Significance analysis of microarray transcript levels in time series experiments

Background: Microarray time series studies are essential to understand the dynamics of molecular events. In order to limit the analysis to those genes that change expression over time, a first necessary step is to select differentially expressed transcripts. A variety of methods have been proposed to this purpose; however, these methods are seldom applicable in practice since they require a large number of replicates, often available only for a limited number of samples. In this data-poor context, we evaluate the performance of three selection methods, using synthetic data, over a range of experimental conditions. Application to real data is also discussed. Results: Three methods are considered, to assess differentially expressed genes in data-poor conditions. Method 1 uses a threshold on individual samples based on a model of the experimental error. Method 2 calculates the area of the region bounded by the time series expression profiles, and considers the gene differentially expressed if the area exceeds a threshold based on a model of the experimental error. These two methods are compared to Method 3, recently proposed in the literature, which exploits splines fit to compare time series profiles. Application of the three methods to synthetic data indicates that Method 2 outperforms the other two both in Precision and Recall when short time series are analyzed, while Method 3 outperforms the other two for long time series. Conclusion: These results help to address the choice of the algorithm to be used in data-poor time series expression study, depending on the length of the time series

Association of education with dietary intake among young adults in the bi-ethnic Coronary Artery Risk Development in Young Adults (CARDIA) cohort

OBJECTIVE: To examine associations of changes in dietary intake with education in young black and white men and women. DESIGN: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a multi-centre population-based prospective study. Dietary intake data at baseline and year 7 were obtained from an extensive nutritionist-administered diet history questionnaire with 700 items developed for CARDIA. SETTING: Participants were recruited in 1985-1986 from four sites: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. SUBJECTS: Participants were from a general community sample of 703 black men (BM), 1006 black women (BW), 963 white men (WM) and 1054 white women (WW) who were aged 18-30 years at baseline. Analyses here include data for baseline (1985-1986) and year 7 (1992-1993). RESULTS: Most changes in dietary intake were observed among those with high education (\u3eor=12 years) at both examinations. There was a significant decrease in intake of energy from saturated fat and cholesterol and a significant increase in energy from starch for each race-gender group (P\u3c0.001). Regardless of education, taste was considered an important influence on food choice. CONCLUSION: The inverse relationship of education with changes in saturated fat and cholesterol intakes suggests that national public health campaigns may have a greater impact among those with more education

Multiple Causes for Delay in Arrival at Hospital in Acute Stroke Patients in Aydin, Turkey

This descriptive, hospital-based study, performed in western Turkey, was designed to assess the level of pre-hospital delay and reasons for such delay in acute stroke patients, taking into consideration certain factors such as socioeconomic status, availability of transport options at onset of symptoms. Data were collected from hospital records, and a questionnaire was administered that included questions about socio-demographics, self-reported risk factors and questions related to hospital arrival. The rate of patients arriving at the hospital more than 3 hours after symptom onset was found to be 31.6% for this study. Approximately 1/3 of patients delayed going to the hospital because they were waiting for symptoms to go away while 1/3 of patients were not aware of the importance of seeking immediate medical help. There was a significant relationship between the use of ambulance transportation and length of time before arrival at the hospitals, though there was no statistically significantly relationship between the existence of stroke risk factors and hospital arrival delay. These results will likely be helpful to health care decision makers as they develop a model for stroke health care and community based training

Caspase I-related protease inhibition retards the execution of okadaic acid- and camptothecin-induced apoptosis and PAI-2 cleavage, but not commitment to cell death in HL-60 cells

We have previously reported that the putative cytoprotective protease inhibitor, plasminogen activator inhibitor type 2 (PAI-2), is specifically cleaved during okadaic acid-induced apoptosis in a myeloid leukaemic cell line (Br J Cancer (1994) 70: 834–840). HL-60 cells exposed to okadaic acid and camptothecin underwent morphological and biochemical changes typical of apoptosis, including internucleosomal DNA fragmentation and PAI-2 cleavage. Significant endogenous PAI-2 cleavage was observed 9 h after exposure to okadaic acid; thus correlating with other signs of macromolecular degradation, like internucleosomal DNA fragmentation. In camptothecin-treated cells, PAI-2 cleavage was an early event, detectable after 2 h of treatment, and preceding internucleosomal DNA fragmentation. The caspase I selective protease inhibitor, YVAD-cmk, inhibited internucleosomal DNA fragmentation and PAI-2 cleavage of okadaic acid and camptothecin-induced apoptotic cells. YVAD-cmk rather sensitively and non-toxically inhibited camptothecin-induced morphology, but not okadaic acid-induced morphology. In in vitro experiments recombinant PAI-2 was not found to be a substrate for caspase I. The results suggest that caspase I selective protease inhibition could antagonize parameters coupled to the execution phase of okadaic acid- and camptothecin-induced apoptosis, but not the commitment to cell death. © 1999 Cancer Research Campaig

