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The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1+/− mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1+/− mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including ‘Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling’. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1+/− mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity. The integration of liver and plasma quantitative lipidomic and proteomic data from 107 distinct mouse strains provides important insights into regulators of mammalian lipid metabolism.

Objectives. We compared an electronic health record-based influenza-like illness (ILI) surveillance system with manual sentinel surveillance and virologic data to evaluate the utility of the automated system for routine ILI surveillance. Methods. We obtained weekly aggregate ILI reports from the Electronic medical record Support for Public Health (ESP) disease-detection and reporting system, which used an automated algorithm to identify ILI visits among a patient population of about 700,000 in Eastern Massachusetts. The percentage of total visits for ILI (“percent ILI”) in ESP, percent ILI in the Massachusetts Department of Public Health's sentinel surveillance system, and percentage of laboratory specimens submitted to participating Massachusetts laboratories that tested positive for influenza were compared for the period October 2007–September 2011. We calculated Spearman's correlation coefficients and compared ESP and sentinel surveillance systems qualitatively, in terms of simplicity, flexibility, data quality, acceptability, timeliness, and usefulness. Results. ESP and sentinel surveillance percent ILI always peaked within one week of each other. There was 80% correlation between the two and 71%–73% correlation with laboratory data. Sentinel surveillance percent ILI was higher than ESP percent ILI during influenza seasons. The amplitude of variation in ESP percent ILI was greatest for 5- to 49-year-olds and typically peaked for the 5- to 24-year-old age group before the others. Conclusions. The ESP system produces percent ILI data of similar quality to sentinel surveillance and offers the advantages of shifting disease reporting burden from clinicians to information systems, allowing tracking of disease by age group, facilitating efficient surveillance for very large populations, and producing consistent and timely reports.

Electronic medical record (EMR) systems have rich potential to improve integration between primary care and the public health system at the point of care. EMRs make it possible for clinicians to contribute timely, clinically detailed surveillance data to public health practitioners without changing their existing workflows or incurring extra work. New surveillance systems can extract raw data from providers’ EMRs, analyze them for conditions of public health interest, and automatically communicate results to health departments. We describe a model EMR-based public health surveillance platform called Electronic Medical Record Support for Public Health (ESP). The ESP platform provides live, automated surveillance for notifiable diseases, influenza-like illness, and diabetes prevalence, care, and complications. Results are automatically transmitted to state health departments.

The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects.We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P=0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P=0.0007 for pooled data). Overall, the mean (±SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2±1.6% vs. 9.4±1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma.

Genetic variation at the MYH9 locus is linked to the high incidence of focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease among African Americans. To further define risk alleles with FSGS we performed a genome-wide association analysis using more than one million single-nucleotide polymorphisms in 56 African-American and 61 European-American patients with biopsy-confirmed FSGS. Results were compared to 1641 European Americans and 1800 African Americans as unselected controls. While no association was observed in the cohort of European Americans, the case-control comparison of African Americans found variants within a 60 kb region of chromosome 22 containing part of the APOL1 and MYH9 genes associated with increased risk of FSGS. This region spans different linkage disequilibrium blocks, and variants associating with disease within this region are in linkage disequilibrium with variants which have shown signals of natural selection. APOL1 is a strong candidate for a gene that has undergone recent natural selection and is known to be involved in the infection by Trypanosoma brucei, a parasite common in Africa that has recently adapted to infect human hosts. Further studies will be required to establish which variants are causally related to kidney disease, what mutations caused the selective sweep, and to ultimately determine if these are the same.

Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10(-91) to 7 × 10(-4)). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10(-6)), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.

Comparative effectiveness research, medical product safety evaluation, and quality measurement will require the ability to use electronic health data held by multiple organizations. There is no consensus about whether to create regional or national combined (eg, "all payer") databases for these purposes, or distributed data networks that leave most Protected Health Information and proprietary data in the possession of the original data holders.Demonstrate functions of a distributed research network that supports research needs and also address data holders concerns about participation. Key design functions included strong local control of data uses and a centralized web-based querying interface.We implemented a pilot distributed research network and evaluated the design considerations, utility for research, and the acceptability to data holders of methods for menu-driven querying. We developed and tested a central, web-based interface with supporting network software. Specific functions assessed include query formation and distribution, query execution and review, and aggregation of results.This pilot successfully evaluated temporal trends in medication use and diagnoses at 5 separate sites, demonstrating some of the possibilities of using a distributed research network. The pilot demonstrated the potential utility of the design, which addressed the major concerns of both users and data holders. No serious obstacles were identified that would prevent development of a fully functional, scalable network.Distributed networks are capable of addressing nearly all anticipated uses of routinely collected electronic healthcare data. Distributed networks would obviate the need for centralized databases, thus avoiding numerous obstacles.

Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003).Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.

Rationale: Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma. Objectives: To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility. Methods: Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing. Measurements and Main Results: We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin β3 [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons. Conclusions: We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true “asthma genes.”

