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1.
Int J Stroke ; : 1747493019858780, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31237833

RESUMO

BACKGROUND: The benefits of aspirin for primary prevention of stroke are uncertain. METHODS: We performed a cumulative meta-analysis of trials investigating aspirin for primary prevention of cardiovascular disease with a focus on stroke. We assessed the effects of aspirin on non-fatal stroke, hemorrhagic stroke, non-fatal myocardial infarction, all-cause mortality, cardiovascular mortality, major gastrointestinal bleeding, and an analysis of net clinical effect, in populations without a history of clinical or subclinical cardiovascular disease. SUMMARY OF REVIEW RESULTS: Among 11 trials (157,054 participants), aspirin was not associated with a statistically significant reduction in non-fatal stroke (odds ratio, 0.94; 95% CI, 0.85 to 1.04) but was associated with an increased risk of hemorrhagic stroke (odds ratio, 1.29; 95% CI, 1.06 to 1.56). Aspirin was not associated with a statistically significant reduction in all-cause mortality (odds ratio, 0.97; 95% CI, 0.92 to 1.03) or cardiovascular mortality (odds ratio, 0.94; 95% CI, 0.85 to 1.03). Aspirin was associated with a reduction in non-fatal myocardial infarction (odds ratio, 0.80; 95% CI, 0.69 to 0.94) and an increased risk of major gastrointestinal bleeding (odds ratio, 1.83; 95% CI, 1.43 to 2.35). Using equal weighting for non-fatal events and major bleeding, we observed no net clinical benefit with aspirin use for primary prevention. CONCLUSION: Our meta-analysis reports no benefit of aspirin for primary stroke prevention.

3.
J Stroke Cerebrovasc Dis ; 28(6): 1703-1709, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878368

RESUMO

BACKGROUND: The association of lipid lowering therapy and intracerebral hemorrhage risk is controversial. METHODS: We performed a cumulative meta-analysis of lipid lowering trials that reported intracerebral hemorrhage. Statin, fibrate, ezetimibe, PCSK9, and CETP trials were included. We explored whether the association of lipid lowering therapy and risk of intracerebral hemorrhage may vary by baseline low-density lipoprotein (LDL) level, mean change in LDL or baseline cardiovascular risk of population. RESULTS: Among 39 trials (287,651 participants), lipid lowering therapy was not associated with a statistically significant increased risk of intracerebral hemorrhage (ICH) in primary and secondary prevention trials combined (odds ratio [OR], 1.12; 95% confidence interval [CI], .98-1.28). Lipid lowering was associated with an increased risk of ICH in secondary prevention trials (OR, 1.18; 95% CI, 1.00-1.38), but not in primary prevention trials (OR, 1.01; 95% CI, .78-1.30), but the test for interaction was not significant (P for interaction = .31). Meta-regression of baseline LDL or difference in LDL reduction between active and control did not explain significant heterogeneity between studies for ICH risk. Of 1000 individuals treated for 1 year for secondary prevention, we estimated 9.17 (95% CI, 5.78-12.66) fewer ischemic strokes and .48 (95% CI, .06-1.02) more ICH, and a net reduction of 8.69 in all stroke per 1000 person-years. CONCLUSIONS: The benefits of lipid lowering therapy in prevention of ischemic stroke greatly exceed the risk of ICH. Concern about ICH should not discourage stroke clinicians from prescribing lipid lowering therapy for secondary prevention of ischemic stroke.


Assuntos
Isquemia Encefálica/prevenção & controle , Hemorragia Cerebral/induzido quimicamente , Dislipidemias/tratamento farmacológico , Hipolipemiantes/efeitos adversos , Lipoproteínas LDL/sangue , Acidente Vascular Cerebral/prevenção & controle , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/epidemiologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Humanos , Prevenção Primária/métodos , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Prevenção Secundária/métodos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento
4.
Molecules ; 23(7)2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021979

RESUMO

The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step.


Assuntos
Materiais Biomiméticos/química , Materiais Biomiméticos/síntese química , Descoberta de Drogas , Ozônio/química , Peptídeos/química , Peptídeos/síntese química
5.
Lancet ; 391(10134): 2019-2027, 2018 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-29864018

RESUMO

BACKGROUND: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels. METHODS: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month. FINDINGS: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p<0·0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1·29; 95% CI 1·14-1·44; all p<0·0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1·39; 1·12-1·72) irrespective of other patient and service characteristics. INTERPRETATION: Evidence-based treatments, diagnostics, and stroke units were less commonly available or used in low and middle-income countries. Access to stroke units and appropriate use of antiplatelet treatment were associated with improved recovery. Improved care and facilities in low-income and middle-income countries are essential to improve outcomes. FUNDING: Chest, Heart and Stroke Scotland.


