Short-term effects of particulate matters on pulse pressure in two general population studies.

OBJECTIVES: To explore the association of short-term exposure to particulate matter with aerodynamic diameters less than 10 μm (PM10) with pulse pressure, SBP, and DBP taking outdoor temperature into account in two large population-based studies in Switzerland. METHODS: We used data from the Bus Santé study including 5605 adults in Geneva and the CoLaus study including 6183 adults in Lausanne. PM10 and meteorological data were measured from fixed monitoring stations. We analyzed the association of short-term exposure to PM10 (on the day of examination visit and up to 7 days before) with pulse pressure, SBP, and DBP by linear regression, controlling for potential confounders and effect modifiers. RESULTS: Average PM10 levels were 22.4 μg/m in Geneva and 31.7 μg/m in Lausanne. In adjusted models, for each 10 μg/m increase in 7-day PM10 average, pulse pressure and SBP increased by 0.583 (95% confidence interval, 0.296-0.870) mmHg and 0.490 (0.056-0.925) mmHg in Geneva, and 0.183 (0.017-0.348) mmHg and 0.036 (0.042-0.561) mmHg in Lausanne, respectively. Stronger associations of pulse pressure and SBP with PM10 were observed when outdoor temperature was above 5°C. CONCLUSION: Positive associations of pulse pressure and SBP with short-term exposure to PM10 were found and replicated in the Swiss adult population. Our results suggest that even low levels of air pollution may substantially impact cardiovascular risk in the general population.

Individual differences in gene expression : insights from transcriptional control of the CSL gene and from human population studies

CSL is a key transcription factor, mostly acting as a repressor, which has been shown to have a highly context-dependent function. While known as the main effector of Notch signaling, it can also exert Notch-independent functions. The downstream effects of the Notch/CSL signaling pathway and its involvement in several biological processes have been intensively studied. We recently showed that CSL is important to maintain skin homeostasis, as its specific deletion in mouse dermal fibroblasts -or downmodulation in human stromal fibroblasts- creates an inducing environment for squamous cell carcinoma (SCC) development, possibly due to the conversion of stromal fibroblasts into cancer associated fibroblasts (CAFs). Despite the wide interest in CSL as a transcriptional regulator, the mechanism of its own regulation has so far been neglected. We show here that CSL expression levels differ between individuals, and correlate among others with genes involved in DNA damage response. Starting from this finding we show that in dermal fibroblasts CSL is under transcriptional control of stress inducers such as UVA irradiation and Reactive Oxygen Species (ROS) induction, and that a main player in CSL transcriptional regulation is the transcription factor p53. In a separate line of work, we focused on individual variability, studying the differences in gene expression between human populations in various cancer types, particularly focusing on the Caucasian and African populations. It is indeed widely known that these populations have different incidences and mortalities for various cancers, and response to cancer treatment may also vary between them. We show here several genes that are differentially expressed and could be of interest in the study of population differences in cancer. -- CSL est un facteur de transcription agissant essentiellement comme répresseur, et qui a une fonction hautement dépendant du contexte. C'est l'effecteur principal de la voie de signalisation de Notch, mais il peut également exercer ses fonctions dans une façon Notch- indépendante. Nous avons récemment montré que CSL est important pour maintenir l'homéostasie de la peau. Sa suppression spécifique dans les fibroblastes dermiques de la souris ou dans les fibroblastes stromales humaines crée un environnement favorable pour le développement du carcinome épidermoïde (SCC), probablement en raison de la conversion des fibroblastes en fibroblastes associé au cancer (CAF). Malgré le grand intérêt de CSL comme régulateur transcriptionnel, le mécanisme de sa propre régulation a été jusqu'ici négligée. Nous montrons ici que dans les fibroblastes dermiques CSL est sous le contrôle transcriptionnel de facteurs de stress tels que l'irradiation UVA et l'induction des ROS dont p53 est l'acteur principal de cette régulation. Nous montrons aussi que les niveaux d'expression de CSL varient selon les individus, en corrélation avec d'autres gènes impliqués dans la réponse aux dommages de l'ADN. Dans une autre axe de recherche, concernant la variabilité individuelle, nous avons étudié les différences dans l'expression des gènes dans différents types de cancer entre les populations humaines, en se concentrant particulièrement sur les populations africaines et caucasiennes. Il est en effet bien connu que ces populations montrent des variations dans l'incidence des cancers, la mortalité, ainsi que pour les réponses au traitement. Nous montrons ici plusieurs gènes qui sont exprimés différemment et pourraient être digne d'intérêt dans l'étude du cancer au sein de différentes populations.

New anthropometry-based age- and sex-specific reference values for urinary 24-hour creatinine excretion based on the adult Swiss population (epublish)

BACKGROUND: Urinary creatinine excretion is used as a marker of completeness of timed urine collections, which are a keystone of several metabolic evaluations in clinical investigations and epidemiological surveys. METHODS: We used data from two independent Swiss cross-sectional population-based studies with standardised 24-hour urinary collection and measured anthropometric variables. Only data from adults of European descent, with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and reported completeness of the urinary collection were retained. A linear regression model was developed to predict centiles of the 24-hour urinary creatinine excretion in 1,137 participants from the Swiss Survey on Salt and validated in 994 participants from the Swiss Kidney Project on Genes in Hypertension. RESULTS: The mean urinary creatinine excretion was 193 ± 41 μmol/kg/24 hours in men and 151 ± 38 μmol/kg/24 hours in women in the Swiss Survey on Salt. The values were inversely correlated with age and body mass index (BMI). CONCLUSIONS: We propose a validated prediction equation for 24-hour urinary creatinine excretion in the general European population, based on readily available variables such as age, sex and BMI, and a few derived normograms to ease its clinical application. This should help healthcare providers to interpret the completeness of a 24-hour urine collection in daily clinical practice and in epidemiological population studies.

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The pharmacokinetic profile of imatinib has been assessed in healthy subjects and in population studies among thousands of patients with CML or GIST. Imatinib is rapidly and extensively absorbed from the GI tract, reaching a peak plasma concentration (Cmax) within 1-4 h following administration. Imatinib bioavailability is high (98%) and independent of food intake. Imatinib undergoes rapid and extensive distribution into tissues, with minimal penetration into the central nervous system. In the circulation, it is approximately 95% bound to plasma proteins, principally α1-acid glycoprotein (AGP) and albumin. Imatinib undergoes metabolism in the liver via the cytochrome P450 enzyme system (CYP), with CYP3A4 being the main isoenzyme involved. The N-desmethyl metabolite CGP74588 is the major circulating active metabolite. The typical elimination half-life for imatinib is approximately 14-22 h. Imatinib is characterized by large inter-individual pharmacokinetic variability, which reflects in a wide spread of concentrations observed under standard dosage. Besides adherence, several factors have been shown to influence this variability, especially demographic characteristics (sex, age, body weight and disease diagnosis), blood count characteristics, enzyme activity (mainly CYP3A4), drug interactions, activity of efflux transporters and plasma levels of AGP. Additionally, recent retrospective studies have shown that drug exposure, reflected in either the area under the concentration-time curve (AUC) or more conveniently the trough level (Cmin), correlates with treatment outcomes. Increased toxicity has been associated with high plasma levels, and impaired clinical efficacy with low plasma levels. While no upper concentration limit has been formally established, a lower limit for imatinib Cmin of about 1000 ng/mL has been proposed repeatedly for improving outcomes in CML and GIST patients. Imatinib is licensed for use in chronic phase CML and GIST at a fixed dose of 400 mg once daily (600 mg in some other indications) despite substantial pharmacokinetic variability caused by both genetic and acquired factors. The dose can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Imatinib would, however, meet traditional criteria for a therapeutic drug monitoring (TDM) program: long-term therapy, measurability, high inter-individual but restricted intra-individual variability, limited pharmacokinetic predictability, effect of drug interactions, consistent association between concentration and response, suggested therapeutic threshold, reversibility of effect and absence of early markers of efficacy and toxic effects. Large-scale, evidence-based assessments of drug concentration monitoring are therefore still warranted for the personalization of imatinib treatment.

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.

Heritability of the retinal microcirculation in flemish families.

