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Biomedical subjects

C Perret

Publications and source records attributed to C Perret.

At least 19 recordsLinked to original sources
PubMed2002

Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers.

BACKGROUND: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. METHODS: Twelve young (18-40 years) and 12 elderly (>65 years and </=85 years) subjects received a single 800-mg oral dose of telithromycin or an intravenous infusion of 400 mg (young subjects) or 480 mg (elderly subjects) of telithromycin over 2.5 h in two treatment periods, separated by a 1-week washout period. The plasma concentrations and pharmacokinetic parameters of telithromycin and its major metabolite, RU 76363, were determined. Absolute oral bioavailability was calculated using the area under the plasma concentration-time curve (AUC) from zero hours to infinity. RESULTS: The absolute oral bioavailability of telithromycin was 57% in both young and elderly subjects. The AUC for the metabolite was lower after intravenous infusion of telithromycin, indicating first-pass loss following oral administration. Telithromycin was well tolerated in both groups of subjects. CONCLUSIONS: Telithromycin has an absolute oral bioavailability of 57% in young and elderly subjects and is well tolerated.

Administration, Oral↗
PubMed2001

Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene.

Autosomal dominant polycystic kidney disease (ADPKD) is common and is a major cause of renal failure. Although the genetics of ADPKD are well known and have led to the discovery of polycystins, a new protein family, the pathogenesis of the disease remains largely unknown. Recent studies have indicated that the beta-catenin signaling pathway is one of the targets of the transduction pathway controlled by the polycystins. We have generated transgenic mice that overproduce an oncogenic form of beta-catenin in the epithelial cells of the kidney. These mice developed severe polycystic lesions soon after birth that affected the glomeruli, proximal, distal tubules and collecting ducts. The phenotype of these mice mimicked the human ADPKD phenotype. Cyst formation was associated with an increase in cell proliferation and apoptosis. The cell proliferation and apoptotic indexes was increased 4-5-fold and 3-4-fold, respectively, in cystic tubules of the transgenic mice compared to that of littermate controls. Our findings provide experimental genetic evidence that activation of the Wnt/beta-catenin signaling pathway causes polycystic kidney disease and support the view that dysregulation of the Wnt/beta-catenin signaling is involved in its pathogenesis.

Animals↗
PubMed2001

Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history.

Recently, founder BRCA1 and BRCA2 mutations were identified in Canadian breast cancer and breast-ovarian cancer families of French ancestry. The presence of a breast cancer case diagnosed at younger than 36 years of age was strongly predictive of the presence of any founder mutation screened. Here we report the occurrence of founder BRCA1 and BRCA2 mutations in a series of 61 French Canadian women with invasive breast cancer diagnosed at age 40 or younger, unselected for family history of breast and ovarian cancer. Germline mutations in BRCA1 (n = 4) and BRCA2 (n = 4) were identified in 8 of 61 (13%) cases. All BRCA1 mutations were found in invasive ductal carcinomas, the most common histologic type of tumor in this series. In contrast, the BRCA2 mutations were found in tumors of various histologic types: two ductal carcinomas, a tumor containing both ductal and lobular histologic types and an invasive lobular carcinoma. Of the 37 women with at least one first-, second- or third-degree relative with breast or ovarian cancer and the 24 women with no history of these cancers, 7 (19%) and 1 (4%), respectively, were mutation carriers. The seven mutation carriers with a family history of cancer had at least one first-, second- or third-degree relative with a breast cancer diagnosis at less than 51 years of age. The identification of founder BRCA1 and BRCA2 mutations in young-onset breast cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.

Adult↗
PubMed2001

Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions.

Breast cancer is the most frequent malignancy among women. Since genetic factors such as BRCA1 and BRCA2 as well as reproductive history constitute only 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved in the biotransformation of xenobiotics (from tobacco smoke, diet or other environmental sources) might play a role in breast carcinogenesis. Since individuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 207 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele was found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% CI 1.1-9.7), particularly among post-menopausal women (OR = 4.0, 95% CI 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smokers (OR = 2.6, 95% CI 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR = 4.4, 95% CI 1.0-18.9). These data suggest that CYP1A1*4, NAT1 and NAT2 variants are involved in the susceptibility to breast carcinoma by modifying the impact of exogenous and/or endogenous exposures.