Assuntos
Padrões de Prática Médica , Acidente Vascular Cerebral/terapia , Idoso , Estudos de Casos e Controles , Países Desenvolvidos , Países em Desenvolvimento , Medicina Baseada em Evidências , Feminino , Acesso aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Pobreza , Inquéritos e Questionários , Análise de Sobrevida , Resultado do Tratamento
6.
N Engl J Med ; 378(23): 2191-2201, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29766772

RESUMO

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).


Assuntos
Aspirina/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Embolia Intracraniana/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Idoso , Aspirina/efeitos adversos , Isquemia Encefálica/prevenção & controle , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/efeitos adversos , Rivaroxabana/efeitos adversos , Prevenção Secundária/métodos , Acidente Vascular Cerebral/etiologia
7.
Am J Hypertens ; 30(3): 319-327, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28391289

RESUMO

BACKGROUND: Impaired sleep quality is common and associated with an increased risk of cardiovascular disease (CVD), thought to be mediated through adverse effects on established vascular risk factors, particularly hypertension. We determined if a web-delivered sleep intervention (sleep-hygiene education, stimulus control, and cognitive behavioral therapy) reduces blood pressure compared to vascular risk factor education (standard care) alone. METHODS: Phase II randomized, blinded, controlled trial of 134 participants without CVD with mild sleep impairment and blood pressure 130-160/<110 mm Hg. The primary outcome was the difference in the mean change in 24-hour ambulatory systolic blood pressure (SBP) over 8 weeks between intervention and control groups. Secondary outcomes included measures of sleep quality and psychosocial health, namely Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: Participants in the sleep intervention group showed significantly greater improvements in sleep quality, including ISI [difference in mean improvement 2.8; 95% confidence interval (CI), 1.3-4.4], PSQI (1.1; 95% CI, 0.1-2.2), sleep condition indicator (0.8; 95% CI, 0.2-1.4), and psychosocial health, including BDI (2.0; 95% CI, 0.3-3.7) and BAI (1.4; 95% CI, 0.02-2.8). The mean improvement in 24-hour ambulatory SBP did not differ between the sleep intervention (0.9 mm Hg) and control (0.8 mm Hg) arms, (difference in mean improvement 0.1; 95% CI, -3.4 to 3.2). CONCLUSION: A simple, low-cost, web-delivered sleep intervention is feasible and significantly improves sleep quality and measures of psychosocial health in individuals with mild sleep impairment but does not result in short-term improvements in blood pressure.


Assuntos
Hipertensão/terapia , Transtornos do Sono-Vigília/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/psicologia , Pressão Sanguínea , Depressão/psicologia , Feminino , Educação em Saúde , Nível de Saúde , Humanos , Hipertensão/psicologia , Internet , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Sono , Distúrbios do Início e da Manutenção do Sono/complicações , Transtornos do Sono-Vigília/psicologia , Resultado do Tratamento , Adulto Jovem
8.
Chem Biol Drug Des ; 90(5): 909-918, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28453915

RESUMO

Virtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented.


Assuntos
Aminoácidos/farmacologia , Projeto Auxiliado por Computador , Desenho de Drogas , Descoberta de Drogas/métodos , Peptidomiméticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Aminoácidos/química , Bases de Dados de Produtos Farmacêuticos , Esterificação , Humanos , Ligantes , Simulação de Acoplamento Molecular , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidomiméticos/química , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas/química , Software
9.
11.
Am Heart J ; 178: 145-50, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27502862

