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2.
J Headache Pain ; 22(1): 124, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645382

RESUMO

BACKGROUND: Migraine has been associated with cardiovascular disease (CVD) events among middle-aged adults. The objective of this study was to determine the risk for ischemic stroke and coronary heart disease (CHD) events among older adults with versus without migraine. METHODS: This retrospective cohort study was conducted using data from US adults ≥66 years of age with Medicare health insurance between 2008 and 2017. After stratification by history of CVD, patients with a history of migraine were matched 1:4 to those without a history of migraine, based on calendar year, age, and sex. Patients were followed through December 31, 2017 for ischemic stroke and CHD events including myocardial infarction or coronary revascularization. All analyses were done separately for patients with and without a history of CVD. RESULTS: Among patients without a history of CVD (n = 109,950 including n = 21,990 with migraine and n = 87,960 without migraine), 1789 had an ischemic stroke and 3552 had a CHD event. The adjusted hazard ratio (HR) among patients with versus without migraine was 1.20 (95% confidence interval [95%CI], 1.07-1.35) for ischemic stroke and 1.02 (95%CI, 0.93-1.11) for CHD events. Compared to patients without migraine, those with migraine who were taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.43 [95%CI, 1.20-1.69]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.79 [95%CI, 0.67-0.93]). Among patients with a history of CVD (n = 79,515 including n = 15,903 with migraine and n = 63,612 without migraine), 2960 had an ischemic stroke and 7981 had a CHD event. The adjusted HRs (95%CI) for ischemic stroke and CHD events associated with migraine were 1.27 (1.17-1.39) and 0.99 (0.93-1.05), respectively. Patients with migraine taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.21 [95%CI, 1.07-1.36]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.83 [95%CI, 0.72-0.95]), each versus those without migraine. CONCLUSIONS: Older adults with migraine are at increased risk for ischemic stroke. The risk for ischemic stroke among older adults with migraine may differ by migraine medication classes.


Assuntos
Isquemia Encefálica , Doenças Cardiovasculares , Doença das Coronárias , AVC Isquêmico , Transtornos de Enxaqueca , Acidente Vascular Cerebral , Idoso , Isquemia Encefálica/epidemiologia , Doença das Coronárias/epidemiologia , Humanos , Medicare , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Estados Unidos
3.
Artigo em Inglês | MEDLINE | ID: mdl-34599698

RESUMO

PURPOSE: Adults with atherosclerotic cardiovascular disease (ASCVD) are recommended high-intensity statins, with those at very high risk for recurrent events recommended adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor if their low-density lipoprotein cholesterol (LDL-C) is ≥70 mg/dL. We estimated the number of recurrent ASCVD events potentially averted if all adults in the United States (US) ≥45 years of age with ASCVD achieved an LDL-C <70 mg/dL. METHODS: The number of US adults with ASCVD and LDL-C ≥70 mg/dL was estimated from the National Health and Nutrition Examination Survey 2009-2016 (n = 596). The 10-year cumulative incidence of recurrent ASCVD events was estimated from the REasons for Geographic And Racial Differences in Stroke study (n = 5390), weighted to the US population by age, race, and sex. The ASCVD risk reduction by achieving an LDL-C <70 mg/dL was estimated from meta-analyses of lipid-lowering treatment trials. RESULTS: Overall, 14.7 (95% CI, 13.7-15.8) million US adults had ASCVD, of whom 11.6 (95% CI, 10.6-12.5) million had LDL-C ≥70 mg/dL. The 10-year cumulative incidence of ASCVD events was 24.3% (95% CI, 23.2-25.6%). We projected that 2.823 (95% CI, 2.543-3.091) million ASCVD events would occur over 10 years among US adults with ASCVD and LDL-C ≥70 mg/dL. Overall, 0.634 (95% CI, 0.542-0.737) million ASCVD events could potentially be averted if all US adults with ASCVD achieved and maintained LDL-C <70 mg/dL. CONCLUSION: A substantial number of recurrent ASCVD events could be averted over 10 years if all US adults with ASCVD achieved, and maintained, an LDL-C <70 mg/dL.

