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.

In vivo localisation of radiolabelled monoclonal antibody in human gliomas.

F(ab')2-fragments of the anti-melanoma monoclonal antibody MeI-14 were labelled with 123I for external scanning and with 125I for tissue measurement of radioactivity and injected intravenously into patients scheduled for surgical resection of a glioma. The paired-label study was performed by injecting simultaneously 131I-labelled control (F(ab')2-fragments. The patients were scanned by computerised tomoscintigraphy. After surgery, the activities of 125I and 131I were counted in tumour and normal tissues. The results indicate that there was a low but definite uptake of the antibody in the tumour due to its specificity. The external detection was difficult because of accumulation of antibody fragments in the skull.

Glucosurie rénale [Renal glucosuria].

The occurrence of glucosuria in the absence of hyperglycemia is distinctive for renal glucosuria. SGLT2 mutations provoke familial renal glucosuria characterized by persistent glucosuria in the absence of any other renal tubular dysfunction. Renal glucosuria associated with others proximal tubular dysfunctions points to Fanconi syndrome. This generalized dysfunction of proximal tubule needs to be treated and may progress regarding its aetiology to chronic renal failure. The development and study of models of Fanconi syndrome has recently contributed to a better knowledge of the mechanisms implicated in the tubular transport of glucose and low-molecular-weight-proteins. This article reviews these recent developments.

Relatedness influences signal reliability in evolving robots.

Communication is an indispensable component of animal societies, yet many open questions remain regarding the factors affecting the evolution and reliability of signalling systems. A potentially important factor is the level of genetic relatedness between signallers and receivers. To quantitatively explore the role of relatedness in the evolution of reliable signals, we conducted artificial evolution over 500 generations in a system of foraging robots that can emit and perceive light signals. By devising a quantitative measure of signal reliability, and comparing independently evolving populations differing in within-group relatedness, we show a strong positive correlation between relatedness and reliability. Unrelated robots produced unreliable signals, whereas highly related robots produced signals that reliably indicated the location of the food source and thereby increased performance. Comparisons across populations also revealed that the frequency for signal production-which is often used as a proxy of signal reliability in empirical studies on animal communication-is a poor predictor of signal reliability and, accordingly, is not consistently correlated with group performance. This has important implications for our understanding of signal evolution and the empirical tools that are used to investigate communication.

Gene-flow in a mosaic hybrid zone: is local introgression adaptive?

Genome-wide scans of genetic differentiation between hybridizing taxa can identify genome regions with unusual rates of introgression. Regions of high differentiation might represent barriers to gene flow, while regions of low differentiation might indicate adaptive introgression-the spread of selectively beneficial alleles between reproductively isolated genetic backgrounds. Here we conduct a scan for unusual patterns of differentiation in a mosaic hybrid zone between two mussel species, Mytilus edulis and M. galloprovincialis. One outlying locus, mac-1, showed a characteristic footprint of local introgression, with abnormally high frequency of edulis-derived alleles in a patch of M. galloprovincialis enclosed within the mosaic zone, but low frequencies outside of the zone. Further analysis of DNA sequences showed that almost all of the edulis allelic diversity had introgressed into the M. galloprovincialis background in this patch. We then used a variety of approaches to test the hypothesis that there had been adaptive introgression at mac-1. Simulations and model fitting with maximum-likelihood and approximate Bayesian computation approaches suggested that adaptive introgression could generate a "soft sweep," which was qualitatively consistent with our data. Although the migration rate required was high, it was compatible with the functioning of an effective barrier to gene flow as revealed by demographic inferences. As such, adaptive introgression could explain both the reduced intraspecific differentiation around mac-1 and the high diversity of introgressed alleles, although a localized change in barrier strength may also be invoked. Together, our results emphasize the need to account for the complex history of secondary contacts in interpreting outlier loci.

Scalable inference of heterogeneous reaction kinetics from pooled single-cell recordings.

Mathematical methods combined with measurements of single-cell dynamics provide a means to reconstruct intracellular processes that are only partly or indirectly accessible experimentally. To obtain reliable reconstructions, the pooling of measurements from several cells of a clonal population is mandatory. However, cell-to-cell variability originating from diverse sources poses computational challenges for such process reconstruction. We introduce a scalable Bayesian inference framework that properly accounts for population heterogeneity. The method allows inference of inaccessible molecular states and kinetic parameters; computation of Bayes factors for model selection; and dissection of intrinsic, extrinsic and technical noise. We show how additional single-cell readouts such as morphological features can be included in the analysis. We use the method to reconstruct the expression dynamics of a gene under an inducible promoter in yeast from time-lapse microscopy data.

Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy.

BACKGROUND: Leprosy is characterized by a spectrum of clinical manifestations that depend on the type of immune response against the pathogen. Patients may undergo immunological changes known as "reactional states" (reversal reaction and erythema nodosum leprosum) that result in major clinical deterioration. The goal of the present study was to assess the effect of Toll-like receptor 2 (TLR2) polymorphisms on susceptibility to and clinical presentation of leprosy. METHODS: Three polymorphisms in TLR2 (597C-->T, 1350T-->C, and a microsatellite marker) were analyzed in 431 Ethiopian patients with leprosy and 187 control subjects. The polymorphism-associated risk of developing leprosy, lepromatous (vs. tuberculoid) leprosy, and leprosy reactions was assessed by multivariate logistic regression models. RESULTS: The microsatellite and the 597C-->T polymorphisms both influenced susceptibility to reversal reaction. Although the 597T allele had a protective effect (odds ratio [OR], 0.34 [95% confidence interval {CI}, 0.17-0.68]; P= .002 under the dominant model), homozygosity for the 280-bp allelic length of the microsatellite strongly increased the risk of reversal reaction (OR, 5.83 [95% CI, 1.98-17.15]; P= .001 under the recessive model). These associations were consistent among 3 different ethnic groups. CONCLUSIONS: These data suggest a significant role for TLR-2 in the occurrence of leprosy reversal reaction and provide new insights into the immunogenetics of the disease.

Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy.

Accumulating evidence suggests that polymorphisms in Toll-like receptors (TLRs) influence the pathogenesis of mycobacterial infections, including leprosy, a disease whose manifestations depend on host immune responses. Polymorphisms in TLR2 are associated with an increased risk of reversal reaction, but not susceptibility to leprosy itself. We examined whether polymorphisms in TLR4 are associated with susceptibility to leprosy in a cohort of 441 Ethiopian leprosy patients and 197 healthy controls. We found that two single nucleotide polymorphisms (SNPs) in TLR4 (896G>A [D299G] and 1196C>T [T399I]) were associated with a protective effect against the disease. The 896GG, GA and AA genotypes were found in 91.7, 7.8 and 0.5% of leprosy cases versus 79.9, 19.1 and 1.0% of controls, respectively (odds ratio [OR] = 0.34, 95% confidence interval [CI] 0.20-0.57, P < 0.001, additive model). Similarly, the 1196CC, CT and TT genotypes were found in 98.1, 1.9 and 0% of leprosy cases versus 91.8, 7.7 and 0.5% of controls, respectively (OR = 0.16, 95% CI 0.06--.40, P < 0.001, dominant model). We found that Mycobacterium leprae stimulation of monocytes partially inhibited their subsequent response to lipopolysaccharide (LPS) stimulation. Our data suggest that TLR4 polymorphisms are associated with susceptibility to leprosy and that this effect may be mediated at the cellular level by the modulation of TLR4 signalling by M. leprae.

Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults.

Although both inflammatory and atherosclerosis markers have been associated with coronary heart disease (CHD) risk, data directly comparing their predictive value are limited. The authors compared the value of 2 atherosclerosis markers (ankle-arm index (AAI) and aortic pulse wave velocity (aPWV)) and 3 inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)) in predicting CHD events. Among 2,191 adults aged 70-79 years at baseline (1997-1998) from the Health, Aging, and Body Composition Study cohort, the authors examined adjudicated incident myocardial infarction or CHD death ("hard" events) and "hard" events plus hospitalization for angina or coronary revascularization (total CHD events). During 8 years of follow-up between 1997-1998 and June 2007, 351 participants developed total CHD events (197 "hard" events). IL-6 (highest quartile vs. lowest: hazard ratio = 1.82, 95% confidence interval: 1.33, 2.49; P-trend < 0.001) and AAI (AAI </= 0.9 vs. AAI 1.01-1.30: hazard ratio = 1.57, 95% confidence interval: 1.14, 2.18) predicted CHD events above traditional risk factors and modestly improved global measures of predictive accuracy. CRP, TNF-alpha, and aPWV had weaker associations. IL-6 and AAI accurately reclassified 6.6% and 3.3% of participants, respectively (P's </= 0.05). Results were similar for "hard" CHD, with higher reclassification rates for AAI. IL-6 and AAI are associated with future CHD events beyond traditional risk factors and modestly improve risk prediction in older adults.

High prevalence of major cardiovascular risk factors in first-degree relatives of individuals with familial premature coronary artery disease--the GENECARD project.

BACKGROUND: Hypertension, hypercholesterolemia, obesity and smoking are highly prevalent among patients with familial premature coronary artery disease (FP-CAD). Whether these risk factors equally affect other family members remains unknown. METHODS: We examined 222 FP-CAD patients, 158 unaffected sibs, 197 offspring and 94 spouses in 108 FP-CAD families (> or = 2 sibs having survived CAD diagnosed before age 51 (M)/56 (F)), and compared them to population controls. RESULTS: Unaffected sibs had a higher prevalence of hypertension (49% versus 24%, p<0.001), hypercholesterolemia (47% versus 34%, p=0.002), abdominal obesity (35% versus 24%, p=0.006) and smoking (39% versus 24%, p=0.001) than population controls. Offspring had a higher prevalence of hypertension (females), hypercholesterolemia and abdominal obesity than population controls. No difference was observed between spouses and controls. Compared to unaffected sibs, FP-CAD affected sibs had a similar risk factor profile, except for smoking, which was more prevalent (76% versus 39%, p=0.008). CONCLUSIONS: Hypertension, obesity and hypercholesterolemia are highly prevalent among first-degree relatives, but not spouses, of patients with FP-CAD. These persons deserve special medical attention due to their familial/genetic susceptibility to atherogenic metabolic abnormalities. In these families, smoking may be the trigger for FP-CAD.

Faire entendre sa voix

Dans une société du consentement, chacun devrait pouvoir exprimer sa voix. Mais tout enfant apprend à parler en faisant usage de la parole des autres. Dans quelle mesure ce que dit le nouveau venu n'est-il pas une pure reproduction de ce que disent ses aînés ? Si chacun a la voix de sa communauté, qu'est-ce que peut bien vouloir dire « liberté d'expression » ? J'aimerais montrer qu'une voix n'est pas quelque chose que l'on a, mais quelque chose que l'on fait entendre au cours d'un apprentissage. Le problème est politique : ma voix est liée à ma place dans une communauté. In a society of consent, each and everyone should express their own voice. However, a child learns how to speak using the words of the others. To which extent the newcomer isn't just reproducing what his elders say ? If everyone speaks through their community's voice, what does « freedom of speech » mean ? I want to demonstrate that a voice isn't something that one has, it's something that one acquires through education. This is a political problem : my voice is linked to my place in a community.