Biomedical subjects
M Gerber
Publications and source records attributed to M Gerber.
[Expression of antimicrobial peptide MUC7 in kidneys with pyelonephritis].
BACKGROUND: Mucins are glycoproteins secreted by epithelial cells of various organ systems exerting multiple functions. MG2 as the protein transcript of the MUC7 gene has first been described as secreted by serous salivary glands in the oral cavity. We sought to explore changes of MUC7 expression in the kidney stimulated by bacterial infection of the upper urinary tract. METHODS: We investigated the gene expression of MUC7 by reverse transcriptase-polymerase chain reaction in voided urine specimens from 15 patients with acute pyelonephritis compared to 15 healthy volunteers. Furthermore, the gene and protein expression of MUC7 was studied in 15 renal tissue samples with chronic bacterial pyelonephritis versus 10 normal human kidney samples taken from tumor-bearing organs. RESULTS: MUC7 gene expression was detected in 5 of 15 voided urine samples of patients with pyelonephritis and in 2 samples from 15 healthy volunteers (Fisher's exact test p=0.39). MUC7 gene expression was detected in 7 of 15 tissue samples of kidneys with chronic pyelonephritis and in none of 10 normal renal tissue samples from tumor bearing organs (p=0.02). Immunohistochemical staining with the monoclonal antibody PANH3 revealed protein expression in 6 of the 15 tissue samples with chronic pyelonephritis, but not in normal tissue samples. CONCLUSION: Upregulated MUC7 expression in the urinary tract particularly in renal tubular epithelium can occur under inflammatory conditions. This indicates a putative role of MUC7 as an antimicrobial host defense molecule within the urogenital tract.
Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance.
OBJECTIVE: It was hypothesized that resistin links obesity with diabetes, but this has not been studied in children and adolescents to date. PATIENTS: We determined serum resistin levels of 135 obese (body mass index, 32.0 +/- 6.2 kg/m2; age, 12.6 +/- 3.4 yr) and 201 lean children (body mass index, 18.7 +/- 2.4 kg/m2; age, 12.5 +/- 2.5 yr) by a newly developed and extensively evaluated in-house immunoassay. These results were controlled for their association with markers of puberty, obesity, and insulin sensitivity. RESULTS: The analytical evaluation of our assay revealed different resistin isoforms with major peaks of higher than 660 and 55 kDa in the size exclusion chromatography. Using this assay system we found no difference in the resistin levels of obese compared with lean subjects (P = 0.48). However, resistin was significantly higher in girls than in boys (6.74 +/- 2.42 vs. 5.79 +/- 2.45; P < 0.001). Interestingly, in both obese and lean children, resistin correlated with age (P < 0.01), Tanner stage, and testosterone and estradiol levels (P < 0.05). In contrast, no significant correlation was found with parameters of insulin resistance such as homeostasis model assessment, insulin sensitivity index, or insulin, proinsulin, and glucose concentrations in obese subjects. CONCLUSIONS: Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.
Assessment of the bioequivalence of two nelfinavir tablet formulations under fed and fasted conditions in healthy subjects.
OBJECTIVES: This study was designed to assess the bioequivalence between the commercial 250 mg nelfinavir tablet and the new 625 mg nelfinavir tablet (Roche) which was developed to reduce the daily pill burden for patients from 10 to 4 tablets in a nelfinavir 1250 mg twice daily regimen. METHODS: A total of 52 healthy male subjects were enrolled in this randomized four-period crossover study to receive single oral doses of 1250 mg nelfinavir administered as five commercial 250 mg tablets (reference formulation) and as two new 625 mg tablets (test formulation). Each of the two formulations were taken after an overnight fast and immediately after intake of a standard breakfast (820 kcal) on separate occasions. Blood samples were collected pre-dose and at appropriate intervals after drug administration. Plasma concentrations of nelfinavir and its main metabolite M8 were assayed by a validated LC-MS/ MS assay and the pharmacokinetics of nelfinavir and M8 were derived using standard non-compartmental analysis. RESULTS: The primary parameters for bioequivalence testing were the logarithmically transformed AUC(0-inf) and C(max) of nelfinavir taken from 50 subjects who completed all four treatments. Bioequivalence was accepted if the 90% confidence interval (CI) was contained entirely in the equivalence region (80%, 125%). In the fed state, this criterion was met for AUC (effect ratio = 95%; CI = 87%, 103%) and Cmax (effect ratio = 101%; CI = 94%, 109%) and bioequivalence of the two treatments could be concluded. In the fasted state, AUC clearly failed to meet the bioequivalence criteria (effect ratio = 73%; CI = 59%, 90%) and Cmax was borderline outside the lower acceptance region (effect ratio = 97%; CI = 79.6%, 118%). Therefore, bioequivalence could not be concluded under fasted condition. Food increased the systemic exposure to nelfinavir (as reflected by comparison of the logarithmically transformed AUC(0-inf) values under fed and fasted conditions) by six- and eight-fold after dosing with the 250 mg and the 625 mg tablet, respectively. CONCLUSIONS: Bioequivalence of the new 625 mg nelfinavir tablet relative to the commercial 250 mg tablet, at a dose of 1250 mg, was confirmed in the fed state but not under fasted conditions. As nelfinavir is recommended to be taken with food, the new tablet is well-suited to decrease the daily pill burden for patients on a nelfinavir twice daily regimen and to enhance patient's compliance and adherence.
