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1.
Epidemiology ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33788795

RESUMO

BACKGROUND: Although many studies demonstrated reduced mortality risk with higher greenness, few studies examined the modifying effect of greenness on air pollution-health associations. We evaluated residential greenness as an effect modifier of the association between long-term exposure to fine particles (PM2.5) and mortality. METHODS: We used data from all Medicare beneficiaries in North Carolina (NC) and Michigan (MI) (2001-2016). We estimated annual PM2.5 averages using ensemble prediction models. We estimated mortality risk per 1 µg/m3 increase using Cox proportional hazards modeling, controlling for demographics, Medicaid eligibility, and area-level covariates. We investigated health disparities by greenness using the Normalized Difference Vegetation Index (NDVI) with measures of urbanicity and socioeconomic status. RESULTS: PM2.5 was positively associated with mortality risk. Hazard ratios (HRs) were 1.12 (95% confidence interval (CI) 1.12, 1.13) for NC and 1.01 (95% CI 1.00, 1.01 ) for MI. HRs were higher for rural than urban areas. Within each category of urbanicity, HRs were generally higher in less green areas. For combined disparities, HRs were higher in low greenness or low SES areas, regardless of the other factor. HRs were lowest in high-greenness and high-SES areas for both states. CONCLUSIONS: In our study, those in low SES and high greenness areas had lower associations between PM2.5 and mortality than those in low SES and low greenness areas. Multiple aspects of disparity factors and their interactions may affect health disparities from air pollution exposures. Findings should be considered in light of uncertainties, such as our use of modeled PM2.5 data, and warrant further investigation.

2.
Environ Res ; 195: 110862, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33581087

RESUMO

BACKGROUND: Several studies have reported environmental disparities regarding exposure to concentrated animal feeding operations (CAFOs). Public health implications of environmental justice from the intensive livestock industry are of great concern in North Carolina (NC), USA, a state with a large number and extensive history of CAFOs. OBJECTIVES: We examined disparities by exposure to CAFOs using several environmental justice metrics and considering potentially vulnerable subpopulations. METHODS: We obtained data on permitted animal facilities from NC Department of Environmental Quality (DEQ). Using ZIP code level variables from the 2010 Census, we evaluated environmental disparities by eight environmental justice metrics (i.e., percentage of Non-Hispanic White, Non-Hispanic Black, or Hispanic; percentage living below the poverty level; median household income; percentage with education less than high school diploma; racial residential isolation (RI) for Non-Hispanic Black; and educational residential isolation (ERI) for population without college degree). We applied two approaches to assign CAFOs exposure for each ZIP code: (1) a count method based on the number of CAFOs within ZIP code; and (2) a buffer method based on the area-weighted number of CAFOs using a 15 km buffer. RESULTS: Spatial distributions of CAFOs exposure generally showed similar patterns between the two exposure methods. However, some ZIP codes had different estimated CAFOs exposure for the different approaches, with higher exposure when using the buffer method. Our findings indicate that CAFOs are located disproportionately in communities with higher percentage of minorities and in low-income communities. Distributions of environmental justice metrics generally showed similar patterns for both exposure methods, however starker disparities were observed using a buffer method. CONCLUSIONS: Our findings of the disproportionate location of CAFOs provide evidence of environmental disparities with respect to race and socioeconomic status in NC and have implications for future studies of environmental and health impacts of CAFOs.


Assuntos
Ração Animal , Benchmarking , Afro-Americanos , Animais , Exposição Ambiental , Hispano-Americanos , Humanos , North Carolina
3.
Environ Pollut ; 265(Pt B): 115035, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32806455

