Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 168
Filtrar
1.
Cerebrovasc Dis ; : 1-8, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434100

RESUMO

BACKGROUND AND OBJECTIVES: This paper aims to describe and compare the characteristics of 2 stroke populations in Singapore and in St. Louis, USA, and to document thrombolysis rates and contrast factors associated with its uptake in both populations. METHODS: The stroke populations described were from the Singapore Stroke Registry (SSR) in -Singapore and the Cognitive Rehabilitation Research Group Stroke Registry (CRRGSR) in St. Louis, MO, USA. The registries were compared in terms of demographics and stroke risk factor history. Logistic regression was used to determine factors associated with thrombolysis uptake. RESULTS: A total of 39,323 and 8,106 episodes were recorded in SSR and CRRGSR, respectively, from 2005 to 2012. Compared to CRRGSR, patients in SSR were older, male, and from the ethnic majority. Thrombolysis rates in SSR and CRRGSR were 2.5 and 8.2%, respectively, for the study period. History of ischemic heart disease or atrial fibrillation was associated with increased uptake in both populations, while history of stroke was associated with lower uptake. For SSR, younger age and males were associated with increased uptake, while having a history of smoking or diabetes was associated with decreased uptake. For CRRGSR, ethnic minority status was associated with decreased uptake. CONCLUSIONS: The comparison of stroke populations in Singapore and St Louis revealed distinct differences in clinicodemographics of the 2 groups. Thrombolysis uptake was driven by nonethnicity demographics in Singapore. Ethnicity was the only demographic driver of uptake in the CRRGSR population, highlighting the need to target ethnic minorities in increasing access to thrombolysis.

2.
Neurology ; 93(9): e851-e863, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31366724

RESUMO

OBJECTIVE: To validate the Genot-PA score, a clinical-genetic logistic regression score that stratifies the thrombolytic therapy safety, in a new cohort of patients with stroke. METHODS: We enrolled 1,482 recombinant tissue plasminogen activator (rtPA)-treated patients with stroke in Spain and Finland from 2003 to 2016. Cohorts were analyzed on the basis of ethnicity and therapy: Spanish patients treated with IV rtPA within 4.5 hours of onset (cohort A and B) or rtPA in combination with mechanical thrombectomy within 6 hours of onset (cohort C) and Finnish participants treated with IV rtPA within 4.5 hours of onset (cohort D). The Genot-PA score was calculated, and hemorrhagic transformation (HT) and parenchymal hematoma (PH) risks were determined for each score stratum. RESULTS: Genot-PA score was tested in 1,324 (cohort A, n = 726; B, n = 334; C, n = 54; and D, n = 210) patients who had enough information to complete the score. Of these, 213 (16.1%) participants developed HT and 85 (6.4%) developed PH. In cohorts A, B, and D, HT occurrence was predicted by the score (p = 2.02 × 10-6, p = 0.023, p = 0.033); PH prediction was associated in cohorts A through C (p = 0.012, p = 0.034, p = 5.32 × 10-4). Increased frequency of PH events from the lowest to the highest risk group was found (cohort A 4%-15.7%, cohort B 1.5%-18.2%, cohort C 0%-100%). The best odds ratio for PH prediction in the highest-risk group was obtained in cohort A (odds ratio 5.16, 95% confidence interval 1.46-18.08, p = 0.009). CONCLUSION: The Genot-PA score predicts HT in patients with stroke treated with IV rtPA. Moreover, in an exploratory study, the score was associated with PH risk in mechanical thrombectomy-treated patients.

3.
Pediatr Blood Cancer ; 66(10): e27899, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31267645

RESUMO

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, χ2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.