Psycho-social influences on food choice in Southern France and Central England.
This study used attitudinal scales to investigate the nature of attitudes to diet and health in a northern European country (Central England) and a southern European country (Mediterranean France). Cross-sectional studies were conducted using self-administered postal questionnaires that were distributed simultaneously in April 2001 in Montpellier, France and Nottingham, England. A stratified random sample of 1000 males and 1000 females aged 18-65 years was generated from the electoral roll in each country. The final sample comprised England: n = 826 (58% male and 42% female; mean age=44 years) and France: n = 766 (42% male and 58% female; mean age=42 years). This study has demonstrated that the pleasurable and social aspects of eating, certain food quality issues, as well as health as a value were regarded as priorities by French respondents. On the other hand, English respondents reported that organic and ethical issues and convenience were important factors influencing their food choices. In conclusion, the two populations can be differentiated overall in their attitudes and beliefs to food choice.
The Medi-RIVAGE study (Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms): rationale, recruitment, design, dietary intervention and baseline characteristics of participants.
OBJECTIVE: To report the rationale, recruitment, design, dietary intervention and baseline characteristics of participants in the Medi-RIVAGE study (Mediterranean Diet, Cardiovascular Risks and Gene Polymorphisms). DESIGN: A randomised, parallel trial comparing a new nutritional programme with a conventional programme. SETTING: Centre for Detection and Prevention of Arteriosclerosis, Timone University Hospital, Marseille, France, and collaborating teams. SUBJECTS: Two hundred and twelve male and female volunteers with at least one cardiovascular risk factor. INTERVENTION: A Mediterranean-type diet characterised mainly by the quality of fatty acids, amount of fish, vegetable foodstuffs and fibre was proposed and compared with a usually prescribed, low-fat/cholesterol diet. Body mass index, fasting lipids and lipoproteins, apolipoproteins, glucose, insulin and homocysteine were the main outcome measures. Gene polymorphisms of interest were determined. RESULTS: Characteristics of men in the two arms were comparable with regard to sociodemographic variables, and clinical and biological cardiovascular risk factors. There were few differences between the groups of women (cholesterol-related parameters, P<0.05). There was no difference between arms in allelic distribution of the gene polymorphisms studied. Saturated fat and protein intakes were high while carbohydrate and fibre intakes were low, but with no difference between arms. Overall, the nutritional markers were comparable in both arms with few exceptions. Correlations between nutritional intakes and plasma nutrient levels ranged from 0.19 (beta-carotene) to 0.47 (folate). CONCLUSIONS: The comparability of the two arms is notable and warrants a low risk of biases. Current diet departs from the traditional Mediterranean one. The assessment of nutritional intake is validated by correlations obtained between dietary intake and relevant biomarkers. This will be important to estimate participant compliance and to analyse intervention data.
Dietary and socio-economic factors associated with overweight and obesity in a southern French population.