RESUMO

We investigated the levels and distribution patterns of α- and ß-endosulfan and endosulfan sulfate in air, soil, water, and sediment samples collected from the South Korean persistent organic pollutants (POPs) monitoring networks. In the air samples, the highest concentrations of the total (Σ3) endosulfan (50.3-611 pg/m3, mean: 274 pg/m3) were observed during summer. Spearman analysis revealed a good correlation between agricultural land area and atmospheric concentrations of Σ3 endosulfan except during winter. Regardless of the season, the ratio of the two isomers (α/ß) was 3.6-4.9 in the air samples, higher than that observed in technical mixtures (2.0-2.3), possibly due to the higher volatility of α-endosulfan, compared to ß-endosulfan. Concentrations of Σ3 endosulfan in the soil samples (n.d.-13.4 ng/g, mean: 0.8 ng/g) were not significantly different except at some stations adjacent to large areas of farmland. The average levels of Σ3 endosulfan in the water and sediment samples were 2.1 ng/L and 0.1 ng/g dw, respectively. In analyzing the four largest rivers, it was observed that a few water stations during spring and fall and sediment stations in fall had high concentrations of the two isomers and endosulfan sulfate, particularly around the Yeoungsan and Nakdong Rivers near large areas of agricultural land. Endosulfan sulfate was dominant at most water and sediment sampling stations. This study demonstrates that the endosulfan found in most environmental compartments most probably derives from agricultural areas despite its ban as a pesticide. On the other hand, given that it was also detected in industrial and urban areas, in which pesticide application does not occur, it can be conjectured that endosulfan is aerially transported at higher temperatures and continuously circulates within the environment.


Assuntos
Endossulfano/análise , Inseticidas/análise , Monitoramento Ambiental , República da Coreia , Solo , Água
4.
Sci Total Environ ; 744: 141012, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-32693269

RESUMO

To control the novel coronavirus disease (COVID-19) outbreak, state and local governments in the United States have implemented several mitigation efforts that resulted in lower emissions of traffic-related air pollutants. This study examined the impacts of COVID-19 mitigation measures on air pollution levels and the subsequent reductions in mortality for urban areas in 10 US states and the District of Columbia. We calculated changes in levels of particulate matter with aerodynamic diameter no larger than 2.5 µm (PM2.5) during mitigation period versus the baseline period (pre-mitigation measure) using the difference-in-difference approach and the estimated avoided total and cause-specific mortality attributable to these changes in PM2.5 by state and district. We found that PM2.5 concentration during the mitigation period decreased for most states (except for 3 states) and the capital. Decreases of average PM2.5 concentration ranged from 0.25 µg/m3 (4.3%) in Maryland to 4.20 µg/m3 (45.1%) in California. On average, PM2.5 levels across 7 states and the capital reduced by 12.8%. We estimated that PM2.5 reduction during the mitigation period lowered air pollution-related total and cause-specific deaths. An estimated 483 (95% CI: 307, 665) PM2.5-related deaths was avoided in the urban areas of California. Our findings have implications for the effects of mitigation efforts and provide insight into the mortality reductions can be achieved from reduced air pollution levels.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Infecções por Coronavirus , Coronavirus , Pandemias , Pneumonia Viral , Betacoronavirus , Humanos , Maryland , Material Particulado/análise , Estados Unidos
5.
Health Place ; 62: 102287, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32479364

RESUMO

Understanding the environmental justice implications of the mortality impacts of air pollution exposure is a public health priority, as some subpopulations may face a disproportionate health burden. We examined which residential environmental and social factors may affect disparities in the air pollution-mortality relationship in North Carolina, US, using a time-stratified case-crossover design. Results indicate that air pollution poses a higher mortality risk for some persons (e.g., elderly) than others. Our findings have implications for environmental justice regarding protection of those who suffer the most from exposure to air pollution and policies to protect their health.

