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Benefit-cost and regulatory impact analyses often use atmospheric dispersion models with coarse resolution to estimate the benefits of proposed mobile source emission control regulations. This approach may bias health estimates or miss important intra-urban variability for primary air pollutants. In this study, we estimate primary fine particulate matter (PM2.5) intake fractions (iF; the fraction of a pollutant emitted from a source that is inhaled by the population) for each of 23 398 road segments in the Boston Metro Core area to evaluate the potential for intra-urban variability in the emissions-to-exposure relationship. We estimate iFs using the CAL3QHCR line source model combined with residential populations within 5000 m of each road segment. The annual average values for the road segments range from 0.8 to 53 per million, with a mean of 12 per million. On average, 46% of the total exposure is realized within 200 m of the road segment, though this varies from 0 to 93% largely due to variable population patterns. Our findings indicate the likelihood of substantial intra-urban variability in mobile source primary PM2.5 iF that accounting for population movement with time, localized meteorological conditions, and street-canyon configurations would likely increase. [ABSTRACT FROM AUTHOR]

Background: Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. Methods: In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Results: At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. Conclusions: A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN51125379.) N Engl J Med 2007;357:1716-30. [ABSTRACT FROM AUTHOR]

Previous studies have identified associations between traffic-related air pollution and adverse health effects. Most have used measurements from a few central ambient monitors and/or some measure of traffic as indicators of exposure, disregarding spatial variability and factors influencing personal exposure-ambient concentration relationships. This study seeks to utilize publicly available data (i.e., central site monitors, geographic information system, and property assessment data) and questionnaire responses to predict residential indoor concentrations of traffic-related air pollutants for lower socioeconomic status (SES) urban households. As part of a prospective birth cohort study in urban Boston, we collected indoor and outdoor 3–4 day samples of nitrogen dioxide (NO2) and fine particulate matter (PM2.5) in 43 low SES residences across multiple seasons from 2003 to 2005. Elemental carbon (EC) concentrations were determined via reflectance analysis. Multiple traffic indicators were derived using Massachusetts Highway Department data and traffic counts collected outside sampling homes. Home characteristics and occupant behaviors were collected via a standardized questionnaire. Additional housing information was collected through property tax records, and ambient concentrations were collected from a centrally located ambient monitor. The contributions of ambient concentrations, local traffic and indoor sources to indoor concentrations were quantified with regression analyses. PM2.5 was influenced less by local traffic but had significant indoor sources, while EC was associated with traffic and NO2 with both traffic and indoor sources. Comparing models based on covariate selection using p-values or a Bayesian approach yielded similar results, with traffic density within a 50m buffer of a home and distance from a truck route as important contributors to indoor levels of NO2 and EC, respectively. The Bayesian approach also highlighted the uncertanity in the models. We conclude that by utilizing public databases and focused questionnaire data we can identify important predictors of indoor concentrations for multiple air pollutants in a high-risk population. [Copyright &y& Elsevier]

Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Air pollution exposure patterns may contribute to known spatial patterning of asthma morbidity within urban areas. While studies have evaluated the relationship between traffic and outdoor concentrations, few have considered indoor exposure patterns within low socioeconomic status (SES) urban communities. In this study, part of a prospective birth cohort study assessing asthma etiology in urban Boston, we collected indoor and outdoor 3–4 day samples of nitrogen dioxide (NO2) and fine particulate matter (PM2.5) in 43 residences across multiple seasons from 2003 to 2005. Homes were chosen to represent low SES households, including both cohort and non-cohort residences in similar neighborhoods, and consisted almost entirely of multiunit residences. Reflectance analysis and X-ray fluorescence spectroscopy were performed on the particle filters to determine elemental carbon (EC) and trace element concentrations, respectively. Additionally, information on home characteristics (e.g. type, age, stove fuel) and occupant behaviors (e.g. smoking, cooking, cleaning) were collected via a standardized questionnaire. The contributions of outdoor and indoor sources to indoor concentrations were quantified with regression analyses using mass balance principles. For NO2 and most particle constituents (except outdoor-dominated constituents like sulfur and vanadium), the addition of selected indoor source terms improved the model's predictive power. Cooking time, gas stove usage, occupant density, and humidifiers were identified as important contributors to indoor levels of various pollutants. A comparison between cohort and non-cohort participants provided another means to determine the influence of occupant activity patterns on indoor–outdoor ratios. Although the groups had similar housing characteristics and were located in similar neighborhoods, cohort members had significantly higher indoor concentrations of PM2.5 and NO2, associated with indoor activities. We conclude that the effect of indoor sources may be more pronounced in high-density multiunit dwellings, and that future epidemiological studies in these populations should explicitly consider these sources in assigning exposures.Journal of Exposure Science and Environmental Epidemiology (2007) 17, 433–444; doi:10.1038/sj.jes.7500532; published online 18 October 2006 [ABSTRACT FROM AUTHOR]