Rationale Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. Methods We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for ΔF508, and categories of “severe” (cases) or “mild” (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV1) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR ≤0.5 or >1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent–offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed. Results SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P

Health care providers are legally obliged to report cases of specified diseases to public health authorities, but existing manual, provider-initiated reporting systems generally result in incomplete, error-prone, and tardy information flow. Automated laboratory-based reports are more likely accurate and timely, but lack clinical information and treatment details. Here, we describe the Electronic Support for Public Health (ESP) application, a robust, automated, secure, portable public health detection and messaging system for cases of notifiable diseases. The ESP application applies disease specific logic to any complete source of electronic medical data in a fully automated process, and supports an optional case management workflow system for case notification control. All relevant clinical, laboratory and demographic details are securely transferred to the local health authority as an HL7 message. The ESP application has operated continuously in production mode since January 2007, applying rigorously validated case identification logic to ambulatory EMR data from more than 600,000 patients. Source code for this highly interoperable application is freely available under an approved open-source license at http://esphealth.org.

Inhaled beta-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients.To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists.We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled beta-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts.We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047).These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.

The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.

Although inhaled corticosteroids (ICSs) generally protect against severe exacerbations in asthma, they may result in elevated IgE levels, which are associated with exacerbations.To determine whether variation in the low-affinity IgE receptor gene, FCER2, is associated with severe exacerbations defined as emergency department visits and/or hospitalizations in patients with asthma on ICSs.We resequenced, then genotyped 10 FCER2 single nucleotide polymorphisms (SNPs) in 311 children randomized to inhaled budesonide as part of the Childhood Asthma Management Program. We evaluated the association of FCER2 variants with IgE levels and presence or absence of severe exacerbations over the 4-year clinical trial. We also evaluated differences in cellular expression of the novel FCER2 SNP, T2206C.In white subjects, 3 FCER2 SNPs were significantly associated (P.05) with elevated 4-year IgE level; each was also associated with increased severe exacerbations. Final multivariable models demonstrated associations between T2206C and severe exacerbations in both white and African American children (hazard ratio, 3.95; 95% CI, 1.64-9.51; and hazard ratio, 3.08; 95% CI, 1.00-9.47), despite ICS use. Interaction models supported a true gene-environment effect in white subjects (interaction P = .004). T2206C was also associated with decreased FCER2 expression (P = .02).FCER2 predicts the likelihood of treatment protocol success in asthma. The associations of T2206C with IgE level, severe exacerbations, and FCER2 expression may provide a mechanistic basis for the observed findings.Genetic variation in FCER2 may help form a prognostic model for ICS response in asthma.

Rationale: Computed tomography (CT) scanning of the lung may reduce phenotypic heterogeneity in defining subjects with chronic obstructive pulmonary disease (COPD), and allow identification of genetic determinants of emphysema severity and distribution. Objectives: We sought to identify genes associated with CT scan distribution of emphysema in individuals without α1-antitrypsin deficiency but with severe COPD. Methods: We evaluated baseline CT densitometry phenotypes in 282 individuals with emphysema enrolled in the Genetics Ancillary Study of the National Emphysema Treatment Trial, and used regression models to identify genetic variants associated with emphysema distribution. Measurements and Main Results: Emphysema distribution was assessed by two methods—assessment by radiologists and by computerized density mask quantitation, using a threshold of −950 Hounsfield units. A total of 77 polymorphisms in 20 candidate genes were analyzed for association with distribution of emphysema. GSTP1, EPHX1, and MMP1 polymorphisms were associated with the densitometric, apical-predominant distribution of emphysema (p value range = 0.001–0.050). When an apical-predominant phenotype was defined by the radiologist scoring method, GSTP1 and EPHX1 single-nucleotide polymorphisms were found to be significantly associated. In a case–control analysis of COPD susceptibility limited to cases with densitometric upper-lobe–predominant cases, the EPHX1 His139Arg single-nucleotide polymorphism was associated with COPD (p = 0.005). Conclusions: Apical and basal emphysematous destruction appears to be influenced by different genes. Polymorphisms in the xenobiotic enzymes, GSTP1 and EPHX1, are associated with apical-predominant emphysema. Altered detoxification of cigarette smoke metabolites may contribute to emphysema distribution, and these findings may lead to further insight into genetic determinants of emphysema.

Anti-proliferative and pro-apoptotic effects of Bay leaf (Laurus nobilis) in mammalian cancer and HT-29 adenocarcinoma cells have been previously attributed to effects of polyphenolic and essential oil chemical species. Recently, we demonstrated differentiated growth-regulating effects of high (HFBL) versus low molecular mass (LFBL) aqueous fractions of bay leaf and now confirm by comparative effects on gene expression, that HFBL and LFBL suppress HT-29 growth by distinct mechanisms. Induction of intra-cellular lesions including DNA strand breakage by extra-cellular HFBL, invoked the hypothesis that iron-mediated reactive oxygen species with capacity to penetrate cell membrane, were responsible for HFBL-mediated effects, supported by equivalent effects of HFBL in combination with γ radiation. Activities of HFBL and LFBL were interpreted to reflect differentiated responses to iron-mediated reactive oxygen species (ROS), occurring either outside or inside cells. In the presence of LFBL, apoptotic death was relatively delayed compared with HFBL. ROS production by LFBL mediated p53-dependent apoptosis and recovery was suppressed by promoting G1/S phase arrest and failure of cellular tight junctions. In comparison, intra-cellular anti-oxidant protection exerted by LFBL was absent for extra-cellular HFBL (likely polysaccharide-rich), which potentiated more rapid apoptosis by producing DNA double strand breaks. Differentiated effects on expression of genes regulating ROS defense and chromatic condensation by LFBL versus HFBL, were observed. The results support ferrous iron in cell culture systems and potentially in vivo, can invoke different extra-cellular versus intra-cellular ROS-mediated chemistries, that may be regulated by exogenous, including dietary species.

