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Biomedical subjects

P Chappuis

Publications and source records attributed to P Chappuis.

At least 19 recordsLinked to original sources
PubMed2006

[Wilson disease].

Wilson disease is an autosomal recessive disorder of copper overload. A principal characteristic of this disease is its wide phenotypic and genotypic variability. Its results from mutations of the ATP 7B gene located on chromosome 13, that encodes a hepatic copper transport protein. More than 300 mutations of this gene have been identified. This protein ensures the transport of copper in the hepatocyte, its incorporation with the apoceruloplasmin and its biliary excretion. The clinical manifestations are heterogeneous as well in their presentation, dominated by the neuropsychiatric and hepatic symptoms, as in the age of the first symptoms. Early recognition and initiation of therapy with chelators or zinc are essential for prognosis. Liver transplantation is indicated in cases with fulminant hepatitis, end-stage liver cirrhosis and should be considered in the therapy resistant neurological forms. A regular follow-up with monitoring of adverse effects of treatment and compliance is essential. Any discontinuation of treatments will involve, within a very variable time, but in constant manner, a reappearance or a reaggravation of the signs. Such relapses are often brutal and can be extremely serious, especially since response to subsequent treatment is often poor.

Brain↗
PubMed2006

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

Exons↗
PubMed2001

Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis).

Strontium ranelate (S12911) has previously been shown to stimulate bone formation and inhibit bone resorption in rats. To determine whether strontium ranelate affects normal bone remodeling, we studied the effect of strontium ranelate on alveolar bone in monkeys. Strontium ranelate, at dosages of 100, 275, and 750 mg/kg per day, or vehicle, were given by gavage to 31 normal adult monkeys (Macaca fascicularis) (15 males, 16 females), aged 3-4 years. Treatment for 6 months with strontium ranelate resulted in an increase in plasma strontium concentration. Histomorphometric analyses of indices of bone formation and resorption were determined in standardized areas of alveolar bone. Treatment with strontium ranelate decreased the histomorphometric indices of bone resorption (osteoclast surface and number) with a maximal significant effect at the highest dose tested. In contrast to this inhibitory effect on bone resorption, strontium ranelate maintained bone formation. Although the amount of osteoid tended to increase, strontium ranelate, even at the highest dose, had no deleterious effect on bone mineralization, as evaluated by mineral apposition rate and osteoid thickness. These findings show that strontium ranelate decreases indices of bone resorption while maintaining bone formation in the alveolar bone in monkeys.

Alveolar Bone Loss↗
PubMed1999

N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers.

Hereditary nonpolyposis colorectal cancer (HNPCC), an inherited cancer predisposition syndrome, has been associated with germline mutations in DNA mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a specific cancer phenotype, modifying genes may account in part for the variation in disease expression. We determined the N-acetyltransferase 2 (NAT2) genotype in 26 unaffected and 52 cancer-affected hMLH1/hMSH2 mutation carriers coming from 21 Swiss HNPCC families. Slow acetylators were found to be significantly (P < 0.03) more prevalent in the group of affected mutation carriers. Our results suggest a protective effect of the NAT2 rapid acetylator phenotype, an observation that could have implications for genetic counseling and management of MMR gene mutation carriers.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A new three allele polymorphism at distal 21q22.3, a region relatively devoid of polymorphic markers. Mutations in brief no. 212. Online.

We amplified 305bp of the 3'UT region of COL18A1 from 62 healthy chromosomes from Caucasian individuals. SSCP analysis of these PCR products allowed us to identify 3 alleles which were confirmed through sequencing analysis and ASO. The heterozigosity found for this polymorphic region is 74.2%, and mendelian inheritance was demonstrated in 5 two/three generation families. This polymorphism, located in a region relatively devoid of microsatellites, will be very useful for linkage analysis, particularly for narrowing down candidate regions for genes mapped in this area.

3' Untranslated Regions↗
PubMed1999

PCR-mediated detection of a polymorphism in the ATM gene.

In this report, the frequency of the G-->A transition polymorphism at nucleotide 5557 in exon 39 of the coding sequence of the gene mutated in ataxia-telangiectasia (ATM) was analysed. The frequency of the A and G alleles was estimated in the general population at 0. 15 and 0.85, respectively. This polymorphism can be identified by single-strand conformation polymorphism (SSCP) and by a simple and rapid Dde I digestion after polymerase chain reaction (PCR)-mediated site directed mutagenesis (PSDM).

Alleles↗
PubMed1999

Are copper, zinc and selenium in erythrocytes valuable biological indexes of nutrition and pathology?

