No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Low immunoglobulin levels in patients with cystic fibrosis: reduced inflammation or sign of common variable immunodeficiency syndrome?

Introduction: In children with cystic fibrosis (CF), low immunoglobulin (IgG) levels have been reported to be associated with significantly less severe lung disease. However, decreased IgG can be a sign for common variable immunodeficiency (CVID) and affect clinical outcome. The aim of this study was to analyze clinical and serological data of patients having low IgG levels in routine blood tests at annual assessment, particularly their antibody response to polysaccharide antigens. Method: Retrospective chart review of demographic data of CF patients followed at the pediatric CF clinic throughout 2009. Clinical parameters (genotype, pancreas sufficiency, FEV1), presence of Pseudomonas aeruginosa (PA) and number of exacerbations per year were correlated with immunoglobulin and vaccination antibodies levels (antibodies to pneumococcal serotypes 14, 19, 23, 1, 5 and 7F measured by enzyme-linked immune-sorbent assay). Results: 4 out of 60 patients (6.7%) had lower IgG-levels for age. Ages ranged from 1 year 8 months to 11 years, 2 boys, 2 girls. Three patients were delF508 homozygotes, one heterozygote composite delF508/G542X. All were pancreatic insufficient. FEV1 ranged from 74 to 108%. One patient never had colonization by PA, 2 had intermittent PA colonization and one was chronically infected. After conjugated vaccination all patients had protective antibodies against serotypes 14, 19, 23F. For serotypes not included in the vaccine, only one patient had protective titers for 1 out of 3 serotypes. None of the patients had received unconjugated pneumococcal vaccine. There was no significant clinical difference in FEV1, PA colonization or number of exacerbations according to IgG and vaccination antibody levels. Conclusion: Cystic Fibrosis patients with low immunoglobulin levels have normal antibody response to protein antigens. However, despite recurrent infections, there seems to be delayed or deficient antibody response to polysaccharide antigens. Prospective studies are needed to evaluate the development of polysaccharide antibody responses in CF-patients to monitor for CVID. With early detection of CF by newborn screening program, long term follow up could be started early in childhood.

Combined effect of 25-OH vitamin D plasma levels and genetic vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients.

BACKGROUND: Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date. AIMS: To analyse combined effects of 25-OH vitamin D plasma levels and vitamin D receptor gene (VDR; NR1I1) polymorphisms on fibrosis progression rate in HCV patients. METHODS: 251 HCV patients underwent VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 A and TaqI rs731236 A). Plasma 25-OH vitamin D levels were quantified in a subgroup of 97 patients without advanced fibrosis. The VDR haplotype and genotypes as well as plasma 25-OH vitamin D levels were associated with fibrosis progression. RESULTS: The bAt[CCA]-haplotype was significantly associated with fibrosis progression >0.101 U/year (P = 0.007; OR = 2.02) and with cirrhosis (P = 0.022; OR = 1.84). Forty-five percent of bAt[CCA]-haplotype patients were rapid fibrosers, 21.1% were cirrhotic. Likewise, ApaI rs7975232 CC genotype was significantly associated with fibrosis progression and cirrhosis. Lower plasma 25-OH vitamin D levels were significantly associated with fibrosis progression >0.101 U/year in F0-2 patients (P = 0.013). Combined analysis of both variables revealed a highly significant additive effect on fibrosis progression with 45.5% rapid fibrosers for bAt[CCA]-haplotype and 25-OH vitamin D < 20 μg/L compared with only 9.1% for the most favourable combination (P = 0.006). In multivariate analysis, the bAt-haplotype was an independent risk factor for fibrosis progression (P = 0.001; OR = 2.83). CONCLUSION: Low 25-OH vitamin D plasma levels and the unfavourable VDR bAt[CCA]-haplotype are associated with rapid fibrosis progression in chronic HCV patients. In combination, both variables exert significant additive effects on fibrosis progression.

