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1.  The Impact of Individual Anthropogenic Emissions Sectors on the Global Burden of Human Mortality due to Ambient Air Pollution 
Environmental Health Perspectives  2016;124(11):1776-1784.
Exposure to ozone and fine particulate matter (PM2.5) can cause adverse health effects, including premature mortality due to cardiopulmonary diseases and lung cancer. Recent studies quantify global air pollution mortality but not the contribution of different emissions sectors, or they focus on a specific sector.
We estimated the global mortality burden of anthropogenic ozone and PM2.5, and the impact of five emissions sectors, using a global chemical transport model at a finer horizontal resolution (0.67° × 0.5°) than previous studies.
We performed simulations for 2005 using the Model for Ozone and Related Chemical Tracers, version 4 (MOZART-4), zeroing out all anthropogenic emissions and emissions from specific sectors (All Transportation, Land Transportation, Energy, Industry, and Residential and Commercial). We estimated premature mortality using a log-linear concentration–response function for ozone and an integrated exposure–response model for PM2.5.
We estimated 2.23 (95% CI: 1.04, 3.33) million deaths/year related to anthropogenic PM2.5, with the highest mortality in East Asia (48%). The Residential and Commercial sector had the greatest impact globally—675 (95% CI: 428, 899) thousand deaths/year—and in most regions. Land Transportation dominated in North America (32% of total anthropogenic PM2.5 mortality), and it had nearly the same impact (24%) as Residential and Commercial (27%) in Europe. Anthropogenic ozone was associated with 493 (95% CI: 122, 989) thousand deaths/year, with the Land Transportation sector having the greatest impact globally (16%).
The contributions of emissions sectors to ambient air pollution–related mortality differ among regions, suggesting region-specific air pollution control strategies. Global sector-specific actions targeting Land Transportation (ozone) and Residential and Commercial (PM2.5) sectors would particularly benefit human health.
Silva RA, Adelman Z, Fry MM, West JJ. 2016. The impact of individual anthropogenic emissions sectors on the global burden of human mortality due to ambient air pollution. Environ Health Perspect 124:1776–1784;
PMCID: PMC5089880  PMID: 27177206
European cells & materials  2011;22:43-55.
Biological activity can be added to synthetic scaffolds by incorporating functional peptide sequences that provide enzyme-mediated degradation sites, facilitate cellular adhesion or stimulate signaling pathways. Poly(ethylene glycol) diacrylate is a popular synthetic base for tissue engineering scaffolds because it creates a hydrophilic environment that can be chemically manipulated to add this biological functionality. Furthermore, the acrylate groups allow for encapsulation of cells using photopolymerization under physiological conditions. One complication with the addition of these peptides is that aromatic amino acids absorb light at 285nm and compete with the ultraviolet (UV)-sensitive photoinitiators such as Irgacure™ 2959 (I2959), the most commonly used initiator for cytocompatible photoencapsulation of cells into synthetic scaffolds. In this study we define non-toxic conditions for photoencapsulation of human mesenchymal stem cells (hMSC) in PEGDA scaffolds using a visible light photoinitiator system composed of eosin Y, triethanolamine and 1-vinyl-2-pyrrolidinone. This visible light photoinitiator produced hydrogel scaffolds with an increased viability of encapsulated hMSCs and a more tightly crosslinked network in one-third the time of UV polymerization with I2959.
PMCID: PMC5050040  PMID: 21761391
Eosin Y; visible light photoinitiator; bioresponsive hydrogels; photoencapsulation; photopolymerization; dynamic modulus; tissue engineering; mesenchymal stem cells
3.  Repeating cardiopulmonary health effects in rural North Carolina population during a second large peat wildfire 
Environmental Health  2016;15:12.
Cardiovascular health effects of fine particulate matter (PM2.5) exposure from wildfire smoke are neither definitive nor consistent with PM2.5 from other air pollution sources. Non-comparability among wildfire health studies limits research conclusions.
