviscidose.

Basic and clinical research in cystic fibrosis have led to several new hypothesis to improve the management of the disease. The numerous tracks for new therapies may be explained by the lack of firm patho-physiological explanations for the disease and of knowledge of the best targets to get a significant improvement of the patients. After initial great hopes, there has been important limitations and slow down of gene therapy, imposing to go back to research programs on new vectors. New hopes have arisen with protein therapies, including chaperones molecules that can activate mutated CFTR proteins within the cells. New anti-inflammatory therapies are developed, including proteases inhibitors. The prevention of airway colonisation with Pseudomonas aeruginosa is fundamental and could go through the development of specific vaccines, cellular therapies or molecules directly acting on the virulent factors of the bacteria.

[Acute organophosphate intoxication after using a anti-lice insecticide shampoo]. / Intoxication aiguë par organophosphorés à la suite de l'utilisation d'un insecticide comme shampooing anti-poux.

CASE REPORT: Two children were admitted for poisoning by organophosphate pesticides applied as hair rinses against lice. These chemical agents inhibit the acetylcholinesterase enzyme at various sites. The resultant accumulation of the transmitter acetylcholine causes abnormal signs and symptoms. The diagnosis is based on a reduction in the blood cholinesterase activity. The specific treatment comprises the administration of atropine and pralidoxime. CONCLUSION: Accidental poisoning by organophosphate insecticides may occur, due to the misuse of such substances as shampoo against lice. An accurate information for users is necessary.

Itraconazole in the treatment of aspergillosis: a study of 16 cases.

Itraconazole, a new triazole antifungal agent, has marked in vitro activity against filamentous fungi, particularly Aspergillus. We studied three groups of patients suffering from aspergillosis (16 cases): six affected with aspergilloma, three with allergic bronchopulmonary aspergillosis and seven with invasive aspergillosis. The survey consisted in clinical, radiological, mycological and serological evaluations with respect to drug plasma levels. Itraconazole was given at a dosage of 200-400 mg day-1 for periods ranging from 14 to 488 days. Out of the 16 patients, nine responded to therapy (recovery or improvement) and one failed to respond. Three patients improved but experienced relapses and three others could not be evaluated because of liver function disorders, so that treatment had to be stopped prematurely.

Effect of double-blind crossover selenium supplementation on biological indices of selenium status in cystic fibrosis patients.

Twenty-seven cystic fibrosis patients received selenium supplementation (2.8 micrograms of sodium selenite per kilogram of body weight per day) or a placebo. This 5-month trial was conducted as a double-blind, placebo-controlled study. After an interval of 2 months, treatments of the two groups were interchanged (crossed over) for another 5-month period. A group of healthy subjects, living in the same area, was investigated simultaneously. No selenium deficiency was found either in plasma or in erythrocytes before the supplementation. This result was inconsistent with a previous study performed in 1988 in our laboratory. This change in selenium status can be explained by progress in the nutritional nursing care of children and by the addition of selenium to the diet. During the study, selenium concentrations in plasma decreased when patients received placebo treatment and increased during selenium intake. In one of the two groups a similar variation was found for glutathione peroxidase activities in plasma and erythrocytes, whereas erythrocyte selenium was normal and did not change in any group. Nowadays, in the Grenoble area, the selenium status of cystic fibrosis patients is close to normal. Nevertheless, this study indicates a fragile equilibrium, given that selenium concentrations cn be lowered by placebo or mildly increased by supplementation.

[Serology of anti-Pseudomonas aeruginosa and mucoviscidosis: diagnostic aid in the differentiation between colonization and infection]. / Sérologie anti-Pseudomonas aeruginosa et mucoviscidose: aide au diagnostic des états de colonisation et d'infection.

Serologic test for Pseudomonas aeruginosa have been found useful for differentiating colonization from infection, especially in chronic disease. A Western blot method was compared with the ELISA used routinely. The Western blot detected serum IgGs against P. aeruginosa outer membrane proteins, whereas the ELISA reacted with IgGs against soluble P. aeruginosa antigens. Among the 103 sera from 58 cystic fibrosis patients studied, all those with ELISA reactivity were positive by Western blot. The antibody response was detected earlier by Western blot than by ELISA, suggesting that the former technique may be useful for the early diagnosis of infection.

[In vitro effect of various antibiotics: beta lactams, aminoglycosides and fluoroquinolones alone and in combination against P. aeruginosa isolated from patients with mucoviscidosis]. / Activité in vitro de différents antibiotiques: bêtalactamines, aminoglycosides et fluoroquinolones seuls et en association vis-à-vis de P. aeruginosa isolès patients atteints de mucoviscidose.

The antibacterial activity of fluoroquinolones (ciprofloxacin and ofloxacin) combined with beta lactams (ceftazidime and imipenem) or aminoglycosides (tobramycin and amikacin) against 22 P. aeruginosa isolated from the sputum of patients with cystic fibrosis was determined by the checkerboard method and compared with the combination of beta lactams (with ticarcillin) with aminoglycosides. Synergistic association (defined as FIC index less than ou = 0.5) was founded for 23 to 41% of strains with beta lactams (except imipenem)/aminoglycosides, in 18% with ceftazidime/ciprofloxacin, in 13% with imipenem/ciprofloxacin, in 0 or 13% with quinolones/aminoglycosides. For a FIC index less than ou = 0.75, the values are highest with 82% for ciprofloxacin/ceftazidime and 50% for ofloxacin/ceftazidime. The CMI's achieved in these combinations may allowed concentrations near to sputum concentrations.

Crigler-Najjar type II disease inheritance: a family study.

The inheritance of Crigler-Najjar type II disease is still contested. Autosomal dominant transmission with incomplete penetrance and autosomal recessive transmission have been proposed. We had the opportunity to study the hepatic activity of bilirubin uridinediphosphate glucuronyltransferase in parents whose first child had been affected by Crigler-Najjar type II disease. The demonstration of reduced activity of glucuronidation in the liver of both parents suggests autosomal recessive inheritance. The second infant of this couple was affected by the same disease and was treated with success by phenobarbital.

[Epstein-Barr virus encephalitis. Apropos of a case in a child]. / Encéphalite à virus d'Epstein-Barr. A propos d'un cas chez l'enfant.

Encephalitic illnesses with Epstein-Barr virus (EBV) only represent a small percentage of the causes of viral encephalitis. Clinical symptoms are not specific. Biological standards tests carry few elements of direction, only serologic test of infectious mononucleosis confirms the diagnostic of recent EBV infection. Previous observation shows that the initial study can present similarities with herpes simplex encephalitis, which forces the immediate start of treatment by Acyclovir.

[Extrinsic allergic alveolitis in children. Apropos of 4 cases]. / Alvéolites allergiques extrinsèques chez l'enfant. A propos de 4 observations.

Four cases of extrinsic allergic alveolitis are reported. About them, we discuss: The difficulties of diagnosis that we can only affirm on the association of several clinical, biological, and radiological arguments. The physiopathology: association of immune complex hypersensitivity type III and immediate hypersensitivity type I. It's important to always search for a probable starting infectious factor (mycoplasma). The therapy: antigenic exclusion is the only way to avoid a lung fibrosis.