4.
Trends Cell Biol ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34511324

RESUMO

Solute carrier transporters (SLCs) mediate nutrient and metabolite cellular homeostasis. Immune cells depend on SLCs to induce rapid and robust metabolic reprogramming, thereby controlling diverse immunological responses. Recent studies hint toward an important role of SLCs in immunity. Here, we review the emerging roles of SLCs in immunotherapy via modifying the metabolism and effector functions of immune cells. We focus on the roles of three major nutrient (glucose, amino acid, and lipid)-related transporters in immunity of representative cells [T cells, dendritic cells (DCs), natural killer (NK) cells, and macrophages) in innate and adaptive immunity. Other SLCs, such as ion transporters are also briefly discussed. Finally, we propose some potential strategies for targeting SLCs to augment tumour immunotherapy.

5.
J Clin Lipidol ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34452823

RESUMO

BACKGROUND: Adults with atherosclerotic cardiovascular disease (ASCVD) at very high-risk for recurrent events who have low-density lipoprotein cholesterol ≥ 70 mg/dL despite maximally-tolerated statin therapy are recommended to initiate ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. OBJECTIVE: Compare the initiation of ezetimibe and a PCSK9 inhibitor after a myocardial infarction (MI) among very high-risk ASCVD patients by race/ethnicity and sex. METHODS: We analyzed data from 374,786 adults ≥ 66 years of age with Medicare fee-for-service coverage who had an MI between July 1, 2015 and December 31, 2018, were not taking ezetimibe or a PCSK9 inhibitor, and had very high-risk ASCVD defined by the 2018 American Heart Association/American College of Cardiology multi-society cholesterol guideline. Pharmacy claims through December 31, 2018 were used to determine ezetimibe and PCSK9 inhibitor initiation. RESULTS: Overall, 6980 (1.9%) beneficiaries initiated ezetimibe, and 1433 (0.4%) initiated a PCSK9 inhibitor. Adjusted hazard ratios (aHR) for ezetimibe initiation among non-Hispanic Black, Hispanic, and Asian versus non-Hispanic White beneficiaries were 0.77 (95% confidence interval [95%CI]: 0.70-0.86), 0.92 (95%CI: 0.76-1.11) and 0.73 (95%CI: 0.59-0.89), respectively. Compared to non-Hispanic White beneficiaries, the aHRs for PCSK9 inhibitor initiation were 0.63 (95%CI: 0.48-0.81) among non-Hispanic Black, 0.70 (95%CI: 0.43-1.13) among Hispanic, and 0.93 (95%CI: 0.62-1.39) among Asian beneficiaries. The aHRs for ezetimibe and PCSK9 inhibitor initiation comparing women to men were 1.11 (95%CI: 1.06-1.17) and 1.13 (95%CI: 1.01-1.25), respectively. CONCLUSION: There are race/ethnic and sex disparities in the initiation of ezetimibe and a PCSK9 inhibitor following MI among very high-risk ASCVD patients.

6.
Proc Natl Acad Sci U S A ; 118(35)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34433664

RESUMO

The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn2+ store, and excessive mitochondrial Zn2+ is linked to neurodegeneration. How mitochondria maintain their Zn2+ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn2+ from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to elevated Zn2+ levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in C. elegans, during which Zn2+ exits from mitochondria and acts as an activation signal. In slc-30a9-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an SLC30A9 mutation was found.