We examined cardiovascular and respiratory health outcomes related to peat wildfire smoke exposure in a population where strong associations were previously reported for the 2008 Evans Road peat wildfire. We conducted a population-based epidemiologic investigation of associations between daily county-level modeled wildfire PM2.5 and cardiopulmonary emergency department (ED) visits during the 2011 Pains Bay wildfire in eastern North Carolina. We estimated changes in the relative risk cumulative over 0–2 lagged days of wildfire PM2.5 exposure using a quasi-Poisson regression model adjusted for weather, weekends, and poverty.
Relative risk associated with a 10 μg/m3 increase in 24-h PM2.5 was significantly elevated in adults for respiratory/other chest symptoms 1.06 (1.00–1.13), upper respiratory infections 1.13 (1.05–1.22), hypertension 1.05 (1.00–1.09) and ‘all-cause’ cardiac outcomes 1.06 (1.00–1.13) and in youth for respiratory/other chest symptoms 1.18 (1.06–1.33), upper respiratory infections 1.14 (1.04–1.24) and ‘all-cause’ respiratory conditions 1.09 (1.01–1.17).
Our results replicate evidence for increased risk of cardiovascular outcomes from wildfire PM2.5 and suggest that cardiovascular health should be considered when evaluating the public health burden of wildfire smoke.
Electronic supplementary material
The online version of this article (doi:10.1186/s12940-016-0093-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4728755  PMID: 26818940
Wildfire smoke; Respiratory effects; Cardiovascular effects; Hypertension; Peat fire
4.  A comparison of the recording of comorbidity in primary and secondary care by using the Charlson Index to predict short-term and long-term survival in a routine linked data cohort 
BMJ Open  2015;5(6):e007974.
Hospital admission records provide snapshots of clinical histories for a subset of the population admitted to hospital. In contrast, primary care records provide continuous clinical histories for complete populations, but might lack detail about inpatient stays. Therefore, combining primary and secondary care records should improve the ability of comorbidity scores to predict survival in population-based studies, and provide better adjustment for case-mix differences when assessing mortality outcomes.
Cohort study.
English primary and secondary care 1 January 2005 to 1 January 2010.
All patients 20 years and older registered to a primary care practice contributing to the linked Clinical Practice Research Datalink from England.
The performance of the Charlson index with mortality was compared when derived from either primary or secondary care data or both. This was assessed in relation to short-term and long-term survival, age, consultation rate, and specific acute and chronic diseases.
657 264 people were followed up from 1 January 2005. Although primary care recorded more comorbidity than secondary care, the resulting C statistics for the Charlson index remained similar: 0.86 and 0.87, respectively. Higher consultation rates and restricted age bands reduced the performance of the Charlson index, but the index's excellent performance persisted over longer follow-up; the C statistic was 0.87 over 1 year, and 0.85 over all 5 years of follow-up. The Charlson index derived from secondary care comorbidity had a greater effect than primary care comorbidity in reducing the association of upper gastrointestinal bleeding with mortality. However, they had a similar effect in reducing the association of diabetes with mortality.
These findings support the use of the Charlson index from linked data and show that secondary care comorbidity coding performed at least as well as that derived from primary care in predicting survival.
PMCID: PMC4458584  PMID: 26048212
5.  Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission 
Translational Psychiatry  2015;5(3):e540-.
Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.
PMCID: PMC4429170  PMID: 25826115
6.  Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study 
Bjog  2014;121(12):1471-1481.
To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions.
Population-based cohort study.
Linked UK maternal–child primary care records.
A total of 349 127 singletons liveborn between 1990 and 2009.
Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression.
Main outcome measures
Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups.
Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80).
Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.
PMCID: PMC4232879  PMID: 24612301
Antidepressants; congenital anomaly; depression; SSRIs; TCAs
7.  Variation in the risk of venous thromboembolism in people with colorectal cancer: a population-based cohort study from England 
Patients with colorectal cancer are at high risk of developing venous thromboembolism (VTE), and recent international guidelines have advised extended prophylaxis for some of these patients following surgery or during chemotherapy. However, our understanding of which patients are at increased risk, and to what extent, is limited.
