Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

TRIO LOGIC REGRESSION - DETECTION OF SNP - SNP INTERACTIONS IN CASE-PARENT TRIOS

Statistical approaches to evaluate higher order SNP-SNP and SNP-environment interactions are critical in genetic association studies, as susceptibility to complex disease is likely to be related to the interaction of multiple SNPs and environmental factors. Logic regression (Kooperberg et al., 2001; Ruczinski et al., 2003) is one such approach, where interactions between SNPs and environmental variables are assessed in a regression framework, and interactions become part of the model search space. In this manuscript we extend the logic regression methodology, originally developed for cohort and case-control studies, for studies of trios with affected probands. Trio logic regression accounts for the linkage disequilibrium (LD) structure in the genotype data, and accommodates missing genotypes via haplotype-based imputation. We also derive an efficient algorithm to simulate case-parent trios where genetic risk is determined via epistatic interactions.

Organizational, DS, GS, and depot maintenance manual (including repair parts list) : light target, surveying, u/w range pole, self illuminating, w/carrying case (military design), FSN 6675-612-1187.

"March 1966."

Organizational, DS, GS, and depot maintenance manual including repair parts : light, signal, surveying, 5 in. dia. reflector, grille housing, in carrying case (military design) FSN 6675-641-3537.

"June 1965."

A metacognitive contextual intervention to enhance error awareness and functional outcome following traumatic brain injury: A single-case experimental design

Very few empirically validated interventions for improving metacognitive skills (i.e., self-awareness and self-regulation) and functional outcomes have been reported. This single-case experimental study presents JM, a 36-year-old man with a very severe traumatic brain injury (TBI) who demonstrated long-term awareness deficits. Treatment at four years post-injury involved a metacognitive contextual intervention based on a conceptualization of neuro-cognitive, psychological, and socio-environmental factors contributing to his awareness deficits. The 16-week intervention targeted error awareness and self-correction in two real life settings: (a) cooking at home: and (b) volunteer work. Outcome measures included behavioral observation of error behavior and standardized awareness measures. Relative to baseline performance in the cooking setting, JM demonstrated a 44% reduction in error frequency and increased self-correction. Although no spontaneous generalization was evident in the volunteer work setting, specific training in this environment led to a 39% decrease in errors. JM later gained paid employment and received brief metacognitive training in his work environment. JM's global self-knowledge of deficits assessed by self-report was unchanged after the program. Overall, the study provides preliminary support for a metacognitive contextual approach to improve error awareness and functional Outcome in real life settings.

Case based design of knitwear

In the developed world we are surrounded by man-made objects, but most people give little thought to the complex processes needed for their design. The design of hand knitting is complex because much of the domain knowledge is tacit. The objective of this thesis is to devise a methodology to help designers to work within design constraints, whilst facilitating creativity. A hybrid solution including computer aided design (CAD) and case based reasoning (CBR) is proposed. The CAD system creates designs using domain-specific rules and these designs are employed for initial seeding of the case base and the management of constraints. CBR reuses the designer's previous experience. The key aspects in the CBR system are measuring the similarity of cases and adapting past solutions to the current problem. Similarity is measured by asking the user to rank the importance of features; the ranks are then used to calculate weights for an algorithm which compares the specifications of designs. A novel adaptation operator called rule difference replay (RDR) is created. When the specifications to a new design is presented, the CAD program uses it to construct a design constituting an approximate solution. The most similar design from the case-base is then retrieved and RDR replays the changes previously made to the retrieved design on the new solution. A measure of solution similarity that can validate subjective success scores is created. Specification similarity can be used as a guide whether to invoke CBR, in a hybrid CAD-CBR system. If the newly resulted design is suffciently similar to a previous design, then CBR is invoked; otherwise CAD is used. The application of RDR to knitwear design has demonstrated the flexibility to overcome deficiencies in rules that try to automate creativity, and has the potential to be applied to other domains such as interior design.