In order to estimate the health benefits of reducing mobile source emissions, analysts typically use detailed atmospheric models to estimate the change in population exposure that results from a given change in emissions. However, this may not be feasible in settings where data are limited or policy decisions are needed in the short term. Intake fraction (iF), defined as the fraction of emissions of a pollutant or its precursor that is inhaled by the population, is a metric that can be used to compare exposure assessment methods in a health benefits analysis context. To clarify the utility of rapid-assessment methods, we calculate particulate matter iFs for the Mexico City Metropolitan Area using five methods, some more resource intensive than others. First, we create two simple box models to describe dispersion of primary fine particulate matter (PM2. 5) in the Mexico City basin. Second, we extrapolate iFs for primary PM2. 5, ammonium sulfate, and ammonium nitrate from US values using a regression model. Third, we calculate iFs by assuming a linear relationship between emissions and population-weighted concentrations of primary PM2. 5, ammonium nitrate, and ammonium sulfate (a particle composition method). Finally, we estimate PM iFs from detailed atmospheric dispersion and chemistry models run for only a short period of time. Intake fractions vary by up to a factor of five, from 23 to 120 per million for primary PM2. 5. Estimates of 60, 7, and 0. 7 per million for primary PM, secondary ammonium sulfate, and secondary ammonium nitrate, respectively, represent credible central estimates, with an approximate factor of two uncertainty surrounding each estimate. Our results emphasize that multiple rapid-assessment methods can provide meaningful estimates of iFs in resource-limited environments, and that formal uncertainty analysis, with special attention to model biases and uncertainty, would be important for health benefits analyses. [Copyright &y& Elsevier]

Assessing the public health benefits from air pollution control measures is assisted by understanding the relationship between mobile source emissions and subsequent fine particulate matter (PM2.5) exposure. Since this relationship varies by location, we characterized its magnitude and geographic distribution using the intake fraction (iF) concept. We considered emissions of primary PM2.5 as well as particle precursors SO2 and NO x from each of 3080 counties in the US. We modeled the relationship between these emissions and total US population exposure to PM2.5, making use of a source–receptor matrix developed for health risk assessment. For primary PM2.5, we found a median iF of 1.2 per million, with a range of 0.12–25. Half of the total exposure was reached by a median distance of 150km from the county where mobile source emissions originated, though this spatial extent varied across counties from within the county borders to 1800km away. For secondary ammonium sulfate from SO2 emissions, the median iF was 0.41 per million (range: 0.050–10), versus 0.068 per million for secondary ammonium nitrate from NO x emissions (range: 0.00092–1.3). The median distance to half of the total exposure was greater for secondary PM2.5 (450km for sulfate, 390km for nitrate). Regression analyses using exhaustive population predictors explained much of the variation in primary PM2.5 iF (R 2=0.83) as well as secondary sulfate and nitrate iF (R 2=0.74 and 0.60), with greater near-source contribution for primary than for secondary PM2.5. We conclude that long-range dispersion models with coarse geographic resolution are appropriate for risk assessments of secondary PM2.5 or primary PM2.5 emitted from mobile sources in rural areas, but that more resolved dispersion models are warranted for primary PM2.5 in urban areas due to the substantial contribution of near-source populations. [Copyright &y& Elsevier]

Individuals spend about 25% of their time in non-residential indoor microenvironments. For some of these micro-environments, particularly stores and restaurants, exposures to volatile organic compounds (VOCs), have not been well characterized. In the Boston Exposure Assessment in Microenvironments (BEAM) study, sampling using scripted activities was conducted in stores, restaurants, and transportation in the summer of 2003 and winters of 2004 and 2005. A suite of VOCs including hydrocarbons, several chlorinated compounds, and aldehydes was analyzed. Nine store types were sampled using a composite design to enable a greater number of stores to be visited. Stores had higher concentrations of formaldehyde, toluene, ethylbenzene, xylenes, and styrene than other micro-environments, particularly in certain store types. Geometric mean formaldehyde levels were highest in the housewares stores, at 53 μg/m³ (95% CI = 43, 66). Geometric mean toluene levels were highest in multipurpose stores, at 76 μg/m³ (95% CI = 50, 118). The levels observed in stores were several times higher than levels found in transportation microenvironments, and indicate strong indoor sources. In contrast, benzene did not have significantly higher levels in stores than typically found outdoors. Concentrations of formaldehyde and benzene, ethylbenzene, xylenes, and styrene were strongly influenced by the presence of smoking in the dining microenvironment. Chloroform levels were higher in restaurants than in other microenvironments, with a geometric mean of 1.1 μg/m³ (95% CI = 0.7, 1.8). The V0C concentrations found in stores and restaurants in this study are a potentially important source of exposure for sensitive individuals or people who work in these microenvironments. [ABSTRACT FROM AUTHOR]

