15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

A common biological basis of obesity and nicotine addiction.

Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).

Quasicollapse of oblique solitons of the weakly dissipative derivative nonlinear Schrödinger equation.

Numerical integrations of the derivative nonlinear Schrödinger equation for Alfvén waves, supplemented by a weak dissipative term (originating from diffusion or Landau damping), with initial conditions in the form of a bright soliton with nonvanishing conditions at infinity (oblique soliton), reveal an interesting phenomenon of "quasicollapse": as the dissipation parameter is reduced, larger amplitudes are reached and smaller scales are created, but on an increasing time scale. This process involves an early bifurcation of the initial soliton toward a breather that is analyzed by means of a numerical inverse scattering technique. This evolution leads to the formation of persistent dark solitons that are only weakly affected when crossed by the decaying breather which has the form of either a localized structure or an extended wave packet.

Arrest of Langmuir wave collapse by quantum effects.

The arrest of Langmuir wave collapse by quantum effects, first addressed by Haas and Shukla [Phys. Rev. E 79, 066402 (2009)] using a Rayleigh-Ritz trial function method is revisited, using rigorous estimates and systematic asymptotic expansions. The absence of blow up for the so-called quantum Zakharov equations is proved in two and three dimensions, whatever the strength of the quantum effects. The time-periodic behavior of the solution for initial conditions slightly in excess of the singularity threshold for the classical problem is established for various settings in two space dimensions. The difficulty of developing a consistent perturbative approach in three dimensions is also discussed and a semiphenomenological model is suggested for this case.

CDKN2A mutations and melanoma risk in the Icelandic population.

BACKGROUND: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. METHODS: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. RESULTS: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. CONCLUSIONS: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.

Dynamical model for nonlinear mirror modes near threshold.

Using a reductive perturbative expansion of the Vlasov-Maxwell (VM) equations for magnetized plasmas, a pseudodifferential equation of gradient type is derived for the nonlinear dynamics of mirror modes near the instability threshold. This model, where kinetic effects arise at a linear level only, develops a finite-time singularity, indicating the existence of a subcritical bifurcation. A saturation mechanism based on the local variations of the ion Larmor radius, is then phenomenologically supplemented. In contrast with previous models where saturation is due to the cooling of a population of trapped particles, the resulting equation correctly reproduces results of numerical simulations of VM equations, such as the development of magnetic humps from an initial noise, and the existence of stable large-amplitude magnetic holes both below and slightly above threshold.

Psychoactive drug consumption: performance-enhancing behaviour and pharmacodependence in workers.

PURPOSE: The aim of this study was to investigate factors associated to psychoactive medication use and dependence in working environment during a 1-year period. METHODS: We performed a 1-year-follow-up cohort study including workers from Toulouse metropolitan area. During their annual compulsory examination to assess their aptitude to work, subjects were asked to fill in an anonymous questionnaire at 1 year interval, in May 2000 and May-June 2001. RESULTS: Among a study sample of 1273 subjects (47.4% of men, mean age 39.2 +/- 9.2 years), the prevalence of psychoactive medication use at baseline was 9.1% (4.3% anxiolytic, 1.9% hypnotic, 1.7% antidepressant, 2.1% opiate analgesic and 0.5% antipsychotic drugs, according to ATC classification). Dependence on these drugs was found in 3.5% of workers. This consumption was associated with professional categories (higher in employees versus senior executive, Odds Ratio: 1.80; 95% Confidence Interval [1.04-3.11]), low job satisfaction and outside workplace (1.92; [1.30-2.84] and 3.40; [2.27-5.09] respectively), and patterns of medication use at workplace: for sleeping disorders related to job (18.27; [11.81-28.26]), for enhancing performance at work (28.13; [12.00-65.92]), for relieving unpleasant symptoms at work (22.98; [9.59-55.01]). The risk of psychoactive medication chronic use (psychoactive drug users in 2000 and 2001), and dependence at 1 year were both strongly associated with nicotine dependence (5.99 and 6.23, respectively) and performance-enhancing behaviour with drugs and/or alcohol (8.35 and 3.32 respectively), whereas current use (psychoactive drug users only in 2001) was strongly associated with performance-enhancing behaviour. CONCLUSIONS: Among workers using psychoactive drugs, one out of three are dependent on psychoactive medications. Performance-enhancing behaviour and coping strategies might be a determinant of psychoactive drug use and could lead to dependence in the workplace.