To determine absolute and relative rates of VTE among patients with colorectal cancer according to Dukes stage, surgical intervention, and chemotherapy.
We analyzed data from four linked databases from 1997 to 2006: the Clinical Practice Research Datalink, linked to Hospital Episode Statistics, Cancer Registry data, and Office for National Statistics cause of death data, all from England. Rates were compared by the use of Cox regression.
There were 10 309 patients with colorectal cancer, and 555 developed VTE (5.4%). The incidence varied by Dukes stage, being three-fold higher among Dukes D patients than among Dukes A patients (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.95–4.84), and 40% higher for those receiving chemotherapy than for those not receiving chemotherapy (HR 1.39, 95% CI 1.14–1.69). The risk following surgery varied by stage of disease and chemotherapy, with Dukes A patients having a low incidence of VTE (0.74%; 95% CI 0.28–1.95) at 6 months, with all events occurring within 28 days of surgery, as compared with Dukes B and Dukes C patients, whose risk at 6 months was ∼ 2%.
Twenty-eight days of prophylaxis following surgery for colorectal cancer is appropriate for Dukes A patients. However, Dukes B and Dukes C patients receiving postoperative chemotherapy have a longer duration of risk.
PMCID: PMC4230392  PMID: 24977288
chemotherapy; colorectal cancer; colorectal surgery; incidence; venous thromboembolism
8.  Splash dispersal of Phyllosticta citricarpa conidia from infected citrus fruit 
Scientific Reports  2014;4:6568.
Rain-splash dispersal of Phyllosticta citricarpa (syn. Guignardia citricarpa) conidia (pycnidiospores) from infected oranges was studied in still air and combined with wind. High power microscopy demonstrated the presence of conidia in splash droplets from diseased oranges, which exuded conidia for over one hour during repeated wetting. The largest (5 mm) incident drops produced the highest splashes (up to 41.0 cm). A linear-by-quadratic surface model predicted highest splashes to be 41.91 cm at a horizontal distance of 25.97 cm from the target orange. Large splash droplets contained most conidia (4–5.5 mm splashes averaged 308 conidia), but were splashed <30 cm horizontal distance. Most (80–90%) splashes were <1 mm diameter but carried only 0–4 conidia per droplet. In multiple splash experiments, splashes combined to reach higher maxima (up to 61.7 cm; linear-by-quadratic surface model prediction, 62.1 cm) than in the single splash experiments. In combination with wind, higher wind speeds carried an increasing proportion of splashes downwind travelling horizontally at least 8 m at the highest wind speed tested (7 m/s), due to a small proportion of droplets (<1 mm) being aerosolised. These experiments suggest that P. citricarpa conidia can be dispersed from infected oranges by splashes of water in rainfall events.
PMCID: PMC4190508  PMID: 25298272
9.  The effect of grid resolution on estimates of the burden of ozone and fine particulate matter on premature mortality in the United States 
Air quality, atmosphere, & health  2013;6(3):10.1007/s11869-013-0197-8.
Assessments of human health impacts associated with outdoor air pollution often use air quality models to represent exposure, but involve uncertainties due to coarse model resolution. Here we quantify how estimates of mortality in the United States attributable to ozone (O3) and fine particulate matter (PM2.5) at coarse resolution differ from those at finer resolution. Using the finest modeled concentrations (12 km), we estimate that 66,000 (95% CI, 39,300 – 84,500) all-cause and 21,400 (5,600 – 34,200) respiratory deaths per year are attributable to PM2.5 and O3 concentrations above low-concentration thresholds, respectively. Using model results at 36 km resolution gives mortality burdens that are 11% higher for PM2.5 and 12% higher for O3 than the 12 km estimates, suggesting a modest positive bias. We also scale modeled concentrations at 12 km to coarser resolutions by simple averaging, and repeat the mortality assessment at multiple resolutions from 24 to 408 km, including the resolutions of global models; in doing so, we account for the effect of resolution on population exposure. Coarse grid resolutions produce mortality estimates that are substantially biased low for PM2.5 (30–40% lower than the 12 km estimate at >250 km resolution), but less than 6% higher for O3 at any resolution. Mortality estimates for primary PM2.5 species show greater bias at coarse resolution than secondary species. These results suggest that coarse resolution global models (>100 km) are likely biased low for PM2.5 health effects. For ozone, biases due to coarse resolution may be much smaller, and the effect on modeled chemistry likely dominates.