Assessment of diesel exhaust particulate exposure and surface characteristics in association with levels of oxidative stress biomarkers

Exposure to PM10 and PM2.5 (particulate matter with aerodynamic diameter smaller than 10 μm and 2.5 μm, respectively) is associated with a range of adverse health effects, including cancer, pulmonary and cardiovascular diseases. Surface characteristics (chemical reactivity, surface area) are considered of prime importance to understand the mechanisms which lead to harmful effects. A hypothetical mechanism to explain these adverse effects is the ability of components (organics, metal ions) adsorbed on these particles to generate Reactive Oxygen Species (ROS), and thereby to cause oxidative stress in biological systems (Donaldson et al., 2003). ROS can attack almost any cellular structure, like DNA or cellular membrane, leading to the formation of a wide variety of degradation products which can be used as a biomarker of oxidative stress. The aim of the present research project is to test whether there is a correlation between the exposure to Diesel Exhaust Particulate (DEP) and the oxidative stress status. For that purpose, a survey has been conducted in real occupational situations where workers were exposed to DEP (bus depots). Different exposure variables have been considered: - particulate number, size distribution and surface area (SMPS); - particulate mass - PM2.5 and PM4 (gravimetry); - elemental and organic carbon (coulometry); - total adsorbed heavy metals - iron, copper, manganese (atomic adsorption); - surface functional groups present on aerosols (Knudsen flow reactor). Several biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and several aldehydes) have been determined either in urine or serum of volunteers. Results obtained during the sampling campaign in several bus depots indicated that the occupational exposure to particulates in these places was rather low (40-50 μg/m3 for PM4). Bimodal size distributions were generally observed (5 μm and <1 μm). Surface characteristics of PM4 varied strongly, depending on the bus depot. They were usually characterized by high carbonyl and low acidic sites content. Among the different biomarkers which have been analyzed within the framework of this study, mean urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly (p<0.05) during two consecutive days of exposure for non-smoker workers. On the other hand, no statistically significant differences were observed for serum levels of hexanal, nonanal and 4- hydroxy-nonenal (p>0.05). Biomarkers levels will be compared to exposure variables to gain a better understanding of the relation between the particulate characteristics and the formation of ROS by-products. This project is financed by the Swiss State Secretariat for Education and Research. It is conducted within the framework of the COST Action 633 "Particulate Matter - Properties Related to Health Effects".

Temporal variation in glucocorticoid levels during the resting phase is associated in opposite way with maternal and paternal melanic coloration.

Sex-dependent selection can help maintain sexual dimorphism. When the magnitude of selection exerted on a heritable sex trait differs between the sexes, it may prevent each sex to reach its phenotypic optimum. As a consequence, the benefit of expressing a sex trait to a given value may differ between males and females favouring sex-specific adaptations associated with different values of a sex trait. The level of metabolites regulated by genes that are under sex-dependent selection may therefore covary with the degree of ornamentation differently in the two sexes. We investigated this prediction in the barn owl, a species in which females display on average larger black spots on the plumage than males, a heritable ornament. This melanin-based colour trait is strongly selected in females and weakly counter-selected in males indicating sex-dependent selection. In nestling barn owls, we found that daily variation in baseline corticosterone levels, a key hormone that mediates life history trade-offs, covaries with spot diameter displayed by their biological parents. When their mother displayed larger spots, nestlings had lower corticosterone levels in the morning and higher levels in the evening, whereas the opposite pattern was found with the size of paternal spots. Our study suggests a link between daily regulation of glucocorticoids and sex-dependent selection exerted on sexually dimorphic melanin-based ornaments.

Mycorrhizal dependency of mangaba tree under increasing phosphorus levels

The objective of this study was to evaluate the mycorrhizal dependency of mangaba tree (Hancornia speciosa) plantlets, under increasing levels of phosphorus fertilization. The experimental design was completely randomized in a 4×5 factorial arrangement with three mycorrhizal fungi inocula - Gigaspora margarita, Glomus etunicatum, or a pool of native mycorrhizal fungi (Acaulospora longula, Glomus clarum, Gigaspora albida, Paraglomus sp.) -, and a nonmycorrhizal control, in combination with five levels of phosphorus applied to the substrate: 0, 25, 50, 75, and 100 mg kg-1. After 180 days of growth, plantlets with inoculation of native mycorrhizal pool produced more shoot and root dry biomass and had higher shoot phosphorus content and accumulation. The noninoculated control showed the lowest values, independently of the phosphorus level. The highest relative mycorrhizal dependency occurred with the inoculation of native mycorrhizal fungi. Plants with mycorrhizal fungi did not respond to phosphorus addition above 50 mg kg-1. Mangaba tree is highly dependent on mycorrhiza, but the degree of dependency varies according to phosphorus levels and fungal inocula. In general, mangaba tree is more responsive to mycorrhizal fungi inoculation than to phosphorus addition.