4.
Circ Genom Precis Med ; 12(7): e002338, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31306060

RESUMO

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

5.
Stroke ; 50(6): 1339-1345, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31084338

RESUMO

Background and Purpose- The genetic relationships between stroke risk, stroke severity, and early neurological changes are complex and not completely understood. Genetic studies have identified 32 all stroke risk loci. Polygenic risk scores can be used to compare the genetic architecture of related traits. In this study, we compare the genetic architecture of stroke risk, stroke severity, and early neurological changes with that of 2 stroke risk factors: type 2 diabetes mellitus (T2DM) and hypertension. Methods- We assessed the degree of overlap in the genetic architecture of stroke risk, T2DM, hypertension, and 2 acute stroke phenotypes based on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 for no stroke symptoms to 21 to 42 for a severe stroke: baseline (within 6 hours after onset) and change in NIHSS (ΔNIHSS=NIHSS at baseline-NIHSS at 24 hours). This was done by (1) single-nucleotide polymorphism by single-nucleotide polymorphism comparison, (2) weighted polygenic risk scores with sentinel variants, and (3) whole-genome polygenic risk scores using multiple P thresholds. Results- We found evidence of genetic architecture overlap between stroke risk and T2DM ( P=2.53×10-169), hypertension ( P=3.93×10-04), and baseline NIHSS ( P=0.03). However, there was no evidence of overlap between ΔNIHSS and stroke risk, T2DM, or hypertension. Conclusions- The genetic architecture of stroke risk is correlated with that of T2DM, hypertension, and initial stroke severity (NIHSS within 6 hours of stroke onset). However, the genetic architecture of early neurological change after stroke (ΔNIHSS) is not correlated with that of ischemic stroke risk, T2DM, or hypertension. Thus, stroke risk and early neurological change after stroke have distinct genetic architectures.

6.
Lancet Neurol ; 18(5): 421-422, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981316
7.
Trials ; 20(1): 217, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987667

RESUMO

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is frequent in Asian countries including Korea. The quality of life can be degraded by the symptoms of CHHF. In particular, gynecological disorders such as menstrual pain, infertility, leucorrhea, and irregular bleeding may be related to CHHF. Sipjeondaebo-tang (SDT) is widely used in the treatment of various diseases including CHHF by balancing Yin and Yang, restoring the deterioration of physiological function, and improving immunity. However, the efficacy of SDT in the treatment of CHHF has not been assessed in clinical trials. Therefore, we aimed to investigate the feasibility of a full randomized clinical trial of SDT for the treatment of CHHF in Korean women through this trial. METHODS: This study will be a pilot, randomized, double-blind, two-arm, placebo-controlled, parallel-group, multicenter clinical trial. Women aged 19-59 years who present with CHHF will be recruited from five university hospitals. A total of 60 subjects will be randomly assigned to a treatment group (SDT) or a placebo group at a 1:1 ratio. The subjects will receive 3 g of either SDT or placebo three times daily for 8 weeks. The primary outcome measures will be the Visual Analogue Scale scores of CHHF. The secondary outcome measures will be changes in body temperature in both the hands and the feet as measured using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version. DISCUSSION: This will be the first trial to investigate the efficacy and safety of SDT in the treatment of CHHF. This study will provide basic clinical information regarding Korean herbal medicine treatment of CHHF and a clinical basis for designing a full randomized clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374345 . Registered on 15 February 2018.


Assuntos
Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde) , Projetos Piloto , Tamanho da Amostra , Adulto Jovem
8.
Nat Commun ; 10(1): 1206, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30872570

RESUMO

Arriving rapidly to the hospital after a heart attack or stroke is critical for patients to be within time windows for treatment. Prior research in heart attacks has suggested a paradoxical role of the social environment: those who arrive early are surrounded by nonrelatives, while those who arrive late are surrounded by spouses or family members. Here, we used network methods to more deeply examine the influence of social context in stroke. We examined the relationship of personal social networks and arrival time in 175 stroke patients. Our results confirmed the paradox by showing that small and close-knit personal networks of highly familiar contacts, independent of demographic, clinical, and socioeconomic factors, were related to delay. The closed network structure led to constricted information flow in which patients and close confidants, absent outside perspectives, elected to watch-and-wait. Targeting patients with small, close-knit networks may be one strategy to improve response times.


