Sleep structure and cardiometabolic disorders in the general population : the Hypnolaus study

Objectives: Previous studies using subjective assessments have reported associations between sleep quantity and quality and cardiometabolic disorders, but little is known regarding the associ-ations with objective sleep characteristics. The purpose of this study was to evaluate the association between objective sleep measure sand metabolic syndrome (MS), hypertension, diabetes and obesity. Methods: 2162 subjects (51.2% women, mean age 58,11.1) from the general population were evaluated for hypertension,diabetes, overweight/obesity and MS, and underwent a full polysom-nography (PSG). PSG measured variables included: Total sleep time(TST), percentage and time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep, sleep efficiency and arousal index(ArI) Results: In univariate analyses, MS was associated with decreased TST, SWS, REM sleep, sleep efficiency and increased ArI. After adjustment for age, gender, smoking, alcohol, physical activity, drugsthat affect sleep and depression, the ArI remained significantly higher, but the difference disappeared in subjects without significant sleep disordered breathing (SDB). Differences in sleep structure were also found according to the presence or absence of hypertension, diabetes and overweight/obesity in univariate analysis. However, these differences were attenuated after multivariate adjustment and after excluding subjects with significant SDB. Conclusions: In this population-based sample we found significant associations between sleep structure and MS, hypertension, diabetes and obesity. However, these associations were cancelled after multivariate adjustment. We conclude that normal variations in sleep contribute little if any to MS and associated disorders.

Prevalence, awareness, treatment and control of hypertension in a Swiss general population: the CoLaus Study

Objective: To assess the prevalence levels of awareness, treatment and control of hypertension and associated factors in Switzerland. Methods: Population-based cross-sectional study of 6,182 subjects (52.5% women) aged 35-75 years living in Lausanne, Switzerland. Hypertension was defined as blood pressure ≥140/90 mm Hg or current antihypertensive medication. Results: The overall prevalence of hypertension was 36% (95% CI: 35-38%). Among hypertensive participants, 63% were aware of having hypertension. Among aware hypertensives, 78% were treated, and among treated hypertensives 48% were controlled (BP <140/90 mmHg). In multivariate analysis, prevalence of hypertension was associated with older age, male gender, low educational level, high alcohol intake, awareness of diabetes, awareness of dyslipidaemia, obesity and parental history of myocardial infarction (MI). Awareness of hypertension was associated with older age, female gender, awareness of diabetes, awareness of dyslipidaemia, obesity and parental history of MI. Control was associated with younger age, higher educational level and no alcohol intake. Alone or in combination, sartans were the most often prescribed antihypertensive medication category (41%), followed by diuretics, beta-blockers, ACE inhibitors and calcium channel blockers. Only 31% of treated hypertensives were taking ≥2 antihypertensive medications. Conclusion: Although more than half of the participants with hypertension were aware of being hypertensive and more than three quarters of them received a pharmacological treatment, less than half of those treated were adequately controlled. Treated hypertensive subjects should be followed up more closely.

Peroxisome proliferator-activated receptors: insight into multiple cellular functions.

Peroxisome proliferator-activated receptors, PPARs, (NR1C) are nuclear hormone receptors implicated in energy homeostasis. Upon activation, these ligand-inducible transcription factors stimulate gene expression by binding to the promoter of target genes. The different structural domains of PPARs are presented in terms of activation mechanisms, namely ligand binding, phosphorylation, and cofactor interaction. The specificity of ligands, such as fatty acids, eicosanoids, fibrates and thiazolidinediones (TZD), is described for each of the three PPAR isotypes, alpha (NR1C1), beta (NR1C2) and gamma (NR1C3), so as the differential tissue distribution of these isotypes. Finally, general and specific functions of the PPAR isotypes are discussed, namely their implication in the control of inflammatory responses, cell proliferation and differentiation, the roles of PPARalpha in fatty acid catabolism and of PPARgamma in adipogenesis.

