Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.

BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

Effect of age on toxicokinetics among human volunteers exposed to propylene glycol methyl ether (PGME)

Aging adults represent the fastest growing population segment in many countries. Physiological and metabolic changes in the aging process may alter how aging adults biologically respond to pollutants. In a controlled human toxicokinetic study (exposure chamber; 12 m³), aging volunteers (n=10; >58 years) were exposed to propylene glycol monomethyl ether (PGME, CAS no. 107-98-2) at 50 ppm for 6 h. The dose-dependent renal excretion of oxidative metabolites, conjugated and free PGME could potentially be altered by age. AIMS: (1) Compare PGME toxicokinetic profiles between aging and young volunteers (20-25 years) and gender; (2) test the predictive power of a compartmental toxicokinetic (TK) model developed for aging persons against urinary PGME concentrations found in this study. METHODS: Urine samples were collected before, during, and after the exposure. Urinary PGME was quantified by capillary GC/FID. RESULTS: Differences in urinary PGME profiles were not noted between genders but between age groups. Metabolic parameters had to be changed to fit the age adjusted TK model to the experimental results, implying a slower enzymatic pathway in the aging volunteers. For an appropriate exposure assessment, urinary total PGME should be quantified. CONCLUSION: Age is a factor that should be considered when biological limit values are developed.

Generation of reconstituted human plasma-derived secretory-like IgA and IgM and their protective effect on intestinal epithelium