Objectives To compare the clinicopathologic data of 286 laparoscopic radical prostatectomies (LRPs) and 714 open radical prostatectomies (RRPs) performed at the Massachusetts General Hospital from 2001 to 2005. Methods A total of 1000 radical prostatectomy procedures were analyzed for prostate weight, pathologic stage, Gleason score, surgical margin status, and positive margin location. Results The mean patient age was 58.6 and 59.1 years for the LRP and RRP groups, respectively. The mean preoperative prostate-specific antigen level was 5.96 and 6.00 ng/mL, respectively. Clinical Stage T1c cancer was seen in 86.4% of the LRP and 90.5% of the RRP patients. Gleason score 7 or less disease was seen on biopsy in 97.5% of the LRP and 96.9% of the RRP patients. The average prostate weight was 46.8 g for LRP and 46.0 g for RRP. In the radical prostatectomy specimens, 94.4% of LRP and 93.3% of RRP patients had Gleason score 7 or less disease and 86.0% of LRP and 81.7% of RRP patients had pathologic Stage pT2 cancer. The rate of positive surgical margins was 15.0% and 17.4% for the LRP and RRP groups, respectively. The positive margins occurred mainly at the peripheral and apical regions in both groups. No significant difference was found in the preoperative variables or final pathologic findings between the two surgical groups. Conclusions With similar case selection, LRP and RRP achieve similar pathologic outcomes.

Summary It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low ( 5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r2 > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP.

Objective: The study assessed health-related quality of life (HRQOL) of patients before and after cardiac surgery. Design: This was a prospective repeated-measures observational study. Setting: The study took place in a 650-bed tertiary referral hospital in Sydney, Australia. Methods: HRQOL was measured using the Medical Outcomes Study Short Form 36-item health survey (SF-36) and the 15 Dimensions of Quality of Life questionnaire before surgery, at hospital discharge, and 6 months postdischarge. Results: Participants were representative of the cardiac surgery population. Scores for several concepts deteriorated at hospital discharge when compared with presurgery. There were significant improvements in health status at 6 months postdischarge when compared with previous measures for the majority of SF-36 and 15 Dimensions of Quality of Life questionnaire concepts, although mental health and social functioning demonstrated significant deterioration. SF-36 scores were substantially lower than population norms, but similar to previous studies of patients undergoing cardiac surgery except for mental health. Conclusion: Deterioration in health status at hospital discharge when compared with presurgery status reinforces the need for further patient care and support after discharge. All dimensions improved after 6 months, except mental health. This information can guide patient expectations regarding rehabilitation posthospitalization, and cardiac surgical services should implement and evaluate formal "outreach programs" for these patients. © 2005 Mosby, Inc. All rights reserved.

Asthma affects approximately 300 million individuals worldwide. Medications comprise a substantial portion of asthma expenditures. Despite the availability of three primary therapeutic classes of medications, there are a significant number of nonresponders to therapy. Available data, as well as previous pharmacogenetic studies, suggest that genetics may contribute as much as 60-80% to the interindividual variability in treatment response. In this methodologic review, after providing a broad overview of the asthma pharmacogenetics literature to date, we describe the application of a novel family-based screening algorithm to the analysis of pharmacogenetic data and highlight our approach to identifying and verifying loci influencing asthma treatment response. This approach seeks to address issues related to multiple comparisons, statistical power, population stratification, and failure to replicate from which previous population-based or case-control pharmacogenetic association studies may suffer. Identification of such replicable loci is the next step towards the goal of 'individualized therapy' for asthma.

Background Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. Objective To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. Methods Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. Results One SNP, −384A>G, was associated with asthma among African American families ( P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, −426C and IVS2+199A, were associated with lower serum total IgE levels ( P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, −576C and g.4438C, were associated with higher IgE levels in African American families ( P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV 1 , or airway responsiveness. Conclusion These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.

Background and Objective: The level of agreement between index and proxy respondents on assessment of health status of clinical cohorts is variable. There is limited information regarding agreement between cardiac surgery patients and their proxies, and levels of agreement examined across repeated measures. This study examined the level of agreement between index and proxy respondents' perceptions of the patient's health status prior to and following cardiac surgery. Methods: A prospective, paired-respondent, repeated measures observational study of elective cardiac surgical patients and their next of kin, from the cardiac surgical unit of a tertiary hospital in Sydney, Australia. Health status domains were examined using the15D and SF-36 instruments at three points: prior to surgery, at hospital discharge, and at 6 months post discharge. Results: Moderate to good level of agreement was noted for physical function (physical functioning, role functioning-physical, mobility, breathing, speech, hearing, usual activities, sexual activities) and some psychosocial dimensions (role functioning-emotional, sleeping, depression, mental health). Agreement was highest for presurgery and 6 months post discharge. Differences in scores were not clinically important. Conclusion: Proxy respondents can reliably assess the quality of life of a cardiac surgical patient using 15D or SF-36, particularly for domains reflecting physical function. © 2006 Elsevier Inc. All rights reserved.

T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association.Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels.We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR.These data suggest that T-bet variation contributes to airway responsiveness in asthma.