Genes involved in the metabolism of fatty acids and risk for Crohn's disease in children: a candidate gene study

Contexte - La prévalence de la maladie de Crohn (MC), une maladie inflammatoire chronique du tube digestif, chez les enfants canadiens se situe parmi les plus élevées au monde. Les interactions entre les réponses immunes innées et acquises aux microbes de l'hôte pourraient être à la base de la transition de l’inflammation physiologique à une inflammation pathologique. Le leucotriène B4 (LTB4) est un modulateur clé de l'inflammation et a été associé à la MC. Nous avons postulé que les principaux gènes impliqués dans la voie métabolique du LTB4 pourrait conférer une susceptibilité accrue à l'apparition précoce de la MC. Dans cette étude, nous avons exploré les associations potentielles entre les variantes de l'ADN des gènes ALOX5 et CYP4F2 et la survenue précoce de la MC. Nous avons également examiné si les gènes sélectionnés montraient des effets parent-d'origine, influençaient les phénotypes cliniques de la MC et s'il existait des interactions gène-gène qui modifieraient la susceptibilité à développer la MC chez l’enfant. Méthodes – Dans le cadre d’une étude de cas-parents et de cas-témoins, des cas confirmés, leurs parents et des contrôles ont été recrutés à partir de trois cliniques de gastro-entérologie à travers le Canada. Les associations entre les polymorphismes de remplacement d'un nucléotide simple (SNP) dans les gènes CYP4F2 et ALOX5 ont été examinées. Les associations allélique et génotypiques ont été examinées à partir d’une analyse du génotype conditionnel à la parenté (CPG) pour le résultats cas-parents et à l’aide de table de contingence et de régression logistique pour les données de cas-contrôles. Les interactions gène-gène ont été explorées à l'aide de méthodes de réduction multi-factorielles de dimensionnalité (MDR). Résultats – L’étude de cas-parents a été menée sur 160 trios. L’analyse CPG pour 14 tag-SNP (10 dans la CYP4F2 et 4 dans le gène ALOX5) a révélé la présence d’associations alléliques ou génotypique significatives entre 3 tag-SNP dans le gène CYP4F2 (rs1272, p = 0,04, rs3093158, p = 0.00003, et rs3093145, p = 0,02). Aucune association avec les SNPs de ALOX5 n’a pu être démontrée. L’analyse de l’haplotype de CYP4F2 a montré d'importantes associations avec la MC (test omnibus p = 0,035). Deux haplotypes (GAGTTCGTAA, p = 0,05; GGCCTCGTCG, p = 0,001) montraient des signes d'association avec la MC. Aucun effet parent-d'origine n’a été observé. Les tentatives de réplication pour trois SNPs du gene CYP4F2 dans l'étude cas-témoins comportant 225 cas de MC et 330 contrôles suggèrent l’association dans un de ceux-ci (rs3093158, valeur non-corrigée de p du test unilatéral = 0,03 ; valeur corrigée de p = 0.09). La combinaison des ces deux études a révélé des interactions significatives entre les gènes CYP4F2, ALOX et NOD2. Nous n’avons pu mettre en évidence aucune interaction gène-sexe, de même qu’aucun gène associé aux phénotypes cliniques de la MC n’a pu être identifié. Conclusions - Notre étude suggère que la CYP4F2, un membre clé de la voie métabolique LTB4 est un gène candidat potentiel pour MC. Nous avons également pu mettre en évidence que les interactions entre les gènes de l'immunité adaptative (CYP4F2 et ALOX5) et les gènes de l'immunité innée (NOD2) modifient les risques de MC chez les enfants. D'autres études sur des cohortes plus importantes sont nécessaires pour confirmer ces conclusions.

Family environment patterns in families with bipolar children

Background: We studied the characteristics of family functioning in bipolar children and healthy comparison children. We hypothesized that the family environment of bipolar children would show greater levels of dysfunction as measured by the Family Environment Scale (FES). Methods: We compared the family functioning of 36 families that included a child with DSM-IV bipolar disorder versus 29 comparison families that included only healthy children. All subjects and their parents were assessed with the K-SADS-PL interview. The parents completed the FES to assess their current family functioning. Multivariate analysis of variance was used to compare the family environment of families with and without offspring with bipolar disorder. Results: Parents of bipolar children reported lower levels of family cohesion (p<0.001), expressiveness (p=0.005), active-recreational orientation (p<0.001), intellectual-cultural orientation (p=0.04) and higher levels of conflict (p<0.001) compared to parents with no bipolar children. Secondary analyses within the bipolar group revealed lower levels of organization (p=0.03 1) and cohesion (p=0.014) in families where a parent had a history of mood disorders compared to families where parents had no history of mood disorders. Length of illness in the affected child was inversely associated with family cohesion (r=-0.47, p=0.004). Limitations: Due to the case-control design of the study, we cannot comment on the development of these family problems or attribute their cause specifically to child bipolar disorder. Conclusion: Families with bipolar children show dysfunctional patterns related to interpersonal interactions and personal growth. A distressed family environment should be addressed when treating children with bipolar disorder. (C) 2007 Elsevier B.V. All rights reserved.