Breast cancer risk in airline cabin attendants: a nested case-control study in Iceland.

AIMS: To investigate whether length of employment as a cabin attendant was related to breast cancer risk, when adjusted for reproductive factors. METHODS: Age matched case-control study nested in a cohort of cabin attendants. The cases were found from a nationwide cancer registry (followed up to end of year 2000) and the reproductive factors (age at first childbirth and number of children) from a registry of childbirth, in both instances by record linkage with the cabin attendants' identification numbers. The employment time of the cabin attendants at the airline companies and the reproductive factors had been systematically recorded prior to the diagnosis of breast cancer in the cohort. A total of 35 breast cancer cases and 140 age matched controls selected from a cohort of 1532 female cabin attendants were included in the study. RESULTS: The matched odds ratio from conditional logistic regression of breast cancer risk among cases and controls of cabin attendants was 5.24 (95% CI 1.58 to 17.38) for those who had five or more years of employment before 1971 compared with those with less than five years of employment before 1971, adjusted for age at first childbirth and length of employment from 1971 or later. CONCLUSIONS: The association between length of employment and risk of breast cancer, adjusted for reproductive factors, indicates that occupational factors may be an important cause of breast cancer among cabin attendants; the association is compatible with a long induction period.

Two outbreaks of Salmonella enteritidis phage type 8 linked to the consumption of Cantal cheese made with raw milk, France, 2001.

Salmonelloses are one are the main causes of foodborne infections in industrialised countries. In France, the incidence of human salmonellosis recorded by the National Reference Centre for Salmonella and Shigella (CNRSS) in 2001 was 21 cases per 100,000 inhabitants, and Salmonella serotype Enteritidis represented 39% of cases (1). This article reports the investigation results of two community outbreaks of salmonellosis that occurred simultaneously in the south west of France, and which were linked to the consumption of cheese made from raw milk.

[Consumption of antihypertensive agents in obese patients: a cross-sectional study in a sample of 3,291 wage-earners in the Toulous region]. / Consommation de médicaments antihypertenseurs chez le sujet obèse: enquête transversale auprès d'un échantillon de 3,291 salariés de la région toulousaine.

A cross-sectional study in a sample of 3,291 healthy workers was performed in May 1997 to assess the prevalence of obesity (BMI > or = 30 kg/m2) in a working population, and to compare prescription of antihypertensive drugs in obese and non obese subjects. Obesity was found in 7.4% (245) subjects and morbid obesity concerned 0.4% of the total sample (mean age 37.6 +/- 9.7 [SD] years, 52.4% of males). Risk of obesity was significantly associated with age, male sex, professional classes (higher in blue collars workers, lower in senior executive), business travels, atypical schedules, professional and private difficulties. Albeit the prevalence of drug users (49.7%) was similar whatever the BMI, obese subjects used a higher number of drugs than non obese (2.0 +/- 1.2 versus 1.6 +/- 0.9, p < 0.001). Risk of consumption of cardiovascular drugs was higher in obese than in non obese subjects (OR 2.9, 95% CI [2.2-4.1]). After adjustment on confounding factors, obesity increased specific drug use such as angiotensin converting enzyme inhibitors (OR 3.3, 95% CI [1.7-6.4]), beta-blocking agents (OR 2.83, 95% CI [1.01-8.01]), calcium channel blockers (OR 2.44, 95% CI [1.06-5.63]) or diuretics only in women (OR 5.7, 95% CI [2.1-16.3]). Prescribed antihypertensive drugs were different in obese (beta-blockers = angiotensin converting enzyme inhibitors > diuretics > calcium channels blockers) and non obese (angiotensin converting enzyme inhibitors > calcium channel blockers > diuretics > beta-blockers) subjects.

Effect of a random noise on scaling laws of finite Prandtl number rotating convection near threshold.

A generalized Swift-Hohenberg model including a weak random forcing, viewed as mimicking the intrinsic source of noise due to boundary defects, is used to reproduce the experimentally observed power-law variation of the correlation length of rotating convection patterns as a function of the stress parameter near threshold, and to demonstrate the sensitivity of the exponent to the amplitude of the superimposed random noise. The scaling properties of rotating convection near threshold are thus conjectured to be nonuniversal.