The real significance of the level of trace elements copper, zinc and selenium in erythrocytes is still a matter of debate. This review is an evaluation of the potential value of copper, zinc and selenium in red blood cells in physiology, nutrition and pathology, taking into account the other commonly used indices and the analytical difficulty encountered for erythrocyte determinations. The main analytical methods and reference values in erythrocytes are also presented. The literature of the last 3 decades was analyzed. On the basis of these papers, the role of erythrocyte copper in various pathologies should be re-investigated, especially when they include inflammatory processes or hormonal changes. The main interest of zinc determination in red blood cells concerns thyroid pathology. In general, the value of selenium in erythrocytes agrees with selenium in serum and its determination is often unnecessary.

Copper↗
PubMed1998

Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.

OBJECTIVES: To confirm early, marked decrease in plasma selenium concentrations in patients admitted to a surgical and medical intensive care unit (ICU), and to study this decrease according to the presence or absence of systemic inflammatory response syndrome (SIRS), sepsis, or direct ischemia-reperfusion. DESIGN: Prospective, observational study. SETTINGS: Collaboration between the adult ICU of a 1,100-bed general hospital and a biochemical research laboratory of a university medical center. PATIENTS: One hundred thirty-four consecutive surgical and medical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the first 31 patients, plasma and urine selenium concentrations were measured by electrothermal atomic absorption spectrometry on admission and once weekly during their ICU stay. These values were compared first with severity scores, criteria for SIRS, sepsis, and organ system failure taken on admission, and then with nosocomial infection, organ system failure during ICU stay, and hospital mortality. An early, low mean plasma selenium concentration was observed in these patients compared with selenium laboratory reference values. Plasma selenium, measured on ICU admission, inversely correlated with Acute Physiology and Chronic Health Evaluation II or Simplified Acute Physiology II scores. Patients with SIRS had lower selenium concentrations than those without SIRS. Mean urine selenium losses were normal in the first 31 patients. Plasma selenium concentration was low in all patients with severe sepsis and septic shock (range 0.20 to 0.72 micromol/L) and in those patients with ischemia-reperfusion from aortic cross-clamping (range 0.34 to 0.68 micromol/L). Despite recommended specific selenium supplementation, plasma selenium concentrations remained low for >2 wks in patients with SIRS. However, there was a slight increase in plasma selenium concentrations in surviving SIRS patients, whereas plasma selenium concentrations decreased in nonsurviving patients. The frequency of ventilator-associated pneumonia, organ system failure, and mortality was three times higher in patients with low plasma selenium concentration at the time of admission (selenium < or =0.70 micromol/L) than for the other patients. CONCLUSIONS: In severely ill ICU patients with SIRS, we observed an early 40% decrease in plasma selenium concentrations, reaching values observed in deleterious nutritional selenium deficiency. This prolonged decrease in selenium concentrations could explain the three-fold increase in morbidity and mortality rates in these patients compared with other ICU patients. The efficacy of selenium treatment in SIRS patients with a high gravity index score or hypoperfusion needs further investigation.

APACHE↗
PubMed1997

Zinc and intestinal anaphylaxis to cow's milk proteins in malnourished guinea pigs.

Zinc supplementation could favor recovery from diarrhea in malnourished children. As the recent experimental evidence suggests that oxidative stress and intestinal anaphylaxis may contribute to the intestinal dysfunction associated with malnutrition, we postulated that zinc could act through antioxidant or antianaphylactic properties. Control (C), malnourished (M), and malnourished zinc-treated (MZ) guinea pigs were, respectively, fed a normal 30% protein diet, a low 4% protein diet, and a low 4% protein diet plus 1800 ppm of zinc. Milk proteins were included in the diets to trigger intestinal anaphylaxis. Milk sensitization was assessed by passive cutaneous anaphylaxis (PCA) against beta-lactoglobulin and by intestinal anaphylaxis measured in Ussing chambers by the increase in short circuit-current after addition of beta-lactoglobulin (deltaIsc(betaLg)). Oxidative stress was assessed by intestinal lipid peroxidation. The intestinal secretion was assessed by deltaIsc induced by inflammatory mediators. Malnutrition increased the level of anti-betaLg reaginic antibodies [PCA = 1.19 +/- 0.79 and 0.69 +/- 0.67 log(l/titer) in M versus C guinea pigs, p = 0.07] and enhanced intestinal anaphylaxis (deltaIsc(betaLg)) = 16.4 +/- 9.9 and 9.1 +/- 5.8 microA/cm2 in M versus C guinea pigs, p = 0.07), without inducing intestinal lipid peroxidation. Moreover, malnutrition enhanced significantly the intestinal secretory response to histamine and 5-hydroxytryptamine. Administration of pharmacologic doses of zinc during malnutrition inhibited the increase in milk sensitization induced by malnutrition, both at the systemic [PCA = 0.35 +/- 0.55 log(l/titer) in MZ guinea pigs, p = 0.03 versus M] and intestinal (deltaIsc(betaLg)) = 2.8 +/- 2.5 microA/cm2 in MZ guinea pigs; p = 0.001 versus M) level, and prevented the hypersecretion in response to histamine and 5-hydroxytryptamine. These data suggest that zinc has antianaphylactic and antisecretory properties that may contribute to its capacity to prevent intestinal dysfunction during malnutrition.