C-reactive protein (CRP) is a well-documented marker of atherosclerotic cardiovascular disease risk. We resequenced CRP to identify a comprehensive set of common SNP variants, then studied and replicated their association with baseline CRP level among apparently healthy subjects in the Women's Health Study (WHS; n = 717), Pravastatin Inflammation/CRP Evaluation trial (PRINCE; n = 1,110) and Physicians' Health Study (PHS; n = 509) cohorts. The minor alleles of four SNPs were consistently associated in all three cohorts with higher CRP, while the minor alleles of two SNPs were associated with lower CRP (p0.05 for each). Single marker and haplotype analysis in all three cohorts were consistent with functional roles for the 5'-flanking triallelic SNP -286CTA and the 3'-UTR SNP 1846GA. None of the SNPs associated with higher CRP were associated with risk of incident myocardial infarction (MI) or ischemic stroke in a prospective, nested case-control study design from the PHS cohort (610 case-control pairs). One SNP, -717AG, was unrelated to CRP levels but associated with decreased risk of MI (p = 0.001). Taken together, these data imply significant interactions between both genetic and environmental contributions to the increased CRP levels that predict a greater risk of future atherothrombotic events in epidemiological studies.

Toll-like receptor 6 (TLR6) is one of a series of highly conserved innate immune receptors. We resequenced TLR6 in DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans, identifying 53 SNPs, 22 with an allele frequency >5%. Significant differences in SNP frequencies among the three populations were noted. In all, 11 SNPs caused amino-acid changes, including one with a frequency >5% in all three populations. Utilizing this SNP (Ser249Pro), we performed exploratory nested case–control disease-association studies, including one involving 56 African Americans with asthma and 93 African American controls. The minor allele of this SNP was associated with decreased risk for asthma (odds ratio 0.38, 95% CI 0.16–0.87, P=0.01), an effect consistent with the known biology of the toll-like receptors. Although replication of this finding in other, larger samples is needed, variation in TLR6 may have relevance to the pathogenesis of immunologically mediated diseases.

IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.

Chromosome 12q13-24 is among the regions most frequently identified in genome-wide surveys for asthma susceptibility loci, with reports of two distinct clusters of positive linkage signals: one near the interferon gamma locus, the other near the nitric oxide synthase 1 locus. These results suggest that 12q harbors several asthma susceptibility loci. We evaluated this possibility in a subset of families ascertained through the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study. Fifty-five nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Non-parametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: (i) percent predicted forced expiratory volume in one second (FEV(1)); (ii) dose of methacholine resulting in 20% fall in FEV(1) from baseline (PC(20)); (iii) post-bronchodilator percent change in FEV(1) (BDPR); (iv) serum eosinophil levels (EOS); and (v) total serum IgE levels (IgE). Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P-value=0.05), airways responsiveness (PC(20)) at 147 cM (P=0.01), and indices of pulmonary function (FEV1, BDPR) at 134 cM (P=0.05 and P0.01, respectively). No linkage was observed for the atopy-related phenotypes. We provide further evidence supporting the presence of an asthma susceptibility locus at the proximal end of chromosome 12q, as well as new evidence for additional loci more distally that account for unique features of the asthma phenotype. Fine mapping efforts for these loci are warranted.

Several health plants and other organizations are collaborating with the Centers for Disease Control and Prevention to develop a syndromic surveillance system with national coverage that includes more than 20 million people. A principal design feature of this system is reliance on daily reporting of counts of individuals with syndromes of interest in specified geographic regions rather than reporting of individual encounter-level information. On request from public health agencies, health plans and telephone triage services provide additional information regarding individuals who are part of apparent clusters of illness. This reporting framework has several advantages, including less sharing of protected health information, less risk that confidential information will be distributed inappropriately, the prospect of better public acceptance, greater acceptance by health plans, and less effort and cost for both health plans and public health agencies. If successful, this system will allow any organization with appropriate data to contribute vital information to public health syndromic surveillance systems while preserving individuals’ privacy to the greatest extent possible.

Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.

Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.

The objective of this study was to examine the association of scholastic performance with physical activity and fitness of children. To do so, school ratings of scholastic ability on a five-point scale for a nationally representative sample of 7,961 Australian schoolchildren aged 7–15 years were compared with physical activity and fitness measurements. Consistently across age and sex groups, the ratings were significantly correlated with questionnaire measures of physical activity and with performance on the 1.6-kilometer run, sit-ups and push-ups challenges, 50-meter sprint, and standing long jump. There were no significant associations for physical work capacity at a heart rate of 170 (PWC170). The results are concordant with the hypothesis that physical activity enhances academic performance, but the cross-sectional nature of the observations limits causal inference, and the disparity for PWC170 gives reason to question whether the associations were due to measurement bias or residual confounding.