Les muqueuses sont les membranes tapissant les cavités du corps, tel que le tube digestif, et sont en contact direct avec l'environnement extérieur. Ces surfaces subissent de nombreuses agressions pouvant être provoquées par des agents pathogènes (bactéries, toxines ou virus). Cela étant, les muqueuses sont munies de divers mécanismes de protection dont notamment deux protéines-clés permettant de neutraliser les agents pathogènes : les anticorps ou immunoglobulines sécrétoires A (SIgA) et M (SIgM). Ces anticorps sont, d'une part, fabriqués au niveau de la muqueuse sous forme d'IgA et IgM. Lorsqu'ils sont sécrétés dans l'intestin, ils se lient à une protéine appelée pièce sécrétoire et deviennent ainsi SIgA et SïgM. La présence de la pièce sécrétoire est essentielle pour que les anticorps puissent fonctionner au niveau de la muqueuse. D'autre part, ces anticorps sont également fabriqués dans d'autres parties du corps en général et se retrouvent dans le sang sous forme d'IgA et IgM Chez l'homme, des thérapies basées sur l'injection d'anticorps donnent de bons résultats depuis de nombreuses années notamment dans le traitement des infections. Bien qu'un certain nombre d'études ont montré le rôle protecteur des anticorps de type IgA et IgM, ceux-ci ne sont que rarement utilisés dans les thérapies actuelles. La principale raison de cette faible utilisation réside dans la production ou la purification des IgA/IgM ou SIgA/SIgM (la forme active au niveau des muqueuses) qui est difficile à réaliser à large échelle. Ainsi, le but de la thèse était (1) d'étudier la possibilité d'employer des IgA et des IgM provenant du sang humain pour générer des SIgA et SIgM et (2) de voir si ces anticorps reconstitués pouvaient neutraliser certains agents pathogènes au niveau des muqueuses. Tout d'abord, une analyse biochimique des IgA et des IgM issues du sang a été effectuée. Nous avons observé que ces anticorps avaient des caractéristiques similaires aux anticorps naturellement présents au niveau des muqueuses. De plus, nous avons confirmé que ces anticorps pouvaient être associés à une pièce sécrétoire produite en laboratoire pour ainsi donner des SIgA et SIgM reconstituées. Ensuite, la fonctionnalité des anticorps reconstitués a été testée grâce à un modèle de couche unique de cellules intestinales différenciées (monocouches) en laboratoire imitant la paroi de l'intestin. Ces monocouches ont été infectées par une bactérie pathogène, Shigella flexneri, responsable de la shigellose, une maladie qui provoque des diarrhées sanglantes chez l'homme. L'infection des monocouches par les bactéries seules ou combinées aux SIgA et SIgM reconstituées a été analysée. Nous avons observé que les dommages des cellules étaient moins importants lorsque les SIgA étaient présentes. Il apparaît que les SIgA neutralisent les bactéries en se fixant dessus, ce qui provoque leur agrégation, et diminuent l'inflammation des cellules. La protection s'est montrée encore plus efficace avec les SIgM. De plus, nous avons vu que les SIgA et SIgM pouvaient diminuer la sécrétion de facteurs nocifs produits par les bactéries. Utilisant le même modèle des monocouches, la fonctionnalité des IgA issues du sang humain a aussi été testée contre une toxine sécrétée par une bactérie appelée Clostridium diffìcile. Cette bactérie peut être présente naturellement dans l'intestin de personnes saines, cependant elle peut devenir pathogène dans certaines conditions et être à l'origine de diarrhées et d'inflammations de l'intestin via la sécrétion de toxines. Des préparations d'anticorps contenant une certaine proportion de SIgA reconstituées ont amené à une diminution des dommages et de l'inflammation des monocouches causés par la toxine. L'ensemble de ces résultats prometteurs, montrant que des SIgA et SIgM reconstituées peuvent protéger la paroi de l'intestin des infections bactériennes, nous conduisent à approfondir la recherche sur ces anticorps dans des modèles animaux. L'aboutissement de ce type de recherche permettrait de tester, par la suite, l'efficacité sur l'homme de traitements des infections des muqueuses par injection d'anticorps de type SIgA et SIgM reconstituées. Les muqueuses, telle que la muqueuse gastrointestinale, sont des surfaces constamment exposées à l'environnement et leur protection est garantie par une combinaison de barrières mécaniques, physicochimiques et immunologiques. Parmi les divers mécanismes de protection immunologiques, la réponse humorale spécifique joue un rôle prépondérant et est assurée par les immunoglobulines sécrétoires de type A (SIgA) et M (SIgM). Les thérapies basées sur l'administration d'IgG apportent d'importants bénéfices dans le domaine de la santé. Bien que des études sur les animaux aient montré que l'administration par voie muqueuse d'IgA polymérique (plgA) ou SIgA pouvaient protéger des infections, des IgA/SIgA n'ont été utilisées qu'occasionnellement dans les thérapies. De plus, des études précliniques et cliniques ont démontré que l'administration par voie systémique de préparations enrichies en IgM pouvait aussi protéger des infections. Cependant, l'administration par voie muqueuse d'IgM/SIgM purifiées n'a pas été examinée jusqu'à présent. La principale raison est que la purification ou là production des IgA/SIgA et IgM/SIgM est difficile à réaliser à large échelle. Le but de ce travail de thèse était d'examiner la possibilité d'associer des IgA et IgM polyclonals purifiées à partir du plasma humain avec une pièce sécrétoire recombinante humaine afin de générer des SIgA et SIgM reconstituées fonctionnelles. Tout d'abord, une analyse biochimique des IgA et IgM issues du plasma humain a été effectuée par buvardage de western et Chromatographie. Ces molécules