Arylamine N-Acetyltransferase↗
PubMed2001

Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin.

Inappropriate activation of the Wnt/beta-catenin signaling, resulting mainly from activating mutations of the beta-catenin gene, has been implicated recently in the development of hepatocellular carcinoma (HCC). We have generated transgenic mice expressing an oncogenic form of beta-catenin in their hepatocytes to analyze the effect of deregulated beta-catenin signaling on liver homeostasis. These mice rapidly developed hepatomegaly soon after birth, with livers three to four times heavier than those of nontransgenic littermates. The liver cell hyperplasia resulted from increased cell proliferation without any compensatory apoptosis. Although the genes encoding c-myc and cyclin D1 are potential targets of the beta-catenin signaling pathway, neither of them was overexpressed in the hyperplastic livers of beta-catenin transgenic mice. Thus, the key target genes of the beta-catenin signaling pathway in the liver remain to be identified.

Animals↗
PubMed2001

Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation.

We examined the interplay between the insulin/IGF-1- and beta-catenin-regulated pathways, both of which are suspected to play a role in hepatocarcinogenesis. Insulin and IGF-1 stimulated the transcription of a Lef/Tcf-dependent luciferase reporter gene by 3-4-fold in HepG2 cells. This stimulation was mediated through the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and the inhibition of glycogen synthase kinase-3beta (GSK-3beta) since the effects of insulin and IGF-1 were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3beta. Together with inhibiting GSK-3beta, insulin and IGF-1 increased the cytoplasmic levels of beta-catenin. The PI 3-K/Akt/GSK-3beta pathway was not the sole to mediate insulin and IGF-1 stimulation of Lef/Tcf-dependent transcription. The Ras signalling pathway was also required as (i) the stimulatory effects of insulin and IGF-1 were inhibited by dominant-negative Ras or the MEK1 inhibitor PD98059 and (ii) activated Ha-Ras or constitutively active MEK1 synergized with catalytically inactive GSK-3beta to stimulate Lef/Tcf-dependent transcription. This study provides the first evidence that insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades bifurcating downstream of PI 3-K and involving GSK-3beta inhibition and Ras activation. These findings demonstrate for the first time the ability of insulin and IGF-1 to activate the beta-catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2001

A model of pulmonary adenocarcinoma in transgenic mice expressing the simian virus 40 T antigen driven by the rat Calbindin-D9K (CaBP9K) promoter.

Lung cancer is the most frequent cause of cancer deaths. Its origin and development remain poorly understood, partly because of the lack of pertinent animal models. This study produced transgenic mice expressing the simian virus (SV) 40 T antigen (Tag) driven by a 1011 base-pair DNA fragment of the rat Calbindin-D9K (CaBP9K) promoter. All transgenic animals developed multifocal pulmonary tumours with pathological and ultrastructural features consistent with adenocarcinomas. Using immunohistochemistry, northern blot or western blot, tumours were found to express the transcription factor TTF-1, as well as specific markers of the peripheral airway Clara cells (CC10) and alveolar type II cells (surfactant proteins A, B, C, and D). This model, with its similarities to human adenocarcinoma, should be useful not only for addressing the mechanisms underlying the development and progression of lung cancer, but also for testing new therapeutic approaches.

Adenocarcinoma↗
PubMed2001

Assessment of efficacy and safety of various adjuvant formulations with a total soluble extract of Trichinella spiralis.