7.
Chem Biol Interact ; 347: 109600, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34324853

RESUMO

OBJECTIVE: - To evaluate exposure-response relationships between 1,3-butadiene and styrene and selected diseases among synthetic rubber polymer workers. METHODS: - 21,087 workers (16,579 men; 4508 women) were followed from 1943 through 2009 to determine mortality outcomes. Cox regression models estimated rate ratios (RRs) and 95% confidence intervals (CIs) by quartile of cumulative exposure to butadiene or styrene and exposure-response trends for cancers of the bladder, lung, kidney, esophagus and pancreas, and for all nonmalignant respiratory disease (NMRD), chronic obstructive pulmonary disease (COPD) and pneumonia. RESULTS: - Bladder cancer RRs were 2.13 (95% CI = 1.03 to 4.41) and 1.64 (95% CI = 0.76 to 3.54) in the highest quartiles of cumulative exposure to butadiene and styrene, respectively, and exposure-response trends were positive for both monomers (butadiene, trend p = 0.001; styrene, trend p = 0.004). Further analyses indicated that the exposure-response effect of each monomer on bladder cancer was demonstrated clearly only in the subgroup with high cumulative exposure (at or above the median) to the other monomer. Lung cancer was not associated with either monomer among men. Among women, lung cancer RRs were above 1.0 in each quartile of cumulative exposure to each monomer, but exposure-response was not seen for either monomer. Male workers had COPD RRs slightly above 1.0 in each quartile of cumulative exposure to each monomer, but there was no evidence of exposure-response among the exposed. Monomer exposure was not consistently associated with COPD in women or with the other cancer outcomes. CONCLUSIONS: - This study found a positive exposure-response relationship between monomer exposures and bladder cancer. The independent effects of butadiene and styrene on this cancer could not be delineated. In some analyses, monomer exposure was associated with lung cancer in women and with COPD in men, but inconsistent exposure-response trends and divergent results by sex do not support a causal interpretation of the isolated positive associations.


Assuntos
Butadienos/toxicidade , Carcinógenos/toxicidade , Elastômeros , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Estireno/toxicidade , Idoso , Canadá , Indústria Química/estatística & dados numéricos , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/mortalidade , Modelos de Riscos Proporcionais , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/mortalidade , Fatores Sexuais , Estados Unidos , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/mortalidade
8.
Front Cell Infect Microbiol ; 11: 688007, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34164347

RESUMO

Environmental transmission of viruses to humans has become an early warning for potential epidemic outbreaks, such as SARS-CoV-2 and influenza virus outbreaks. Recently, an H7N9 virus, A/environment/Hebei/621/2019 (H7N9), was isolated by environmental swabs from a live poultry market in Hebei, China. We found that this isolate could be transmitted by direct contact and aerosol in mammals. More importantly, after 5 passages in mice, the virus acquired two adaptive mutations, PB1-H115Q and B2-E627K, exhibiting increased virulence and aerosol transmissibility. These results suggest that this H7N9 virus might potentially be transmitted between humans through environmental or airborne routes.


Assuntos
Exposição Ambiental , Subtipo H7N9 do Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , China/epidemiologia , Humanos , Influenza Aviária/epidemiologia , Influenza Humana/epidemiologia , Camundongos , Aves Domésticas/virologia
9.
Occup Environ Med ; 78(12): 859-868, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34108254

RESUMO

OBJECTIVE: To evaluate exposure-response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers. METHODS: Employees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure-response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin's lymphoma (NHL), multiple myeloma and all B-cell malignancies. RESULTS: Among 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure-response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure-response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma. CONCLUSIONS: We confirmed a positive exposure-response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

10.
Eur J Pharmacol ; 906: 174173, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34033814

RESUMO

According to numerous epidemiological studies, aspirin is a non-steroidal anti-inflammatory drug (NSAID) that reduces the occurrence and mortality of colorectal cancer (CRC). However, the underlying mechanisms are not well identified. In an effort to fill these gaps, we administered aspirin on mice one day before induction in an azoxymethane (AOM)/dextran sulfate sodium (DSS) induced CRC model. In this study, we assessed the effects of aspirin on tumorigenesis and tumor cell proliferation. Multi-layer analyses were carried out to identify changes in cytokines, metabolites, level of gene expressions, and proteins associated with tumorigenesis and aspirin treatment. The results showed that aspirin-treated mice developed fewer colon tumors in response to AOM/DSS, and aspirin can actively block cyclooxygenase (COX) metabolism and reduce levels of pro-inflammatory cytokines. In addition, the transcriptomic and proteomic analyses both indicated that aspirin has an inhibitory effect on the Wnt pathway. The in vitro results further indicated that aspirin inhibits WNT6 production, possibly by suppressing its transcription factor NR4A2, which in turn is regulated by prostaglandin E2, thereby ultimately inhibiting the Wnt pathway. These findings improve our understanding of the mechanisms behind aspirin's chemoprevention effect on CRC.