Objectives: Firstly, to determine the accuracy of the Radiometer ABL 625 lactate electrode (Radiometer Medical Pty Ltd, Nunawading, Victoria, Australia) by comparing the lactate values obtained by this method to those obtained with the Hitachi 917 lactate analyser (Boehringer Mannheim Corporation, Charlottetown, Prince Edward Island, Canada). Secondly, to determine the effect of delay in measurement on blood lactate levels. Methodology: Umbilical venous (UCV) blood samples were obtained from healthy term infants delivered vaginally. Lactate levels were measured with the Radiometer ABL 625 lactate electrode in the Neonatal Intensive Care Unit, Westmead Hospital and with the Hitachi 917 lactate analyser in 49 paired samples. In addition 26 UCV blood samples were placed in ice slurry and a further 26 samples at room temperature and blood lactate was measured at 5-min intervals for 30 min to determine the change of lactate levels with time. Results: The lactate levels obtained from the Radiometer ABL 625 lactate electrode were consistently lower than the levels obtained from the Hitachi 917 lactate analyser (mean difference – 0.24), but the correlation was high (r = 0.97). The blood lactate levels increased at the rate of 0.012 mmol/L per min if the blood was left at room temperature. The lactate levels remained stable for 20 min if the blood was placed in ice slurry. Conclusion: The Radiometer ABL 625 lactate electrode was easy to use and there was high correlation with the values obtained by the standard laboratory method. The blood specimen must be place in an ice slurry if a delay in analysis is anticipated.

OBJECTIVE: To estimate the prevalence of Huntington disease (HD) in New South Wales on Australian Census Day (6 August) 1996. DESIGN: Survey of records of the Huntington Disease Service and major hospitals, and of neurologists, psychiatrists, clinical geneticists and genetic counsellors. SUBJECTS AND SETTING: All patients in NSW who, on Census Day 1996, either had a definite diagnosis of HD (motor signs of chorea or ataxia and family history of HD or positive DNA test result) or would have had signs and later received a definite diagnosis (assessed 1 April 1997 to 1 July 1999). MAIN OUTCOME MEASURES: Prevalence (HD patients per 100,000 population); patient characteristics; year and basis of diagnosis. RESULTS: 380 patients with definite HD were identified, giving a prevalence of HD in NSW in 1996 of 6.29 per 100,000 population (95% CI, 5.68-6.96). A third of HD patients were aged 60 years or older. Diagnosis was confirmed by DNA testing for 171 patients (45%), including 30 (8%) with no recorded family history. Average numbers of new diagnoses per year were 11.8 (1984-1988), 21.8 (1989-1993) and 28.6 (1994-1998). Estimated number of people with a 50% risk of inheriting the HD mutation was 25.2 per 100,000 population. Estimated incidence of HD in 1996 was 0.65 per 100,000 population. CONCLUSIONS: Prevalence of HD in NSW is similar to estimated prevalence in other Australian and Western populations. Increasing numbers of cases are being diagnosed, and the 18 chronic care beds currently designated for HD patients in NSW are unlikely to be sufficient.

Comparison of long-term mortality rates between patients with traumatic brain injury (TBI) and the general population has not been adequately investigated. This project aimed to obtain information on the long-term mortality rate of patients with TBI. Using a rehabilitation database of a major teaching hospital, the search identified 476 patients, of whom 27 were deceased. This mortality rate (5.7%) was compared with the expected mortality rate for an equivalent population without TBI (1.5%) using Australian Life Table data. It was found that patients with TBI had a significantly higher mortality rate than the general population (chi2 = 12.2, p < 0.001). Possible reasons for this finding are discussed.

OBJECTIVE To describe the measured dietary intakes and anthropometry of a large, free-living population of middle-aged and older Australians who participated in the Australian Blue Mountains Eye Study (BMES), and to identify the socio-demographic characteristics associated with attainment or non-attainment of dietary goals. METHOD Anthropometry and dietary intakes were compared with current population dietary goals and Recommended Dietary Intakes for 2,873 people (79% of eligible residents) aged > or = 49 years who participated in the BMES. Nutrient intakes were measured by a validated food frequency questionnaire. RESULTS Nutrients for which mean intakes deviated most from nutrition goals included: percentages of energy from total and saturated fat, carbohydrate and alcohol (men), as well as absolute intakes of calcium, zinc and fibre. More than half the men (60%) and women (54%) were overweight or obese. Several micro-nutrient goals were more likely to be met in households where the respondents and/or their spouses were independent. Married men were more likely to meet goals for fibre and iron, but less likely to meet the goal for cholesterol. Several goals were more likely to be met by men and women who had qualifications after leaving school, those with higher job status and non-pensioners, suggesting an socio-economic status dimension. CONCLUSIONS AND IMPLICATIONS These results indicate that over- rather than under-nutrition is more prevalent among community-dwelling older people, although under-nutrition should not be overlooked. Particular sub-groups that are less likely to meet some dietary goals may require targeting in community nutrition interventions.

Should older people eat more carrots, or at least increase their carotene intake to prevent loss of night vision? Participants in the Blue Mountains Eye Study were asked about their ability to see in the dark. Nutrient and food intake were estimated from a food frequency questionnaire. Associations between self-reported poor night vision and estimated nutrient intake were investigated using logistic regression. Poor night vision among women was associated with higher beta-carotene (P for trend = 0.03) and total vitamin A intake (P for trend = 0.048). Increased consumption of carrots, but no other food high in beta-carotene, was associated with significant increased reporting of poor night vision among women (P for trend = 0.04). While carrot intake may protect against difficulty in seeing at night, it is probable that people attributing poor driving ability to their vision may be eating more carrots in the hope of reversing this decline.