BACKGROUND Few population studies have described the heritability and intrafamilial concordance of the retinal microvessels, or the genetic or environmental correlations of the phenotypes of these vessels. METHODS We randomly selected 413 participants from 70 families (mean age, 51.5 years; 50.1% women) from a Flemish population. We postprocessed retinal images using IVAN software to generate the central retinal arteriole equivalent (CRAE), central retinal venule equivalent (CRVE), and arteriole-to-venule-ratio (AVR) from these images. We used SAGE version 6.2 and SAS version 9.2 to compute multivariate-adjusted estimates of heritability and intrafamilial correlations of the CRAE, CRVE, and AVR of the retinal microvessels in the images. RESULTS Sex, age, mean arterial pressure, and smoking explained up to 12.7% of the variance of the phenotypes of the retinal microvessels of the study participants. With adjustments applied for these covariates, the heritability estimates of CRAE, CRVE, and AVR were 0.213 (P = 0.044), 0.339 (P = 0.010), and 0.272 (P = 0.004), respectively. The parent-offspring correlations for CRAE, CRVE, and AVR were 0.118 (NS), 0.225 (P < 0.01), and 0.215 (P < 0.05), respectively. The corresponding values were 0.222 (P < 0.05), 0.213 (P < 0.05), and 0.390 (P < 0.001) for sib-sib correlations, respectively. The genetic and environmental correlations between CRAE and CRVE were 0.360 and 0.545 (P < 0.001 for both). CONCLUSION Our study showed moderate heritability for CRAE, CRVE, and AVR, and a significant genetic correlation of CRAE with CRVE in the Flemish population of our study. These findings suggest that genetic factors influence the diameter of the retinal microvessels, and that CRAE and CRVE share some genetic determinants.

Susceptibility and adaptation to human TRIM5α alleles at positive selected sites in HIV-1 capsid.

Numerous in vitro studies attribute to human TRIM5α some modest anti-HIV-1 activity and human population studies suggest some differential effect of TRIM5α polymorphisms on disease progression. If the activity of TRIM5α were relevant in vivo, it could result in positive selection on the viral capsid. To address this issue, we identified 10 positively selected sites in HIV-1 capsid from multiple viral strains and generated 17 clade B viruses carrying a minor (i.e. low frequency) residue or an alanine at those positions. All recombinant viruses were susceptible to the modest effect of common human TRIM5α and allelic variants R136Q, and H419Y; H43Y and G249D TRIM5α were generally inactive. Increased sensitivity to TRIM5α was observed for some capsid variants, suggesting that minor residues are selected against in human populations. On the other hand, the modest potency of human TRIM5α does not translate in escape mutations in the viral capsid.

Profiling of steroid metabolites after transdermal and oral administration of testosterone by ultra-high pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

The screening of testosterone (T) misuse for doping control is based on the urinary steroid profile, including T, its precursors and metabolites. Modifications of individual levels and ratio between those metabolites are indicators of T misuse. In the context of screening analysis, the most discriminant criterion known to date is based on the T glucuronide (TG) to epitestosterone glucuronide (EG) ratio (TG/EG). Following the World Anti-Doping Agency (WADA) recommendations, there is suspicion of T misuse when the ratio reaches 4 or beyond. While this marker remains very sensitive and specific, it suffers from large inter-individual variability, with important influence of enzyme polymorphisms. Moreover, use of low dose or topical administration forms makes the screening of endogenous steroids difficult while the detection window no longer suits the doping habit. As reference limits are estimated on the basis of population studies, which encompass inter-individual and inter-ethnic variability, new strategies including individual threshold monitoring and alternative biomarkers were proposed to detect T misuse. The purpose of this study was to evaluate the potential of ultra-high pressure liquid chromatography (UHPLC) coupled with a new generation high resolution quadrupole time-of-flight mass spectrometer (QTOF-MS) to investigate the steroid metabolism after transdermal and oral T administration. An approach was developed to quantify 12 targeted urinary steroids as direct glucuro- and sulfo-conjugated metabolites, allowing the conservation of the phase II metabolism information, reflecting genetic and environmental influences. The UHPLC-QTOF-MS(E) platform was applied to clinical study samples from 19 healthy male volunteers, having different genotypes for the UGT2B17 enzyme responsible for the glucuroconjugation of T. Based on reference population ranges, none of the traditional markers of T misuse could detect doping after topical administration of T, while the detection window was short after oral TU ingestion. The detection ability of the 12 targeted steroids was thus evaluated by using individual thresholds following both transdermal and oral administration. Other relevant biomarkers and minor metabolites were studied for complementary information to the steroid profile, including sulfoconjugated analytes and hydroxy forms of glucuroconjugated metabolites. While sulfoconjugated steroids may provide helpful screening information for individuals with homozygotous UGT2B17 deletion, hydroxy-glucuroconjugated analytes could enhance the detection window of oral T undecanoate (TU) doping.

