2007年神经内科及神经科学进展专栏（征译稿）update May 24，200

Sumatriptan-Naproxen for Acute Treatment of Migraine
A Randomized Trial
英明格和奈普生对急性偏头痛的治疗

Jan Lewis Brandes, MD; David Kudrow, MD; Stuart R. Stark, MD; C. Phillip O’Carroll, MD; James U. Adelman, MD; Francis J. O’Donnell, DO; W. James Alexander, MD, MPH; Susan E. Spruill, MS; Pamela S. Barrett, PharmD; Shelly E. Lener, PharmD
作者等从略

JAMA. 2007;297:1443-1454.
美国医学协会杂志. 2007;297:1443-1454.

Context Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy.
背景：偏头痛症候群的产生涉及到多个致病机制，因而，多机制的有目的的治疗方案可能比单一的治疗方案更具优势。

Objective To evaluate the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine.
目的：评估联合应用英明格和奈普生，与单独应用英明格、单独应用奈普生、单独应用安慰剂相比，在治疗偏头痛时的功效和安全性。

Design, Setting, and Participants Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack.
设计、设定和参与者：双重、随机、双盲、单发、平行的组群研究，研究1包括1461人，研究2包括1495人，这些患者来自118个美国临床中心，均被诊断为偏头痛且在中、重度发作时都接受了研究性治疗。

Interventions Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain.
干涉：将患者群按1：1：1：1的比例随机分为4组，在中、重度偏头痛发作时，分别给予英明格85mg+奈普生500mg；英明格85mg（单一疗法）；奈普生500mg（单一疗法）；单独应用安慰剂。

Main Outcome Measures Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan–naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan–naproxen sodium and each monotherapy.
主要结果的衡量：最重要的结果衡量包括比较予英明格+奈普生和给予安慰剂这两种方式，在给药后2小时头痛缓解、畏光感消失、畏声感消失、恶心感消失上的百分比，以及比较英明格+奈普生、给予英明格单一疗法、给予奈普生单一疗法这三种方式，在持续的疼痛感消失上的百分比。

Results Sumatriptan–naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan–naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan–naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan–naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan–naproxen sodium and sumatriptan monotherapy.
结果：英明格+奈普生比安慰剂更为高效，如下：给药后2小时头痛缓解（研究1：65％对28％，P<.001；研究2：57％对29％，P<.001），畏光感消失（58％对26％，P<.001；50％对32％，P<.001），畏声感消失（61％对38％，P<.001；56％对34％，P<.001）。在研究1中，给药后2小时恶心感消失的百分比，联合用药要高于单独应用安慰剂（71％对65，P= .007），但在研究2中，两者没有明显的差异（65％对64％，P = .71）。在持续性的疼痛消失方面，英明格+奈普生（研究1：25％，研究2：23％，P<.01）要优于单一应用英明格（研究1：16％，研究2：14％），优于单一应用奈普生（研究1：10％，研究2：10％），由于单一应用安慰剂（研究1：8％，研究2：7％）。不良反应的发生率在应用英明格+奈普生疗法和单一应用英明格疗法上是相似的。

Conclusion Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.
结论：英明格85mg+奈普生500mg，作为一种的片剂治疗偏头痛要优于任何一种单独用药治疗（单用英明格或单用奈普生），并且具有更好的适应性及对不良反应的耐受性。

Stroke. 2007 Mar 29; [Epub ahead of print]
Atrial Fibrillation, Stroke, and Cognition. A Longitudinal Population-Based Study of People Aged 85 and Older.
题目：房颤，中风，与认知功能的关系。一项85岁以上老年人纵向人口调查为基础的研究。
Rastas S, Verkkoniemi A, Polvikoski T, Juva K, Niinisto L, Mattila K, Lansimies E, Pirttila T, Sulkava R.作者及单位从略

BACKGROUND AND PURPOSE: The aim of this study was to investigate the association between atrial fibrillation (AF), stroke, dementia, and their correlation with brain pathology in subjects aged 85 years or older.
背景与目的：本研究目的在于调查85岁以上老年人房颤，中风，与痴呆以及脑病理改变之间的关系。