avaient des caractéristiques biochimiques similaires à celles des immunoglobulines issues de la muqueuse. L'association entre plgA ou IgM issues du plasma humain et la pièce sécrétoire recombinante humaine a été confirmée, ainsi que la stoechiométrie 1:1 de l'association. Comme dans les conditions physiologiques, cette association permettait de retarder la dégradation des SIgA et SIgM reconstituées exposées à des protéases intestinales. Ensuite, la fonctionnalité et le mode d'action des IgA et IgM issues du plasma humain, ainsi que des SIgA et SIgM reconstituées, ont été explorés grâce à un modèle in vitro de monocouches de cellules intestinales épithéliales polarisées de type Caco-2, qui imite l'épithélium intestinal. Les monocouches ont été infectées par un pathogène entérique, Shigella flexneri, seul ou combiné aux immunoglobulines issues du plasma humain ou aux immunoglobulines sécrétoires reconstituées. Bien que les dommages des monocouches aient été retardés par les plgA et SIgA reconstituées, les IgM et SIgM reconstituées se sont montrées supérieures dans le maintien de l'intégrité des cellules. Une agrégation bactérienne et une diminution de l'inflammation des monocouches ont été observées avec les plgA et SIgA reconstituées. Ces effets étaient augmentés avec les IgM et SIgM reconstituées. De plus, il s'est révélé que les deux types d'immunoglobulines de type sécrétoire reconstituées agissaient directement sur la virulence des bactéries en réduisant leur sécrétion de facteurs de virulence. La fonctionnalité des IgA issues du plasma humain a aussi été testée contre la toxine A de Clostridium difficile grâce au même modèle de monocouches de cellules épithéliales. Nous avons démontré que des préparations enrichies en IgA provenant du plasma humain pouvaient diminuer les dommages et l'inflammation des monocouches induits par la toxine. L'ensemble de ces résultats démontrent que des IgA et IgM de type sécrétoire peuvent être générées à partir d'IgA et IgM issues du plasma humain en les associant à la pièce sécrétoire et que ces molécules protègent l'épithélium intestinal contre des bactéries pathogènes. Ces molécules pourraient dès lors être testées dans des modèles in vivo. Le but final serait de les utiliser chez l'homme à des fins d'immunisation passive dans le traitement de pathologies associées à la muqueuse telles que les infections. - Mucosal surfaces, such as gastrointestinal mucosa, are constantly exposed to the external environment and their protection is ensured by a combination of mechanical, physicochemical and immunological barriers. Among the various immunological defense mechanisms, specific humoral mucosal response plays a crucial role and is mediated by secretory immunoglobulins A (SIgA) and M (SIgM). Immunoglobulin therapy based on the administration of IgG molecules leads important health benefits. Even though animal studies have shown that mucosal application of polymeric IgA (plgA) or SIgA provided protection against infections, IgA/SIgA have been only used occasionally for therapeutic application. Moreover, preclinical and clinical studies have demonstrated that systemic administration of IgM-enriched preparations could also afford protection against infections. Nevertheless, mucosal application of purified IgM/SIgM has not been examined. The main reason is that the purification or production of IgA/SIgA and IgM/SIgM at large scale is difficult to achieve. The aim of this PhD project was to examine the possibility to associate polyclonal human plasma-derived IgA and IgM with recombinant human secretory component (SC) to generate functional secretoiy-like IgA and IgM. First, biochemical analysis of human plasma IgA and IgM was performed by western blotting and chromatography. These molecules exhibited the same biochemical features as mucosa-derived antibodies (Abs). The association between human plasma plgA or IgM and recombinant human SC was confirmed, as well as the 1:1 stoichiometry of association. Similarly to physiological conditions, this association delayed the degradation of secretory-like IgA or IgM by intestinal proteases. Secondly, the function activity and the mode of action of human plasma IgA and IgM, as well as secretory-like IgA and IgM were explored using an in vitro model of polarized intestinal epithelial Caco-2 cell monolayers mimicking intestinal epithelium. Cell monolayers were infected with an enteropathogen, Shigella flexneri, alone or in combination to plasma Abs or secretory-like Abs. Even though plasma plgA and secretoiy-like IgA resulted in a delay of bacteria-induced damages of cell monolayers, plasma IgM and secretory-like IgM were shown to be superior in maintenance of cell integrity. Polymeric IgA and secretory-like IgA induced bacterial aggregation and decreased cell monolayer inflammation, effects further amplified with IgM and secretory-like IgM. In addition, both secretory-like Abs directly impacted on bacterial virulence leading to a reduction in secretion of virulence factors by bacteria. The functionality of human plasma IgA was also tested against Clostridium difficile toxin A using Caco-2 cell monolayers. Human plasma IgA- enriched preparations led to a diminution of cell monolayer damages and a decrease of cellular inflammation induced by the toxin. The sum of these results demonstrates that secretory-like IgA and IgM can be generated from purified human plasma IgA and IgM associated to SC and that these molecules are functional to protect intestinal epithelium from bacterial infections. These molecules could be now tested using in vivo models. The final goal would be to use them by passive immunization in the treatment of mucosa-associated pathologies like infections in humans.