6.
Environ Res ; 176: 108546, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31247430

RESUMO

Heat waves are anticipated to worsen with climate change. India, an understudied area with >15% of the world's population, commonly experiences temperature extremes and already resembles potential future climates of more temperate regions. Registry data from local municipal corporations and government offices were collected and translated, yielding daily all-cause mortality for 4 communities in Northwest India for all or part of the period 2000-2012. Heat waves were defined as ≥2 days with local temperature ≥97th percentile for that community. An alternate definition matching that used by the Indian Meteorological Department was also developed, to enhance policy relevance. Community-specific average daily maximum temperature over the entire record ranged from 32.5 to 34.2 °C (90.5-93.6 °F). Across communities, total mortality increased 18.1% during heat wave days compared with non-heat-wave days [95% confidence interval (CI): -5.3%, 47.3%], with the highest risk in Jaipur (29.9% [95% CI: 24.6%, 34.9%]). Evidence of effect modification by heat wave characteristics (intensity, duration, and timing in season) was limited. Findings indicate health risks associated with heat waves in communities with high baseline temperatures. Results can inform heat wave-health assessments in temperate regions in future, and improve our understanding of temperature-health associations under climate change. Further investigation of potential effect modification by heat wave characteristics is needed.


Assuntos
Mudança Climática , Exposição Ambiental/estatística & dados numéricos , Temperatura Alta , Mortalidade/tendências , Humanos , Índia/epidemiologia , Estações do Ano , Temperatura
7.
Environ Res ; 168: 460-466, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30396130

RESUMO

BACKGROUND: Few studies have examined temperature's effect on adverse birth outcomes and relevant effect modifiers. OBJECTIVES: We investigated associations between heat and adverse birth outcomes and how individual and community characteristics affect these associations for Seoul, Korea, 2004-2012. METHODS: We applied logistic regression to estimate associations between heat index during pregnancy, 4 weeks before delivery, and 1 week before delivery and risk of preterm birth and term low birth weight. We investigated effect modification by individual (infant's sex, mother's age, and mother's educational level) and community characteristics (socioeconomic status (SES) and percentage of green areas near residence at the gu level, which is similar to borough in Western countries). We also evaluated associations by combinations of individual- and community-level SES. RESULTS: Heat exposure during whole pregnancy was significantly associated with risk of preterm birth. An interquartile (IQR) increase (5.5 °C) in heat index during whole pregnancy was associated with an odds ratio (OR) of 1.033 (95% CI 1.005, 1.061) with NO2 adjustment, and 1.028 (95% CI 0.998, 1.059) with PM10 adjustment, for preterm birth. We also found significant associations with heat exposure during 4 weeks before delivery and 1 week before delivery on preterm birth. We did not observe significant associations with term low birth weight. Higher risk of heat on preterm birth was associated with some individual characteristics such as infants with younger or older mothers and lower community-level SES. For combinations of individual- and community-level SES, the highest and most significant estimated effect was found for infants with low educated mothers living in low SES communities, with suggestions of effects of both individual-and community-level SES. CONCLUSIONS: Our findings have implications for evaluating impacts of high temperatures on birth outcomes, estimating health impacts of climate change, and identifying which subpopulations and factors are most relevant for disparities in this association.


Assuntos
Temperatura Alta , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , República da Coreia , Seul , Temperatura
9.
Int J Mol Sci ; 19(3)2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518978

RESUMO

The binding of the tumor necrosis factor α (TNFα) to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab-pegol (Cimzia®), and golimumab (Simponi®), are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα-TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Terapia de Alvo Molecular , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Reumatoide/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Linfotoxina-alfa/antagonistas & inibidores , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/metabolismo
10.
Nat Commun ; 9(1): 1200, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29572471

RESUMO

BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF-belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF-receptor interaction, but also disrupting the formation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fator Ativador de Células B/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Motivos de Aminoácidos , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Cromatografia em Gel , Cristalografia por Raios X , Epitopos/química , Humanos , Imunossupressores/farmacologia , Ligantes , Mutação , Ligação Proteica
11.
Am J Epidemiol ; 187(5): 992-1000, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053768