METHODS: This is a prospective 9-year follow-up population based study in Vantaa, a town in Southern Finland; 553 subjects (92% of the total population) aged 85 years or older were clinically examined by a neurologist. The presence of AF was collected from the medical records or examined by ECG or ambulatory ECG. Neuropathological examination was conducted in more than half of the clinically examined subjects.
方法：这是一项前瞻性研究，在芬兰的南部万塔市进行了9年的人口跟踪调查；由神经专科医生对553名（占总人口的92%）85岁以上老年人进行了检查。通过收集病史、心电图检查或门诊心电图获得关于房颤的信息。对一半以上临床检查对象进行了神经病理检查。

RESULTS: AF was significantly associated with stroke at baseline; 32% of patients with AF had clinical evidence of stroke compared with 16.7% of those without such evidence (P<0.001). Dementia at baseline was significantly associated with age, clinical stroke, and the presence of apolipoprotein E epsilon4 allele, but not with sex, education, or vascular risk factors.
结果：在基线水平，房颤与中风显著相关；32%房颤患者存在中风的临床证据，无房颤对照组仅16.7%(P<0.001)；同时，痴呆与年龄、临床确诊中风及载脂蛋白E4等位基因显著相关，与性别、教育程度及血管病危险因素无关。

Multiple regression analysis including neuropathological results showed that dementia was significantly associated with education (OR, 0.89; 95% CI, 0.80 to 0.98; P=0.019), the beta-amyloid load in the brain (OR, 1.26; 95% CI, 1.13 to 1.39; P<0.001) and with the vascular pathology (OR, 2.03; 95% CI, 1.14 to 3.62; P=0.016), but not with sex, age at death, apolipoprotein E epsilon4 allele, or vascular risk factors. 包括神经病理损害在内的多元回归分析结果则显示，痴呆与教育水平(OR, 0.89; 95% CI, 0.80 to 0.98; P=0.019)、脑组织β淀粉样蛋白沉积(OR, 1.26; 95% CI, 1.13 to 1.39; P<0.001)、血管病理改变 (OR, 2.03; 95% CI, 1.14 to 3.62; P=0.016)显著相关，而与性别、死亡年龄、载脂蛋白E4等位基因或血管病危险因素无关。

CONCLUSIONS: AF is a significant and preventable risk factor for stroke but not for dementia in the very old. The etiology of dementia syndrome in the very old is multifactorial. Both Alzheimer disease pathology and vascular pathology, particularly multiple small infarcts, contribute to cognitive decline.

结论：在85岁以上高龄期，房颤是中风的可预防性重要危险因素，但与痴呆发生无关；而痴呆综合征的病因学则是多因素的，Alzheimer病、血管病，尤其是多发小梗死会导致认知功能下降。

(Stroke. 2007;38:1154.)

Incidence and Risk Factors for Stroke in Type 2 Diabetic Patients
The DAI Study
题目：2型糖尿病患者的卒中发病率和危险因素——DAI研究

Carlo Bruno Giorda, MD; Angelo Avogaro, MD; Marina Maggini, PhD; Flavia Lombardo, PhD; Edoardo Mannucci, MD; Salvatore Turco, MD; Stefania Spila Alegiani, PhD; Roberto Raschetti, PhD; Mario Velussi, MD; Ele Ferrannini, MD The DAI Study Group

From Metabolism and Diabetes Unit (C.B.G.), ASL 8, Regione Piemonte, Chieri, Italy; Division of Metabolic Diseases (A.A.), University of Padova, Italy; National Institute of Health (M.M., F.L., S.S.A., R.R.), Rome, Italy; University of Florence and Azienda Ospedaliera Careggi (E.M.), Florence, Italy; Federico II University (S.T.), Naples, Italy; Casa di Cura Pineta del Carso (M.V.), Aurisina, Trieste, Italy; University of Pisa School of Medicine (E.F.), Pisa, Italy.