Profiles of drug users in Switzerland and effects of early-onset intensive use of alcohol, tobacco and cannabis on other illicit drug use.

QUESTIONS UNDER STUDY / PRINCIPLES: The main aim of this study was to investigate profiles of drug users, with a particular focus on illicit drugs other than cannabis, and to explore the effect of early-onset intensive use (drunkenness, daily smoking, high on cannabis) on profiles of illicit drug use. METHODS: Baseline data from a representative sample of 5,831 young Swiss men in the ongoing Cohort Study on Substance Use Risk Factors were used. Substance use (alcohol, tobacco, cannabis and 15 types of other illicit drug) and age of onset of intensive use were assessed. The Item Response Theory (IRT) and prevalence rates at different ages of onset were used to reveal different profiles of illicit drug use. RESULTS: In addition to cannabis, there were two profiles of other illicit drug use: (a) "softer" drug users (uppers, hallucinogens and inhaled drugs), among which ecstasy had the highest discriminatory potential (IRT slope = 4.68, standard error (SE) = 0.48; p <0.001); and (b) "harder" drug users (heroin, ketamine, gamma-hydroxybutyrate/gamma-hydroxylactone, research chemicals, crystal meth and spice), among which ketamine had the highest discriminatory potential (slope = 4.05; SE = 0.63; p <0.001). Onset of intensive use at the age of 12 years or younger also discriminated between these two profiles. CONCLUSION: Both the IRT model and the effect of onset of intensive use enabled two groups of illicit drugs to be identified. In particular, very early onset (at 12 years or younger) intensive use of any substance was a marker for later use of the second group of drugs.

The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse.

Catecholamines and alpha(1)-adrenergic receptors (alpha(1)-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main alpha(1)-AR subtypes, alpha(1A/C) and alpha(1B). Here we tested whether alpha(1)-ARs are required for developmental cardiac hypertrophy by generating alpha(1A/C) and alpha(1B) double KO (ABKO) mice, which had no cardiac alpha(1)-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. alpha(1)-AR stimulation did not activate extracellular signal-regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, alpha(1)-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress.

Alcohol consumption and incidence of type 2 diabetes. Results from the CoLaus study.

BACKGROUND AND AIMS: Moderate alcohol consumption has been shown to decrease the risk of type 2 diabetes (T2DM), but whether this association is also valid for impaired fasting glucose (IFG) is less well known. We aimed at assessing the impact of alcohol consumption and of type of alcoholic beverage on the incidence of T2DM and T2DM + IFG. METHODS AND RESULTS: As many as 4765 participants (2613 women, mean age 51.7 ± 10.5 years) without T2DM at baseline and followed for an average of 5.5 years. The association between alcohol consumption, type of alcoholic beverage and outcomes was assessed after adjustment for a validated T2DM risk score. During follow-up 284 participants developed T2DM and 643 developed IFG. On bivariate analysis, alcohol consumption was positively associated with the risk of developing T2DM or T2DM + IFG. Moderate (14-27 units/week) alcohol consumption tended to be associated with a lower risk of T2DM, but no protective effect was found for T2DM + IFG. Multivariable-adjusted odds ratio (OR) and (95% confidence interval) for T2DM: 0.89 (0.65-1.22), 0.66 (0.42-1.03) and 1.63 (0.93-2.84) for 1-13, 14-27 and 28 + units/week, respectively (p for quadratic trend < 0.005). For T2DM + IFG, the corresponding ORs were 1.09 (0.90-1.32), 1.33 (1.02-1.74) and 1.54 (0.99-2.39), respectively, p for trend = 0.03. No specific effect of alcoholic beverage (wine, beer or spirits) was found for T2DM or for T2DM + IFG. CONCLUSION: Moderate alcohol consumption is associated with a reduced risk of developing T2DM, but not of developing T2DM + IFG. No specific effect of type of alcoholic beverage was found.