Objective: To determine the interobserver reliability of the click test, a rapid bedside test of surfactant function. Methodology: One hundred samples (48 amniotic fluid, 28 gastric aspirates, 24 tracheal aspirates) were obtained from pregnant women, term and preterm infants managed at two perinatal centres. Gestational ages of the pregnancies or infants at time of sampling ranged from 24 to 40 weeks (mean±sd: 31±5). The click test was performed independently by two observers, with differing levels of experience, and blinded to each other’s results. Interobserver reliability was determined for samples classified as negative (no clicking bubbles), equivocal (a few clicking bubbles seen after 2 min of looking), and positive (clicking bubbles seen easily on first look). As negative and equivocal test results suggest surfactant dysfunction, these results were also combined to provide a dichotomised result. Results: For samples classified as negative, equivocal and positive the interobserver agreement was 0.83, with agreement beyond chance shown by a quadratic weighted Kappa of 0.74 (95% CI=0.62–0.86). When negative and equivocal results were combined, the simple Kappa was 0.73 (95% CI=0.59–0.87). Conclusions: The click test has a high level of interobserver reliability. It is rapid, simple, accurate and able to be taught to medical and nursing staff with appropriate training. It has many potential applications including the prediction of fetal lung maturity in women with premature rupture of membranes, and in term and preterm infants who require the bedside testing of surfactant function.

Although obesity and insulin levels are generally associated in cross-sectional data, the temporal and causal nature of their association is not yet clear. Increased obesity may have preceded increased insulin levels or vice versa. The authors examined the temporal relations between fasting insulin blood levels and weight in longitudinal data from the ongoing Normative Aging Study. Two insulin measurements from which a rate of change (delta Insulin) could be calculated were available from 376 non-diabetic male subjects (mean age = 62.1 years). Rate of change in weight could be calculated for the previous inter-examination period (delta Weight1), the contemporaneous period (delta Weight2), and the inter-examination period following the second insulin measurement (delta Weight3). delta Weight2 was a significant predictor (p = 0.0005) of delta insulin in multiple linear regression models that included control for potential confounders (body mass index, waist-to-hip ratio, antihypertensive and diuretic medication use, and age) and for correlation between the initial level and change in insulin (mean fasting insulin). delta Weight1 was added to the model and was found not to be statistically significant (p = 0.15). When the model was stratified by age tertile, the regression coefficient on delta Weight1 was -0.44 (p = 0.018) for the youngest stratum, -0.06 (p = 0.72) for the middle stratum, and 0.21 (p = 0.19) for the oldest men. Similarly, delta Insulin was a significant predictor of delta Weight3 (p = 0.026) in a separate regression model. These findings are consistent with both possible temporal sequences of association between changes in insulin and obesity. The intricate homeostatic mechanisms that regulate changes in insulin and obesity may not be readily amenable to description in terms of cause and effect.

Hyperinsulinemia is associated with insulin resistance and with the development of diabetes, hypertension, and coronary heart disease. Physical activity appears to be negatively associated with insulin resistance, although the mechanism is unclear. The relationship between physical activity and insulin resistance could be mediated, in part, by direct effects on skeletal muscle, a significant site for insulin-mediated glucose disposal. This report examines the relationship between skeletal muscle strength (as measured by handgrip dynamometry) and fasting insulin levels in a cohort of men in the ongoing Normative Aging Study (NAS). Handgrip strength was negatively associated (P = .013) with logarithmic (log) fasting insulin in cross-sectional data from 655 subjects after adjustment for potential confounders including age, body mass index (BMI), ratio of abdominal girth to hip breadth (AG/HB), usual physical activity level, and alcohol intake in a multiple regression model. In data collected prospectively among 1,195 subjects, handgrip strength measured at study entry was negatively predictive of log fasting insulin (P = .017) measured 22.9 +/- 2.6 years later, after adjustment for age, BMI, and AG/HB at study entry in a multiple linear regression model. A cross-sectional association was confirmed in an analysis of prospective data on the relationship between handgrip strength and fasting insulin levels. The findings suggest that skeletal muscle weakness may precede and predict the development of insulin resistance, and raise the intriguing possibility of some common cause in skeletal muscle pathophysiology.

This article reviews some basic principles of meta-analysis techniques for comparative clinical trials data and also discusses the use of logistic regression when comparative data are not easily available. In comparing a treatment drug and a control drug, a common problem in meta-analysis is that not many comparative clinical trials are available in the literature on the selected pair of drugs. There are, however, many clinical studies done separately on each of the drugs of interest. The situation is discussed where conventional meta-analysis results might not produce significant findings due to relatively few comparative studies involving the control drug of interest, while the logistic regression done by pooling all available individual and comparative trials could provide some insights on how the treatment and control drugs are different after controlling on covariates such as study design, patient age groups, disease groups, and so forth.

Childhood obesity is associated with a range of adverse consequences, and the prevalence is increasing in developed nations. Most of the literature on obesity and ventilatory function in children concerns samples selected for gross obesity with relatively little detail available from random population samples. This report examines the effect of total body fat as a percentage of weight (TBF%) on ventilatory function in a nationally representative sample of 2,464 Australian school children aged 9, 12, and 15 years. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were used as measures of ventilatory function. TBF% was estimated from skinfold thickness measurements. Ventilatory function was adjusted (for height and then for both height and weight) using linear regression on a logarithmic scale. Adjustment was performed within separate strata of age and gender. Analysis of covariance was used for hypothesis testing. Height-adjusted FVC and FEV1 values increased significantly with increasing weight within each age and gender group and for all subjects combined (P < 0.0001). The effect of TBF% independent of lean tissue was examined using FVC and FEV1 values adjusted for both height and weight, because body weight measures both lean and fat mass. Adjusted FVC and FEV1 values decreased significantly with increasing TBF% within each age and gender group and for all subjects combined (P < 0.0001). Ventilatory function decreased with increasing proportions of body fat. This is consistent with previous findings on lean tissue mass and ventilatory function. Although the magnitude of the effect was relatively small in clinical terms, from a public health perspective our findings indicate yet another adverse consequence of childhood obesity.