Correspondence to Dr Carlo Bruno Giorda, Metabolism and Diabetes Unit, ASL 8, Via De Maria, 1 10023 Chieri (TO), Italy. E-mail giordaca@tin.it

Background and Purpose— Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations.
背景和目的：2型糖尿病是脑血管病的一种强烈预测因素，但仅有少数研究在未经选择的2型糖尿病人群中对卒中的发病率和其他危险因素的作用进行过评价。

Methods— We prospectively followed-up 14 432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables.
方法：我们对入组时有或无心血管病史的14432例年龄为40~97岁的2型糖尿病患者进行前瞻性随访，估算卒中的发病率和临床变量的风险比率。

Results— During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes.
结果：在4年随访期间，共记录到296次偶发性卒中事件。对于无心血管病史者，男性的年龄标化卒中发病率（每1000人-年）为5.5（95% CI 4.2~6.8），女性为6.3（95% CI 4.5~8.2）；对于有心血管病史者，男性和女性的年龄标化卒中发病率分别为13.7（95% CI 7.5~19.8）和10.8（95% CI 7.4~14.4）。卒中发病的风险比率随着年龄、性别和心血管病史而变化。在无心血管病史的男性中，HbA1c和吸烟是卒中的预测因素。在有心血管病史的患者中，男性的危险因素为胰岛素+口服降糖药治疗、高总胆固醇和低HDL胆固醇，而微血管并发症是女性的危险因素。对于男女两性而言，既往卒中病史都是卒中的一种强烈预测因素。

Conclusions— Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.
结论：年龄和既往卒中病史是糖尿病患者发生卒中的主要预测因素。HbA1c、微血管并发症、低HDL胆固醇以及胰岛素+口服降糖药治疗的联合作用强调了糖尿病史和临床背景在卒中发病中的重要性。

感谢斑竹给我第1分，我要再接再厉，在广大站友的关心和帮助下茁壮成长。
(Stroke. 2007;38:1257.)

CT Angiography "Spot Sign" Predicts Hematoma Expansion in Acute Intracerebral Hemorrhage
题目：CT血管造影“斑点征”预测急性脑出血血肿扩大

Ryan Wada, MD; Richard I. Aviv, MBChB; Allan J. Fox, MD; Demetrios J. Sahlas, MD; David J. Gladstone, MD; George Tomlinson, PhD Sean P. Symons, MD

From the Divisions of Neuroradiology (R.W., R.I.A., A.J.F., S.P.S.) and Neurology (D.J.S., D.J.G.) and the North and East GTA Regional Stroke Centre, Sunnybrook Health Sciences Centre, and the Department of Public Health Sciences (G.T.), University of Toronto, Toronto, Canada.

Correspondence to Dr R. Aviv, Diagnostic Imaging, Division of Neuroradiology, AG 31, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, M4N 3M5 Canada. E-mail richardaviv@lineone.net

Background and Purpose— Morbidity and mortality in spontaneous intracerebral hemorrhage (ICH) are correlated with hematoma progression. We hypothesized that the presence of tiny, enhancing foci ("spot sign") within acute hematomas is associated with hematoma expansion.
背景和目的：自发性脑出血（ICH）的残疾率和死亡率与血肿扩大有关。我们假设急性血肿内微小增强病灶的存在（“斑点征”）与血肿扩大有关。

Methods— We prospectively studied 39 consecutive patients with spontaneous ICH by computed tomography angiography within 3 hours of symptom onset. Scans were reviewed by 3 readers. Patients were dichotomized according to the presence or absence of the spot sign. Clinical and radiological outcomes were compared between groups. The predictive value of this sign was assessed in a multivariate analysis.
方法：我们应用计算机断层扫描血管造影术在发病3 h内对连续39例自发性ICH患者进行前瞻性研究。由3位阅片者对扫描结果进行评价，根据是否存在斑点征把患者分为两组，比较组间的临床和放射学结局。在多变量分析中对这一征象的预测价值进行评价。