Predicted effect of climate change on the invasibility and distribution of the Western corn root-worm

1 Insect pests, biological invasions and climate change are considered to representmajor threats to biodiversity, ecosystem functioning, agriculture and forestry.Deriving hypothesis of contemporary and/or future potential distributions of insectpests and invasive species is becoming an important tool for predicting the spatialstructure of potential threats.2 The western corn rootworm (WCR) Diabrotica virgifera virgifera LeConte is apest of maize in North America that has invaded Europe in recent years, resultingin economic costs in terms of maize yields in both continents. The present studyaimed to estimate the dynamics of potential areas of invasion by the WCR under aclimate change scenario in the Northern Hemisphere. The areas at risk under thisscenario were assessed by comparing, using complementary approaches, the spatialprojections of current and future areas of climatic favourability of the WCR. Spatialhypothesis were generated with respect to the presence records in the native rangeof the WCR and physiological thresholds from previous empirical studies.3 We used a previously developed protocol specifically designed to estimatethe climatic favourability of the WCR. We selected the most biologicallyrelevant climatic predictors and then used multidimensional envelope (MDE) andMahalanobis distances (MD) approaches to derive potential distributions for currentand future climatic conditions.4 The results obtained showed a northward advancement of the upper physiologicallimit as a result of climate change, which might increase the strength of outbreaksat higher latitudes. In addition, both MDE and MD outputs predict the stability ofclimatic favourability for the WCR in the core of the already invaded area in Europe,which suggests that this zone would continue to experience damage from this pestin Europe.

Maternal effect on female caste determination in a social insect.

Caste differentiation and division of labor are the hallmarks of social insect colonies [1, 2]. The current dogma for female caste differentiation is that female eggs are totipotent, with morphological and physiological differences between queens and workers stemming from a developmental switch during the larval stage controlled by nutritional and other environmental factors (e.g., [3-8]). In this study, we tested whether maternal effects influence caste differentiation in Pogonomyrmex harvester ants. By conducting crossfostering experiments we identified two key factors in the process of caste determination. New queens were produced only from eggs laid by queens exposed to cold. Moreover, there was a strong age effect, with development into queens occurring only in eggs laid by queens that were at least two years old. Biochemical analyses further revealed that the level of ecdysteroids was significantly lower in eggs developing into queens than workers. By contrast, we found no significant effect of colony size or worker exposure to cold, suggesting that the trigger for caste differentiation may be independent of the quantity and quality of resources provided to larvae. Altogether these data demonstrate that the developmental fate of female brood is strongly influenced by maternal effects in ants of the genus Pogonomyrmex.

Efficacy of brief motivational intervention at army conscription to address alcohol use and related problems: a randomized controlled trial

Objectives: The aim of this study was to evaluate the efficacy of brief motivational intervention (BMI) in reducing alcohol use and related problems among binge drinkers randomly selected from a census of 20 year-old French speaking Swiss men and to test the hypothesis that BMI contributes to maintain low-risk drinking among non-bingers. Methods: Randomized controlled trial comparing the impact of BMI on weekly alcohol use, frequency of binge drinking and occurrence of alcohol-related problems. Setting: Army recruitment center. Participants: A random sample of 622 men were asked to participate, 178 either refused, or missed appointment, or had to follow military assessment procedures instead, resulting in 418 men randomized into BMI or control conditions, 88.7% completing the 6-month follow-up assessment. Intervention: A single face-to-face BMI session exploring alcohol use and related problems in order to stimulate behaviour change perspective in a non-judgmental, empathic manner based on the principles of motivational interviewing (MI). Main outcome measures: Weekly alcohol use, binge drinking frequency and the occurrence of 12 alcohol-related consequences. Results: Among binge drinkers, we observed a 20% change in drinking induced by BMI, with a reduction in weekly drinking of 1.5 drink in the BMI group, compared to an increase of 0.8 drink per week in the control group (incidence rate ratio 0.8, 95% confidence interval 0,66 to 0,98, p = 0.03). BMI did not influence the frequency of binge drinking and the occurrence of 12 possible alcohol-related consequences. However, BMI induced a reduction in the alcohol use of participants who, after drinking over the past 12 months, experienced alcohol-related consequences, i.e., hangover (-20%), missed a class (-53%), got behind at school (-54%), argued with friends (-38%), engaged in unplanned sex (-45%) or did not use protection when having sex (-64%). BMI did not reduce weekly drinking in those who experienced the six other problems screened. Among non-bingers, BMI did not contribute to maintain low-risk drinking. Conclusions: At army conscription, BMI reduced alcohol use in binge drinkers, particularly in those who recently experienced alcohol-related adverse consequences. No preventive effect of BMI was observed among non-bingers. BMI is an interesting preventive option in young binge drinkers, particularly in countries with mandatory army recruitment.