PMCID: PMC3862082  PMID: 24348882
Air pollution; exposure assessment; grid resolution; human health; ozone; PM2.5
10.  Differences in socioeconomic position, lifestyle and health-related pregnancy characteristics between Pakistani and White British women in the Born in Bradford prospective cohort study: the influence of the woman's, her partner's and their parents’ place of birth 
BMJ Open  2014;4(6):e004805.
To examine differences between Pakistani and White British women in relation to socioeconomic position, lifestyle and health-related pregnancy characteristics, and to determine whether these differences vary depending on the woman's, her partner's and both of their parents’ place of birth.
Prospective cohort study.
Bradford, UK
3656 Pakistani and 3503 White British women recruited to the Born in Bradford study.
Main outcome measures
Socioeconomic position (employment status; level of education; receipt of benefits; housing tenure), lifestyle characteristics (body mass index (BMI) at the start of pregnancy; smoking during pregnancy) and health-related pregnancy characteristics (hypertensive disorders of pregnancy; gestational diabetes; fasting glucose, postload glucose and fasting insulin at ∼27 weeks gestation).
Fewer Pakistani women were employed (OR 0.17, 95% CI 0.15 to 0.19), the difference being markedly less for UK born women. UK born Pakistani women were more likely, and South Asian born less likely, to be educated post 16 than White British women. Smoking was uncommon among Pakistani women, though the difference comparing UK born Pakistani women to White British women was less than for other groups. BMI was lower among Pakistani compared to White British women (adjusted mean difference −1.12, 95% CI −1.43 to −0.81), the difference being greatest when partners were UK born irrespective of the woman’s place of birth. Pakistani women had higher fasting and postload glucose (mean difference 0.20 mmol/L, 95% CI 0.17 to 0.24; 0.37, 95% CI 0.28 to 0.45), higher fasting insulin and were more likely to have gestational diabetes (GDM).
Our results suggest that some socioeconomic, lifestyle and pregnancy characteristics could be beginning to change in response to migration to the UK, with generally beneficial changes, that is, improving education and employment prospects, lower BMI and no evidence that being UK born has further increased the risk of GDM, but some negative, that is, slight increases in smoking.
PMCID: PMC4067825  PMID: 24948746
Epidemiology; Ethnicity; Lifestyle
11.  Co-benefits of Global Greenhouse Gas Mitigation for Future Air Quality and Human Health 
Nature climate change  2013;3(10):885-889.
Actions to reduce greenhouse gas (GHG) emissions often reduce co-emitted air pollutants, bringing co-benefits for air quality and human health. Past studies1–6 typically evaluated near-term and local co-benefits, neglecting the long-range transport of air pollutants7–9, long-term demographic changes, and the influence of climate change on air quality10–12. Here we simulate the co-benefits of global GHG reductions on air quality and human health using a global atmospheric model and consistent future scenarios, via two mechanisms: a) reducing co-emitted air pollutants, and b) slowing climate change and its effect on air quality. We use new relationships between chronic mortality and exposure to fine particulate matter13 and ozone14, global modeling methods15, and new future scenarios16. Relative to a reference scenario, global GHG mitigation avoids 0.5±0.2, 1.3±0.5, and 2.2±0.8 million premature deaths in 2030, 2050, and 2100. Global average marginal co-benefits of avoided mortality are $50–380 (ton CO2)−1, which exceed previous estimates, exceed marginal abatement costs in 2030 and 2050, and are within the low range of costs in 2100. East Asian co-benefits are 10–70 times the marginal cost in 2030. Air quality and health co-benefits, especially as they are mainly local and near-term, provide strong additional motivation for transitioning to a low-carbon future.