Response to symptoms of stroke in the UK: a systematic review

<p>Abstract</p> <p>Background</p> <p>The English National Stroke Strategy suggests that there is a need to improve the response of patients and witnesses to the symptoms of acute stroke to increase rapid access to specialist care. We wished to review the evidence base regarding the knowledge, attitudes and behaviours of stroke patients, witnesses and the public to the symptoms of stroke and the need for an urgent response at the onset of symptoms.</p> <p>Methods</p> <p>We conducted a systematic review of UK articles reporting empirical research on a) awareness of and response to the symptoms of acute stroke or TIA, and b) beliefs and attitudes about diagnosis, early treatment and consequences of acute stroke or TIA. Nine electronic databases were searched using a robust search strategy. Citations and abstracts were screened independently by two reviewers. Data were extracted by two researchers independently using agreed criteria.</p> <p>Results</p> <p>11 studies out of 7144 citations met the inclusion criteria. Methods of data collection included: postal survey (n = 2); interview survey (n = 6); review of hospital documentation (n = 2) and qualitative interviews (n = 1). Limited data reveal a good level of knowledge of the two commonest stroke symptoms (unilateral weakness and speech disturbance), and of the need for an emergency response among the general public and at risk patients. Despite this, less than half of patients recognised they had suffered a stroke. Symptom recognition did not reduce time to presentation. For the majority, the first point of contact for medical assistance was a general practitioner.</p> <p>Conclusions</p> <p>There is an assumption that, in the UK, public knowledge of the symptoms of stroke and of the need for an emergency response is lacking, but there is little published research to support this. Public awareness raising campaigns to improve response to the symptoms of stroke therefore may not produce an increase in desired behaviours. Further research is needed to understand why people who experience or witness stroke symptoms frequently do not call emergency services.</p

Body mass index and height over three generations: evidence from the Lifeways cross-generational cohort study

Background: Obesity and its measure of body mass index are strongly determined by parental body size. Debate continues as to whether both parents contribute equally to offspring body mass which is key to understanding the aetiology of the disease. The aim of this study was to use cohort data from three generations of one family to examine the relative maternal and paternal associations with offspring body mass index and how these associations compare with family height to demonstrate evidence of genetic or environmental cross-generational transmission. Methods: 669 of 1082 families were followed up in 2007/8 as part of the Lifeways study, a prospective observational cross-generation linkage cohort. Height and weight were measured in 529 Irish children aged 5 to 7 years and were self-reported by parents and grandparents. All adults provided information on self-rated health, education status, and indicators of income, diet and physical activity. Associations between the weight, height, and body mass index of family members were examined with mixed models and heritability estimates computed using linear regression analysis. Results: Self-rated health was associated with lower BMI for all family members, as was age for children. When these effects were accounted for evidence of familial associations of BMI from one generation to the next was more apparent in the maternal line. Heritability estimates were higher (h2 = 0.40) for mother-offspring pairs compared to father-offspring pairs (h2 = 0.22). In the previous generation, estimates were higher between mothersparents (h2 = 0.54-0.60) but not between fathers-parents (h2 = -0.04-0.17). Correlations between mother and offspring across two generations remained significant when modelled with fixed variables of socioeconomic status, health, and lifestyle. A similar analysis of height showed strong familial associations from maternal and paternal lines across each generation. Conclusions: This is the first family cohort study to report an enduring association between mother and offspring BMI over three generations. The evidence of BMI transmission over three generations through the maternal line in an observational study corroborates the findings of animal studies. A more detailed analysis of geno and phenotypic data over three generations is warranted to understand the nature of this maternal-offspring relationship.TS 24.4.1