11.
Cell Rep ; 35(3): 109025, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33882315

RESUMO

Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we show that SLC22A14 is a riboflavin transporter localized at the inner mitochondrial membrane of the spermatozoa mid-piece and show by genetic, biochemical, multi-omic, and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we find that fatty acid ß-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from the TCA cycle (the citric acid cycle) but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrate that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wild-type mice treated with a riboflavin-deficient diet mimics those in Slc22a14 knockout mice, confirming that an altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for the development of male contraceptives.

12.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895786

RESUMO

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Simulação por Computador , Reposicionamento de Medicamentos , Modelos Biológicos , SARS-CoV-2/metabolismo , Humanos
13.
Am J Cardiol ; 148: 84-93, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667443

RESUMO

Given the role of comorbid conditions in the pathophysiology of HFpEF, we aimed to identify and rank the importance of comorbid conditions associated with post-hospitalization outcomes of older adults hospitalized for HFpEF. We examined data from 4,605 Medicare beneficiaries hospitalized in 2007-2014 for HFpEF based on ICD-9-CM codes for acute diastolic heart failure (428.31 or 428.33). To identify characteristics with high importance for prediction of mortality, all-cause rehospitalization, rehospitalization for heart failure, and composite outcome of mortality or all-cause rehospitalization up to 1 year, we developed boosted decision tree ensembles for each outcome, separately. For interpretability, we estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox proportional hazards models. Age and frailty were the most important characteristics for prediction of mortality. Frailty was the most important characteristic for prediction of rehospitalization, rehospitalization for heart failure, and the composite outcome of mortality or all-cause rehospitalization. In Cox proportional hazards models, a 1-SD higher frailty score (0.1 on theoretical range of 0 to 1) was associated with a HR of 1.27 (1.06 to 1.52) for mortality, 1.16 (1.07 to 1.25) for all-cause rehospitalization, 1.24 (1.14 to 1.35) for HF rehospitalization, and 1.15 (1.07 to 1.25) for the composite outcome of mortality or all-cause rehospitalization. In conclusion, frailty is an important predictor of mortality and rehospitalization in adults aged ≥66 years with HFpEF.


Assuntos
Fragilidade/epidemiologia , Insuficiência Cardíaca/epidemiologia , Mortalidade , Readmissão do Paciente/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Árvores de Decisões , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Medicare , Modelos de Riscos Proporcionais , Volume Sistólico , Estados Unidos/epidemiologia
14.
Biomaterials ; 271: 120713, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33618219

RESUMO

A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell production. Here we described a simplified and chemically defined medium (AATS) for endothelial cells (ECs) and smooth muscle cells (SMCs) differentiation. AATS medium does not contain insulin, enabling the rapid and highly efficient vascular mesoderm formation through accelerating metabolic and autophagy-enhanced mesoderm induction. Transcriptome profiling confirmed that hPSC-derived ECs and SMCs in the AATS medium closely resembled primary ECs and SMCs formed in vivo. ECs appeared to adhere and grow better in the AATS medium over other cell types, which allowed the purification of CD31+CD144+ double-positive cells. Furthermore, the AATS medium was compatible with 3D microscaffold (MS) culture, which may facilitate large-scale bioproduction of ECs. HPSC-derived ECs and SMCs in the AATS medium exhibited strong revascularization potential in treating murine ischemic models. Our study provided a cost-effective and efficient medium system to manufacture GMP compatible, off-the-shelf ECs, and SMCs to model human diseases and vascular repair.