Synergistic effect of calcitriol and interferon-α on hepatitis C virus replication in vitro

Background and aims: V itamin D is an important modulator o fnumerous c ellular processes, including innate and adaptive immunepathways. A recent large-scale genetic validation study performed withinthe framework of the Swiss Hepatitis C Cohort S tudy has demonstratedan association between t he 1α-hydroxylase promoter single nucleotidepolymorphism CYP27B1-1260 rs10877012 and sustained virologicresponse (SVR) after pegylated interferon-α ( PEG-IFN-α) plus ribavirintreatment of c hronic hepatitis C in patients w ith a p oor-response IL28Bgenotype. This suggests an intrinsic role o f vitamin D signaling in theresponse t o treatment of chronic hepatitis C, especially in patients withlimited sensitivity to IFN-α. In the present study, we investigated theeffect of 1,25-(OH)2 v itamin D3 (calcitriol) alone or in combination withIFN-α on the hepatitis C virus (HCV) life cycle in vitro.Methods: H uh-7.5 cells harboring Con1- or JFH-1-derived HCVreplicons or cell culture-derived HCV were exposed to 0.1-100 nMcalcitriol ± 1 -100 IU/ml IFN-α. The effect on HCV RNA replication andviral particle production was investigated by quantitative r eal-time PCR,immunoblot analyses, and infectivity titration analyses. The expression ofinterferon-stimulated genes (ISGs) and of calcitriol target genes wasassessed by quantitative real-time PCR.Results: Calcitriol had no relevant effect on the viability of Huh-7.5 cells.Calcitriol strongly induced and repressed the expression of the calcitrioltarget genes CYP24A1 and CCNC, respectively, confirming that Huh-7.5cells c an respond to c alcitriol signaling. P hysiological doses of calcitrioldid not significantly a ffect HCV RNA replication or i nfectious particleproduction in vitro, and calcitriol alone h ad no significant effect on theexpression of several ISGs. However, calcitriol in combination with IFN-αsubstantially increased the expression of ISGs compared to IFN-α alone.In addition, calcitriol plus IFN-α s ynergistically inhibited HCV RNAreplication.Conclusions: C alcitriol at physiological concentrations and IFN-α a ctsynergistically on the expression of I SGs and HCV RNA replication i nvitro. Experiments exploring the underlying mechanisms are underway.

Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

BACKGROUND: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. METHODS: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). RESULTS: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). CONCLUSIONS: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases.

Effect of age toxicokinetics among human volunteers exposed to propylene glycol monomethyl ether (PGME)

Rationale: Aging adults represent the fastest growing population segment in many countries. Physiological and metabolic changes in the aging process may alter how aging adults respond to exposures compared to younger workers. Current preventive workplace exposure measures may therefore not be sufficiently protective for the aging workforce. In a controlled human toxicokinetic study (exposure chamber; 12m3), the volunteers (n=11) were men and women over the age of 58 years and exposed to a commonly used, low neurotoxic glycol ether; PGME (CAS no. 107-98- 2) (50 ppm, 6 hours). Oxidative metabolism (Michaelis-Menten) is the major pathway and conjugation the minor in humans. Metabolites, conjugated and free PGME are eliminated through the kidneys, and the elimination kinetics is dose-dependent (0 order). Scope: (1) compare the toxicokinetic profile of PGME obtained in the aging volunteers (58- 62 years) to young volunteers (20-25 years) from a previous study; (2) Test the predictive power of an existing PGME toxicokinetic compartment model for aging persons against urinary PGME concentrations found in volunteers from our experimental study. Experimental procedure: Urine samples were collected before, every 2-hour during exposures for six hours, and ad-lib for additional 20 hours. Urinary analysis of free and total PGME was performed using capillary GC/FID. The toxicokinetic model (Berkley Madonna software) was ageadjusted. Results. Urinary free and total PGME concentration rose rapidly, and did not reach an apparent plateau level during exposure. Less conjugation was observed in the older group. The predictive model developed for the young group predicted well total PGME in the aging group but not free PGME. The age adjusted toxicokinetic model's Vmax1 had to be changed for the aging group, implying slower enzymatic pathway. Conclusion: The toxicokinetic model did not predict well if only the physiological parameters were adjusted for aging adults (existing model); a substance specific metabolic rate parameter was also needed.

