Improving metabolic stability of fluorine-18 labeled verapamil analogs

INTRODUCTION: Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [18F]1 and [18F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7. METHODS: The following deuterium containing tracers were synthesized and evaluated in mice and rats: [18F]1-d4, [18F]2-d4, [18F]3-d3 and [18F]3-d7. RESULTS: The deuterated analogs [18F]2-d4, [18F]3-d3 and [18F]3-d7 showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [18F]3-d3 and [18F]3-d7 might be caused by steric hindrance for enzymes. CONCLUSION: The striking similar in vivo behavior of [18F]3-d7 to that of (R)-[11C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [18F]3-d7 as a PET radiopharmaceutical for P-gp evaluation

Gene Expression Profiles of Chicken Embryo Fibroblasts in Response to Salmonella Enteritidis Infection

The response of chicken to non-typhoidal Salmonella infection is becoming well characterised but the role of particular cell types in this response is still far from being understood. Therefore, in this study we characterised the response of chicken embryo fibroblasts (CEFs) to infection with two different S. Enteritidis strains by microarray analysis. The expression of chicken genes identified as significantly up- or down-regulated (≥3-fold) by microarray analysis was verified by real-time PCR followed by functional classification of the genes and prediction of interactions between the proteins using Gene Ontology and STRING Database. Finally the expression of the newly identified genes was tested in HD11 macrophages and in vivo in chickens. Altogether 19 genes were induced in CEFs after S. Enteritidis infection. Twelve of them were also induced in HD11 macrophages and thirteen in the caecum of orally infected chickens. The majority of these genes were assigned different functions in the immune response, however five of them (LOC101750351, K123, BU460569, MOBKL2C and G0S2) have not been associated with the response of chicken to Salmonella infection so far. K123 and G0S2 were the only 'non-immune' genes inducible by S. Enteritidis in fibroblasts, HD11 macrophages and in the caecum after oral infection. The function of K123 is unknown but G0S2 is involved in lipid metabolism and in β-oxidation of fatty acids in mitochondria

High-level integration of murine intestinal transcriptomics data highlights the importance of the complement system in mucosal homeostasis.

BACKGROUND: The mammalian intestine is a complex biological system that exhibits functional plasticity in its response to diverse stimuli to maintain homeostasis. To improve our understanding of this plasticity, we performed a high-level data integration of 14 whole-genome transcriptomics datasets from samples of intestinal mouse mucosa. We used the tool Centrality based Pathway Analysis (CePa), along with information from the Reactome database. RESULTS: The results show an integrated response of the mouse intestinal mucosa to challenges with agents introduced orally that were expected to perturb homeostasis. We observed that a common set of pathways respond to different stimuli, of which the most reactive was the Regulation of Complement Cascade pathway. Altered expression of the Regulation of Complement Cascade pathway was verified in mouse organoids challenged with different stimuli in vitro. CONCLUSIONS: Results of the integrated transcriptomics analysis and data driven experiment suggest an important role of epithelial production of complement and host complement defence factors in the maintenance of homeostasis

The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome

<p>Abstract</p> <p>Background</p> <p>Cardiovascular diseases and their associated risk factors remain the main cause of mortality in western societies. In order to assess the prevalence of cardiovascular risk factors (CVRFs) in the Caucasian population of Lausanne, Switzerland, we conducted a population-based study (Colaus Study). A secondary aim of the CoLaus study will be to determine new genetic determinants associated with CVRFs.</p> <p>Methods</p> <p>Single-center, cross-sectional study including a random sample of 6,188 extensively phenotyped Caucasian subjects (3,251 women and 2,937 men) aged 35 to 75 years living in Lausanne, and genotyped using the 500 K Affymetrix chip technology.</p> <p>Results</p> <p>Obesity (body mass index ≥ 30 kg/m²), smoking, hypertension (blood pressure ≥ 140/90 mmHg and/or treatment), dyslipidemia (high LDL-cholesterol and/or low HDL-cholesterol and/or high triglyceride levels) and diabetes (fasting plasma glucose ≥ 7 mmol/l and/or treatment) were present in 947 (15.7%), 1673 (27.0%), 2268 (36.7%), 2113 (34.2%) and 407 (6.6%) of the participants, respectively, and the prevalence was higher in men than in women. In both genders, the prevalence of obesity, hypertension and diabetes increased with age.</p> <p>Conclusion</p> <p>The prevalence of major CVRFs is high in the Lausanne population in particular in men. We anticipate that given its size, the depth of the phenotypic analysis and the availability of dense genome-wide genetic data, the CoLaus Study will be a unique resource to investigate not only the epidemiology of isolated, or aggregated CVRFs like the metabolic syndrome, but can also serve as a discovery set, as well as replication set, to identify novel genes associated with these conditions.</p

Recent results on electron cyclotron current drive and MHD activity in RTP

The RTP tokamak (R = 0.72 m, a = 0.164 m, B-phi &lt; 2 5.T, I-p = &lt; 150 kA) is equipped with three gyrotrons (2 x 60 GHz, 180 kW, 100 ms each; 1 x 110 GHz, 500 kW, 200 ms) for electron cyclotron heating (ECH) and current drive (ECCD). The power from one of the 60 GHz gyrotrons is launched via an adjustable mirror from the high field side (HFS) in the 1X-mode. The power of both other gyrotrons is sent in perpendicularly to the toroidal magnetic field from the low field side (LFS). A comprehensive set of high-resolution multichannel plasma diagnostics is available to study the detailed behaviour of various plasma phenomena. First, recent diagnostic innovations are briefly discussed. Then, new physics results are presented for ohmic and EC heated plasmas. ECCD, slide-away discharges, discharges with a hollow temperature profile and MHD phenomena, including sawteeth and disruptions. are treated

Determinants of (sustained) overweight and complaints in children and adolescents in primary care: The DOERAK cohort study design

Background: Almost half of the adult Dutch population is currently overweight and the prevalence of overweight children is rising at alarming rates as well. Obese children consult their general practitioner (GP) more often than normal weight children. The Dutch government has assigned a key role to the GP in the prevention of overweight. The DOERAK cohort study aims to clarify differences between overweight and non-overweight children that consult the GP; are there differences in number of consultations and type and course of complaints? Is overweight associated with lower quality of life or might this be influenced by the type of complaint? What is the activity level of overweight children compared to non-overweight children? And is (sustained) overweight of children associated with parameters related to the energy balance equation? Methods/Design: A total of 2000 overweight (n = 500) and non-overweight children (n = 1500) aged 2 to 18 years who consult their GP, for any type of complaint in the South-West of the Netherlands are included. At baseline, height, weight and waist circumference are measured during consultation. The number of GP consultations over the last twelve months and accompanying diagnoses are acquired from the medical file. Complaints, quality of life and parameters related to the energy balance equation are assessed with an online questionnaire children or parents fill out at home. Additionally, children or parents keep a physical activity diary during the baseline week, which is validated in a subsample (n = 100) with an activity monitor. Parents fill out a questionnaire about demographics, their own activity behaviour and perceptions on dietary habits and activity behaviour, health and weight status of their child. The physical and lifestyle behaviour questions are repeated at 6, 12 and 24 months follow-up. The present study is a prospective observational cohort in a primary care setting. Discussion: The DOERAK cohort study is the first prospective study that investigates a large cohort of overweight and non-overweight children in primary care. The total study population is expected to be recruited by 2013, results will be available in 2015