OBJECTIVE: To investigate the socio-economic and dietary factors associated with overweight and obesity, respectively, in southern France. DESIGN: Cross-sectional analysis of socio-economic, lifestyle and nutritional characteristics of a representative population sample. A questionnaire elicited information on anthropometric measurements, socio-economic factors, physical activity, tobacco use, and alcohol and food intakes. Non-parametric tests, multiple linear regression models and correspondence factorial analysis (CFA) were used to estimate the association of the various factors with overweight and obesity. SETTING: French Southwest and Mediterranean areas. SUBJECTS: In total, 1169 subjects (578 women and 552 men), aged 30-77 years, were recruited at random. RESULTS: Overweight and obesity were associated with age and education in both genders, reproductive factors in women and tobacco use in men. A few dietary factors were identified (high energy intake and low intake of carbohydrates), but all these variables explained little of the variation (18.5% in women and 14.6% in men). The CFA further investigated the association of lifestyle and nutritional factors, giving more weight to nutritional behaviour for overweight men and women. Factors for obesity differed from those for overweight by being different in men and women, possibly related to psychological behaviour, and there were fewer of them, suggesting an insufficient coverage by the usual questionnaires. CONCLUSIONS: Overweight and obesity appear as two different entities. Energy imbalance induced by various lifestyle factors plays a major role in the development of overweight, whereas obesity represents a more complex entity where psychological and genetic factors that are difficult to assess may be more important. General nutritional guidelines appear more adapted to the prevention of overweight than to that of obesity, and individual counselling to the prevention of obesity.
Interaction between genetic polymorphism of cytochrome P450-1B1 and environmental pollutants in breast cancer risk.
Cytochrome P450 1B1 (CYP1B1) is implicated in the activation of potentially carcinogenic xenobiotics and oestrogens. The polymorphism of the CYP1B1 gene at codon 432 (Val-->Leu) is associated with change in catalytic function. In a case-series study of breast cancer patients, we investigated the interaction between this polymorphism and environmental exposure. The women carrying the Val CYP1B1 allele and who had lived near to a waste incinerator for more than 10 years had a higher risk of breast cancer than those never exposed with the Leu/Leu genotype (odds ratio of interactions (ORi)=3.26, 95% confidence interval (CI) 1.20-8.84). Also, the Val CYP1B1 allele increased the susceptibility to breast cancer for women exposed during their life to agricultural products used in farming (ORi = 2.18, 95% CI 1.10-4.32). These xenobiotics, mainly organochlorine hydrocarbons, are known to bind to the aromatic hydrocarbon receptor (AhR), and to induce the expression of CYP1B1 enzyme. The excess risk for exposed women with a Val CYP1B1 homo/heterozygous genotype could result from a higher exposure to activated metabolites of pesticides or dioxin-like substances. Also, a higher induction of CYP1B1 enzyme by xenobiotics could increase the formation of genotoxic catechol-oestrogens among exposed women carrying the Val CYP1B1 allele. Our results suggested that the Val CYP1B1 allele increases the susceptibility to breast cancer in women exposed to waste incinerator or agricultural pollutants.
Endovascular stent-grafting for diseases of the descending thoracic aorta.
PRINCIPLES: Endoluminal stent-grafts are emerging as a less invasive alternative to conventional open surgery in the management of descending thoracic aortic dissections and aneurysms. We describe our experience with endovascular stent-grafting in the treatment of thoracic aorta pathology. METHODS: 17 Patients were treated with 23 endovascular stents. The underlying pathology was an atherosclerotic aneurysm verum (n = 5), a type B dissection with contained rupture (n = 3), an intramural haematoma with contained rupture (n = 1) and a false aneurysm of unknown origin (n = 1). One patient had Marfan's syndrome and six patients had a traumatic rupture of the descending aorta. RESULTS: Overall 23 stent-grafts were implanted. In one patient, conversion to an open graft replacement of the descending aorta was necessary. One patient died. In four patients (23.5%) a left carotid-subclavia bypass or transposition was performed to achieve a sufficient neck for the proximal stent-graft landing zone. The postoperative control-CT scans revealed a total of six endoleaks (EL) (four type I, one type II and one type IV). Two patients needed a graft extension in a second operation (4 days and 18 month after the first operation), two EL (one type I and one type II) disappeared after 9 and 18 months, respectively and two EL are still under observation. One patient developed a paresis after conversion to open graft replacement. CONCLUSIONS: A variety of diseases of the descending aorta can be treated by endoluminal stent-grafting, which seems to be a valid alternative to open repair in well selected cases. Mortality and morbidity in our small series were low. Continuous follow-up is mandatory.