Live trapping design for the harvest mouse (Micromys minutus) in its summer habitat

documented accurately since 1960. Most records are based on nest findings and there have been few direct observations or captures, mainly because live trapping of this species is not simple. Therefore, an efficient trapping technique is needed for population studies and to facilitate the management of its habitat. By combining the methods used to capture very small (Suncus etruscus) and climbing (Muscardinus avellanarius) mammals, we developed a design using Longworth traps with mouse excluders set on suspended platforms. This allowed us to trap more harvest mice in four field sessions of 60 trap-nights than have ever been caught previously since its discovery in Switzerland.

Trimodal therapy for invasive bladder cancer: is it really equal to radical cystectomy?

PURPOSE OF REVIEW: Trimodal therapy (TMT) is considered the most effective bladder-sparing approach for muscle-invasive urothelial carcinoma of the bladder (MIBC) and an alternative to radical cystectomy. The purpose of this article was to review and summarize the current knowledge on the equivalence of TMT and radical cystectomy based on the recent literature. RECENT FINDINGS: TMT consists of a maximal transuretral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy, limiting salvage radical cystectomy to nonresponder tumors or muscle-invasive recurrence. In large population studies, less than 6% of the patients with nonmetastatic MIBC receive a chemoradiation therapy and this rate is stable. A growing body of evidence exists that TMT provides good oncologic outcomes with low morbidity when compared with radical cystectomy. TMT requires, however, a close follow-up because of the high risk of local recurrence and salvage radical cystectomy in up to 30% of the patients. Salvage radical cystectomy can be performed with adequate results but does not offer the same opportunity of reconstruction and functional outcomes than primary radical cystectomy. SUMMARY: Although radical cystectomy is still the treatment of reference for most of the patients with localized MIBC, TMT represents a reasonable alternative in highly selected patients. Any firm conclusion on the equivalence or superiority of one treatment to the other is still limited by the lack of randomized controlled trials and the heterogeneity of the available literature. Future studies and multidisciplinary approach are mandatory to optimize the patient selection and regimen of TMT.

A systematic review of longitudinal population-based studies on the predictors of smoking cessation in adolescent and young adult smokers