Much remains to be clarified in the apparently protective effect of moderate alcohol use against coronary heart disease risk. Insulin levels are positively associated with coronary heart disease risk, so recent reports of decreased insulin sensitivity among nondrinkers and lower fasting insulin levels with increasing alcohol intake suggest the possibility that insulin may play a role. Between 1987 and 1991, the authors examined fasting insulin concentrations and the empiric fasting insulin resistance index in relation to reported alcohol intake (mean, 15.3 g/day; standard deviation, 19.6; range, 0-120.6) and potential confounders. The latter included age, obesity, fat distribution, smoking, energy, saturated fat intake, antihypertensive medication, and physical activity. Participants in this cross-sectional analysis were 938 nondiabetic men from the Boston, Massachusetts, area who were part of the Normative Aging Study. Unadjusted fasting insulin levels were significantly different (p = 0.008) between categories of alcohol intake, as were fasting insulin resistance index values (p = 0.01). After adjustment for potential confounders, analysis revealed that subjects consuming moderate amounts of alcohol had the lowest fasting insulin and fasting insulin resistance index values. Compared with values from moderate drinkers, fasting insulin resistance index values were higher in those subjects reporting no alcohol intake (p = 0.011), low intake (p = 0.004), and high intake (p = 0.04). A similar pattern was observed for fasting insulin values. Among this sample of nondiabetic men, moderate drinkers had the lowest levels of fasting insulin resistance index and fasting insulin, consistent with lower levels of insulin resistance and thus lower risk for coronary heart disease. These findings suggest the possibility that the coronary heart disease-protective effects of moderate alcohol use are at least partially mediated by insulin.

Objective Although the influence of obesity on ventilatory function has long been recognized, the nature of the relationship and the mechanisms are not yet clear. The purpose of this report was to examine the effects of overall obesity and fat distribution on ventilatory function. Methods Multiple measurements over >30 years from 507 subjects with lifelong tobacco consumption of ≤1 pack-year were analyzed separately in five age decades from 30 to 79 years. FVC, FEV 1 , ratio of FEV 1 to FVC, and maximal midexpiratory flow rate (MMEF) were each adjusted for age and stature. Relative adiposity (or obesity) was assessed using the body mass index (BMI). Subscapular skinfold thickness, abdominal girth, and the ratio of abdominal girth to hip breadth (AG/HB) were used as measures of body fat distribution. Multiple linear regression was used to explore the effects of overall adiposity and body fat distribution on ventilatory function. Results BMI was positively associated with the ratio of FEV 1 to FVC at all ages (p 1 (p≤0.02) among men aged 30 to 59 years, whereas AG/HB was negatively associated with FVC and FEV 1 in men aged 50 to 59 years only (p≤0.0004). Conclusions Body fat distribution has independent effects on ventilatory function after adjustment for overall obesity in men. The finding that age modifies this association has implications for future research.

Neutrophils serve as an intriguing model for the study of innate immune cellular activity induced by physiological stress. We measured changes in the transcriptome of circulating neutrophils following an experimental exercise trial (EXTRI) consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Blood samples were taken at baseline, 3 h, 48 h, and 96 h post-EXTRI from eight healthy, endurance-trained, male subjects. RNA was extracted from isolated neutrophils. Differential gene expression was evaluated using Illumina microarrays and validated with quantitative PCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Blood concentrations of muscle damage indexes, neutrophils, interleukin (IL)-6 and IL-10 were increased ( P < 0.05) 3 h post-EXTRI. Upregulated groups of functionally related genes 3 h post-EXTRI included gene sets associated with the recognition of tissue damage, the IL-1 receptor, and Toll-like receptor (TLR) pathways (familywise error rate, P value < 0.05). The core enrichment for these pathways included TLRs, low-affinity immunoglobulin receptors, S100 calcium binding protein A12, and negative regulators of innate immunity, e.g., IL-1 receptor antagonist, and IL-1 receptor associated kinase-3. Plasma myoglobin changes correlated with neutrophil TLR4 gene expression ( r = 0.74; P < 0.05). Neutrophils had returned to their nonactivated state 48 h post-EXTRI, indicating that their initial proinflammatory response was transient and rapidly counterregulated. This study provides novel insight into the signaling mechanisms underlying the neutrophil responses to endurance exercise, suggesting that their transcriptional activity was particularly induced by damage-associated molecule patterns, hypothetically originating from the leakage of muscle components into the circulation.

Electronic medical record (EMR) systems are a rich potential source for detailed, timely, and efficient surveillance of large populations. We created the Electronic medical record Support for Public Health (ESP) system to facilitate and demonstrate the potential advantages of harnessing EMRs for public health surveillance. ESP organizes and analyzes EMR data for events of public health interest and transmits electronic case reports or aggregate population summaries to public health agencies as appropriate. It is designed to be compatible with any EMR system and can be customized to different states’ messaging requirements. All ESP code is open source and freely available. ESP currently has modules for notifiable disease, influenza-like illness syndrome, and diabetes surveillance. An intelligent presentation system for ESP called the RiskScape is under development. The RiskScape displays surveillance data in an accessible and intelligible format by automatically mapping results by zip code, stratifying outcomes by demographic and clinical parameters, and enabling users to specify custom queries and stratifications. The goal of RiskScape is to provide public health practitioners with rich, up-to-date views of health measures that facilitate timely identification of health disparities and opportunities for targeted interventions. ESP installations are currently operational in Massachusetts and Ohio, providing live, automated surveillance on over 1 million patients. Additional installations are underway at two more large practices in Massachusetts.

