16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn.

OBJECTIVE:: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. DESIGN:: Descriptive case report. SETTING:: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS:: None. PATIENT:: We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. MEASUREMENTS AND MAIN RESULTS:: An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. CONCLUSIONS:: Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Prevalence of overweight and obesity among migrants in Switzerland: association with country of origin.

Migrants tend to present higher overweight and obesity levels, but whether this relationship applies to all nationalities has seldom been studied. The present study aimed to assess the prevalence of overweight and obesity according to nationality in adults. Cross-sectional population-based samples. Five-year nationwide interview surveys (Swiss Health Surveys - SHS) from 1992 to 2007 (n 63 766) and a local examination survey (CoLaus Study in Lausanne 2004-2006, n 6743). Participants were separated into Swiss, French, German, Italian, Portuguese, Spanish nationals, those from the former Republic of Yugoslavia and from other European and other countries. Compared with Swiss nationals, German and French nationals presented a lower prevalence of overweight and obesity, whereas nationals from Italy, Spain, Portugal and the former Republic of Yugoslavia presented higher levels. Adjusting the SHS data for age, gender, education, smoking, leisure-time physical activity and survey year, a lower risk for overweight and obesity was found for German (OR = 0·80, 95 % CI 0·70, 0·92) and French (OR = 0·74, 95 % CI 0·61, 0·89) nationals, whereas higher risks were found for participants from Italy (OR = 1·45, 95 % CI 1·33, 1·58), Spain (OR = 1·36, 95 % CI 1·15, 1·61), Portugal (OR = 1·25, 95 % CI 1·06, 1·47) and the former Republic of Yugoslavia (OR = 1·98, 95 % CI 1·69, 2·32). Similar findings were observed in the CoLaus Study for Italian (OR = 1·63, 95 % CI 1·29, 2·06), Spanish (OR = 1·54, 95 % CI 1·17, 2·04) and Portuguese (OR = 1·49, 95 % CI 1·16, 1·91) participants and for those from the former Republic of Yugoslavia (OR = 5·34, 95 % CI 3·00, 9·50). Overweight and obesity are unevenly distributed among migrants in Switzerland. Migrants from Southern Europe and from the former Republic of Yugoslavia present higher prevalence rates. This suggests that preventive messages should be tailored to these specific populations.

Effect of Emotion and Personality on Deviation from Purely Rational Decision-Making

Human decision-making has consistently demonstrated deviation from "pure" rationality. Emotions are a primary driver of human actions and the current study investigates how perceived emotions and personality traits may affect decision-making during the Ultimatum Game (UG). We manipulated emotions by showing images with emotional connotation while participants decided how to split money with a second player. Event-related potentials (ERPs) from scalp electrodes were recorded during the whole decision-making process. We observed significant differences in the activity of central and frontal areas when participants offered money with respect to when they accepted or rejected an offer. We found that participants were more likely to offer a higher amount of money when making their decision in association with negative emotions. Furthermore, participants were more likely to accept offers when making their decision in association with positive emotions. Honest, conscientious, and introverted participants were more likely to accept offers. Our results suggest that factors others than a rational strategy may predict economic decision-making in the UG.

Socio-cultural determinants of adiposity and physical activity in preschool children: a cross-sectional study.

Both individual socio-cultural determinants such as selected parental characteristics (migrant background, low educational level and workload) as well as the regional environment are related to childhood overweight and physical activity (PA). The purpose of the study was to compare the impact of distinct socio-cultural determinants such as the regional environment and selected parental characteristics on adiposity, PA and motor skills in preschool children. Forty preschools (N = 542 children) of two culturally different urban regions (German and French speaking part of Switzerland) participated in the study (Ballabeina Study). Outcome measures included adiposity (BMI and skinfold thickness), objectively measured sedentary activities and PA (accelerometers) and agility performance (obstacle course). Parental characteristics (migrant status, educational level and workload) were assessed by questionnaire. Children from the French speaking areas had higher adiposity, lower levels of total and of more intense PA, were more sedentary and less agile than children from the German speaking regions (percent differences for all outcome parameters except for BMI ≥10%; all p ≤ 0.04). Differences in skinfold thickness, sedentary activities and agility, but not in PA, were also found between children of Swiss and migrant parents, though they were ≤8% (p ≤ 0.02). While paternal workload had no effect, maternal workload and parental education resulted in differences in some PA measures and/or agility performance (percent differences in both: ≤9%, p ≤ 0.008), but not in adiposity or sedentary activities (p = NS). Regional differences in skinfold thickness, PA, sedentary activities and agility performance persisted after adjustment for parental socio-cultural characteristics, parental BMI and, where applicable, children's skinfolds (all p ≤ 0.01). The regional environment, especially the broader social environment, plays a prominent role in determining adiposity, PA and motor skills of young children and should be implicated in the prevention of obesity and promotion of PA in children. clinicaltrials.gov NCT00674544.