Maternal antecedents for cerebral palsy in extremely preterm babies: A case-controlled study

The study aimed to identify significant antenatal risk factors for cerebral palsy (CP) among extremely preterm infants with a matched case-control design. Infants born between 1989 and 1996 at 24 to 27 weeks' gestation who survived to hospital discharge were evaluated: 30 with a proven diagnosis of CP at 2 years corrected for prematurity and 120 control children matched for gestational age without CP. Information on maternal obstetric risk factors and medication was obtained. Matched analyses were performed and odds ratios (OR) and 95% confidence intervals (CI) were calculated. An antenatal diagnosis of intrauterine growth restriction was associated with an increased risk of CP (OR 6.6; 95% CI 1.8 to 25.2), while maternal administration of corticosteroids was associated with a reduced risk of CP (OR 0.4; 95% CI 0.1 to 0.98). A high rate of placental histopathology was achieved but no relation between clinical or histological chorioamnionitis or funisitis and CP was demonstrated. Maternal preeclampsia was not associated with a statistically significant reduction in the risk of CP. It is concluded that a reduced risk of CP in extremely preterm infants is associated with the antenatal use of corticosteroids.

General practitioner attitudes to case conferences: how can we increase participation and effectiveness?

Objectives: To identify general practitioners' views on the barriers to using case conferencing (as outlined in the Medical Benefits Schedule (MBS) Enhanced Primary Care package) and to develop a set of principles to encourage greater GP participation in case conferences. Design: Qualitative study, involving semistructured questions administered to focus groups of GPs, conducted between April and July 2001 as part of a broader study of case coordination in palliative care. Participants: 29 GPs from urban, regional, and rural areas of Queensland. Principal findings: Many of the GPs' work practices militated against participation in traditionally structured case conferences. GPs thought the range of MBS item numbers should be expanded to cover alternative methods of liaison (eg, phone consultations with other service providers). The onerous bureaucratic processes required to claim reimbursement were an additional disincentive. Conclusions: GPs would probably be more likely to participate in case conferences if they were initiated by specialist services and arranged more flexibly to suit GP work schedules.

Weather parameters and nosocomial bloodstream infection: a case-referent study

OBJECTIVE To evaluate if temperature and humidity influenced the etiology of bloodstream infections in a hospital from 2005 to 2010.METHODS The study had a case-referent design. Individual cases of bloodstream infections caused by specific groups or pathogens were compared with several references. In the first analysis, average temperature and humidity values for the seven days preceding collection of blood cultures were compared with an overall “seven-days moving average” for the study period. The second analysis included only patients with bloodstream infections. Several logistic regression models were used to compare different pathogens and groups with respect to the immediate weather parameters, adjusting for demographics, time, and unit of admission.RESULTS Higher temperatures and humidity were related to the recovery of bacteria as a whole (versus fungi) and of gram-negative bacilli. In the multivariable models, temperature was positively associated with the recovery of gram-negative bacilli (OR = 1.14; 95%CI 1.10;1.19) or Acinetobacter baumannii (OR = 1.26; 95%CI 1.16;1.37), even after adjustment for demographic and admission data. An inverse association was identified for humidity.CONCLUSIONS The study documented the impact of temperature and humidity on the incidence and etiology of bloodstream infections. The results correspond with those from ecological studies, indicating a higher incidence of gram-negative bacilli during warm seasons. These findings should guide policies directed at preventing and controlling healthcare-associated infections.

Migration and urban schistosomiasis. The case of São Lourenço da Mata, Northeast of Brazil

A population-based case-control design was used to investigate the association between migration, urbanisation and schistosomiasis in the Metropolitan Region of Recife, Northeast of Brazil. 1022 cases and 994 controls, aged 10 to 25, were selected. The natives and the migrants who come from endemic areas have a similar risk of infection. On the other hand, the risk of infection of migrants from nonendemic areas seems to be related with the time elapsed since their arrival in São Lourenço da Mata; those who have been living in that urban area for 5 or more years have a risk of infection similar to that of the natives. Those arriving in the metropolitan region of Recife mostly emigrate from "zona da mata" and "zona do agreste" in the state of Pernambuco. Due to the changes in the sugar agro-industry and to the increase in the area used for cattle grazing these workers were driven to villages and cities. The pattern of urbanisation created the conditions for the establishment of foci of transmission in São Lourenço da Mata.

Design of a balanced scorecard-type management system for a back-office department in a bank

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA – School of Business and Economics