Anaphylaxis↗
PubMed1996

Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc.

BACKGROUND: Zinc has been shown to have beneficial effects in vitro on epithelial barrier function, and in vivo to reduce intestinal permeability in malnourished children with diarrhoea. AIMS: To determine whether malnutrition alters intestinal paracellular permeability, and whether zinc prevents such alterations. METHODS: Guinea pigs were fed a normal protein diet (NP group), a low protein diet (LP group), or a low protein diet enriched with 1800 ppm zinc (LPZn group) for three weeks. Intestinal permeability was measured on jejunal segments mounted in Ussing chambers by measuring ionic conductance and mucosal to serosal fluxes of 14C-mannitol, 22Na, and horseradish peroxidase. Tight junction morphology was assessed on cryofracture replicas. RESULTS: Mannitol and Na fluxes and ionic conductance increased in the LP group compared with the NP group but remained normal in the LPZn group. Accordingly, jejunal epithelia from the LP group, but not from the LPZn group, showed a small decrease in number of tight junctional strands compared with epithelia from the NP group. Neither malnutrition nor zinc treatment modified horseradish peroxidase fluxes. CONCLUSIONS: Malnutrition is associated with increased intestinal paracellular permeability to small molecules, and pharmacological doses of zinc prevent such functional abnormality.

Animals↗
PubMed1996

[Selenium, glutathione peroxidase, peroxides and platelet functions].

In the last five years, there has been a renewal of interest in the protective role of selenium in vascular disorders, inspired by experimental evidence that this trace element could modulate leukotriene and prostaglandin synthesis in both endothelial cells and platelets. In people living in low-selenium areas, a relationship has been established between a decrease in plasma selenium and an increase in the risk of coronary disease, atherosclerosis, platelet hyperaggregability and synthesis of proaggregant and proinflammatory compounds like thromboxane A2 and leukotrienes. Selenium, as an essential part of glutathione peroxidase, takes part in the reduction of hydrogen peroxides and lipid peroxides. The concentration of these peroxides, in turn, regulates the activities of cyclooxygenase and lipooxygenase pathways, ultimately influencing the production of eicosanoids and modulating the balance between a proaggregatory and antiaggregatory state. Recent evidence shows that selenium, via its action on glutathione peroxidase activity, may be primarily responsible for the regulation of the endogenous hydroperoxide level. In human platelets, the activity of glutathione peroxidase is particularly high and is very sensitive to the requirement of selenium. This sensitivity could explain why platelets of selenium-deficient subjects show increased aggregation, thromboxane B2 production and synthesis of the lipoxygenase-derived compounds. In these deficient subjects, selenium administration increases platelet glutathione peroxidase activity and inhibits platelet hyperaggregation and leukotriene synthesis. These results support the hypothesis that selenium supplementation has a positive effect on platelet aggregation in selenium-deficient subjects. In France, more than 10% of the population is selenium-deficient and long-term supplementation with low doses of selenium could have a beneficial effect on the prevention of both thrombosis and coronary heart disease in these subjects.

Animals↗
PubMed1995

A simple p53 functional assay for screening cell lines, blood, and tumors.

Mutations in the p53 gene are implicated in the pathogenesis of half of all human tumors. We have developed a simple functional assay for p53 mutation in which human p53 expressed in Saccharomyces cerevisiae activates transcription of the ADE2 gene. Consequently, yeast colonies containing wild-type p53 are white and colonies containing mutant p53 are red. Since this assay tests the critical biological function of p53, it can distinguish inactivating mutations from functionally silent mutations. By combining this approach with gap repair techniques in which unpurified p53 reverse transcription-PCR products are cloned by homologous recombination in vivo it is possible to screen large numbers of samples and multiple clones per sample for biologically important mutations. This means that mutations can be detected in tumor specimens contaminated with large amounts of normal tissue. In addition, the assay detects temperature-sensitive mutants, which give pink colonies. We show here that this form of p53 functional assay can be used rapidly to detect germline mutations in blood samples, somatic mutations in tumors, and mutations in cell lines.

Adolescent↗
PubMed1994

[Practical advice concerning biological fluids for analysis of trace-elements].

Sampling conditions are of utmost importance for the determination of trace elements in biological fluids. However, many biologists still underevaluate this critical step. This reports deals with collection of biological fluids from a routine point of view: detailed and careful descriptions of the contaminating role of air and the general handling of specimens are given in a practical and critical manner. The main commercial systems, made about needles, catheters, tubes (open and evacuated systems) and anticoagulants are reviewed. Choices and elementary rules, applicable in a hospital setting, are proposed.