The distribution of congenital anomalies within the VACTERL association among tumor necrosis factor antagonist-exposed pregnancies is similar to the general population.

OBJECTIVE: To compare the distribution of congenital anomalies within the VACTERL association (vertebral defects, anal atresia, cardiac, tracheoesophageal, renal, and limb abnormalities) between patients exposed to tumor necrosis factor-α (TNF-α) antagonist and the general population. METHODS: Analysis for comparison of proportional differences to a previous publication between anomaly subgroups, according to subgroup definitions of the European Surveillance of Congenital Anomalies (EUROCAT), a population-based database. RESULTS: Most EUROCAT subgroups belonging to the VACTERL association contained only one or 2 records of TNF-α antagonist exposure, so comparison of proportions was imprecise. Only the category "limb abnormalities" showed a significantly higher proportion in the general population. CONCLUSION: The high number of congenital anomalies belonging to the VACTERL association from a report of pregnancies exposed to TNF-α antagonists could not be confirmed using a population-based congenital anomaly database.

Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array.

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P=1.2×10(-8)). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4×10(-6)). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: <0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.

How critical is timing for the diagnosis of influenza in general practice?

Résumé La performance diagnostic des signes et symptômes de la grippe a principalement été étudiée dans le cadre d'études contrôlées avec des critères d'inclusion stricts. Il apparaît nécessaire d'évaluer ces prédicteurs dans le cadre d'une consultation ambulatoire habituelle en tenant compte du délai écoulé entre le début des symptômes et la première consultation ainsi que la situation épidémiologique. Cette étude prospective a été menée à la Policlinique Médicale Universitaire durant l'hiver 1999-2000. Les patients étaient inclus s'ils présentaient un syndrome grippal et si le praticien suspectait une infection à Influenza. Le médecin administrait un questionnaire puis une culture d'un frottis de gorge était réalisée afin de documenter l'infection. 201 patients ont été inclus dans l'étude. 52% avaient une culture positive pour Influenza. En analyse univariée, une température > 37.8° (OR 4.2; 95% CI 2.3-7.7), une durée des symptômes < 48h (OR 3.2; 1.8-5.7), une toux (OR 3.2; 1-10.4) et des myalgies (OR 2.8; 1.0-7.5) étaient associés au diagnostic de grippe. En analyse de régression logistique, le modèle le plus performant qui prédisait la grippe était l'association d'une durée des symptômes <48h, une consultation en début d'épidémie, une température > 37.8° et une toux (sensibilité 79%, spécificité 69%, valeur prédictive positive 67%, une valeur prédictive négative de 73% et aire sous la courbe (ROC) de 0.74). En plus des signes et symptômes prédicteurs de la grippe, le médecin de premier recours devrait prendre en compte dans son jugement la durée des symptômes avant la première consultation et le contexte épidémiologique (début, pic, fin de l'épidémie), car ces deux paramètres modifient considérablement la valeurs des prédicteurs lors de l'évaluation de la probabilité clinique d'un patient d'avoir une infection à Influenza.

Structural prediction of peptides bound to MHC class I.

An ab initio structure prediction approach adapted to the peptide-major histocompatibility complex (MHC) class I system is presented. Based on structure comparisons of a large set of peptide-MHC class I complexes, a molecular dynamics protocol is proposed using simulated annealing (SA) cycles to sample the conformational space of the peptide in its fixed MHC environment. A set of 14 peptide-human leukocyte antigen (HLA) A0201 and 27 peptide-non-HLA A0201 complexes for which X-ray structures are available is used to test the accuracy of the prediction method. For each complex, 1000 peptide conformers are obtained from the SA sampling. A graph theory clustering algorithm based on heavy atom root-mean-square deviation (RMSD) values is applied to the sampled conformers. The clusters are ranked using cluster size, mean effective or conformational free energies, with solvation free energies computed using Generalized Born MV 2 (GB-MV2) and Poisson-Boltzmann (PB) continuum models. The final conformation is chosen as the center of the best-ranked cluster. With conformational free energies, the overall prediction success is 83% using a 1.00 Angstroms crystal RMSD criterion for main-chain atoms, and 76% using a 1.50 Angstroms RMSD criterion for heavy atoms. The prediction success is even higher for the set of 14 peptide-HLA A0201 complexes: 100% of the peptides have main-chain RMSD values &lt; or =1.00 Angstroms and 93% of the peptides have heavy atom RMSD values &lt; or =1.50 Angstroms. This structure prediction method can be applied to complexes of natural or modified antigenic peptides in their MHC environment with the aim to perform rational structure-based optimizations of tumor vaccines.