PMCID: PMC4051351  PMID: 24926321
12.  Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females 
The European respiratory journal  2009;34(5):1093-1099.
Mutations in bone morphogenetic protein receptor type 2 (BMPR2) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation.
Genotypes for CYP1B1 Asn453Ser (N453S) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case–control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16α-hydroxyoestrone (16α-OHE1)) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers).
Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p=0.005). Consistent with this finding, the 2-OHE/16α-OHE1 ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p=0.006).
Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.
PMCID: PMC3742124  PMID: 19357154
Bone morphogenetic protein receptor 2; CYP1B1; genetic polymorphism; oestrogen; pulmonary hypertension; sex
13.  Effects of N-acetylcysteine on matrix metalloproteinase-9 secretion and cell migration of human corneal epithelial cells 
Eye  2012;26(8):1138-1144.
Matrix metalloproteinase-9 (MMP-9) secreted by corneal epithelial cells has a role in the remodelling of extracellular matrix and migration of epithelial cells. Elevated levels of MMP-9 activity in the ocular surface may be involved in the pathogenesis of corneal diseases. N-acetylcysteine (NAC) has been used to treat corneal diseases, including recurrent epithelial erosions. In this study, its effects on the MMP-9 secretion and human corneal epithelial (HCE) cell migration were evaluated in vitro.
Confluent HCE cell cultures were treated with 0–20 mM NAC, and tested for MMP-9 secretion and epithelial cell migration by gelatin zymography and scratch wound assay, respectively. Comparisons between different treatment groups were made using analysis of variance, followed by multiple pairwise comparisons.
Twenty mM NAC inhibited the secretion of MMP-9 significantly. Cell migration, assessed after 24 h of wounding, showed a highly significant dose-dependent inhibitory effect.
This study shows that NAC reduces MMP-9 production by HCE cells and inhibits cell migration in vitro. This information helps to elucidate the mechanisms by which NAC may be beneficial therapeutically and suggests that NAC may be useful for managing corneal erosions and related conditions.
PMCID: PMC3420048  PMID: 22766540
cornea; epithelium; healing; recurrent corneal erosions (RCE); N-acetylcysteine (NAC)
14.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI 
Neurology  2006;67(5):834-842.
To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI).
Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis.
The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level.
Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.
PMCID: PMC3488276  PMID: 16966547
15.  Global Air Quality and Health Co-benefits of Mitigating Near-Term Climate Change through Methane and Black Carbon Emission Controls 
Environmental Health Perspectives  2012;120(6):831-839.
Background: Tropospheric ozone and black carbon (BC), a component of fine particulate matter (PM ≤ 2.5 µm in aerodynamic diameter; PM2.5), are associated with premature mortality and they disrupt global and regional climate.
Objectives: We examined the air quality and health benefits of 14 specific emission control measures targeting BC and methane, an ozone precursor, that were selected because of their potential to reduce the rate of climate change over the next 20–40 years.
Methods: We simulated the impacts of mitigation measures on outdoor concentrations of PM2.5 and ozone using two composition-climate models, and calculated associated changes in premature PM2.5- and ozone-related deaths using epidemiologically derived concentration–response functions.
Results: We estimated that, for PM2.5 and ozone, respectively, fully implementing these measures could reduce global population-weighted average surface concentrations by 23–34% and 7–17% and avoid 0.6–4.4 and 0.04–0.52 million annual premature deaths globally in 2030. More than 80% of the health benefits are estimated to occur in Asia. We estimated that BC mitigation measures would achieve approximately 98% of the deaths that would be avoided if all BC and methane mitigation measures were implemented, due to reduced BC and associated reductions of nonmethane ozone precursor and organic carbon emissions as well as stronger mortality relationships for PM2.5 relative to ozone. Although subject to large uncertainty, these estimates and conclusions are not strongly dependent on assumptions for the concentration–response function.