Background: Patients who have pain and dysfunction from glenohumeral arthritis associated with severe rotator cuff deficiency have few treatment options. The goal of this study was to retrospectively evaluate the short-term results of arthroplasty with use of the Reverse Shoulder Prosthesis in the management of this problem.Methods: We report the results for sixty patients (sixty shoulders) with a rotator cuff deficiency and glenohumeral arthritis who were followed for a minimum of two years. Thirty-five patients had no previous shoulder surgery, whereas twenty-three had had either an open or arthroscopic rotator cuff repair, one had had a subacromial decompression, and one had had a biceps tendon repair. All patients were assessed preoperatively and postoperatively with the American Shoulder and Elbow Surgeons scoring system for pain and function and with visual analog scales for pain and function. They were also asked to rate their satisfaction with the outcome. The shoulder range of motion was measured preoperatively and postoperatively.Results: The average age of the patients was seventy-one years. The average duration of follow-up was thirty-three months. All measures improved significantly (p < 0.0001). The mean total score on the American Shoulder and Elbow Surgeons system improved from 34.3 to 68.2; the mean function score, from 16.1 to 29.4; and the mean pain score, from 18.2 to 38.7. The score for function on the visual analog scale improved from 2.7 to 6.0, and the score for pain on the visual analog scale improved from 6.3 to 2.2. Forward flexion increased from 55.0 degrees to 105.1 degrees , and abduction increased from 41.4 degrees to 101.8 degrees . Forty-one of the sixty patients rated the outcome as good or excellent; sixteen were satisfied, and three were dissatisfied. There were a total of thirteen complications in ten patients (17%). Seven patients (12%) had eight failures, requiring revision surgery to another Reverse Shoulder Prosthesis in five patients (one shoulder had two revisions) and revision to a hemiarthroplasty in two patients because of deep infection.Conclusions: The data from this study suggest that arthroplasty with the Reverse Shoulder Prosthesis may be a viable treatment for patients with glenohumeral arthritis and a massive rotator cuff tear. However, future studies will be necessary to determine the longevity of the implant and whether it will provide continued improvement in function. [ABSTRACT FROM AUTHOR]

Obesity is a major health problem, and many family-based studies have suggested that it has a strong genetic basis. We performed a genome-wide quantitative trait linkage scan for loci influencing BMI in 573 pedigrees from the U.K. We identified genome-wide significant linkage (logarithm of odds = 3.74, between D10S208 and D10S196, genomewide P = 0.0186) on chromosome 10p. The size of our study population and the statistical significance of our findings provide substantial contributions to the body of evidence for a locus on chromosome 10p. We examined eight single nucleotide polymorphisms (SNPs) in GAD2, which maps to this linkage region, tagging the majority of variation in the gene, and observed marginally significant (0.01 < P < 0.05) associations between four common variants and BMI. However, these SNPs did not account for our evidence of linkage to BMI, and they did not replicate (in direction of effect) the previous associations. We therefore conclude that these SNPs are not the etiological variants underlying this locus. We cannot rule out the possibility that other untagged variations in GAD2 may, in part, be involved, but it is most likely that alternative gene(s) within the broad gene-rich region of linkage on 10p are responsible for variation in body mass and susceptibility to obesity. [ABSTRACT FROM AUTHOR]