Intergenerational differences in cardiovascular risk factor levels in Switzerland

Background: There is little information regarding cardiovascular risk factor (CV RF) trends in Switzerland. We aimed at assessing generation differences in CV RFs by comparing CV RFs levels within selected age groups separated by a 20 year time lag. Design: Two population-based surveys. Methods: Data from the Monica (1984-1986) and Colaus (2004-2006) surveys were used. Analyses were stratified by sex and age groups (35-44, 45-54, 55-64 and 65-75 years). Results: No changes were found for BMI levels and status between surveys: in men, 26}3, 26}3, 27}4 and 27}4 kg/m2 for age groups 35-44, 45-54, 55-64 and 65-74, respectively, in MONICA, vs. 26}4, 26}4, 27}4 and 28}4 kg/m2 in COLAUS, p=NS, in women: 24}4, 26}4, 26}4 and 26}5 kg/m2 in MONICA, vs. 24}5, 25}5, 26}5 and 26}5 kg/m2 in COLAUS, p=NS. Similar results were found after adjusting for education. Smoking prevalence increased in men: 28, 30, 22 and 15% for age groups 35-44, 45-54, 55-64 and 65-74, respectively, in MONICA, vs. 35, 29, 28 and 21% in COLAUS. In women, changes differed according to age: 39, 26, 16 and 18%, in MONICA vs. 28, 30, 22 and 15% in COLAUS. Blood pressure decreased in the younger age groups and remained constant in the older ones: in men, systolic blood pressure was 129}15, 133}16, 138}18 and 143}21 mm Hg in MONICA, vs. 125}12, 129}15, 137}16 and 144}19 mm Hg in COLAUS, p<0.01. Similar findings were obtained after adjusting for education. Prevalence of hypertension increased, due to an increase in the prevalence of treated subjects, in men : 4, 8, 16 and 19% for age groups 35-44, 45-54, 55-64 and 65-74, respectively, in MONICA, vs. 5, 14, 31 and 46% in COLAUS, p<0.05; in women: 2, 10, 16, and 24% in MONICA, vs. 4, 12, 24, and 34% in COLAUS, p<0.05. This increase was stronger in men: 14, 17, 23 and 31% for age groups 35-44, 45-54, 55-64 and 65-74, respectively, in MONICA vs. 10, 21, 41 and 55% in COLAUS, p<0.01 and smaller in women: 6, 15, 24 and 44% in MONICA vs. 6, 16, 30 and 42% in COLAUS, p=NS. Similar findings were obtained after adjusting for education. Conclusion: With the exception of BMI, the newer Swiss generations appear to have a worse CV profile than the older generations. This is especially true regarding smoking and hypertension.

Variabilité des concentrations plasmatiques de l'angiotensinogène et risque d'hypertension artérielle chez le rat transgénique [Variability of plasma angiotensinogen levels and risk of hypertension in a transgenic rat model].