RESUMO

Identifying periods of increased vulnerability to air pollution during pregnancy with respect to the development of adverse birth outcomes can improve understanding of possible mechanisms of disease development and provide guidelines for protection of the child. Exposure to air pollution during pregnancy is typically based on the mother's residence at delivery, potentially resulting in exposure misclassification and biasing the estimation of critical windows of pregnancy. In this study, we determined the impact of maternal residential mobility during pregnancy on defining weekly exposure to particulate matter less than or equal to 10 µm in aerodynamic diameter (PM10) and estimating windows of susceptibility to term low birth weight. We utilized data sets from 4 Connecticut birth cohorts (1988-2008) that included information on all residential addresses between conception and delivery for each woman. We designed a simulation study to investigate the impact of increasing levels of mobility on identification of critical windows. Increased PM10 exposure during pregnancy weeks 16-18 was associated with an increased probability of term low birth weight. Ignoring residential mobility when defining weekly exposure had only a minor impact on the identification of critical windows for PM10 and term low birth weight in the data application and simulation study. Identification of critical pregnancy windows was robust to exposure misclassification caused by ignoring residential mobility in these Connecticut birth cohorts.


Assuntos
Poluição do Ar/efeitos adversos , Peso ao Nascer , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Adulto , Estudos de Coortes , Simulação por Computador , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Modelos Estatísticos , Dinâmica Populacional , Gravidez , Adulto Jovem
12.
Am J Epidemiol ; 186(11): 1268-1276, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29121205

RESUMO

Many studies have found associations between particulate matter having an aerodynamic diameter of ≤2.5 µm (PM2.5) and adult mortality. Comparatively few studies evaluated particles and infant mortality, although infants and children are particularly vulnerable to pollution. Moreover, existing studies mostly focused on short-term exposure to larger particles. We investigated PM2.5 exposure during pregnancy and lifetime and postneonatal infant mortality. The study included 465,682 births with 385 deaths in Massachusetts (2001-2007). Exposures were estimated from PM2.5-prediction models based on satellite imagery. We applied extended Cox proportional hazards modeling with time-dependent covariates to total, respiratory, and sudden infant death syndrome mortality. Exposure was calculated from birth to death (or end of eligibility for outcome, at age 1 year) and pregnancy (gestation and each trimester). Models adjusted for sex, birth weight, gestational length, season of birth, temperature, relative humidity, and maternal characteristics. Hazard ratios for total, respiratory, and sudden infant death syndrome mortality per-interquartile-range increase (1.3 µg/m3) in lifetime PM2.5 exposure were 2.66 (95% confidence interval (CI): 2.11, 3.36), 3.14 (95% CI: 2.39, 4.13), and 2.50 (95% CI: 1.56, 4.00), respectively. We did not observe a statistically significant relationship between gestational exposure and mortality. Our findings provide supportive evidence that lifetime exposure to PM2.5 increases risk of infant mortality.


Assuntos
Mortalidade Infantil , Exposição Materna/efeitos adversos , Material Particulado/efeitos adversos , Adulto , Escolaridade , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estado Civil , Massachusetts/epidemiologia , Idade Materna , Material Particulado/análise , Gravidez , Modelos de Riscos Proporcionais , Adulto Jovem
13.
Am J Epidemiol ; 186(5): 573-580, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911012

RESUMO

Air pollution is known to lead to a substantial health burden, but the majority of evidence is based on data from North America and Europe. Despite rising pollution levels, very limited information is available for South Asia. We investigated the impact of particulate matter with an aerodynamic diameter less than or equal to 10 µm (PM10) on hospitalization, by cause and subpopulation, in the Kathmandu Valley, an understudied and rapidly urbanizing region in Nepal. Individual-level daily inpatient hospitalization data (2004-2007) were collected from each of 6 major hospitals, as Nepal has no central data collection system. Time-stratified case-crossover analysis was used with interaction terms for potential effect modifiers (e.g., age, sex, and socioeconomic status), with adjustment for day of the week and weather. Daily PM10 concentrations averaged 120 µg/m3, with the daily maximum reaching 403 µg/m3. A 10-µg/m3 increase in PM10 level was associated with increased risks of hospitalization of 1.00% (95% confidence interval (CI): 0.62, 1.38), 1.70% (95% CI: 0.18, 3.25), and 2.29% (95% CI: 0.18, 4.43) for total, respiratory, and cardiovascular admissions, respectively. We did not find strong evidence of effect modification by age, sex, or socioeconomic status. These results, in combination with the high levels of exposure, indicate a potentially serious human health burden from air pollution in the Kathmandu Valley.