Hepatitis G virus in clotting factor concentrates.
Blood-borne hepatitis is a well-known complication in patients with bleeding disorders. A recently discovered parentally transmitted virus, hepatitis G [GB virus C (GBV-C)] has an increased prevalence in patients with haemophilia. Clotting factor concentrates derived from pools of human plasma currently undergo viral inactivation techniques known to be effective against hepatitis B, C and HIV; however, the effectiveness of current purification and viral inactivation techniques against newly discovered viruses such as GBV-C is unknown. A total of 37 vials of clotting factor concentrates manufactured in the USA from 1981 to 1995 were tested for the presence of GBV-C virus. All samples that did not undergo a specific viral inactivation step were positive for GBV-C. Viral inactivation techniques that did not uniformly remove GBV-C included vapour heat treatment and dry heat treatments for less than 144 h. All samples treated by pasteurization, solvent detergent or dry heat for 144 h, were negative for the presence of GBV-C.
Common femoral artery--uncommon aneurysms.
BACKGROUND AND AIMS: Femoral artery aneurysms are rare. Their natural history, tendency to embolize or rupture are not well known. MATERIAL AND METHODS: Data of all patients seen 1996-2002 with femoral artery aneurysms at the Swiss Cardiovascular Center were analysed. Nine patients with 13 aneurysms of the common femoral artery (CFA) were identified. Only true aneurysms with a diameter of at least 2.5 cm were included. All patients were male, mean age 70 years (range: 57-85 years). Four patients had bilateral femoral aneurysms. Risk factors included hypertension (9/9), smoking (7/9). One of the aneurysms was palpable in 5/9. Four patients were asymptomatic, 5 had Fontaine class II claudication. Five patients also had an aortic aneurysm (AAA), one a thoracic aneurysm; and 6/9 popliteal aneurysms. In all patients, diagnosis was confirmed with duplex scan. Angiography was performed preoperatively. RESULTS: The aneurysms were operated on electively using aneurysm secclusion and interposition grafting. There were no significant perioperative complications. Median hospital stay was 8 days. CONCLUSION: CFA aneurysms are rare. They are palpable in nearly half of the cases. They rarely cause thrombotic or embolic complications, but are almost always connected to other aneurysms. Patients with CFA aneurysms should be screened with duplex scan. Operative therapy is straightforward, few complications can be expected. Postoperative follow-up with annual duplex scans is suggested.
Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.
PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.
Reproductive factors and breast cancer risk. Do they differ according to age at diagnosis?
Studies yielding results on risk factors stratified by age at diagnosis or menopausal status were reviewed to better understand the role of hormonal factors and to determine whether reproductive events influence breast cancer risk differently according to age at diagnosis of breast cancer. Through a Medline/Pubmed search, 26 articles providing risk estimates by age at diagnosis of breast cancer or by menopausal status were analysed. A decrease of about 9% of breast cancer risk was found for each additional year at menarche when breast cancer was diagnosed early or before the menopause, and of about 4% when diagnosed late or after. Breast cancer risk increased with increasing age at FFTP by 5% per year for breast cancer diagnosed early or before the menopause and by 3% for cancers diagnosed late or after the menopause. Each full term pregnancy (or child) led to a 3% reduction in the risk of breast cancer diagnosed early or before the menopause, whereas the reduction attained 12% for the breast cancers diagnosed later. No change in the effect of these three factors with time (date of diagnosis of the breast cancer before 1980 or after) was observed. These results support the hypothesis of an age-specific effect of the three breast cancer risk factors considered herein, based on the time of initiation of the carcinogenic process. These observations underline the importance of the time of initiation of the carcinogenic process in determining the effect of promoters such as reproductive factors. This largely unexplored aspect of breast carcinogenesis might open the way for new prevention approaches.
[Alcohol consumption by young adults from three cities in Southern France].