RESUMO

BACKGROUND: Clinical and subclinical (covert) stroke is a cause of cognitive loss and functional impairment. In the AVERROES trial, we performed serial brain magnetic resonance imaging (MRI) scans in a subgroup to explore the effect of apixaban, compared with aspirin, on clinical and covert brain infarction and on microbleeds in patients with atrial fibrillation. METHODS: We performed brain MRI (T1, T2, fluid-attenuated inversion recovery, and T2* gradient echo sequences) in 1,180 at baseline and in 931 participants at follow-up. Mean interval from baseline to follow-up MRI scans was 1.0 year. The primary outcome was a composite of clinical ischemic stroke and covert embolic pattern infarction (defined as infarction >1.5 cm, cortical-based infarction, or new multiterritory infarction). Secondary outcomes included new MRI-detected brain infarcts and microbleeds and change in white matter hyperintensities. RESULTS: Baseline MRI scans revealed brain infarct(s) in 26.2% and microbleed(s) in 10.5%. The rate of the primary outcomes was 2.0% in the apixaban group and 3.3% in the aspirin group (hazard ratio [HR] 0.55; 0.27-1.14) from baseline to follow-up MRI scan (mean duration of follow-up: 1 year). In those who completed baseline and follow-up MRI scans, the rate of new infarction detected on MRI was 2.5% in the apixaban group and 2.2% in the aspirin group (HR 1.09; 0.47-2.52), but new infarcts were smaller in the apixaban group (P = .03). There was no difference in proportion with new microbleeds on follow-up MRI (HR 0.92; 0.53-1.60) between treatment groups. CONCLUSIONS: Apixaban treatment was associated with a nonsignificant trend toward reduction in the composite of clinical ischemic stroke and covert embolic-pattern infarction and did not increase the number of microbleeds in patients with atrial fibrillation compared with aspirin.


Assuntos
Aspirina/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Infarto Encefálico/prevenção & controle , Hemorragia Cerebral/induzido quimicamente , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Idoso , Fibrilação Atrial/complicações , Encéfalo/diagnóstico por imagem , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/etiologia , Hemorragia Cerebral/diagnóstico por imagem , Embolia/etiologia , Embolia/prevenção & controle , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
12.
Stroke ; 47(9): 2197-202, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27507860

RESUMO

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. METHODS: Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. RESULTS: Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6-29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6-12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3-5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). CONCLUSIONS: This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF-associated stroke were typically elderly (>75 years old) and more often women.


Assuntos
Fibrilação Atrial/complicações , Isquemia Encefálica/epidemiologia , Embolia Intracraniana/epidemiologia , Ataque Isquêmico Transitório/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Fatores Etários , Idoso , Isquemia Encefálica/etiologia , Isquemia Encefálica/mortalidade , Eletrocardiografia , Feminino , Humanos , Incidência , Embolia Intracraniana/etiologia , Embolia Intracraniana/mortalidade , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/mortalidade , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores Sexuais , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Taxa de Sobrevida
13.
Lancet ; 388(10046): 761-75, 2016 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-27431356

RESUMO

BACKGROUND: Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. METHODS: We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. FINDINGS: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). INTERPRETATION: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.


Assuntos
Isquemia Encefálica/epidemiologia , Hemorragia Cerebral/epidemiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Comportamento de Redução do Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto , África/epidemiologia , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Ásia/epidemiologia , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Austrália/epidemiologia , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Estudos de Casos e Controles , Hemorragia Cerebral/sangue , Hemorragia Cerebral/complicações , China/epidemiologia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/prevenção & controle , Europa (Continente)/epidemiologia , Medicina Baseada em Evidências , Comportamento Alimentar , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Hipertensão/sangue , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Oriente Médio/epidemiologia , Atividade Motora , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Razão de Chances , Fatores de Risco , Autorrelato , Fumar/efeitos adversos , Fumar/epidemiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Relação Cintura-Quadril
14.
Int J Stroke ; 11(5): 526-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27256472

RESUMO

BACKGROUND: Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS). AIMS: We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions. METHODS: Consecutive patients hospitalized for ischemic stroke were retrospectively surveyed from 19 stroke research centers in 19 different countries to collect patients meeting criteria for ESUS. RESULTS: Of 2144 patients with recent ischemic stroke, 351 (16%, 95% CI 15% to 18%) met ESUS criteria, similar across global regions (range 16% to 21%), and an additional 308 (14%) patients had incomplete evaluation required for ESUS diagnosis. The mean age of ESUS patients (62 years; SD = 15) was significantly lower than the 1793 non-ESUS ischemic stroke patients (68 years, p ≤ 0.001). Excluding patients with atrial fibrillation (n = 590, mean age = 75 years), the mean age of the remaining 1203 non-ESUS ischemic stroke patients was 64 years (p = 0.02 vs. ESUS patients). Among ESUS patients, hypertension, diabetes, and prior stroke were present in 64%, 25%, and 17%, respectively. Median NIHSS score was 4 (interquartile range 2-8). At discharge, 90% of ESUS patients received antiplatelet therapy and 7% received anticoagulation. CONCLUSIONS: This cross-sectional global sample of patients with recent ischemic stroke shows that one-sixth met criteria for ESUS, with additional ESUS patients likely among those with incomplete diagnostic investigation. ESUS patients were relatively young with mild strokes. Antiplatelet therapy was the standard antithrombotic therapy for secondary stroke prevention in all global regions.