Conclusions: In addition to climate benefits, our findings indicate that the methane and BC emission control measures would have substantial co-benefits for air quality and public health worldwide, potentially reversing trends of increasing air pollution concentrations and mortality in Africa and South, West, and Central Asia. These projected benefits are independent of carbon dioxide mitigation measures. Benefits of BC measures are underestimated because we did not account for benefits from reduced indoor exposures and because outdoor exposure estimates were limited by model spatial resolution.
PMCID: PMC3385429  PMID: 22418651
air quality; climate change; health impact analysis; outdoor air; particulate matter
16.  Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease 
Neuropsychology  2011;25(3):306-318.
Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance.
Three groups of participants were recruited: 1) Imminent and early manifest HD (early HD, n=8); 2) premanifest (presymptomatic) CAG+ (preHD, n=10); and 3) CAG unexpanded (CAG−) controls (n=12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional magnetic resonance imaging during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis.
Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG− group decreased progressively in a well-documented reward detection network that includes the pre-supplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG− group.
These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD.
PMCID: PMC3086952  PMID: 21401260
Huntington disease; premanifest; saccades; functional MRI; error monitoring
17.  The Pathology of Bleomycin induced Fibrosis is Associated with Loss of Resident Lung Mesenchymal Stem cells which Regulate Effector T-cell Proliferation 
Stem Cells (Dayton, Ohio)  2011;29(4):725-735.
Tissue resident mesenchymal stem cells (MSC) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Here we define a population of resident lung mesenchymal stem cells (luMSC) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin induced loss of these endogenous luMSC and elicited fibrosis (PF), inflammation and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSC attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T cell proliferation in vitro. Global gene expression analysis indicated that the luMSC are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and pro-fibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity following injury however when endogenous MSC are lost this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury.
PMCID: PMC3322548  PMID: 21312316
resident lung mesenchymal stem cells; pulmonary fibrosis; pulmonary hypertension; stem cells
20.  An Estimate of the Global Burden of Anthropogenic Ozone and Fine Particulate Matter on Premature Human Mortality Using Atmospheric Modeling 
Environmental Health Perspectives  2010;118(9):1189-1195.
Ground-level concentrations of ozone (O3) and fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM2.5)] have increased since preindustrial times in urban and rural regions and are associated with cardiovascular and respiratory mortality.
We estimated the global burden of mortality due to O3 and PM2.5 from anthropogenic emissions using global atmospheric chemical transport model simulations of preindustrial and present-day (2000) concentrations to derive exposure estimates.
Attributable mortalities were estimated using health impact functions based on long-term relative risk estimates for O3 and PM2.5 from the epidemiology literature. Using simulated concentrations rather than previous methods based on measurements allows the inclusion of rural areas where measurements are often unavailable and avoids making assumptions for background air pollution.
Anthropogenic O3 was associated with an estimated 0.7 ± 0.3 million respiratory mortalities (6.3 ± 3.0 million years of life lost) annually. Anthropogenic PM2.5 was associated with 3.5 ± 0.9 million cardiopulmonary and 220,000 ± 80,000 lung cancer mortalities (30 ± 7.6 million years of life lost) annually. Mortality estimates were reduced approximately 30% when we assumed low-concentration thresholds of 33.3 ppb for O3 and 5.8 μg/m3 for PM2.5. These estimates were sensitive to concentration thresholds and concentration–mortality relationships, often by > 50%.
Anthropogenic O3 and PM2.5 contribute substantially to global premature mortality. PM2.5 mortality estimates are about 50% higher than previous measurement-based estimates based on common assumptions, mainly because of methodologic differences. Specifically, we included rural populations, suggesting higher estimates; however, the coarse resolution of the global atmospheric model may underestimate urban PM2.5 exposures.