The etiopathological relationship between latent autoimmune diabetes in adults (LADA) and classical type 1 (insulin dependent) diabetes remains unclear. Variation at the insulin gene variable number of tandem repeats (VNTR) minisatellite influences susceptibility to type 1 diabetes, but studies in LADA have been small and inconsistent. We examined the role of insulin gene variation (using flanking variants as surrogates for VNTR subtypes) in the largest case-control study of LADA to date (400 case and 332 control subjects). Highly significant associations were identified with disease, with dominant protective effects of the T allele at -23HphI (odds ratio [OR] 0.42 [95% CI 0.31-0.58], P = 2.4 X 10-8), A allele at +1,404Fnu4HI (0.50 [0.36-0.70], P = 3.2 x 10-5), and C allele at +3,580MspI (0.55 [0.35-0.85], P = 0.0046). As with type 1 diabetes, the -23HphI variant (a surrogate for the subdivision of VNTR into class I and III alleles) most clearly defined susceptibility in LADA. However, there was no association with age at diagnosis or requirement for insulin therapy 6 years postdiagnosis. This study establishes that variation within the insulin gene region does influence susceptibility to LADA, with the direction and magnitude of effect indistinguishable from that previously reported for type 1 diabetes. In conclusion, differences in VNTR-encoded susceptibility do not explain the differences in clinical presentation that distinguish classical type 1 diabetes and LADA. [ABSTRACT FROM AUTHOR]

The article responds to comment on fuels for urban transit buses. In response to the cost-effectiveness analysis of alternative propulsion technologies for urban transit buses, researchers noted two points. First, they note that emission controlled diesel (ECD) technology is improving rapidly. Any comparative evaluation of propulsion systems is of course complicated by the "moving target" nature of the technologies, a factor that is relevant to both the ECD and compressed natural gas (CNG) technologies. Second, the wide ranges reported for the number of Quality Adjusted Life Years saved by ECD and CNG as evidence that quantifying in this way is not useful.

Abstract: The over-expression of the islet amyloid polypeptide (IAPP) gene could be a causal factor for islet amyloidosis and β-cell destruction in Type 2 diabetes (T2DM). An IAPP gene promoter polymorphism, IAPP-132G to A, has been associated with T2DM in Spain. To investigate this polymorphism in other cohorts and in relation to therapy, DNA from 425 T2DM and 279 unrelated, non-diabetic UK subjects (ND) and 102 T2DM and 80 ND Finnish subjects was examined. The relationship of amyloid severity (percent amyloid/islet) to prevalence (number of islets affected) and the association of IAPP-132G/A with amyloid was determined in post-mortem pancreas from 38 T2DM subjects. The -132G/A was not associated with T2DM in the UK cohorts (4.5% T2DM; 3.2% ND) or associated with requirement for insulin therapy by 6 years. The mutation was and undetected in the Finnish samples but a new variant, -166T/C, was identified in 2 Finnish T2DM subjects. -132G/A was found in 2/38 diabetic, amyloid-containing and 3/19 ND, amyloid-free subjects. The islet amyloid severity was linearly correlated with the prevalence in T2DM. The IAPP-132G/A promoter polymorphism is not associated with T2DM, a requirement for insulin therapy or with the degree of islet amyloidosis in cohorts from the UK or Finland. [Copyright &y& Elsevier]

The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44]) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect. [ABSTRACT FROM AUTHOR]

Asthma in the US is widespread, with incidence rates and morbidity increasing dramatically over the last 2 decades. The cost of asthma-related morbidity and mortality is large. There is substantial and convincing evidence that environmental factors are associated with asthma exacerbation, and more limited evidence that environmental factors play a role in the development of asthma. Educational interventions, which include an avoidance of ‘triggers’ or focus on reducing exposure to cigarette smoke, have been shown to be moderately effective. While various interventions have been shown to reduce environmental exposures, fewer studies have collected sufficient information on their effectiveness in reducing morbidity. Cost-effectiveness analyses on educational interventions suggest that reductions in direct costs are most prominently seen for severe asthma, with the interpretation of study findings impaired by a lack of methodological consistency. One analysis from a study that included physical interventions found that the incremental cost-effectiveness ratio was $US9.20 per symptom-free day (95% CI -$US12.56, $US55.29), with potential cost savings for more severe asthma. We point out that current practice in managed care organizations (MCOs), as well as in other settings, rarely conforms to the current clinical practice guidelines for asthma. Two reviews of the policies and actions of MCOs found that while some were integrating environmental controls into their asthma disease management plans, their commitment to these strategies was limited by lack of a strong evidence base. We recommend the following: (i) continuation of educational programs; (ii) continuation and expansion of case management, including home visits; (iii) full integration of smoking cessation programs into asthma disease management; (iv) development of policies around reimbursement for durable goods; (v) participation in the setting of a policy agenda for population-based approaches to controlling key environmental factors; (vi) development of exploratory programs to address occupational asthma; (vii) integration, analysis and dissemination of environmental data collected by MCOs; and (viii) widespread MCO participation in research on environmental prevention of asthma. [ABSTRACT FROM AUTHOR]