Assuntos
Tomada de Decisões , Emergências/psicologia , Rede Social , Acidente Vascular Cerebral/terapia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Socioeconômicos , Fatores de Tempo
9.
Blood ; 133(22): 2436-2444, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30858231

RESUMO

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

10.
Exp Brain Res ; 237(6): 1493-1502, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30915491

RESUMO

Remote limb ischemic conditioning (RLIC) is a technique in which tissues distant from the target organ are exposed to brief, sub-lethal bouts of ischemia. The effects of remotely applied ischemic conditioning are systemically transferred to the target organ, and typically manifested as protection from subsequent ischemic injury. Previous studies in our lab have found and confirmed that RLIC enhances learning and retention during motor training on a balance task. The current study tested the effect of RLIC dose (number of cycles) on learning enhancement in young, healthy adults. Forty healthy participants age 18-40 years were randomized to receive 5 cycles of sham conditioning (n = 9), 3 cycles of RLIC (n = 11), 4 cycles of RLIC (n = 10), or 5 cycles of RLIC (n = 10) using a blood pressure cuff around the upper arm once a day for 7 consecutive weekdays (Days 1-7). Participants concurrently trained on a balance task, bimanual cup stacking task, and a discrete sequence production task on Days 3-7. Change in performance on each of the three tasks was compared across groups. Participants in all four groups improved their performance on each of the three tasks over time. However, RLIC at any dose did not enhance learning on any of the three tasks. While RLIC is safe, inexpensive, and clinically feasible, reproducibility may be challenged by unidentified factors, raising critical challenges to the straightforward translation of RLIC for improving rehabilitation outcomes in individuals recovering from neurological injury.

11.
Neurology ; 92(12): e1271-e1283, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30796134

RESUMO

OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8. RESULTS: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). CONCLUSIONS: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

12.
Medicine (Baltimore) ; 98(5): e14170, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702569

RESUMO

BACKGROUND: Primary dysmenorrhea is a condition characterized by painful menstrual cramps that usually occurs in the absence of any identifiable pathological condition among menstruating women, with the prevalence estimates varying between 45% and 95%. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered as a standard treatment for primary dysmenorrhea; however, the failure rate of NSAIDs is often 20% to 25% and these drugs commonly cause adverse effects. In this review, we investigated the current evidence related to the effectiveness of Xuefu Zhuyu decoction (XZD) or Hyeolbuchukeo-tang, a traditional herbal formula, as a treatment for primary dysmenorrhea. METHODS: Literature search was conducted about randomized controlled trials (RCTs) for XZD on primary dysmenorrhea. PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure Database, Oriental Medicine Advanced Searching Integrated System, and other Chinese, Korean, Japanese databases were searched up to December 20, 2017. Two independent reviewers extracted and assessed the data. The main outcome domains were visual analogue scale (VAS) score and response rate. RESULTS: Among 475 publications, 8 RCTs involving 1048 patients were finally included. Methodological quality of included RCTs was relatively low. In 4 add-on design studies, XZD plus western medication (WM) group showed better response rate as compared to the WM sole therapy (relative risk 1.18, 95% confidence interval [1.11, 1.25], P < .01). VAS score after the 3rd month of treatment in the XZD plus WM group was also lower than that in the WM group (mean difference -0.45, 95% confidence interval [-0.79, -0.12], P < .01). In 4 XZD versus WM design studies, XZD sole therapy showed better response rate than did WM sole therapy (relative risk 1.26, 95% confidence interval [1.06, 1.49], P < .01). CONCLUSION: The existing trials showed a favorable effect of XZD for the management of primary dysmenorrhea. However, the efficacy of XZD on primary dysmenorrhea is not conclusive owing to the small number of studies and the high risk of bias. Large-scale, long-term RCTs with rigorous methodological input are needed to clarify the role of XZD for the management of primary dysmenorrhea. TRIAL REGISTRATION NUMBER: CRD42016050447 in PROSPERO 2016.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Dismenorreia/terapia , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Pacing Clin Electrophysiol ; 42(3): 341-348, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30620091