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila.

Ionotropic glutamate receptors (iGluRs) mediate neuronal communication at synapses throughout vertebrate and invertebrate nervous systems. We have characterized a family of iGluR-related genes in Drosophila, which we name ionotropic receptors (IRs). These receptors do not belong to the well-described kainate, AMPA, or NMDA classes of iGluRs, and they have divergent ligand-binding domains that lack their characteristic glutamate-interacting residues. IRs are expressed in a combinatorial fashion in sensory neurons that respond to many distinct odors but do not express either insect odorant receptors (ORs) or gustatory receptors (GRs). IR proteins accumulate in sensory dendrites and not at synapses. Misexpression of IRs in different olfactory neurons is sufficient to confer ectopic odor responsiveness. Together, these results lead us to propose that the IRs comprise a novel family of chemosensory receptors. Conservation of IR/iGluR-related proteins in bacteria, plants, and animals suggests that this receptor family represents an evolutionarily ancient mechanism for sensing both internal and external chemical cues.

Perception of the damaging effects of smoking, and brief cessation counselling by doctors.

An open prospective study was conducted among the patients visiting an urban medical policlinic for the first time without an appointment to assess whether the immigrants (who represent more than half of our patients) are aware of the health effects of smoking, whether the level of acculturation influences knowledge, and whether doctors give similar advice to Swiss and foreign smokers. 226 smokers, 105 Swiss (46.5%), and 121 foreign-born (53.5%), participated in the study. 32.2% (95% CI [24.4%; 41.1%]) of migrants and 9.6% [5.3%; 16.8%] of Swiss patients were not aware of negative effects of smoking. After adjustment for age, the multivariate model showed that the estimated odds of "ignorance of health effects of smoking" was higher for people lacking mastery of the local language compared with those mastering it (odds ratio (OR) = 7.5 [3.6; 15.8], p < 0.001), and higher for men (OR = 4.3 [1.9; 10.0], p < 0.001). Advice to stop smoking was given with similar frequency to immigrants (31.9% [24.2%; 40.8%] and Swiss patients (29.0% [21.0%; 38.5%]). Nonintegrated patients did not appear to receive less counselling than integrated patients (OR = 1.1 [0.6; 2.1], p = 0.812). We conclude that the level of knowledge among male immigrants not integrated or unable to speak the local language is lower than among integrated foreign-born and Swiss patients. Smoking cessation counselling by a doctor was only given to a minority of patients, but such counselling seemed irrespective of nationality.

Swiss consensus statement: Recommendations for optimising re-treatment with MabThera (rituximab) in rheumatoid arthritis.

Rituximab is an effective treatment of rheumatoid arthritis (RA), which has been approved for the treatment of moderate to severe disease in patients with an inadequate response to anti-TNF therapies. Rituximab differs from other available biological agents for RA by way of its unique mode of action and unrivalled long dosing interval. The efficacy of rituximab subsides progressively over time and re-therapy is generally required to maintain long term disease control. The timing of re-treatment is currently not well established and varies widely in clinical practice. The present document is a concise recommendation regarding re-treatment with rituximab, based on validated outcomes such as the DAS28 and the EULAR response criteria. The recommendation was established through consensus between practitioners familiar with rituximab therapy in RA. Optimisation of the rituximab re-treatment schedule may improve patient outcomes and balance risks and benefits for the individual patient.

Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study.

Increased serum levels of homocysteine and uric acid have each been associated with cardiovascular risk. We analyzed whether homocysteine and uric acid were associated with glomerular filtration rate (GFR) and albuminuria independently of each other. We also investigated the association of MTHFR polymorphisms related to homocysteine with albuminuria to get further insight into causality. This was a cross-sectional population-based study in Caucasians (n = 5913). Hyperhomocysteinemia was defined as total serum homocysteine ≥ 15 μmol/L. Albuminuria was defined as urinary albumin-to-creatinine ratio > 30 mg/g. Uric acid was associated positively with homocysteine (r = 0.246 in men and r = 0.287 in women, P < 0.001). The prevalence of albuminuria increased across increasing homocysteine categories (from 6.4% to 17.3% in subjects with normal GFR and from 3.5% to 14.5% in those with reduced GFR, P for trend < 0.005). Hyperhomocysteinemia (OR = 2.22, 95% confidence interval: 1.60-3.08, P < 0.001) and elevated serum uric acid (OR = 1.27, 1.08-1.50, per 100 μmol/L, P = 0.004) were significantly associated with albuminuria, independently of hypertension and type 2 diabetes. The 2-fold higher risk of albuminuria associated with hyperhomocysteinemia was similar to the risk associated with hypertension or diabetes. MTHFR alleles related to higher homocysteine were associated with increased risk of albuminuria. In the general adult population, elevated serum homocysteine and uric acid were associated with albuminuria independently of each other and of renal function.

Biosafety of Recombinant Adeno-associated Virus Vectors.

It is hoped that the use of gene transfer technology to treat both monogenetic and acquired diseases may soon become a common therapy option in medicine. For gene therapy to achieve this objective, any gene delivery method will have to meet several criteria, including ease of manufacturing, efficient gene transfer to target tissue, long-term gene expression to alleviate the disease, and most importantly safety in patients. Viral vectors are an attractive choice for use in gene therapy protocols due to their relative efficiency in gene delivery. Since there is inherent risk in using viruses, investigators in the gene therapy community have devoted extensive efforts toward reengineering viral vectors for enhance safety. Here we review the approaches and technologies that are being evaluated for the use of recombinant vectors based upon adeno-associated virus (AAV) in the treatment of a variety of human diseases. AAV is currently the only known human DNA virus that is non-pathogenic and AAV-based vectors are classified as Risk Group 1 agents for all laboratory and animal studies carried out in the US. Although its apparent safety in natural infection and animals appears well documented, we examine the accumulated knowledge on the biology and vectorology of AAV, lessons learned from gene therapy clinical trials, and how this information is impacting current vector design and manufacturing with an overall emphasis on biosafety.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Current trends in illegal drug use and drug related health problems in Switzerland.

As part of the evaluation of the Confederation's measures to reduce drug related problems, a review of available data on drug use and drug related problems in Switzerland has been conducted. Source of data included: population surveys (adults and teenagers), surveys among drug users, health statistics (drug related and AIDS related deaths, HIV case reporting, drug treatments) police statistics (denunciations for consumption). The aims of reducing the number of dependent hard drug users have been achieved where heroin is concerned. In particular, there seems to have been a decrease in the number of people becoming addicted to this substance. For all other illegal substances, especially cannabis, the trend is towards an increased use, as in many European countries. As regards dependent drug users, especially injecting drug users, progress has been made in the area of harm reduction and treatment coverage. This epidemiological assessment can be used in the discussions currently engaged about the revision of the Law governing narcotics and will be a baseline for future follow up of the situation.

Health correlates of overweight and obesity in adults aged 50 years and over: results from the Survey of Health, Ageing and Retirement in Europe (SHARE)

QUESTIONS UNDER STUDY: To examine the association between overweight/obesity and several self-reported chronic diseases, symptoms and disability measures. METHODS: Data from eleven European countries participating in the Survey of Health, Ageing and Retirement in Europe were used. 18,584 non-institutionalised individuals aged 50 years and over with BMI > or = 18.5 (kg/m2) were included. BMI was categorized into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9) and obesity (BMI > or = 30). Dependent variables were 13 diagnosed chronic conditions, 11 health complaints, subjective health and physical disability measures. For both genders, multiple logistic regressions were performed adjusting for age, socioeconomic status and behaviour risks. RESULTS: The odds ratios for high blood pressure, high cholesterol, diabetes, arthritis, joint pain and swollen legs were significantly increased for overweight and obese adults. Compared to normal-weight individuals, the odds ratio (OR) for reporting > or = 2 chronic diseases was 2.4 (95% CI 1.9-2.9) for obese men and 2.7 (95% CI 2.2-3.1) for obese women. Overweight and obese women were more likely to report health symptoms. Obesity in men (OR 0.5, 95% CI 0.4-0.6), and overweight (OR 0.5, 95% CI 0.4-0.6) and obesity (OR 0.4, 95% CI 0.3-0.5) in women, were associated with poorer subjective health (i.e. a decreased risk of reporting excellent, very good or good subjective health). Disability outcomes were those showing the greatest differences in strength of association across BMI categories, and between genders. For example, the OR for any difficulty in walking 100 metres was non-significant at 0.8 for overweight men, at 1.9 (95% CI 1.3-2.7) for obese men, at 1.4 (95% CI 1.1-1.8) for overweight women, and at 3.5 (95% CI 2.6-4.7) for obese women. CONCLUSIONS: These results highlight the impact of increased BMI on morbidity and disability. Healthcare stakeholders of the participating countries should be aware of the substantial burden that obesity places on the general health and autonomy of adults aged over 50.