Type II SH2 domain-containing inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity. INPPL1 mutations affecting gene function have been found in rat models of type 2 diabetes and hypertension and in type 2 diabetic patients. We investigated the influence of nucleotide variation in INPPL1 on components of the metabolic syndrome. Following comprehensive resequencing of the gene, we genotyped 12 informative polymorphisms in 1,304 individuals from 424 British type 2 diabetes families that were characterized for several metabolic phenotypes. We have found highly significant associations of single nucleotide polymorphisms (SNPs) and haplotypes of INPPL1 with hypertension as well as with other components of the metabolic syndrome. In a cohort of 905 French type 2 diabetic patients, we found evidence of association of INPPL1 SNPs with the presence of hypertension. We conclude that INPPL1 variants may impact susceptibility to disease and/or to subphenotypes involved in the metabolic syndrome in some diabetic patients. [ABSTRACT FROM AUTHOR]

Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes. [ABSTRACT FROM AUTHOR]

The effects of both ambient air pollution and socioeconomic position (SEP) on health are well documented. A limited number of recent studies suggest that SEP may itself play a role in the epidemiology of disease and death associated with exposure to air pollution. Together with evidence that poor and working-class communities are often more exposed to air pollution, these studies have stimulated discussion among scientists, policy makers, and the public about the differential distribution of the health impacts from air pollution. Science and public policy would benefit from additional research that integrates the theory and practice from both air pollution and social epidemiologies to gain a better understanding of this issue. In this article we aim to promote such research by introducing readers to methodologic and conceptual approaches in the fields of air pollution and social epidemiology; by proposing theories and hypotheses about how air pollution and socioeconomic factors may interact to influence health, drawing on studies conducted worldwide; by discussing methodologic issues in the design and analysis of studies to determine whether health effects of exposure to ambient air pollution are modified by SEP; and by proposing specific steps that will advance knowledge in this field, fill information gaps, and apply research results to improve public health in collaboration with affected communities. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor published in the November 2003 issue of the "American Journal of Human Genetics," regarding the meta-analysis of the role of Calpain-10 Variation in type 2 diabetes susceptibility.

A young onset of type 2 diabetes is likely to result, in part, from greater genetic susceptibility. Young-onset families may therefore represent a group in which genes are more easily detectable by linkage. To test this hypothesis, we conducted age at diagnosis (AAD) stratified linkage analyses in the Diabetes UK Warren 2 sibpairs. In the previously published unstratified analysis, evidence for linkage (logarithm of odds [LOD] >1.18) was found at seven loci. The LOD scores at these seven loci were higher in the 245 families with AAD <55 years (L55) compared with the 328 families with AAD >55 years (G55). Five of these seven loci (1q24-25, 5q13, 8p21-22, 8q24.2, and 10q23.2) had LOD scores >1.18 in the L55 subset but only one (8p21-22) did in the G55 subset. Two additional loci (8q21.13 and 21q22.2) showed evidence for linkage in the L55 subset alone. Another locus (22q11) showed evidence for linkage in a subset of families with AAD <45 years. Using a locus-counting approach, the L55 subset had significantly more loci (P approximately 0.01) than expected under the null hypothesis of no linkage across the LOD score range 0.59-3.0. In contrast, the G55 subset contained no more susceptibility loci than that expected by chance. In conclusion, young-onset families provide both disproportionate evidence for linkage to known loci and evidence for additional novel loci. Our data confirm our hypothesis that families segregating young-onset type 2 diabetes represent a more powerful resource for defining susceptibility genes by linkage. [ABSTRACT FROM AUTHOR]

The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE support an important role in glucose homeostasis. We sought evidence for association between IDE variation and diabetes by mutation screening, defining local haplotype structure, and genotyping variants delineating common haplotypic diversity. An initial case-control analysis (628 diabetic probands from multiplex sibships and 604 control subjects) found no haplotypic associations, although one variant (IDE2, -179T-->C) showed modest association with diabetes (odds ratio [OR]1.25, P = 0.03). Linkage partitioning analyses failed to support this association, but provided borderline evidence for a different variant (IDE10, IVS20-405A-->G) (P = 0.06). Neither variant was associated with diabetes when replication was sought in 377 early onset diabetic subjects and 825 control subjects, though combined analysis of all typed cohorts indicated a nominally significant effect at IDE2 (OR 1.21 [1.04-1.40], P = 0.013). In the absence of convincing support for this association from linkage partitioning or analyses of continuous measures of glycemia, we conclude that analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans. [ABSTRACT FROM AUTHOR]

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles. [ABSTRACT FROM AUTHOR]

Examines the potential importance of the concept of particulate matter exposure efficiency. History of the development of the concept; Discussion on previous estimates of exposure efficiency for particulate matter and air pollutants; Approaches to the estimation of exposure efficiency.

Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans. [ABSTRACT FROM AUTHOR]

We have analyzed data from 573 pedigrees from the United Kingdom for evidence for linkage to loci influencing adult stature. Our data set comprised 1,214 diabetic and 163 nondiabetic siblings for whom height data were available. We used variance-components analysis implemented in GENEHUNTER 2 and a modification of the Haseman-Elston regression method, HE-COM. We found evidence for a locus on 3p26 (LOD score 3.17) influencing height in this adult sample, with less-significant evidence for loci on chromosomes 7, 10, 15, 17, 19, and 20. Our findings extend similar recent studies in Scandinavian and Quebecois populations, adding further evidence that height is indeed under the control of multiple genes. [ABSTRACT FROM AUTHOR]

Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Reports issues related to medicine. Spread of salmonella via fecal contaminated inseminators; Use of antibiotics in pyogenic liver abscess; Contraception by female sterilization.

Localized variations in traffic volume and speed can influence air pollutant emissions and corresponding concentrations in nearby communities, but most studies have utilized only aggregated traffic activity data. In this study, we compared the estimated influence of highway traffic activity on concentrations of primary oxides of nitrogen (NO x) and fine particulate matter (PM 2.5) in communities near highways using a dispersion model informed by highly spatiotemporally-resolved variations of traffic volume and flow compared to the use of Annual Average Daily Traffic (AADT) data at a few locations. We used two sources of traffic activity data on 500 half-mile roadway segments on the five major highways in the Washington State Puget Sound during 2013. The first consisted of vehicle counts available every half-mile and 5 min; the second was traffic information (e.g., AADT) aggregated across the year and roadway network. Using the Motor Vehicle Emissions Simulator (MOVES) and the Research Line source dispersion model (RLINE), we modeled hourly concentrations of primary NO x and PM 2.5 generated by highway traffic at nearly 4000 residences within 1 km of major highways. These concentrations were aggregated to daily and annual average concentrations, which were compared by input data source. At most locations, concentrations of primary NO x and PM 2.5 modeled using the resolved traffic data had similar spatial and temporal distributions to concentrations predicted using the AADT data. However, several areas showed large differences. For example, 25% of residences within 150 m of a highway had concentrations that differed by more than 19% (8 ppb) for NO x and 32% (0.7 μg/m3) for PM 2.5 , and the AADT data consistently predicted lower concentrations than the resolved traffic data. Our findings indicate that temporal and spatial variation in traffic patterns can result in complex spatiotemporal variations of air pollutant concentrations that can be captured with the use of dispersion modeling with the appropriate inputs. The use of spatiotemporally resolved traffic activity data can improve exposure estimates and help reduce exposure measurement error in epidemiological studies, especially in communities near highly congested highways. • Traffic and congestion vary considerably over time and place. • Few analyses account for this spatiotemporal variation. • Areas closer to highways had the largest spatiotemporal variations in concentrations. • In regions with low congestion, AADT data was sufficient to capture pollution patterns. • In regions with high congestion, resolved data captured greater variation in pollution. [ABSTRACT FROM AUTHOR]