Assuntos
Doenças Cardiovasculares/epidemiologia , Exposição Ambiental/efeitos adversos , Material Particulado/efeitos adversos , Admissão do Paciente/estatística & dados numéricos , Transtornos Respiratórios/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Doenças Cardiovasculares/etiologia , Estudos Cross-Over , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nepal/epidemiologia , Material Particulado/análise , Transtornos Respiratórios/etiologia , Classe Social , Adulto Jovem
14.
Environ Res ; 158: 748-752, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28750343

RESUMO

BACKGROUND: Although numerous studies have shown increased risk of mortality from elevated temperatures for adults, limited studies have examined temperature's effect on mortality for infants. Our study investigated the city-specific and overall effects of ambient temperature on infant mortality in seven major cities in Korea, 2004-2007. METHODS: Birth cohort using a linked birth and death records included 777,570 births with 557 all-cause deaths. We estimated city-specific hazard ratios for each city using an extended Cox proportional hazards model with time-dependent covariates. Then we combined city-specific hazard ratios to generate overall hazard ratio across the seven cities using a Bayesian hierarchical model. Stratified analyses were conducted by cause of death (total and SIDS), exposure period (whole gestation, each trimester, lifetime, 1 month before death, and 2 weeks before death), sex, and maternal characteristics. RESULTS: Overall across the cities, we found significantly positive associations between ambient temperature during 1 month before death or 2 weeks before death and infant mortality from total or SIDS. The overall hazard ratio of infant mortality from total deaths and SIDS for a 1°C increase during 1 month before death was 1.52 (95% CI, 1.46-1.57) and 1.50 (95% CI, 1.35-1.66), respectively. We also found suggestive evidence that some factors such as mother's age may modify the association. CONCLUSIONS: Our findings have implications for establishment of policy to reduce the risk of infant mortality from high ambient temperature under climate change.


Assuntos
Temperatura Alta/efeitos adversos , Morte Súbita do Lactente/epidemiologia , Adolescente , Adulto , Fatores Etários , Teorema de Bayes , Cidades , Mudança Climática , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mães , Modelos de Riscos Proporcionais , República da Coreia/epidemiologia , Fatores de Risco , Fatores Sexuais , Fatores Socioeconômicos , Morte Súbita do Lactente/etiologia , Adulto Jovem
15.
Environ Geochem Health ; 39(2): 279-291, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28197871

RESUMO

For monitoring and risk assessment, levels and distributions of Σ29 PCBs in paddy soil samples collected from Gwangyang (10 sites) and Ulsan (20 sites), heavily industrialized cities in Korea, were investigated using high-resolution gas chromatography/high-resolution mass spectrometry. Overall, total concentrations of Σ29 PCBs in Gwangyang (216.4-978.6 pg g-1 dw) and Ulsan (273.8-1824.1 pg g-1 dw) were higher than those (106.6-222.6 pg g-1 dw) in agricultural soil from Anseong in Korea. The TEQ (toxic equivalency) values from Gwangyang (0.06-0.40 ng TEQ kg-1 dw) and Ulsan (0.06-0.22 ng TEQ kg-1 dw) were higher than those (0.04-0.11 ng TEQ kg-1 dw) in Anseong but lower than the WHO threshold level (20 ng TEQ kg-1). However, one of the most toxic congeners, PCB 126, gave the highest concentration, possibly posing a risk to the biota. Seven indicator PCB congeners contributed to 50-80% of the total concentration of Σ29 PCBs, indicating the 7 PCBs can be used as valuable indicators for monitoring. The principal component analysis and cluster analysis for the homologue profiles of PCBs indicated that all the samples from both cities had the similar PCB contamination patterns, and the major sources of the PCB contamination were most likely from the usage of Aroclor 1254 than those of Aroclors 1242 and 1260. These PCB technical mixtures were possibly significantly used by various industries including iron and steel industries in Gwangyang and petrochemical and shipbuilding industries in Ulsan.