Assuntos
Isquemia Encefálica/epidemiologia , Embolia/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Estudos Transversais , Feminino , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco
15.
J Rheumatol ; 43(5): 855-60, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26980577

RESUMO

OBJECTIVE: To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF). METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to April 15, 2014. We included double-blind randomized controlled trials (RCT) of LEF versus placebo or active comparator agents in adults with RA. Studies with fewer than 50 subjects or shorter than 12 weeks were excluded. Two investigators independently searched both databases. All authors reviewed selected studies. We compared RR differences using the Mantel-Haenszel random-effects method to assess total respiratory adverse events, infectious respiratory adverse events, noninfectious respiratory adverse events, interstitial lung disease, and death. RESULTS: Our literature search returned 5673 results. A total of 8 studies, 4 with placebo comparators, met our inclusion criteria. There were 708 respiratory adverse events documented in 4579 participants. Six cases of pneumonitis occurred, all in the comparator group. Four pulmonary deaths were reported, none in the LEF group. LEF was not associated with an increased risk of total adverse respiratory events (RR 0.99, 95% CI 0.56-1.78) or infectious respiratory adverse events (RR 1.02, 95% CI 0.58-1.82). LEF was associated with a decreased risk of noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41-0.97). CONCLUSION: Our study found no evidence of increased respiratory adverse events in RCT of LEF treatment.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Imunossupressores/efeitos adversos , Isoxazóis/efeitos adversos , Pneumopatias/induzido quimicamente , Humanos , Imunossupressores/uso terapêutico , Isoxazóis/uso terapêutico , Leflunomida , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
16.
Molecules ; 21(3): 350, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26999079

RESUMO

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields.


Assuntos
Aminas/química , Ácidos Carboxílicos/química , Prolina/síntese química , Técnicas de Síntese em Fase Sólida , Aminoácidos Cíclicos/química , Prolina/química
17.
Stroke ; 47(3): 652-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26846866

RESUMO

BACKGROUND AND PURPOSE: A limitation when making early decisions on stroke management is the lack of rapid diagnostic and prognostic testing. Our study sought to identify peripheral blood RNA biomarkers associated with stroke. The secondary aims were to assess the discriminative capacity of RNA biomarkers for primary stroke type and stroke prognosis at 1-month. METHODS: Whole-blood gene expression profiling was conducted on the discovery cohort: 129 first-time stroke cases that had blood sampling within 5 days of symptom onset and 170 control participants with no history of stroke. RESULTS: Through multiple regression analysis, we determined that expression of the gene MCEMP1 had the strongest association with stroke of 11 181 genes tested. MCEMP1 increased by 2.4-fold in stroke when compared with controls (95% confidence interval, 2.0-2.8; P=8.2×10(-22)). In addition, expression was elevated in intracerebral hemorrhage when compared with ischemic stroke cases (P=3.9×10(-4)). MCEMP1 was also highest soon after symptom onset and had no association with stroke risk factors. Furthermore, MCEMP1 expression independently improved discrimination of 1-month outcome. Indeed, discrimination models for disability and mortality that included MCEMP1 expression, baseline modified Rankin Scale score, and primary stroke type improved discrimination when compared with a model without MCEMP1 (disability Net Reclassification Index, 0.76; P=3.0×10(-6) and mortality Net Reclassification Index, 1.3; P=1.1×10(-9)). Significant associations with MCEMP1 were confirmed in an independent validation cohort of 28 stroke cases and 34 controls. CONCLUSIONS: This study demonstrates that peripheral blood expression of MCEMP1 may have utility for stroke diagnosis and as a prognostic biomarker of stroke outcome at 1-month.