Land use regression (LUR) models have been widely used to estimate air pollution exposures at high spatial resolution. However, few LUR models were developed for rapidly developing urban cores, which have substantially higher densities of population and built-up areas than the surrounding areas within a city's administrative boundary. Further, few studies incorporated vertical variations of air pollution in exposure assessment, which might be important to estimate exposures for people living in high-rise buildings. A LUR model was developed for the urban core of Lanzhou, China, along with a model of vertical concentration gradients in high-rise buildings. In each of four seasons in 2016–2017, NO 2 was measured using Ogawa badges for 2 weeks at 75 ground-level sites. PM 2.5 was measured using DataRAM for shorter time intervals at a subset (N = 38) of the 75 sites. Vertical profile measurements were conducted on 9 stories at 2 high-rise buildings (N = 18), with one building facing traffic and another facing away from traffic. The average seasonal concentrations of NO 2 and PM 2.5 at ground level were regressed against spatial predictors, including elevation, population, road network, land cover, and land use. The vertical variations were investigated and linked to ground-level predictions with exponential models. We developed robust LUR models at the ground level for estimated annual averages of NO 2 (R2: 0.71, adjusted R2: 0.67, and Leave-One-Out Cross Validation (LOOCV) R2: 0.64) and PM 2.5 (R2: 0.77, adjusted R2: of 0.73, and LOOCV R2: 0.67) in the urban core of Lanzhou, China. The LUR models for the estimated seasonal averages of NO 2 showed similar patterns. Vertical variation of NO 2 and PM 2.5 differed by windows orientation with respect to traffic, by season or by time of a day. Vertical variation functions incorporated the ground-level LUR predictions, in a form that could allow for exposure assessment in future epidemiological investigations. Ground-level NO 2 and PM 2.5 showed substantial spatial variations, explained by traffic and land use patterns. Further, vertical variation of air pollution levels is significant under certain conditions, suggesting that exposure misclassification could occur with traditional LUR that ignores vertical variation. More studies are needed to fully characterize three-dimensional concentration patterns to accurately estimate air pollution exposures for residents in high-rise buildings, but our LUR models reinforce that concentration heterogeneity is not captured by the limited government monitors in the Lanzhou urban area. • LUR models incorporating vertical variations were developed in Lanzhou urban core. • Ground-level NO 2 and PM 2.5 concentrations have different spatial patterns. • Universal kriging models outperformed linear regression models in the study area. • Vertical variations differed by building orientation regarding traffic or by time. [ABSTRACT FROM AUTHOR]

The article presents the findings of a study that aims to assess the impact on health related quality of life (HRQOL) of diabetes mellitus among South Asian men who have erectile dysfunction (ED). The International Index of Erectile Function (IIEF5) was used to assess ED. It mentions the association of ED with a significantly poorer quality of life when assessed by both generic and disease specific HRQOL measures.

Background: Elevated cardiovascular disease risk has been reported with proximity to highways or busy roadways, but proximity measures can be challenging to interpret given potential confounders and exposure error.Methods: We conducted a cross sectional analysis of plasma levels of C-Reactive Protein (hsCRP), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha receptor II (TNF-RII) and fibrinogen with distance of residence to a highway in and around Boston, Massachusetts. Distance was assigned using ortho-photo corrected parcel matching, as well as less precise approaches such as simple parcel matching and geocoding addresses to street networks. We used a combined random and convenience sample of 260 adults >40 years old. We screened a large number of individual-level variables including some infrequently collected for assessment of highway proximity, and included a subset in our final regression models. We monitored ultrafine particle (UFP) levels in the study areas to help interpret proximity measures.Results: Using the orthophoto corrected geocoding, in a fully adjusted model, hsCRP and IL-6 differed by distance category relative to urban background: 43% (-16%,141%) and 49% (6%,110%) increase for 0-50 m; 7% (-39%,45%) and 41% (6%,86%) for 50-150 m; 54% (-2%,142%) and 18% (-11%,57%) for 150-250 m, and 49% (-4%, 131%) and 42% (6%, 89%) for 250-450 m. There was little evidence for association for TNF-RII or fibrinogen. Ortho-photo corrected geocoding resulted in stronger associations than traditional methods which introduced differential misclassification. Restricted analysis found the effect of proximity on biomarkers was mostly downwind from the highway or upwind where there was considerable local street traffic, consistent with patterns of monitored UFP levels.Conclusion: We found associations between highway proximity and both hsCRP and IL-6, with non-monotonic patterns explained partly by individual-level factors and differences between proximity and UFP concentrations. Our analyses emphasize the importance of controlling for the risk of differential exposure misclassification from geocoding error. [ABSTRACT FROM AUTHOR]

A correction to the article "Effects of Exposure Measurement Error in the Analysis of Health Effects From Traffic-Related Air Pollution," by Lisa K. Baxter and colleagues in a 2010 issue is presented.