Assuntos
Células Endoteliais , Células-Tronco Pluripotentes , Animais , Diferenciação Celular , Humanos , Camundongos , Músculo Liso , Miócitos de Músculo Liso
15.
J Int Neuropsychol Soc ; 27(10): 1048-1057, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33563358

RESUMO

OBJECTIVES: It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults. METHODS: Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes. RESULTS: There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV. CONCLUSION: Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.


Assuntos
LDL-Colesterol/sangue , Cognição , Adolescente , Adulto , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Teste de Stroop , Adulto Jovem
16.
J Int Med Res ; 49(1): 300060520982832, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33472481

RESUMO

OBJECTIVE: Influenza season occurs every year in China, but its presentation was unusual in the period from December 2017 to early 2018. During this period, influenza activity was increasing across the country and was much greater than during the same period in previous years, with great harm to people's health. METHODS: In this study, we isolated two human influenza virus strains-A/Hebei/F076/2018(H1N1) and B/Hebei/16275B/2018-from patients with severe influenza in Hebei, China, during the flu season in January 2018, and explored their genetic characteristics, pathogenicity, and transmissibility. RESULTS: A/Hebei/F076/2018(H1N1) belongs to the human-like H1N1 influenza virus lineage, whereas B/Hebei/16275B/2018 belongs to the Victoria lineage and is closely related to the World Health Organization reference strain B/Brisbane/60/2008. Pathogenicity tests revealed that A/Hebei/F076/2018(H1N1) replicated much more strongly in mice, with mice exhibiting 40% mortality, whereas B/Hebei/16275B/2018 was not lethal. Both viruses could be transmitted through direct contact and by the aerosol route between guinea pigs, but the H1N1 strain exhibited higher airborne transmissibility. CONCLUSIONS: These results may contribute to the monitoring of influenza mutation and the prevention of an influenza outbreak.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Animais , China , Cobaias , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/epidemiologia , Camundongos , Virulência
17.
J Am Coll Cardiol ; 76(15): 1751-1760, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33032737

RESUMO

BACKGROUND: Women have lower age-specific rates of incident coronary heart disease (CHD) than men. It is unclear whether women remain at lower risk for CHD events versus men following a myocardial infarction (MI). OBJECTIVES: This study assessed sex differences in recurrent MI, recurrent CHD events, and mortality among patients with MI and compared these associations with sex differences in a control group without a history of CHD. METHODS: This study analyzed data for 171,897 women and 167,993 men age 21 years or older with health insurance in the United States who had a MI hospitalization in 2015 or 2016. Patients with a MI were frequency matched by age and calendar year to 687,588 women and 671,972 men without CHD. Beneficiaries were followed until December 2017 for MI, CHD (i.e., MI or coronary revascularization), and in Medicare for all-cause mortality. RESULTS: Age-standardized rates of MI per 1,000 person-years were 4.5 in women and 5.7 in men without CHD (hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.62 to 0.67) and 60.2 in women and 59.8 in men with MI (HR: 0.94; 95% CI: 0.92 to 0.96). CHD rates in women versus men were 6.3 versus 10.7 among those without CHD (HR: 0.53; 95% CI: 0.51 to 0.54) and 84.5 versus 99.3 among those with MI (HR: 0.87; 95% CI: 0.85 to 0.89). All-cause mortality rates in women versus men were 63.7 versus 59.0 among those without CHD (HR: 0.72; 95% CI: 0.71 to 0.73) and 311.6 versus 284.5 among those with MI (HR: 0.90; 95% CI: 0.89 to 0.92). CONCLUSIONS: The lower risk for MI, CHD, and all-cause mortality in women versus men is considerably attenuated following a MI.