PMCID: PMC2944076  PMID: 20382579
air pollution; atmospheric chemistry model; health effects of air pollution; health impact analysis; ozone; particulate matter
21.  Peroxisome Proliferator-Activated Receptor-γ Agonist Treatment Increases Septation and Angiogenesis and Decreases Airway Hyperresponsiveness in a Model of Experimental Neonatal Chronic Lung Disease 
Chronic lung disease (CLD) affects premature newborns requiring supplemental oxygen and results in impaired lung development and subsequent airway hyperreactivity. We hypothesized that the maintenance of peroxisome proliferator-activated receptor gamma (PPARγ) signaling is important for normal lung morphogenesis and treatment with PPARγ agonists could protect against CLD and airway hyperreactivity (AHR) following chronic hyperoxic exposure. This was tested in an established hyperoxic murine model of experimental CLD. Newborn mice and mothers were exposed to room air (RA) or moderate hyperoxia (70% oxygen) for 10 days and fed a standard diet or chow impregnated with the PPARγ agonist rosiglitazone (ROSI) for the duration of study. Following hyperoxic exposure (HE) animals were returned to RA until postnatal day (P) 13 or P41. The accumulation of ROSI in neonatal and adult tissue was confirmed by mass spectrometry. Analyses of body weight and lung histology were performed on P13 and P41 to localize and quantitate PPARγ expression, determine alveolar and microvessel density, proliferation and alpha-smooth muscle actin (α-SMA) levels as a measure of myofibroblast differentiation. Microarray analyses were conducted on P13 to examine transcriptional changes in whole lung. Pulmonary function and airway responsiveness were analyzed at P55. ROSI treatment during HE preserved septation and vascular density. Key array results revealed ontogeny groups differentially affected by hyperoxia including cell cycle, angiogenesis, matrix and muscle differentiation/contraction. These results were further confirmed by histological evaluation of myofibroblast and collagen accumulation. Late AHR to methacholine was present in mice following HE and attenuated with ROSI treatment. These findings suggest that rosiglitazone maintains downstream PPARγ effects and may be beneficial in the prevention of severe CLD with AHR.
PMCID: PMC2873208  PMID: 19484746
Chronic Lung Disease (CLD); Rosiglitazone; PPAR gamma; Lung simplification; airway hyperresonsiveness (AHR)
22.  Author's reply 
Gut  2007;56(2):310-311.
PMCID: PMC1856768
23.  The antecedents of biliary cancer: a primary care case–control study in the United Kingdom 
British Journal of Cancer  2008;100(1):178-180.
In a case–control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity.
PMCID: PMC2634685  PMID: 19018260
cholangiocarcinoma; gall bladder cancer; risk factors; non-steroidal anti-inflammatory drugs; database study
24.  Coeliac disease and risk of tuberculosis: a population‐based cohort study 
Thorax  2007;62(1):1-2.
Are patients with coeliac disease at higher risk of tuberculosis?
PMCID: PMC2111272  PMID: 17189527
25.  Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK 
Thorax  2006;61(11):980-985.
Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are common diagnoses in patients attending chest clinics, but little is known about the epidemiology of these diseases. We used data from a general practice database to provide information on the current incidence of IPF and sarcoidosis in the UK.
Data were extracted for all patients with a diagnosis of IPF or sarcoidosis between 1991 and 2003. The whole population of the database was used to calculate disease incidence stratified by age, sex, region, and time period. Poisson regression was used to compare the incidence between populations and Cox regression was used to compare survival between populations.
920 cases of IPF (mean age 71 years, 62% male) and 1019 cases of sarcoidosis (mean age 47 years, 47% male) were identified. The overall incidence rate per 100 000 person‐years was 4.6 for IPF and 5.0 for sarcoidosis. The incidence of IPF increased progressively between 1991 and 2003 (p<0.00001), and was highest in Northern England and Scotland (p<0.0001). The survival of patients with IPF was stable over time. In contrast, the incidence of sarcoidosis was highest in London, West Midlands and Northern Ireland and remained stable over time.
The incidence of IPF has more than doubled between 1990 and 2003; this is not due to the ageing of the UK population or an increased ascertainment of milder cases. The incidence of sarcoidosis has not changed during this time period. Our findings suggest that more than 4000 new cases of IPF and 3000 new cases of sarcoidosis are currently diagnosed each year in the UK.
PMCID: PMC2121155  PMID: 16844727
idiopathic pulmonary fibrosis; sarcoidosis; epidemiology

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