Background: Airports represent a complex source type of increasing importance contributing to air toxics risks. Comprehensive atmospheric dispersion models are beyond the scope of many applications, so it would be valuable to rapidly but accurately characterize the risk-relevant exposure implications of emissions at an airport.Methods: In this study, we apply a high resolution atmospheric dispersion model (AERMOD) to 32 airports across the United States, focusing on benzene, 1,3-butadiene, and benzo [a]pyrene. We estimate the emission rates required at these airports to exceed a 10(-6) lifetime cancer risk for the maximally exposed individual (emission thresholds) and estimate the total population risk at these emission rates.Results: The emission thresholds vary by two orders of magnitude across airports, with variability predicted by proximity of populations to the airport and mixing height (R2 = 0.74-0.75 across pollutants). At these emission thresholds, the population risk within 50 km of the airport varies by two orders of magnitude across airports, driven by substantial heterogeneity in total population exposure per unit emissions that is related to population density and uncorrelated with emission thresholds.Conclusion: Our findings indicate that site characteristics can be used to accurately predict maximum individual risk and total population risk at a given level of emissions, but that optimizing on one endpoint will be non-optimal for the other. [ABSTRACT FROM AUTHOR]

Background: There is a growing body of literature linking GIS-based measures of traffic density to asthma and other respiratory outcomes. However, no consensus exists on which traffic indicators best capture variability in different pollutants or within different settings. As part of a study on childhood asthma etiology, we examined variability in outdoor concentrations of multiple traffic-related air pollutants within urban communities, using a range of GIS-based predictors and land use regression techniques.Methods: We measured fine particulate matter (PM2.5), nitrogen dioxide (NO2), and elemental carbon (EC) outside 44 homes representing a range of traffic densities and neighborhoods across Boston, Massachusetts and nearby communities. Multiple three to four-day average samples were collected at each home during winters and summers from 2003 to 2005. Traffic indicators were derived using Massachusetts Highway Department data and direct traffic counts. Multivariate regression analyses were performed separately for each pollutant, using traffic indicators, land use, meteorology, site characteristics, and central site concentrations.Results: PM2.5 was strongly associated with the central site monitor (R2 = 0.68). Additional variability was explained by total roadway length within 100 m of the home, smoking or grilling near the monitor, and block-group population density (R2 = 0.76). EC showed greater spatial variability, especially during winter months, and was predicted by roadway length within 200 m of the home. The influence of traffic was greater under low wind speed conditions, and concentrations were lower during summer (R2 = 0.52). NO2 showed significant spatial variability, predicted by population density and roadway length within 50 m of the home, modified by site characteristics (obstruction), and with higher concentrations during summer (R2 = 0.56).Conclusion: Each pollutant examined displayed somewhat different spatial patterns within urban neighborhoods, and were differently related to local traffic and meteorology. Our results indicate a need for multi-pollutant exposure modeling to disentangle causal agents in epidemiological studies, and further investigation of site-specific and meteorological modification of the traffic-concentration relationship in urban neighborhoods. [ABSTRACT FROM AUTHOR]

The extent and interrelations of diabetes related sexual problems are not well documented. Purpose of this study was to assess prevalence and inter relationships of erectile dysfunction (ED), problems with sexual desire, and premature ejaculation (PE) among men with type 2 diabetes in Sri Lanka. Two hundred and fifty three men with type 2 diabetes, aged between 20-80 years, who had opportunity for sexual activity and attending a diabetic clinic in Sri Lanka were recruited in the study. Data were collected using a structured interviewer administered questionnaire and the erectile function was assessed using a translated version of International Index of Erectile Function (IIEF5). Those who had IIEF score ≤22 were considered to have normal erectile function while others were categorized as follows 21-17 mild ED,16-12 mild-to-moderate ED, 11-8 moderate-to-severe ED and 1-7 severe or complete ED.Participants were asked to grade their general sexual desire from a four category scale according to their subjective experience. Those who suffer from persistent rapid ejaculation causing distress to themselves and to their partners were considered as having PE. Relevant physical examination and biochemical investigations were carded out. Mean age 55.9 (SD±10.7)years, duration of diabetes 7.2 (SD±6.5) years. Mean HbA1c and cholesterol were 7.2 %(SD±1.6) and 5.0 mmol/l(SD±l.2) respectively.185(73.1%) had any degree of ED, 60(23.7%) had mild, 51(20.2%) mild to moderate, 25(9.9%) moderate and 49(19.4%) had severe ED. Only 87(33%) graded their desire for sexual activity as good, 102(43%) as fair, 31(12%) as poor, and 33(13%) as very poor. 96(37.9%) of the patients had PE. ED is significantly associated with PE (p<.001) and poor libido (p<.001). Sexual desire progressively reduced with increasing severity of ED. However association of PE and ED shows a non linier relationship with 70% of those who had mild to moderate ED having PE as opposed to only 20% of the men with normal erectile function having PE. ED, poor libido and PE are significant complication among men with diabetes in Sri Lanka. Awareness of close association between ED, poor sexual desire, and PE could have significant beating in managing sexual dysfunction among men with diabetes. [ABSTRACT FROM AUTHOR]