Effect of multiple oral doses of androgenic anabolic steroids on endurance performance and serum indices of physical stress in healthy male subjects.

Anabolic androgenic steroids (AAS) are doping agents that are mostly used for improvement of strength and muscle hypertrophy. In some sports, athletes reported that the intake of AAS is associated with a better recovery, a higher training load capacity and therefore an increase in physical and mental performances. The purpose of this study was to evaluate, the effect of multiple doses of AAS on different physiological parameters that could indirectly relate the physical state of athletes during a hard endurance training program. In a double blind settings, three groups (n = 9, 8 and 8) were orally administered placebo, testosterone undecanoate or 19-norandrostenedione, 12 times during 1 month. Serum biomarkers (creatine kinase, ASAT and urea), serum hormone profiles (testosterone, cortisol and LH) and urinary catecholamines (noradrenalin, adrenalin and dopamine) were evaluated during the treatment. Running performance was assessed before and after the intervention phase by means of a standardized treadmill test. None of the measured biochemical variables showed significant impact of AAS on physical stress level. Data from exercise testing on submaximal and maximal level did not reveal any performance differences between the three groups or their response to the treatment. In the present study, no effect of multiple oral doses of AAS on endurance performance or bioserum recovery markers was found.

Role of substrate utilization and thermogenesis on body-weight control with particular reference to alcohol.

Alcohol (ethanol; EtOH) provides fuel energy to the body (29.7 kJ (7. 1 kcal)/g, 23.4 kJ (5.6 kcal)/ml), as do other macronutrients, but no associated essential nutrients. The thermogenic effect of EtOH (on average 15 % of its metabolizable value) is much greater than that of the main substrates utilized by the body, i.e. fat and carbohydrates (CHO), suggesting a lower net efficiency of energy utilization for EtOH than for fat and CHO. EtOH cannot be stored in the body and is toxic, so that there is an obligatory continuous oxidation of EtOH and it becomes the priority fuel to be metabolized. In contrast to CHO, its rate of oxidation does not depend on the dose ingested. As with CHO intake, it engenders a shift in postprandial substrate utilization (decrease in fat oxidation), but by a non-insulin-mediated mechanism. A limited amount of EtOH can be converted to fatty acids by hepatic de novo lipogenesis (as occurs with high levels of CHO feeding) from acetate production, which inhibits lipolysis in peripheral tissues. There is no evidence that EtOH consumed under normoenergetic conditions (i.e. isoenergetically replacing CHO or fat) leads to greater body fat storage than fat or CHO. However, there is still a lack of experimental studies on the influence of EtOH on the level of spontaneous physical activity in man. This effect may well depend on the dose of EtOH consumed as well as other intrinsic factors.

Housewife or working mum--each to her own? The relevance of societal factors in the association between social roles and alcohol use among mothers in 16 industrialized countries.

Aims To investigate whether differences in gender-income equity at country level explain national differences in the links between alcohol use, and the combination of motherhood and paid labour. Design Cross-sectional data in 16 established market economies participating in the Gender, Alcohol and Culture: An International Study (GenACIS) study. Setting Population surveys. Participants A total of 12 454 mothers (aged 25-49 years). Measurements Alcohol use was assessed as the quantity per drinking day. Paid labour, having a partner, gender-income ratio at country level and the interaction between individual and country characteristics were regressed on alcohol consumed per drinking day using multi-level modelling. Findings Mothers with a partner who were in paid labour reported consuming more alcohol on drinking days than partnered housewives. In countries with high gender-income equity, mothers with a partner who were in paid labour drank less alcohol per occasion, while alcohol use was higher among working partnered mothers living in countries with lower income equity. Conclusion In countries which facilitate working mothers, daily alcohol use decreases as female social roles increase; in contrast, in countries where there are fewer incentives for mothers to remain in work, the protective effect of being a working mother (with partner) on alcohol use is weaker. These data suggest that a country's investment in measures to improve the compatibility of motherhood and paid labour may reduce women's alcohol use.