The association between workplace smoking bans and self-perceived, work-related stress among smoking workers

<p>Abstract</p> <p>Background</p> <p>There is substantial empirical evidence on the benefits of smoking bans; however, the unintended consequences of this anti-smoking measure have received little attention. This paper examines whether workplace smoking bans (WSB's) are associated with higher self-perceived, work-related stress among smoking workers.</p> <p>Methods</p> <p>A longitudinal representative sample of 3,237 individuals from the Canadian National Population Health Survey from 2000 to 2008 is used. Work-related stress is derived from a 12-item job questionnaire. Two categories of WSB's, full and partial, are included in the analysis, with no ban being the reference category. Analysis also controls for individual socio-demographic characteristics, health status, provincial and occupational fixed-effects. We use fixed-effects linear regression to control for individual time-invariant confounders, both measured and unmeasured, which can affect the relationship between WSB's and work-related stress. To examine the heterogeneous effects of WSB's, the analysis is stratified by gender and age. We check the robustness of our results by re-estimating the baseline specification with the addition of different control variables and a separate analysis for non-smokers.</p> <p>Results</p> <p>Multivariate analysis reveals a positive and statistically significant association between full <it>(β = 0.75, CI = 0.19-1.32) </it>or partial <it>(β = 0.69, CI = 0.12-1.26) </it>WSB's, and the level of self-perceived, work-related stress among smoking workers compared to those with no WSB. We also find that this association varies by gender and age. In particular, WSB's are significantly associated with higher work stress only for males and young adults (aged 18-40). No statistically significant association is found between WSB's and the level of self-perceived work-related stress among non-smoking workers.</p> <p>Conclusion</p> <p>The results of this study do not imply that WSB's are the main determinant of self-perceived, work-related stress among smokers but provides suggestive evidence that these may be positively related.</p

Restoration of IFNγR Subunit Assembly, IFNγ Signaling and Parasite Clearance in Leishmania donovani Infected Macrophages: Role of Membrane Cholesterol

Despite the presence of significant levels of systemic Interferon gamma (IFNγ), the host protective cytokine, Kala-azar patients display high parasite load with downregulated IFNγ signaling in Leishmania donovani (LD) infected macrophages (LD-MØs); the cause of such aberrant phenomenon is unknown. Here we reveal for the first time the mechanistic basis of impaired IFNγ signaling in parasitized murine macrophages. Our study clearly shows that in LD-MØs IFNγ receptor (IFNγR) expression and their ligand-affinity remained unaltered. The intracellular parasites did not pose any generalized defect in LD-MØs as IL-10 mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation remained unaltered with respect to normal. Previously, we showed that LD-MØs are more fluid than normal MØs due to quenching of membrane cholesterol. The decreased rigidity in LD-MØs was not due to parasite derived lipophosphoglycan (LPG) because purified LPG failed to alter fluidity in normal MØs. IFNγR subunit 1 (IFNγR1) and subunit 2 (IFNγR2) colocalize in raft upon IFNγ stimulation of normal MØs, but this was absent in LD-MØs. Oddly enough, such association of IFNγR1 and IFNγR2 could be restored upon liposomal delivery of cholesterol as evident from the fluorescence resonance energy transfer (FRET) experiment and co-immunoprecipitation studies. Furthermore, liposomal cholesterol treatment together with IFNγ allowed reassociation of signaling assembly (phospho-JAK1, JAK2 and STAT1) in LD-MØs, appropriate signaling, and subsequent parasite killing. This effect was cholesterol specific because cholesterol analogue 4-cholestene-3-one failed to restore the response. The presence of cholesterol binding motifs [(L/V)-X1–5-Y-X1–5-(R/K)] in the transmembrane domain of IFNγR1 was also noted. The interaction of peptides representing this motif of IFNγR1 was studied with cholesterol-liposome and analogue-liposome with difference of two orders of magnitude in respective affinity (KD: 4.27×10−9 M versus 2.69×10−7 M). These observations reinforce the importance of cholesterol in the regulation of function of IFNγR1 proteins. This study clearly demonstrates that during its intracellular life-cycle LD perturbs IFNγR1 and IFNγR2 assembly and subsequent ligand driven signaling by quenching MØ membrane cholesterol