Trichinellosis, a re-emerging zoonosis in several countries and pig, is the main species responsible for its transmission to human. Vaccination of swine could be an alternative to prevent the risk of human contamination. In order to develop an efficient and safe inactivate vaccine, the choice of the adjuvant is an important issue. The aim of this study was to develop and select potent and safe adjuvants by screening them in an experimental model with a crude soluble antigen from L1 muscular larvae (ML) of Trichinella spiralis (Ts). The efficacy was checked by the quantification of specific antibody levels. Specific and non-specific IgE antibody levels were also assessed. Safety was checked by the assessment of the local reaction at the injection site. Various Montanide ISA adjuvant formulations including water in oil, oil in water and multiphasic emulsions, but also nanoparticles or microbeads were tested. The results clearly showed differences between the antibody responses induced by the adjuvants and demonstrated the necessity to use an adjuvant to obtain a specific IgG (IgG1 or IgG2a) response directed against the total soluble extract of Ts. All the formulations enhanced the humoral immune response. The origin of the oil contained in the emulsions played an important role on the efficacy. Indeed emulsions based on mineral oils were more efficient than those based on metabolisable oils. However it was linked with stronger local reactions. Multiphasic and oil in water emulsions but also nanoparticles failed to induce IgG2a antibody levels. Microbeads and water in oil formulations based on mineral oils were more efficient. This experimentation allowed then the selection of several adjuvants which efficacy will be further investigated by a challenge test and an analysis of the cellular populations involved in the mechanism of the immune response.

Adjuvants, Immunologic↗
PubMed2001

Pelvic mobility when bending forward in standing position: validity and reliability of 2 motion analysis devices.

OBJECTIVE: To evaluate the validity and reliability of 2 measurement devices that assess pelvic mobility in persons bending forward while in a standing position. DESIGN: Validity and reliability studies. PATIENTS: The validity study included 10 patients (4 men, 6 women) aged 42 (range, 33--51yr). The reliability study included 50 subjects (25 men, 25 women) aged 30 (range, 18--49yr). INTERVENTIONS: A 3-dimensional ultrasound motion analyzer (CMS 50) and a spine motion analyzer using potentiometers (Rachimètre). METHODS: Two lateral radiographs of the patients' lumbosacral junction were taken, the first in neutral position, the second in full trunk flexion. Correlations between mobilities assessed by radiographs and both devices were evaluated by Spearman's rank correlation coefficient. Reliability was studied in healthy volunteers using the intraclass coefficient correlation (ICC) and the Bland and Altman plot. RESULTS: Spearman's coefficient between radiographic measures and the Rachimètre and the CMS 50 evaluations were.89 and.81, respectively. For the Rachimètre, ICC was.65 and increased with a better standardization of the measurement procedures. For the CMS 50, ICC was.85, and the Bland and Altman plot revealed no systematic trend. CONCLUSIONS: The Rachimètre and the CMS 50 have acceptable metric properties. Because few simple clinical measurements are available to evaluate pelvic mobility during trunk flexion in standing position, these 2 devices could be useful in the clinical evaluation of low back pain.

Adult↗
PubMed2001

Validity, reliability, and responsiveness of the fingertip-to-floor test.

OBJECTIVE: To evaluate the validity, reliability, and responsiveness of the fingertip-to-floor test to assess total mobility when bending forward in standing position. DESIGN: Experimental, prospective, correlational. SETTING: Rehabilitation and radiology departments in a university hospital in France. PARTICIPANTS: Ten patients (6 women, 4 men; mean age, 42yr) with chronic low back pain (LBP) in the validity study; 32 LBP patients (16 women, 16 men; mean age, 52yr) in the reliability study; and 72 LBP patients (22 women, 50 men; mean age, 30yr) in the responsiveness study. INTERVENTIONS: Dynamic radiographs and fingertip-to-floor test. MAIN OUTCOME MEASURES: For the validity study, 2 lateral radiographs of the upper dorsal spine, 1 in neutral position, and then 1 in full trunk flexion, were made. Validity was assessed by means of Spearman's correlation coefficient. Reliability was studied by using intraclass correlation coefficient (ICC) and the Bland and Altman method. Responsiveness was assessed by the effect size and the standardized response mean (SRM). RESULTS: The Spearman's correlation coefficient for trunk flexion assessed by the test and the radiologic measure was excellent (r(s) = -.96). The intra- and interobserver reliability were excellent (ICC = .99). The Bland and Altman method showed no systematic trend. The values observed for the test were .97 for SRM and .87 for effect size. CONCLUSIONS: Because the fingertip-to-floor test has excellent validity, reliability, and responsiveness, it can be used in clinical practice and therapeutic trials.