Cytochemical and immunocytochemical characterization of nuclear bodies during hibernation.

Brown adipose tissue and liver of hibernating, arousing and euthermic individuals of the dormouse Muscardinus avellanarius were studies using ultrastructural cytochemistry and immunocytochemistry with the aim to investigate possible fine structural modifications of the cell nucleus during the seasonal cycle. The general morphology of brown adipocyte and hepatocyte nuclei was similar in the three experimental groups. However, three nuclear structural constituents were identified only in hibernating individuals: coiled bodies (CBs) and amorphous bodies (ABs) were observed in hepatocytes and, together with bundles of nucleoplasmic fibrils (NF), were present in brown adipocytes of hibernating dormice. In arousing animals only some structural constituents suggestive of poorly structured CBs were found. The latter showed the same immunocytochemical features as CBs of hibernating individuals, suggesting that they are disappearing CBs. A possible involvement of CBs in storing and/or processing RNA which must be rapidly and abundantly released upon arousal is discussed. ABs similarly to CBs contain RNA and nucleoplasmic ribonucleoproteins (RNPs) and could also be involved in mRNA pathways. NF do not contain nucleic acids or RNPs and seem to be composed of protein-aceous material; their functional role in the nuclear metabolism of hibernating brown adipocytes remains unclear.

Influence of CRTC1 Polymorphisms on Body Mass Index and Fat Mass in Psychiatric Patients and the General Adult Population.

IMPORTANCE There is a high prevalence of obesity in psychiatric patients, possibly leading to metabolic complications and reducing life expectancy. The CREB-regulated transcription coactivator 1 (CRTC1) gene is involved in energy balance and obesity in animal models, but its role in human obesity is unknown. OBJECTIVE To determine whether polymorphisms within the CRTC1 gene are associated with adiposity markers in psychiatric patients and the general population. DESIGN, SETTING, AND PARTICIPANTS Retrospective and prospective data analysis and population-based samples at Lausanne and Geneva university hospitals in Switzerland and a private clinic in Lausanne, Switzerland. The effect of 3 CRTC1 polymorphisms on body mass index (BMI) and/or fat mass was investigated in a discovery cohort of psychiatric outpatients taking weight gain-inducing psychotropic drugs (sample 1, n = 152). The CRTC1 variant that was significantly associated with BMI and survived Bonferroni corrections for multiple comparison was then replicated in 2 independent psychiatric samples (sample 2, n = 174 and sample 3, n = 118) and 2 white population-based samples (sample 4, n = 5338 and sample 5, n = 123 865). INTERVENTION Noninterventional studies. MAIN OUTCOME AND MEASURE Difference in BMI and/or fat mass between CRTC1 genotype groups. RESULTS Among the CRTC1 variants tested in the first psychiatric sample, only rs3746266A>G was associated with BMI (Padjusted = .003). In the 3 psychiatric samples, carriers of the rs3746266 G allele had a lower BMI than noncarriers (AA genotype) (sample 1, P = .001; sample 2, P = .05; and sample 3, P = .0003). In the combined analysis, excluding patients taking other weight gain-inducing drugs, G allele carriers (n = 98) had a 1.81-kg/m2 lower BMI than noncarriers (n = 226; P < .0001). The strongest association was observed in women younger than 45 years, with a 3.87-kg/m2 lower BMI in G allele carriers (n = 25) compared with noncarriers (n = 48; P < .0001), explaining 9% of BMI variance. In the population-based samples, the T allele of rs6510997C>T (a proxy of the rs3746266 G allele; r2 = 0.7) was associated with lower BMI (sample 5, n = 123 865; P = .01) and fat mass (sample 4, n = 5338; P = .03). The strongest association with fat mass was observed in premenopausal women (n = 1192; P = .02). CONCLUSIONS AND RELEVANCE These findings suggest that CRTC1 contributes to the genetics of human obesity in psychiatric patients and the general population. Identification of high-risk subjects could contribute to a better individualization of the pharmacological treatment in psychiatry.