Air Pollutants, Occupational↗
PubMed1993

Urinary serotonin metabolite excretion during cisplatin chemotherapy.

BACKGROUND: Nausea and vomiting associated with cisplatin chemotherapy is a source of major morbidity that remains difficult to control. Acute phase (0-24 hours after induction of chemotherapy) nausea and vomiting parallels plasma serotonin release, which explains the effectiveness of 5HT3 antagonists; serotonin release in the delayed phase (24-48 hours after induction), during which consistent antiemetic control remains elusive, has not been investigated. The effect of propofol, a recent addition to the antiemetic armamentarium, on this serotonin release has not been studied. METHODS: Ten women with nausea and vomiting refractory to ondansetron and dexamethasone prophylaxis in their first cisplatin chemotherapy cycle were studied. Serial urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were determined during a 48-hour period in 30 subsequent cycles, conducted under ondansetron/dexamethasone prophylaxis together with a propofol infusion. RESULTS: There was a significant urinary 5-HIAA peak 6 hours after induction of chemotherapy, with no peaks thereafter. Propofol did not inhibit serotonin release. CONCLUSIONS: Cisplatin chemotherapy is associated with serotonin release in the acute phase. There is no serotonin release during the delayed phase. Thus the use of 5HT3 antagonists for delayed-phase nausea and vomiting would appear questionable.

Adult↗
PubMed1993

Restoration of the thymus in aging mice by in vivo zinc supplementation.

A multiparametric study of the thymus was performed in normal aging mice (12-15 months old) submitted to a mild oral zinc supplementation during 3-6 months as compared to age-matched control mice. First, this study demonstrated that in rodents, zinc levels are significantly reduced with aging and can be restored to values close to those observed in young animals after 6 months of zinc supplementation. Second, our data showed that oral zinc administration stimulates thymus growth and partially restores the microenvironmental as well as lymphoid compartments of the organ. Regarding thymic endocrine function, a significant increase in thymulin levels and a concomitant decrease in plasma thymulin inhibitors were observed, suggesting that the age-related decline of thymic function might at least partially be due to extrinsic factors, such as zinc deficiency. The total number of thymic lymphocytes was consistently increased, without significant changes in CD4/CD8 defined thymocyte subsets. Finally, structural changes of the thymus epithelium were also detected, including the disappearance of epithelial cysts frequently observed in old animals, reappearance of a normal pattern of the thymic epithelial cell network, and a decrease in the extracellular matrix network. Taken together, these data suggest that aging-related physiological zinc deficiency induces some relevant changes in thymus structure and function which can be partially corrected by a mild oral zinc supplementation.

Administration, Oral↗
PubMed1993

Selenium status of healthy immigrant Parisian preschool children.

Plasma selenium (Se) concentration and erythrocyte glutathione peroxidase activity (GPx) were assessed in a population of healthy preschool children two to five years old, residing in the city of Paris. In the 118 subjects, mean (+/- SD) plasma Se concentration was 62.10 +/- 13.96 micrograms/L, and mean GPx activity was 23.58 +/- 8.52 U/g Hb. Mean plasma Se of male children was significantly (p = 0.001) higher (12%) than levels of girls. Plasma selenium levels were not correlated with erythrocyte GPx activity. Children from Mediterranean origin had a slightly lower erythrocyte GPx activity (p < 0.05) than children from other regions. Mean plasma Se concentration of this group corresponded to the lower limit of intervals, which characterizes geographical regions of intermediate selenium concentrations.

Analysis of Variance↗
PubMed1993

Plasma zinc and copper in Paris area preschool children with growth impairment.

Plasma zinc, copper, and parameters of growth were measured in a group of 116 French preschool children, 2-5 yr-old from low-income households. Participants were selected on the basis of Z-scores of weight for height (WHZ) and height for age (HAZ). Zinc and copper concentrations of children with growth impairment (GI), defined by a WHZ and/or HAZ < -1 Z-score, were compared to those of age, sex, and ethnic origin matched controls (WHZ and HAZ > -1 Z-score). Mean (+/- SD) plasma zinc concentration was 12.58 +/- 1.84 mumol/L in the GI group, and 13.27 +/- 1.98 mumol/L in the controls. The difference of the means of paired samples was 0.69 +/- 2.34, and by paired t-test the significance reached p = 0.028. This effect was primarily a result of the weight retarded group (WHZ < -1 Z-score, p < 0.009) and to the girls (p < 0.05). There were no significant differences in plasma copper concentrations between groups. These results suggest the presence of marginal zinc deficiency in French preschool children with low weight for height Z-scores.

Age Factors↗