Le tabagisme est responsable de plus de 5 million de décès par an à travers le monde. En Suisse (2010), la prévalence de fumeurs chez les 14-19 ans était de 22% et la prévalence d'ex-fumeurs de 3%, taux qui reste relativement stable au fil des dernières années. La plupart des jeunes fumeurs désirant arrêter de fumer rencontrent des difficultés pour y parvenir. Les revues empiriques ont conclu que les programmes ayant pour but l'arrêt du tabagisme chez les jeunes ont une efficacité limitée. Afin de fournir une base solide de connaissances pour les programmes d'interventions contre le tabagisme, les déterminants de l'auto-cessation ont besoin d'être compris. Nous avons systématiquement recherché dans PUBMED et EMBASE des études longitudinales, basées sur la population, portant sur les déterminants de l'auto-cessation chez des adolescents et des jeunes adultes fumeurs. Nous avons passé en revue 4'502 titres et 871 abstracts, tous examinés indépendamment par deux et trois examinateurs, respectivement. Les critères d'inclusion étant : articles publiés entre janvier 1984 et août 2010, concernant les jeunes entre 10 et 29 ans et avoir une définition de cessation de fumer d'au moins 6 mois. Neuf articles ont été retenus pour une analyse détaillée. Les données suivantes ont été extraites de chaque article : le lieu de l'étude, la période étudiée, la durée du suivi, le nombre de collecte de données, la taille de l'échantillon, l'âge ou l'année scolaire des participants, le nombre de participants qui arrêtent de fumer, le status tabagique lors de la première collecte, la définition de cessation, les co-variantes et la méthode analytique. Le nombre d'études qui montrent une association significativement significative entre un déterminant et l'arrêt du tabagisme a été tabulé à partir de toutes les études qui ont évalués ce déterminant. Trois des neufs articles retenus ont défini l'arrêt du tabagisme comme une abstinence de plus de 6 mois et les six autres comme 12 mois d'abstinence. Malgré l'hétérogénéité des méthodes utilisées, cinq facteurs principaux ressortent comme prédicteur de l'arrêt du tabagisme : 1) ne pas avoir d'amis qui fument, 2) ne pas avoir l'intention de continuer de fumer dans le futur, 3) résister à la pression sociale, 4) être âgé de plus de 18 ans lors de la première cigarette, et 5) avoir un avis négatif au sujet du tabagisme. D'autres facteurs sont significatifs mais ne sont évalués que dans peu d'articles. La littérature au sujet des prédicteurs de cessation chez les adolescents et les jeunes adultes est peu développée. Cependant, nous remarquons que les facteurs que nous avons mis en évidence ne dépendent pas que de l'individu, mais aussi de l'environnement. La prévention du tabagisme peut se centrer sur les bienfaits de l'arrêt (p.ex., par rapport à l'asthme ou les performances sportives) et ainsi motiver les jeunes gens à songer d'arrêter de fumer. Une taxation plus lourde sur le prix des cigarettes peut être envisagée afin de retarder l'âge de la première cigarette. Les publicités anti-tabagiques (non sponsorisées par les entreprises de tabac) peuvent influencer la perception des jeunes par rapport au tabagisme, renforçant ou créant une attitude anti-tabagique. Les prochaines campagnes anti- tabac devraient donc tenir compte de ces différents aspects.

Pragmatic approach for interpreting antiretroviral drug concentrations based on a systematic review of population pharmacokinetic studies

Objectives: The study objective was to derive reference pharmacokinetic curves of antiretroviral drugs (ART) based on available population pharmacokinetic (Pop-PK) studies that can be used to optimize therapeutic drug monitoring guided dosage adjustment.¦Methods: A systematic search of Pop-PK studies of 8 ART in adults was performed in PubMed. To simulate reference PK curves, a summary of the PK parameters was obtained for each drug based on meta-analysis approach. Most models used one-compartment model, thus chosen as reference model. Models using bi-exponential disposition were simplified to one-compartment, since the first distribution phase was rapid and not determinant for the description of the terminal elimination phase, mostly relevant for this project. Different absorption were standardized for first-order absorption processes.¦Apparent clearance (CL), apparent volume of distribution of the terminal phase (Vz) and absorption rate constant (ka) and inter-individual variability were pooled into summary mean value, weighted by number of plasma levels; intra-individual variability was weighted by number of individuals in each study.¦Simulations based on summary PK parameters served to construct concentration PK percentiles (NONMEM®).¦Concordance between individual and summary parameters was assessed graphically using Forest-plots. To test robustness, difference in simulated curves based on published and summary parameters was calculated using efavirenz as probe drug.¦Results: CL was readily accessible from all studies. For studies with one-compartment, Vz was central volume of distribution; for two-compartment, Vz was CL/λz. ka was directly used or derived based on the mean absorption time (MAT) for more complicated absorption models, assuming MAT=1/ka.¦The value of CL for each drug was in excellent agreement throughout all Pop-PK models, suggesting that minimal concentration derived from summary models was adequately characterized. The comparison of the concentration vs. time profile for efavirenz between published and summary PK parameters revealed not more than 20% difference. Although our approach appears adequate for estimation of elimination phase, the simplification of absorption phase might lead to small bias shortly after drug intake.¦Conclusions: Simulated reference percentile curves based on such an approach represent a useful tool for interpretating drug concentrations. This Pop-PK meta-analysis approach should be further validated and could be extended to elaborate more sophisticated computerized tool for the Bayesian TDM of ART.

Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.

Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.