Adult↗
PubMed2001

[Complications in children with varicella in 4 hospitals in Santiago, Chile: clinical spectrum and estimation of direct costs].

BACKGROUND: The knowledge of varicella complications and their associated cost may help for a better evaluation of varicella immunization benefits. AIM: To determine frequency, type, outcome and affected population of varicella complications in children requiring hospitalization, and to estimate their direct costs. MATERIAL AND METHODS: Retrospective analysis of medical records of children admitted to four hospitals in Santiago, Chile, due to varicella complications between January 1997 and February 1999. Calculation of direct costs of hospitalizations in a sample of 30 patients. RESULTS: One hundred fifty four patients were identified, 74% were younger than 5 years old, only one was immunocompromised. Complications identified were skin and soft tissue infections in 63%, invasive infections in 25.3%, neurological in 7.1% and miscellaneous in 4.5%. Staphylococcus aureus and Group A beta-haemolytic Streptococcus (GABS) were predominantly isolated. S. aureus was the main agent identified in superficial infections and GABS in invasive infections (sterile sites). Two patients died due to invasive infections (streptococcal toxic shock and S. aureus septicaemia) and 11 required surgical procedures. The average cost per hospitalization was US$ 600 in public hospitals and US$ 1,800 in the private hospital. CONCLUSIONS: Varicella complications requiring hospitalization are due mainly to bacterial infections and they affect immunocompetent toddlers. These complications can be severe and even fatal.

Adolescent↗
PubMed2000

Trichinella in horses: a low frequency infection with high human risk.

After the initial report in 1976 of a trichinellosis epidemic caused by the consumption of infected horsemeat, 12 other outbreaks have been described in Europe. Since the first serious human outbreak several experiments have confirmed the susceptibility of horses to Trichinella species and the rapid disappearance of specific antibodies in this host that prevents the use of serological methods for routine screening. A review of the distribution of parasite burdens in muscles of naturally or experimentally infected horses indicates that the tongue is the most likely sample to contain detectable numbers of Trichinella larvae in low level infections. Requirements for testing of horsemeat are specified in legislation of the European Union, and other recommendations are published elsewhere. The EEC directives have evolved into very specific requirements which specify the testing of at least 5g of tongue, masseter or diaphragm per horse using a pooled digestion assay. More recently, France has revised the requirement for sample size to 10g for horsemeat originating from countries with high prevalence of Trichinella. To address the continuing outbreaks of human trichinellosis due to infected horsemeat, the development and implementation of a quality assurance system for testing is being considered.

Animals↗
PubMed2000

Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles.

The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of beta-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of beta-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Delta mice harbored either a deletion of the wt p53 allele or a beta-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene. Oncogene (2000).

Animals↗
PubMed2000

Transforming growth factor-beta1 modulates angiotensin II-induced calcium release in vascular smooth muscle cells from spontaneously hypertensive rats.

OBJECTIVES: To investigate the role of transforming growth factor-beta1 (TGF-beta1) on Ca2+-dependent mechanisms elicited by angiotensin II in aortic vascular smooth muscle cells (VSMC) of Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Cai2+ release induced by angiotensin II (1 micromol/ l) was studied in cultured VSMC isolated from the aortas of 6-week-old WKY rats and SHR. Intracellular Ca2+ (Cai2+) was assessed in Fura-2 loaded cells using fluorescent imaging microscopy. Angiotensin II receptors were analysed by binding studies. RESULTS: Pretreatment of VSMC for 24 h with TGF-beta1 significantly increased angiotensin II-induced Cai2+ mobilization from internal stores in SHR, while Ca2+ influx was not altered. This effect involves tyrosine kinase and is not due to an increase in angiotensin II binding sites, or a change in the affinity of the receptors. By contrast, TGF-beta1 did not modify the response of VSMC from WKY rats to angiotensin II. CONCLUSIONS: These results help our understanding of the interactions between the pathways activated by TGF-beta1 and the G protein-coupled receptor signalling pathway, and their role in genetic hypertension.

Angiotensin II↗