Assuntos
Perfilação da Expressão Gênica/métodos , Internacionalidade , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Acidente Vascular Cerebral/diagnóstico
18.
Can J Cardiol ; 32(3): 319-26, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26454468

RESUMO

BACKGROUND: Although salt intake derived from data on urinary sodium excretion in free-living populations has been used in public policy, a population study on urinary sodium excretion has not been done in Canada. We assessed dietary sodium and potassium intake using a 24-hour urine collection in a large survey of urban and rural communities from 4 Canadian cities and determined the association of these electrolytes with blood pressure (BP). METHODS: One thousand seven hundred consecutive individuals, aged 37-72 years, attending their annual follow-up visits of the ongoing Prospective and Urban Rural Epidemiology (PURE) study in Vancouver, Hamilton, Ottawa, and Quebec City, Canada, collected a 24-hour urine sample using standardized procedures. RESULTS: Mean sodium excretion was 3325 mg/d and mean potassium excretion was 2935 mg/d. Sodium excretion ranged from 3093 mg/d in Vancouver to 3642 mg/d in Quebec City, after adjusting for covariates. Potassium excretion ranged from 2844 mg/d in Ottawa to 3082 mg/d in Quebec City. Both electrolytes were higher in men than in women and in rural populations than in urban settings (P < 0.001 for all). Sodium excretion was between 3000 and 6000 mg/d in 48.3% of the participants, < 3000 mg/d in 46.7%, and > 6000 mg/d in only 5%. No significant association between sodium or potassium excretion and BP was found. CONCLUSIONS: Sodium consumption in these Canadians is within a range comparable to other Western countries, and intake in most individuals is < 6000 mg/d, with only 5% at higher levels. Within this range, sodium or potassium levels were not associated with BP.


Assuntos
Hipertensão/epidemiologia , Avaliação Nutricional , Vigilância da População , Potássio na Dieta/administração & dosagem , Potássio/urina , Sódio na Dieta/administração & dosagem , Sódio/urina , Adulto , Idoso , Canadá/epidemiologia , Ritmo Circadiano , Feminino , Seguimentos , Humanos , Hipertensão/fisiopatologia , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Estudos Prospectivos , População Rural , População Urbana , Urinálise
19.
Am J Hypertens ; 29(7): 796-805, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26683344

RESUMO

BACKGROUND: Information on actual sodium intake and its relationships with blood pressure (BP) and clinical events in South America is limited. The aim of this cohort study was to assess the relationship of sodium intake with BP, cardiovascular (CV) events, and mortality in South America. METHODS: We studied 17,033 individuals, aged 35-70 years, from 4 South American countries (Argentina, Brazil, Chile, and Colombia). Measures of sodium excretion, estimated from morning fasting urine, were used as a surrogate for daily sodium intake. We measured BP and monitored the composite outcome of death and major CV events. RESULTS: Overall mean sodium excretion was 4.70±1.43g/day. A positive, nonuniform association between sodium and BP was detected, with a significant steeper slope for the relationship at higher sodium excretion levels (P < 0.001 for interaction). With a median follow-up of 4.7 years, the primary composite outcome (all-cause death, myocardial infarction, stroke, or heart failure) occurred in 568 participants (3.4%). Compared with sodium excretion of 5-6g/day (reference group), participants who excreted >7g/day had increased risks of the primary outcome (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.24 to 2.40; P < 0.001), as well as death from any cause (OR 1.87; 95% CI 1.23 to 2.83; P = 0.003) and major CV disease (OR 1.77; 95% CI 1.12 to 2.81; P = 0.014). Sodium excretion of <3g/day was associated with a statistically nonsignificant increased risk of the primary outcome (OR 1.20; 95% CI 0.86 to 1.65; P = 0.26) and death from any cause (OR 1.25; 95% CI 0.81 to 1.93; P = 0.29), and a significant increased risk of major CV disease (OR 1.50; 95% CI 1.01 to 2.24; P = 0.048), as compared to the reference group. CONCLUSIONS: Our results support a positive, nonuniform association between estimated urinary sodium excretion and BP, and a possible J-shaped pattern of association between sodium excretion over the entire range and clinical outcomes.


Assuntos
Pressão Sanguínea , Doenças Cardiovasculares/urina , Sódio/urina , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Sul/epidemiologia
20.
Lancet ; 388(1046): 761-775, 2016. tab
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-34758

RESUMO

Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifi able risk factors for stroke in diff erent regions of the world,and in key populations and primary pathological subtypes of stroke. Methods We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute fi rst stroke (within 5 days of symptom onset and72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke,and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks(PARs) were calculated, with 99% confi dence intervals...(AU)


Assuntos
Acidente Vascular Cerebral , Controle , Risco
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