Assuntos
Monitoramento Ambiental/métodos , Bifenilos Policlorados/análise , Medição de Risco/métodos , Poluentes do Solo/análise , Agricultura , Cidades , Cromatografia Gasosa-Espectrometria de Massas/métodos , Indústrias , Bifenilos Policlorados/toxicidade , Análise de Componente Principal , República da Coreia , Poluentes do Solo/toxicidade
16.
Int J Mol Sci ; 18(1)2017 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-28124979

RESUMO

Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα.


Assuntos
Anticorpos Neutralizantes/imunologia , Doenças Autoimunes/tratamento farmacológico , Certolizumab Pegol/imunologia , Certolizumab Pegol/uso terapêutico , Inflamação/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Sequência de Aminoácidos , Doenças Autoimunes/complicações , Certolizumab Pegol/química , Cristalografia por Raios X , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Inflamação/complicações , Cinética , Mutagênese/genética , Proteínas Mutantes/química , Ligação Proteica , Estrutura Secundária de Proteína , Fator de Necrose Tumoral alfa/química
17.
Epidemiology ; 28(1): 77-85, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27648592

RESUMO

BACKGROUND: The health impacts of wildfire smoke, including fine particles (PM2.5), are not well understood and may differ from those of PM2.5 from other sources due to differences in concentrations and chemical composition. METHODS: First, for the entire Western United States (561 counties) for 2004-2009, we estimated daily PM2.5 concentrations directly attributable to wildfires (wildfires-specific PM2.5), using a global chemical transport model. Second, we defined smoke wave as ≥2 consecutive days with daily wildfire-specific PM2.5 > 20 µg/m, with sensitivity analysis considering 23, 28, and 37 µg/m. Third, we estimated the risk of cardiovascular and respiratory hospital admissions associated with smoke waves for Medicare enrollees. We used a generalized linear mixed model to estimate the relative risk of hospital admissions on smoke wave days compared with matched comparison days without wildfire smoke. RESULTS: We estimated that about 46 million people of all ages were exposed to at least one smoke wave during 2004 to 2009 in the Western United States. Of these, 5 million are Medicare enrollees (≥65 years). We found a 7.2% (95% confidence interval: 0.25%, 15%) increase in risk of respiratory admissions during smoke wave days with high wildfire-specific PM2.5 (>37 µg/m) compared with matched non smoke wave days. We did not observe an association between smoke wave days with wildfire-specific PM2.5 ≤ 37 µg/mand respiratory or cardiovascular admissions. Respiratory effects of wildfire-specific PM2.5 may be stronger than that of PM2.5 from other sources. CONCLUSION: Short-term exposure to wildfire-specific PM2.5was associated with risk of respiratory diseases in the elderly population in the Western United States during severe smoke days. See video abstract at, http://links.lww.com/EDE/B137.


Assuntos
Hospitalização/estatística & dados numéricos , Material Particulado , População Rural/estatística & dados numéricos , Fumaça , População Urbana/estatística & dados numéricos , Incêndios Florestais/estatística & dados numéricos , Idoso , Humanos , Medicare , Meio-Oeste dos Estados Unidos , Noroeste dos Estados Unidos , Sudoeste dos Estados Unidos , Estados Unidos , Tempo (Meteorologia)
18.
Nat Commun ; 7: 13354, 2016 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-27796306

RESUMO

Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four therapeutic antibodies targeting these checkpoint molecules have been approved by the FDA for the treatment of several types of cancer. Here, we report the crystal structures of checkpoint molecules in complex with the Fab fragments of therapeutic antibodies, including PD-1/pembrolizumab, PD-1/nivolumab, PD-L1/BMS-936559 and CTLA-4/tremelimumab. These complex structures elucidate the precise epitopes of the antibodies and the molecular mechanisms underlying checkpoint blockade, providing useful information for the improvement of monoclonal antibodies capable of attenuating checkpoint signalling for the treatment of cancer.