AIM: Genetic polymorphisms of the human angiotensinogen gene are frequent and may induce up to 30% increase of plasma angiotensinogen concentrations with a blood pressure increase of up to 5mmHg. Their role for the pathogenesis of human arterial hypertension remains unclear. High plasma angiotensinogen levels could increase the sensitivity to other blood pressure stressors. METHODS: Male transgenic rats with a 9-fold increase of plasma angiotensinogen concentrations and male non-transgenic rats aged 10 weeks were treated or not with NG-Nitro-L-arginine-methyl ester for 3 weeks in their drinking water (n=3/group). Systolic blood pressure and body weight were measured at baseline and at the end of the study when left ventricular weight and ventricular expression of angiotensin I-converting enzyme and procollagen Iα1 were determined (polymerase chain reaction). RESULTS: At baseline, transgenic rats had +18mmHg higher bood pressure and -8% lower body weight compared to non-transgenic rats (P<0.05) without significant changes for the vehicle groups throughout the study (P>0.05). NG-Nitro-L-arginine-methyl ester increased blood pressure, left ventricular weight and left ventricular weight indexed for body weight by +41%, +17.6% and +18.6% (P<0.05) in transgenic and +25%, +5.3% and +6.7% (P>0.05) in non-transgenic rats compared to untreated animals, respectively. Cardiac gene expression showed no differences between groups (P>0.05). CONCLUSION: Increased plasma angiotensinogen levels may sensitize to additional blood pressure stressors. Our preliminary results point towards an independent role of angiotensinogen in the pathogenesis of human hypertension and associated end-organ damage.

Increased macrophage migration inhibitory factor (MIF) plasma levels in acute HIV-1 infection.

Considering macrophage migratory inhibitory factor (MIF) as a critical pro-inflammatory cytokine of the immune system, we evaluated plasma MIF levels in 89 HIV-infected adults. Plasma MIF levels were higher in HIV-infected than in HIV-negative individuals. Highest MIF levels were observed during acute HIV infection (AHI) whilst patients on antiretroviral therapy (ART) had lower MIF levels, regardless of ART efficacy. Our results suggest that MIF is an integral component of the cytokine storm characteristic of AHI.

Potassium permanganate effects in postharvest conservation of the papaya cultivar Sunrise Golden

The objective of this work was to evaluate the effects of KMnO4 on the extension of postharvest life of 'Sunrise Golden' papaya, stored under modified atmosphere and refrigeration. Fruit with up to 10% yellow peel were harvested in a commercial orchard in Linhares, state of Espírito Santo, Brazil. Sets of three fruit (unit mass of 289.9±18.5 g) were wrapped in low-density polyethylene films (28 ¼m thick) containing sachets of KMnO4 at 0, 0.5, 1, 1.5, and 2 g per bag. The bags were sealed and stored at 10.4±0.9°C and 90±5% relative humidity for 25 days. After this period, the fruit were removed from the bags and maintained at 21±0.8°C and 90±5% relative humidity until complete ripening. Four days after bag sealing, CO2 concentration stabilized in all treatments, and was higher in bags without KMnO4. In all treatments, fruit reached the climacteric respiratory peak on the third day after bag removal, coinciding with peel color index of 3.5. Increasing the KMnO4 dose reduced the losses in fruit fresh matter, consistency and pulp electrolyte leakage. Potassium permanganate was effective in maintaining the fruit at the pre-climacteric stage during the 25-day storage, and did not interfere with normal ripening after bag removal.

Distribution of plasma levels of adiponectin and leptin in an adult Caucasian population.

OBJECTIVES: Little is known regarding the distribution and the determinants of leptin and adiponectin levels in the general population. DESIGN: Cross-sectional study. PATIENTS: Women (3004) and men (2552) aged 35-74 living in Lausanne, Switzerland. MEASUREMENTS: Plasma levels of leptin and adiponectin (ELISA measurement). RESULTS: Women had higher leptin and adiponectin levels than men. In both genders, leptin and adiponectin levels increased with age. After adjusting for fat mass, leptin levels were significantly and negatively associated with age in women: 18.1 +/- 0.3, 17.1 +/- 0.3, 16.7 +/- 0.3 and 15.5 +/- 0.4 ng/ml (adjusted mean +/- SE) for age groups [35-44], [45-54], [55-64] and [65-75], respectively, P < 0.001. A similar but nonsignificant trend was also found in men. Conversely, the age-related increase of adiponectin was unrelated to body fat in both genders. Post-menopausal women had higher leptin and adiponectin levels than premenopausal women, independently of hormone replacement therapy. Although body fat mass was associated with leptin and adiponectin, the associations were stronger with body mass index (BMI), waist and hip in both genders. Finally, after adjusting for age and anthropometry, no relationships were found between leptin or adiponectin levels with alcohol, caffeine consumption and physical activity, whereas smoking and diabetes decreased leptin and adiponectin levels in women only. CONCLUSIONS: The age-related increase in leptin levels is attributable to changes in fat mass in women and probably also in men. Leptin and adiponectin levels are more related to BMI than to body fat mass. The effects of smoking and diabetes appear to be gender-specific.

Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods, [and] Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes

Rapport de synthèse1. Partie de laboratoireCette première étude décrit le développement et la validation, selon les standards internationaux, de deux techniques de mesure des concentrations sanguines de voriconazole, un nouvel agent antifongique à large spectre: 1) la chromatographic en phase liquide à haute pression et 2) le bio-essai utilisant une souche mutante de Candida hypersensible au voriconazole. Ce travail a aussi permis de mettre en évidence une importante et imprévisible variabilité inter- et intra-individuelle des concentrations sanguines de voriconazole malgré l'utilisation des doses recommandées par le fabriquant. Ce travail a été publié dans un journal avec "peer-review": "Variability of voriconazole plasma levels measured by new high- performance liquid chromatography and bioassay methods" by A. Pascual, V. Nieth, T. Calandra, J. Bille, S. Bolay, L.A. Decosterd, T. Buclin, P.A. Majcherczyk, D. Sanglard, 0. Marchetti. Antimicrobial Agents Chemotherapy, 2007; 51:137-432. Partie CliniqueCette deuxième étude a évalué de façon prospective l'impact clinique des concentrations sanguines de voriconazole sur l'efficacité et sécurité thérapeutique chez des patients atteints d'infections fongiques. Des concentrations sanguines élevées étaient significativement associés à la survenue d'une toxicité neurologique (encéphalopathie avec confusion, hallucinations et myoclonies) et des concentrations sanguines basses à une réponse insuffisante au traitement antifongique (persistance ou progression des signes cliniques et radiologiques de l'infection). Dans la majorité des cas, un ajustement de la dose de voriconazole, sur la base des concentrations mesurées, a abouti à une récupération neurologique complète ou à une résolution de l'infection, respectivement. Ce travail a été publié dans un journal avec "peer-review": " Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes" by A. Pascual, T. Calandra, S. Bolay, T. Buclin, J. Bille, and O. Marchetti. Clinical Infectious Diseases, 2008 January 15; 46(2): 201-11.Ces deux études, financées de façon conjointe par un "grant" international de la Société suisse d'infectiologie et la Société internationale de maladies infectieuses et par la Fondation pour le progrès en microbiologie médicale et maladies infectieuses (FAMMID, Lausanne), ont été réalisées au sein du Service des Maladies Infectieuses, Département de Médecine, au CHUV, en étroite collaboration avec la Division de Pharmacologie Clinique, Département de Médecine, au CHUV et l'Institut de Microbiologie du CHUV et de l'Université de Lausanne.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Cardiac hypertrophy, low blood pressure, and low aldosterone levels in mice devoid of the three circadian PAR bZip transcription factors DBP, HLF, and TEF.

The cardiovascular system is under the control of the circadian clock, and disturbed circadian rhythms can induce cardiovascular pathologies. This cyclic regulation is probably brought about by the circadian expression of genes encoding enzymes and regulators involved in cardiovascular functions. We have previously shown that the rhythmic transcription of output genes is, in part, regulated by the clock-controlled PAR bZip transcription factors DBP (albumin D-element Binding Protein), HLF (Hepatic Leukemia Factor), and TEF (Thyrotroph Embryonic Factor). The simultaneous deletion of all three PAR bZip transcription factors leads to increased morbidity and shortened life span. Here, we demonstrate that Dbp/Tef/Hlf triple knockout mice develop cardiac hypertrophy and left ventricular dysfunction associated with a low blood pressure. These dysfunctions are exacerbated by an abnormal response to this low blood pressure characterized by low aldosterone levels. The phenotype of PAR bZip knockout mice highlights the importance of circadian regulators in the modulation of cardiovascular functions.