AIM: To identify potential factors of change in alcohol consumption and regional differences which could explain why and how habits are evolving. SUBJECTS AND METHODS: Four hundred and thirty three subjects aged 20 to 34 years, were recruited by random sampling in Marseilles, Montpellier and Toulouse. A quantitative food frequency questionnaire was used to collect data on alcohol consumption. A stepwise logistic regression was applied to the total sample, to the sub-sample of drinkers, and to the sub-samples of drinkers of each type of alcoholic beverage. Factors associated with each type of alcoholic consumption were analyzed by city. RESULTS: Montpellier and Toulouse samples were pooled because of the similarity in alcoholic consumption, which was different from that in Marseilles. There are significantly more drinkers in Montpellier/Toulouse than in Marseilles (74.4% versus 53.8%; p=0.001) and also more binge drinking subjects (31.1% versus 10.3%; p=0.001). Age, tobacco, leisure physical activity are independently associated with alcoholic consumption, female sex and Marseilles, being inversely associated. These two last factors are similarly associated with binge drinking, as well as age. CONCLUSION: The study of the factors for alcoholic consumption by site suggests that differences in behavior could explain these results. These distinct characteristics should be considered when implementing anti-alcoholic prevention in youth.
Subregional variations of dietary consumption and incidences of cancers in southern France.
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Drosophila ELL is associated with actively elongating RNA polymerase II on transcriptionally active sites in vivo.
Several factors have been biochemically characterized based on their ability to increase the overall rate of transcription elongation catalyzed by the multiprotein complex RNA polymerase II (Pol II). Among these, the ELL family of elongation factors has been shown to increase the catalytic rate of transcription elongation in vitro by suppressing transient pausing. Several fundamental biological aspects of this class of elongation factors are not known. We have cloned the Drosophila homolog (dELL) in order to test whether ELL family proteins are actually associated with the elongating Pol II in vivo. Here we report that dELL is a nuclear protein, which, like its mammalian homologs, can increase the catalytic rate of transcription elongation by Pol II in vitro. Interestingly, we find that dELL co-localizes extensively with the phosphorylated, actively elongating form of Pol II at transcriptionally active sites on Drosophila polytene chromosomes. Furthermore, dELL is relocalized from a widespread distribution pattern on polytenes under normal conditions to very few transcriptionally active puff sites upon heat shock. This observation indicates a dynamic pattern of localization of dELL in cells, which is a predicted characteristic of a Pol II general elongation factor. We also demonstrate that dELL physically interacts with Pol II. Our results strongly suggest that dELL functions with elongating RNA polymerase II in vivo.
Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception.
BACKGROUND: Studies have reported a temporal association between a first dose of rotavirus vaccine (Rotashield) and infant intussusception. We investigated the effect of Rotashield vaccination use on intussusception admissions in ten US states. METHODS: We analysed electronic databases containing 100% hospital discharge records for 1993-99 from ten US states, where an estimated 28% of the birth cohort had received Rotashield (based on manufacturer's net sales data). We examined records of infants admitted to hospital (<365 days old) with any mention of intussusception (International Classification of Diseases, ninth revision, clinical modification code 560.0). Excess admissions for intussusception during the period of Rotashield availability (October 1998 to June 1999) were estimated by direct comparison with the corresponding period of October 1997 to June 1998 (before Rotashield was available) and with adjustment for secular trends during 1993-98 by Poisson regression. FINDINGS: Hospital admission for intussusception among infants younger than 365 days of age during the Rotashield period compared with previously was 4% lower (10 cases) by direct comparison and 10% lower (27 cases) by trend comparison, corresponding to a negative population attributable risk. Among infants aged 45-210 days (target age range for a first Rotashield dose), we estimated an increase in intussusception admissions of 1% (one excess admission) by direct comparison and 4% (4.6 excess admissions) by trend comparison, corresponding to a population attributable risk range of one excess admission in 66000-302000. INTERPRETATION: We found no evidence of increased infant intussusception admissions during the period of Rotashield availability. The total intussusception admission risk attributable to Rotashield was substantially lower than previous estimates based on studies focusing on the immediate postvaccination weeks.
Embedding of multidimensional time-dependent observations.
A method is proposed to reconstruct dynamic attractors by embedding of multivariate observations of dynamic nonlinear processes. The Takens embedding theory is combined with independent component analysis to transform the embedding into a vector space of linearly independent vectors (phase variables). The method is successfully tested against prediction of the unembedded state vector in two case studies of simulated chaotic processes.