Assuntos
Anticorpos Monoclonais/química , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Animais , Anticorpos Monoclonais Humanizados/química , Cristalografia por Raios X , Epitopos/química , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Nivolumabe , Receptor de Morte Celular Programada 1/química , Ligação Proteica , Transdução de Sinais
19.
Environ Res ; 151: 728-733, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27644031

RESUMO

Urban areas are particularly vulnerable to heat-related health outcomes. Simultaneous trends of climate change and urbanization may increase the urban heat-related health burden. We investigated the effects of urban vegetation on heat-related mortality, and evaluated whether different levels of vegetation and individuals' characteristics affect the temperature-mortality associations within Seoul, Korea 2000-2009. We used Normalized Difference Vegetation Index (NDVI) to assess the urban vegetation within Seoul. We applied an overdispersed Poisson generalized linear model with interaction term between temperature and indicator of NDVI group (categorized in 3 levels) to assess the effect modification of the temperature-mortality association by urban vegetation. We conducted stratified analysis to explore whether associations are affected by individual characteristics of sex and age. The association between total mortality and a 1°C increase in temperature above the 90th percentile (25.1°C) (the "heat effect") was the highest for gus with low NDVI. The heat effect was a 4.1% (95% confidence interval (CI) 2.3, 5.9%), 3.0% (95% CI 0.2, 5.9%), and 2.2% (95% CI -0.5, 5.0%) increase in mortality risk for low, medium, and high NDVI group, respectively. Estimated risks showed similar effects by sex and age. Our findings suggest a higher mortality effect of high temperature in areas with lower vegetation in Seoul, Korea.


Assuntos
Monitoramento Ambiental/métodos , Raios Infravermelhos/efeitos adversos , Mortalidade/tendências , Desenvolvimento Vegetal , Urbanização , Idoso , Poluentes Atmosféricos/análise , Mudança Climática , Feminino , Sistemas de Informação Geográfica , Humanos , Masculino , Pessoa de Meia-Idade , Material Particulado/análise , Seul/epidemiologia , Reforma Urbana/estatística & dados numéricos
20.
Sci Total Environ ; 565: 271-278, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27177133

RESUMO

Air pollution has been linked to cardiovascular disease, which is the leading cause of death worldwide. The aim of this study was to evaluate the epidemiological association between the yearly concentration of air pollution and regional prevalence of cardiovascular disease in South Korea. In this cross-sectional study, data regarding the regional prevalence of cardiovascular disease (i.e., hypertension, stroke, myocardial infarction, and angina) and health behaviors were obtained from the Korean Community Health Survey conducted in 108 communities of South Korea in 2008-2010. Data on carbon monoxide (CO; ppb), nitrogen dioxide (NO2; ppb), and particulate matter up to 10µm in size (PM10; µg/m(3)) were collected from the National Institute of Environmental Research. We used a distributed lag model with generalized estimating equations to represent the corrected lag-response and correlation among repeated observations. Cumulative odds ratios of hypertension, hypertension in those aged >30years, stroke, and angina with an increase of 10µg/m(3) in PM10 were 1.042 (95% confidence interval [CI]: 1.009, 1.077), 1.044 (CI: 1.009, 1.079), 1.044 (CI: 0.979, 1.114), and 0.977 (CI: 0.901, 1.059), respectively; a 10ppb increase in NO2 was associated with an odds ratio of 1.077 (CI: 1.044, 1.112), 1.08 (CI: 1.043, 1.118), 1.073 (CI: 0.994, 1.157), and 1.047 (CI: 0.968, 1.134), respectively. A 10ppb increase in CO was associated with an odds ratio of 1.123 (CI: 0.963, 1.31), 1.129 (CI: 0.963, 1.387), and 1.336 (CI: 0.9887, 2.011) for hypertension, hypertension in patients >30years, and stroke >50, respectively. We found suggestive evidence of an association between the long-term exposure (i.e., delayed for 5years) to air pollutants (i.e., PM10, NO2, and CO) and the regional prevalence of chronic cardiovascular disease (i.e., hypertension, stroke, myocardial infarction, and angina) in 108 communities in South Korea.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/etiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , República da Coreia/epidemiologia , Fatores de Tempo
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