Seasonal influenza epidemics cause several million cases of illnesses cases and about 250,000 to 500,000 deaths worldwide each year. Other pandemics like the 1918 "Spanish Flu" may change into devastating event. Reducing the impact of these threats is of paramount importance for health authorities, and studies have shown that effective interventions can be taken to contain the epidemics, if early detection can be made. In this thesis, we introduce Social Network Enabled Flu Trends (SNEFT), a continuous data collection framework which monitors flu related messages on online social networks (OSN's) such as Twitter and Facebook and track the emergence and spread of influenza within United States across different regions and among different age groups. We expect these flu related messages posted by OSN users to be highly correlated to the number of Influenza like Illness (ILI) cases provided by Centers for Disease Control and Prevention (CDC). We attempt to validate our model by measuring how well it fits the CDC ILI rates over a course of two years from 2009 to 2011. We show that text mining significantly enhances the correlation between OSN data and the ILI rates. For accurate prediction, we implemented an auto-regression with exogenous input (ARX) model which uses current OSN data and CDC ILI rates from previous weeks to predict current influenza statistics. Our results show that, while previous ILI data from the CDC offer a true (but delayed) assessment of a flu epidemic, OSN data provides a real-time assessment of the current epidemic condition and can be used to compensate for the lack of current ILI data. We observe that the OSN data is highly correlated with the ILI rates across different regions within USA and can be used to effectively improve the accuracy of our prediction. Therefore, OSN data can act as supplementary indicator to gauge influenza levels within the population and helps to discover flu trends ahead of CDC. Using our approach to achieve faster, near real time prediction of the emergence and spread of influenza epidemic, through continuous tracking of flu related OSN messages originating within United States, we intend to provide a snapshot of the current epidemic condition and a preview of what to expect, on a daily basis. This would significantly enhances public health awareness and preparedness against the influenza epidemic and other large scale pandemics.

OBJECTIVE To determine the prevalence of latex allergy in dental workers. DESIGN Questionnaire survey of staff of a dental school. SETTING The Westmead Dental School, a large dental facility in western Sydney. PARTICIPANTS 230 staff members of the Westmead Dental School (consisting of general and specialist dentists, chairside assistants and registered nurses, laboratory technicians, dental therapists and hygienists) received questionnaires. MAIN OUTCOME MEASURES The prevalence of latex allergy, defined by prompt onset of hand urticaria with or without generalised symptoms, and the prevalence of hand dermatitis and other glove-related symptoms. Also, the relationship between latex allergy and associated atopic status. RESULTS 177 staff (77%) responded by the set collection date; 33% reported symptoms related to wearing gloves and 22% satisfied the criteria for glove dermatitis. Sixteen respondents (9%) reported characteristics suggestive of latex-glove allergy. CONCLUSIONS Confirmation of the 9% prevalence of latex allergy among dental workers will require further studies incorporating an objective measure of IgE-mediated hypersensitivity.

Marital status and indices of social support are associated with mortality due to coronary heart disease and stroke. This association seems not entirely due to differences in recognised cardiovascular disease risk factors. The Western Sydney Stroke risk in the Elderly Study examined the relationship between marital status, living arrangements, widowhood and extent of social support, and risk factors for cardiovascular disease in men and women aged over 65 years. Unmarried men had the lowest mean HDL-C levels. Men living alone had the highest mean systolic blood pressures. The lower mean HDL-C levels and higher DBP levels seen among widows were not statistically significant after adjustment for differences in past medical history and education levels. The extent of social support was not associated with any significant differences in cardiovascular risk factor levels among men or women. We conclude that some of the increased risk of cardiovascular disease associated with socio-demographic factors among men in this age-group may be due to differences in primary cardiovascular disease risk factors. However, some of the mechanisms underlying risk of cardiovascular disease in this age-group remains obscure.

In order to evaluate the repeatability of nutrient values estimated from a semiquantitative food frequency questionnaire being used in a longitudinal study of the relationships between diet, hemostatic factors, and stroke risk in the elderly in Western Sydney, a subsample of 62 participants (24 men, 38 women) completed a repeat questionnaire approximately 1 month after baseline data were collected. The mean age was 78 years (range, 65 to 88; median, 78). Nutrient values calculated from the repeat questionnaire were not significantly different from the baseline results by paired t test. Intraclass correlation coefficients ranged from 0.63 for beta carotene to 0.82 for saturated fat. Quadratic weighted kappa values were calculated for quintile categories and these ranged from 0.50 for fiber to 0.86 for ethanol. These values are comparable to previously published results in elderly subjects and confirm that repeatability of nutrient intakes estimated using semiquantitative food frequency questionnaires is very high in the elderly. Older subjects may be more established in their dietary habits than younger subjects, so any tendency for repeatability to decrease due to impaired memory associated with advanced age is offset by a lower intraindividual variability in dietary habit.