RESUMO

BACKGROUND: Cardiovascular implantable electronic device (CIED) leads are a nidus for right atrial thrombi. Right-to-left thromboembolism across a patent foramen ovale (PFO) is a putative mechanism for ischemic stroke and PFO has been associated with stroke. We used a novel unbiased case-only study design to assess the effect modification of PFO-associated ischemic stroke risk by presence of CIED. We hypothesized that presence of CIED, as a nidus for right atrial thrombus formation, magnifies the PFO-ischemic stroke relationship; therefore, among hospitalized ischemic stroke patients we would find a higher prevalence of CIED in patients with PFO. METHODS: We included consecutive first ischemic stroke patients admitted to our hospital from 2006 to 2015, who were enrolled in a prospectively maintained stroke registry. PFO was ascertained from documentation on echocardiography, and presence of CIED at time of stroke was determined from chest radiography reports at or prior to hospitalization. We measured distributions of CIED within PFO and control groups and used Fisher's exact test to evaluate the PFO-CIED association among ischemic stroke patients. RESULTS: We included 7089 patients (age: 64.5 ± 14.9 years, 51% female). Echocardiography diagnosed PFO in 760 (10.7%) patients and CIED was reported on chest radiography in 752 (10.6%) patients. Prevalence of CIED was lower in the PFO (61/760, 8.0%) compared to control group (691/6329, 10.9%), P = 0.015. CONCLUSION: Among admitted ischemic stroke patients, we did not find a higher prevalence of CIED in patients with PFO compared to controls. Therefore, in the underlying source population, the presence of CIED did not increase the PFO-associated ischemic stroke risk.

14.
Cell Rep ; 26(3): 594-607.e7, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650354

RESUMO

Alternative translation initiation and stop codon readthrough in a few well-studied cases have been shown to allow the same transcript to generate multiple protein variants. Because the brain shows a particularly abundant use of alternative splicing, we sought to study alternative translation in CNS cells. We show that alternative translation is widespread and regulated across brain transcripts. In neural cultures, we identify alternative initiation on hundreds of transcripts, confirm several N-terminal protein variants, and show the modulation of the phenomenon by KCl stimulation. We also detect readthrough in cultures and show differential levels of normal and readthrough versions of AQP4 in gliotic diseases. Finally, we couple translating ribosome affinity purification to ribosome footprinting (TRAP-RF) for cell-type-specific analysis of neuronal and astrocytic translational readthrough in the mouse brain. We demonstrate that this unappreciated mechanism generates numerous and diverse protein isoforms in a cell-type-specific manner in the brain.

15.
Stroke ; 50(2): 298-304, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30661490

RESUMO

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

16.
Circulation ; 139(2): 256-268, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30586705

RESUMO

BACKGROUND: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study. METHODS: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data. RESULTS: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls. CONCLUSIONS: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.

17.
Circ Res ; 124(1): 114-120, 2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30582445

RESUMO

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, ß=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

18.
Trials ; 19(1): 662, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497488

RESUMO

BACKGROUND: This study aims to evaluate the safety, efficacy, and feasibility of a full randomized clinical trial of Ojeok-san in Korean female patients with cold hypersensitivity in the hands and feet. METHODS: This study is a multicenter, double-blinded, randomized, placebo-controlled, two-arm, parallel-group pilot clinical trial. A total of 60 participants will be enrolled and randomly assigned to the Ojeok-san treatment group or the placebo control group, in a 1:1 ratio using an Internet-based randomization system. Each group will be administered Ojeok-san or placebo three times per day for 8 weeks. The primary outcome will be the mean change in the Visual Analog Scale scores of cold hypersensitivity in the hands from baseline to week 8. Secondary outcomes will include the mean changes in the skin temperature of the extremities, recovery rate of the skin temperature of hands after cold stress test, and the score of Korean version of the WHO Quality of Life Scale abbreviated version. DISCUSSION: The findings of this study should provide meaningful information for a further large-scale, randomized controlled trial to confirm the safety and efficacy of Ojeok-san on cold hypersensitivity in the hands and feet in female patients. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03083522 . Registered on 20 March 2017.

19.
Ann Neurol ; 2018 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-30450637

RESUMO

OBJECTIVE: Agonism of the protease activated receptor (PAR) 1 by activated protein C (APC) provides neuroprotection and vasculoprotection in experimental neuro-injury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurologic injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded, trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial RHAPSODY used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360 and 540µg/kg 3K3A-APC. After intravenous tissue plasminogen activator, intraarterial mechanical thrombectomy, or both, patients were randomized to one of the four doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017 we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest dose 3K3A-APC tested, 540µg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p=0.046), and total hemorrhage volume from an average of 2.1±5.8 mL in placebo to 0.8±2.1 mL in the combined treatment arms (p=0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540µg/kg for the PAR1 active cytoprotectant 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. This article is protected by copyright. All rights reserved.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA