Myocardial perfusion reserve compared with peripheral perfusion reserve: a [13N]ammonia PET study

13N]ammonia PET allows quantification of myocardial perfusion. The similarity between peripheral flow and myocardial perfusion is unclear. We compared perfusion flow in the myocardium with the upper limb during rest and adenosine stress [13N]ammonia PET to establish whether peripheral perfusion reserve (PPR) correlates with MPR. [13N]ammonia myocardial perfusion PET-scans of 58 patients were evaluated (27 men, 31 women, age 64 +/- A 13 years) and were divided in four subgroups: patients with coronary artery disease (CAD, n = 15), cardiac syndrome X (SX, n = 14), idiopathic dilating cardiomyopathy (DCM, n = 16), and normal controls (NC, n = 13). Peripheral limb perfusion was measured in the muscular tissue of the proximal upper limb and quantified through a 2-tissue-compartment model and the PPR was calculated (stress/rest ratio). MPR was also calculated by a 2-tissue-compartment model. The PPR results were compared with the MPR findings. Mean myocardial perfusion increased significantly in all groups as evidenced by the MPR (CAD 1.99 +/- A 0.47; SX 1.39 +/- A 0.31; DCM 1.72 +/- A 0.69; NC 2.91 +/- A 0.78). Mean peripheral perfusion also increased but not significantly and accompanied with great variations within and between groups (mean PPR: CAD 1.30 +/- A 0.79; SX 1.36 +/- A 0.71; DCM 1.60 +/- A 1.22; NC 1.27 +/- A 0.63). The mean difference between PPR and MPR for all subpopulations varied widely. No significant correlations in flow reserve were found between peripheral and myocardial microcirculatory beds in any of the groups (Total group: r = -0.07, SEE = 0.70, CAD: r = 0.14, SEE = 0.48, SX: r = 0.17, SEE = 0.30, DCM: r = -0.11, SEE = 0.71, NC: r = -0.19, SEE = 0.80). No correlations between myocardial and peripheral perfusion (reserve) were found in different patient populations in the same PET session. This suggests a functional difference between peripheral and myocardial flow in the response to intravenously administered adenosine stress

Psychological determinants of using evidence based smoking cessation aids in the Netherlands

**Objectives** The utilization of effective cessation aids, such as professional help and pharmaceutics, will increase the likelihood of successful quitting. In the Netherlands, there is a wide array of effective smoking cessation aids available. A combination of behavioral therapy and pharmaceutics is regarded as the most effective method, boosting success rates with a factor 2 to 4. However, uptake of cessation aids is low: currently only 26% of Dutch quitters use effective cessation aids, which is lower compared to many other countries. This study sought to understand why some smokers do and others do not use these aids, in order to be able to develop better implementation strategies for these evidence based methods. **Methods **We used the I-Change model (De Vries, Lezwijn, Hol & Honing, 2005) to select determinants of using cessation aids when making a quit attempt. This model integrates elements from various models of behavioral change. Behavior is the result of intentions and abilities. If one is not able to make specific plans for executing a certain behavior, it will be less likely for the behavior to occur. This implies that being unable to make plans regarding quitting smoking and using cessation aids will decrease the likelihood of using smoking aids. Intention is influenced by motivational factors (i.e., attitudes, social influences and self-efficacy regarding smoking cessation and using cessation aids). Finally, the model incorporates influences of predisposing factors, such as age, gender, socio-economic status, and level of tobacco addiction as measured by the Heaviness of Smoking Index. A representative sample of 982 Dutch smokers aged 15 years and older, who took part of the Continuous Survey of Smoking Habits, completed the questionnaire. Participants only filled in the questionnaire section on determinants of using cessation aids, when they indicated they wanted to quit at least in some point in their life. Data will be analyzed using a hierarchal regression model. **Results **The results will be presented during the conference. Additionally, we will present a strategy outlining how to better reach and inform smokers about evidence based methods for smoking cessation. **Implementation **In 2011, pharmaceutics for smoking cessation will be reimbursed through the Dutch national health care insurance system when one attends behavioral therapy. The results of this study can be used to develop interventions, particularly mass media approaches as well as tailored interventions, to effectively reach and inform smokers about using evidence based cessation aids and to increase the adoption of these aids for quittin

Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo

Abstract BACKGROUND: We have treated three patients with carboxy-anhydrase-IX (CAIX) positive metastatic renal cell cancer (RCC) by adoptive transfer of autologous T-cells that had been gene-transduced to express a single-chain antibody-G250 chimeric receptor [scFv(G250)], and encountered liver toxicity necessitating adaptation of the treatment protocol. Here, we investigate whether or not the in vivo activity of the infused scFv(G250)(+) T cells is reflected by changes of selected immune parameters measured in peripheral blood. METHODS: ScFv(G250)-chimeric receptor-mediated functions of peripheral blood mononuclear cells (PBMC) obtained from three patients during and after treatment were compared to the same functions of scFv(G250)(+) T lymphocytes prior to infusion, and were correlated with plasma cytokine levels. RESULTS: Prior to infusion, scFv(G250)(+) T lymphocytes showed in vitro high levels of scFv(G250)-chimeric receptor-mediated functions such as killing of CAIX(+) RCC cell lines and cytokine production upon exposure to these cells. High levels of IFN-gamma were produced, whilst production of TNF-alpha, interleukin-4 (IL-4), IL-5 and IL-10 was variable and to lower levels, and that of IL-2 virtually absent. PBMC taken from patients during therapy showed lower levels of in vitro scFv(G250)-receptor-mediated functions as compared to pre-infusion, whilst IFN-gamma was the only detectable cytokine upon in vitro PBMC exposure to CAIX. During treatment, plasma levels of IFN-gamma increased only in the patient with the most prominent liver toxicity. IL-5 plasma levels increased transiently during treatment in all patients, which may have been triggered by the co-administration of IL-2. CONCLUSION: ScFv(G250)-receptor-mediated functions of the scFv(G250)(+) T lymphocytes are, by and large, preserved in vivo upon administration, and may be reflected by fluctuations in plasma IFN-gamma levels

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

This is the final version of the article. Available from the publisher via the DOI in this record.Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.Peer reviewe

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Effectiveness of a web-based self-help smoking cessation intervention: protocol of a randomised controlled trial

BACKGROUND: Cigarette smoking is a major risk factor for many chronic and fatal illnesses. Stopping smoking directly reduces those risks. The aim of this study is to investigate the effectiveness of a web-based interactive self-help programme for smoking cessation, known as the StopSite, by comparing it to an online self-help guide. Both interventions were based on cognitive-behavioural and self-control principles, but the former provided exercises, feedback and interactive features such as one-to-one chatrooms and a user forum, which facilitated mutual support and experience sharing. METHODS AND DESIGN: We conducted a randomised controlled trial to compare the interactive intervention with the self-help guide. The primary outcome measure was prolonged abstinence from smoking. Secondary outcomes were point-prevalence abstinence, number of cigarettes smoked, and incidence of quit attempts reported at follow-up assessments. Follow-up assessments took place three and six months after a one-month grace period for starting the intervention after baseline. Analyses were based on intention-to-treat principles using a conservative imputation method for missing data, whereby non-responders were classified as smokers. DISCUSSION: The trial should add to the body of knowledge on the effectiveness of web-based self-help smoking cessation interventions. Effective web-based programmes can potentially help large numbers of smokers to quit, thus having a major public health impact. TRIAL REGISTRATION: ISRCTN7442376