Assuntos
Doença das Coronárias/epidemiologia , Hospitalização/estatística & dados numéricos , Cobertura Universal do Seguro de Saúde/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte/tendências , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Distribuição por Sexo , Fatores Sexuais , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia , Adulto Jovem
18.
Circ Heart Fail ; 13(11): e006977, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33045844

RESUMO

BACKGROUND: Despite potential harm that can result from polypharmacy, real-world data on polypharmacy in the setting of heart failure (HF) are limited. We sought to address this knowledge gap by studying older adults hospitalized for HF derived from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). METHODS: We examined 558 older adults aged ≥65 years with adjudicated HF hospitalizations from 380 hospitals across the United States. We collected and examined data from the REGARDS baseline assessment, medical charts from HF-adjudicated hospitalizations, the American Hospital Association annual survey database, and Medicare's Hospital Compare website. We counted the number of medications taken at hospital admission and discharge; and classified each medication as HF-related, non-HF cardiovascular-related, or noncardiovascular-related. RESULTS: The vast majority of participants (84% at admission and 95% at discharge) took ≥5 medications; and 42% at admission and 55% at discharge took ≥10 medications. The prevalence of taking ≥10 medications (polypharmacy) increased over the study period. As the number of total medications increased, the number of noncardiovascular medications increased more rapidly than the number of HF-related or non-HF cardiovascular medications. CONCLUSIONS: Defining polypharmacy as taking ≥10 medications might be more ideal in the HF population as most patients already take ≥5 medications. Polypharmacy is common both at admission and hospital discharge, and its prevalence is rising over time. The majority of medications taken by older adults with HF are noncardiovascular medications. There is a need to develop strategies that can mitigate the negative effects of polypharmacy among older adults with HF.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/tendências , Polimedicação , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Fármacos Cardiovasculares/efeitos adversos , Comorbidade , Prescrições de Medicamentos , Quimioterapia Combinada , Uso de Medicamentos/tendências , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Padrões de Prática Médica/tendências , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
19.
Cancer Cell ; 38(4): 551-566.e11, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32860752

RESUMO

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Proteínas Serina-Treonina Quinases/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Células Jurkat , Células K562 , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/imunologia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Vet Microbiol ; 246: 108742, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32605747

RESUMO

Porcine epidemic diarrhea virus (PEDV) causes severe clinical diarrhea in neonatal piglets, with reported mortality rates between 70-100%. The humoral immunity, especially the local intestinal IgA responses, plays an important role in the immune protection against PEDV infection. In this study, we evaluated the isotype antibody responses against the PEDV nucleocapsid (N) protein and the spike (S) protein subunits 1 (S1) and 2 (S2) in the serum and intestine of piglets. We also determined its serum neutralizing activity against the PEDV field strain HBMC2012 in 21-day-old piglets. Enzyme-linked immunosorbent assays (ELISA) revealed that the production of IgM against the N protein and S1 subunit was higher compared to the S2 subunit. The anti-S2 IgA antibodies were higher than the anti-N protein and anti-S1 IgA at 3 days post-infection (dpi). The specific IgA responses to the S2 subunit were higher than the responses observed in S1. The specific IgG responses against S1 and S2 subunits exceeded those of N protein. The serum neutralizing activities against PEDV were relatively low with a tendency to decline over time. No isotype-specific antibodies were found in the intestinal contents from infected pigs, except the one with weak IgA responses against N protein at 28 dpi. Immunohistochemical staining showed that a few IgM, IgA, and IgG antibody-secreting cells were mainly located in the mucosa of the duodenum and ileum of PEDV-infected pigs at 3 dpi. This study suggests poor systemic and intestinal isotype-specific antibody responses, especially those of IgA, and weak serum neutralizing activities against the field PEDV strain in piglets.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Coronavirus/veterinária , Imunidade Humoral , Vírus da Diarreia Epidêmica Suína/imunologia , Doenças dos Suínos/imunologia , Animais , Anticorpos Neutralizantes/sangue , Infecções por Coronavirus/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Intestinos/imunologia , Intestinos/virologia , Vírus da Diarreia Epidêmica Suína/genética , Suínos/imunologia , Suínos/virologia , Doenças dos Suínos/virologia , Eliminação de Partículas Virais
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