Noninvasive imaging of 5-HT3 receptor trafficking in live cells: from biosynthesis to endocytosis.

Sequential stages in the life cycle of the ionotropic 5-HT(3) receptor (5-HT(3)R) were resolved temporally and spatially in live cells by multicolor fluorescence confocal microscopy. The insertion of the enhanced cyan fluorescent protein into the large intracellular loop delivered a fluorescent 5-HT(3)R fully functional in terms of ligand binding specificity and channel activity, which allowed for the first time a complete real-time visualization and documentation of intracellular biogenesis, membrane targeting, and ligand-mediated internalization of a receptor belonging to the ligand-gated ion channel superfamily. Fluorescence signals of newly expressed receptors were detectable in the endoplasmic reticulum about 3 h after transfection onset. At this stage receptor subunits assembled to form active ligand binding sites as demonstrated in situ by binding of a fluorescent 5-HT(3)R-specific antagonist. After novel protein synthesis was chemically blocked, the 5-HT(3) R populations in the endoplasmic reticulum and Golgi cisternae moved virtually quantitatively to the cell surface, indicating efficient receptor folding and assembly. Intracellular 5-HT(3) receptors were trafficking in vesicle-like structures along microtubules to the cell surface at a velocity generally below 1 mum/s and were inserted into the plasma membrane in a characteristic cluster distribution overlapping with actin-rich domains. Internalization of cell surface 5-HT(3) receptors was observed within minutes after exposure to an extracellular agonist. Our orchestrated use of spectrally distinguishable fluorescent labels for the receptor, its cognate ligand, and specific organelle markers can be regarded as a general approach allowing subcellular insights into dynamic processes of membrane receptor trafficking.

Adding diversity to ruthenium (II)-arene anticancer (RAPTA) compounds via click chemistry: the influence of hydrophobic chains

The application of click chemistry to develop libraries of organometallic ruthenium-arene complexes with potential anticancer properties has been investigated. A series of ruthenium-imidazole-triazole complexes, with hydrophobic tails, were prepared from a common precursor via click chemistry. The tail could be attached to the ligand prior to coordination to the ruthenium complex were screened for cytotoxicity in tumourigenic and non-tumourigenic cell lines, and while the compounds were only moderately cytotoxic, good selectivity for tumourigenic cells were abserved.

Major depressive disorders in the general hospital: how to implement guidelines.

OBJECTIVE: An implementation study that evaluated the impact of previously adopted guidelines on the clinical practice of medical residents was conducted to improve the recognition and treatment of major depressive disorders (MDDs) in hospitalized patients with somatic diseases. METHODS: Guidelines were implemented in two wards (ENT and oncology) using intranet diffusion, interactive sessions with medical residents, and support material. Discharge letters of 337 and 325 patients, before and after the intervention, respectively, were checked for statement of diagnosis or treatment of MDDs and, in a post hoc analysis, for any mention about psychiatric management. RESULTS: No difference was found in the number of diagnosed or treated MDDs before and after the intervention. However, significantly more statements about psychological status (29/309 vs. 13/327) and its management (36/309 vs. 19/327) were observed after the intervention (P<.01). CONCLUSION: The intervention was not successful in improving the management of MDDs. However, a possible effect on general psychological aspects of medical diseases was observed.

Perioperative visual loss: a rare complication of general surgery

BACKGROUND: Perioperative visual loss (PVL) refers to the loss of vision following surgery performed at distance from the visual pathways. An ischemic optic neuropathy (ION) is the most frequent clinical presentation of PVL, and can be bilateral. PATIENTS AND METHODS: A retrospective chart review of 11 consecutive patients with PVL examined between 2002 and 2007 was undertaken. RESULTS: An ION was found in all 11 cases: 8 were anterior (AION) and 3 were posterior (PION). Visual loss was bilateral in 9 patients. Mean visual acuity (VA) was 0.2 on the Snellen chart (0.74 LogMAR). Most frequently an arcuate/altitudinal visual field defect was present. PVL followed orthopedic (6), spinal (1), cardiac (2) and vascular (2) procedures. The average delay between surgery and visual loss was 32 hours (range: 0-96 hours). Average lowest perioperative hemoglobin level was 75 g/L. Average follow-up time was 14.7 months. VA improved by at least 2 Snellen lines in 5/20 eyes (25 %). CONCLUSIONS: PVL is a rare but dreadful complication of surgery, and is usually associated with severe anemia. Like other causes of ION, there is no specific therapy. Prompt correction of the anemia might decrease the rate of this complication

Patterns of sex work contact among men in the general population of Switzerland, 1987-2000

OBJECTIVES: To analyse the prevalence of lifetime recourse to prostitution (LRP) among men in the general population of Switzerland from a trend and cohort perspective. METHODS: Using nine repeated representative cross-sectional surveys from 1987 to 2000, age-specific estimates of LRP were computed. Trends and period effect were analysed as the evolution of cross-sectional population estimates within age groups and overall. Cohort analysis relied on cohorts constructed from the 1989 survey and followed in subsequent waves. Age and cohort effects were modelled using logistic regression and non-parametric monotone regression. RESULTS: Whereas prevalence for the younger groups was found to be logically lower, there was no consistent increasing or decreasing trend over the years; there was no significant period effect. For the 17-30 year age group, the mean estimate over 1987-2000 was 11.5% (range 8.3 to 12.7%); for the 31-45 year group, the mean was 21.5% (range over 1989-2000 20.3 to 23.0%). Regarding cohort analysis, the prevalence of LRP was found to increase steeply in the youngest ages before reaching a plateau near the age of 40 years. At the age of 43 years, the prevalence was estimated to be 22.6% (95% CI 21.1% to 24.1%). CONCLUSIONS: The steep increase in the cohort-wise prevalence of LRP in younger ages calls for a concentration of prevention activities in young people. If the plateauing at approximately 40 years of age is not followed by a further increase later in life, which is not known, then consumers of paid sex would be repeat buyers only, a fact that should be taken into account by prevention.

Maturation-dependent neurotoxicity of lead acetate in vitro: implication of glial reactions.

Despite a wealth of data on the neurotoxic effects of lead at the cellular and molecular levels, the reasons for its development-dependent neurotoxicity are still unclear. Here, the maturation-dependent effects of lead acetate were analyzed in immature and differentiated brain cells cultured in aggregates. Markers of general cytotoxicity as well as cell-type-specific markers of glial and neuronal cells showed that immature brain cells were more sensitive to lead than the differentiated counterparts, demonstrating that the development-dependent neurotoxicity of lead can be reproduced in aggregating brain cell cultures. After 10 days of treatment, astrocytes were found to be more affected by lead acetate than neurons in immature cultures, and microglial cells were strongly activated. Eleven days after cessation of the treatment, lead acetate caused a partial loss of astrocytes and an intense reactivity of the remaining ones. Furthermore, microglial cells expressed a macrophagic phenotype, and the loss of activity of neuron-specific enzymes was aggravated. In differentiated cultures, no reactive gliosis was found. It is hypothetized that the intense glial reactions (microgliosis and astrogliosis) observed in immature cultures contribute to the development-dependent neurotoxicity of lead.