Results— Thirteen patients (33%) demonstrated 31 enhancing foci. Baseline clinical variables were similar in both groups. Hematoma expansion occurred in 11 patients (28%) on follow-up. Seventy-seven percent of patients with and 4% without hematoma expansion demonstrated the spot sign (P<0.0001). Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio for expansion were 91%, 89%, 77%, 96%, and 8.5, respectively. Interobserver agreement was high (=0.92 to 0.94). In patients with the spot sign, mean volume change was greater (P=0.008), extravasation more common (P=0.0005), and median hospital stay longer (P=0.04), and fewer patients achieved a good outcome (modified Rankin Scale score <2), although the latter was not significant (P=0.16). No differences in hydrocephalus (P=1.00), surgical intervention (P=1.00), or death (P=0.60) were noted between groups. In multiple regression, the spot sign independently predicted hematoma expansion (P=0.0003).
结果：在13例患者（33%）中发现31处增强病灶。两组之间的基线临床变量相似。随访时在11例患者中观察到血肿扩大。在出现血肿扩大的患者中，77%存在斑点征；而在未出现血肿扩大的患者中，仅有4%存在斑点征（P<0.0001）。斑点征预测血肿扩大的敏感性、特异性、阳性预测值、阴性预测值和似然比分别为91%、89%、77%、96%和8.5。观察者之间的一致性很高（k=0.92~0.94）。存在斑点征的患者中，平均血肿体积改变更大(P=0.008)，外渗现象更常见(P=0.0005)，中位数住院时间更长(P=0.04)，获得良好结局（改良Rankin量表评分<2分）的患者更少，尽管后者没有统计学显著性(P=0.16)。未发现脑积水(P=1.00)、手术干预(P=1.00)或死亡(P=0.60)情况存在组间差异。在多变量回归分析中，斑点征能够独立预测血肿扩大(P=0.0003)。

Conclusions— The computed tomography angiography spot sign is associated with the presence and extent of hematoma progression. Fewer patients achieve a good clinical outcome and hospital stay was longer. Further studies are warranted to validate the ability of this sign to predict clinical outcomes.
结论：CT血管造影的斑点征与血肿扩大的存在和程度有关。当存在斑点征时，获得良好临床结局的患者更少，并且住院时间更长。有必要开展进一步研究来验证这一征象预测临床结局的能力。

Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK)

Prof Christopher S Gray MDa, , , Anthony J Hildreth MPhila, Peter A Sandercock DMb, Janice E O'Connell FRCPa, Donna E Johnstona, Niall EF Cartlidge FRCPa, John M Bamford MDc, Oliver F James FRCPa, K George MM Alberti MDa and for the GIST Trialists Collaboration‡

aSchool of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK
bUniversity of Edinburgh, Edinburgh, UK
cDepartment of Neurology, St James Hospital, Leeds, UK

Summary
Background
Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days.

Methods
Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6·0–17·0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4–7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803)

Findings
The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1·14, 95% CI 0·86–1·51, p=0·37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0·57 mmol/L, p<0·001; mean difference in blood pressure 9·0 mmHg, p<0·0001).

Interpretation
GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.

lancet neurology

Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study

Prof Ka Sing Wong FRCPa, , , Christopher Chen FRCPb, Ping Wing Ng FRCPc, Tak Hong Tsoi FRCPd, Ho Lun Li MRCPe, Wing Chi Fong MRCPf, Jonas Yeung FRCPg, Chi Keung Wong FRCPh, Kin Keung Yip MRCPi, Hong Gao MDj, Hwee Bee Wong MScj and for the FISS-tris Study Investigators‡

aDepartments of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
bDepartment of Neurology, Singapore General Hospital, Singapore
cDepartment of Medicine, United Christian Hospital, Hong Kong
dDepartment of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong
eDepartment of Medicine, Princess Margaret Hospital, Hong Kong
fDepartment of Medicine, Queen Elizabeth Hospital, Hong Kong
gDepartment of Medicine, Alice Ho Nethersole Hospital, Hong Kong
hDepartment of Medicine, North District Hospital, Hong Kong
iDepartment of Medicine, Ruttonjee Hospital, Hong Kong SAR, China
jClinical Trials and Epidemiology Research Unit, Singapore

Summary
Background
Acute stroke patients with large artery occlusive disease (LAOD) have a distinct pathophysiology and may respond differently to anticoagulation treatments. We compared the efficacy of a low-molecular-weight heparin (LMWH), nadroparin calcium, with aspirin in Asian acute stroke patients with LAOD.

Methods
Acute ischaemic stroke patients with onset of symptoms less than 48 h and LAOD (diagnosed by transcranial doppler imaging, carotid duplex scan, or magnetic resonance angiography) were recruited. Patients were randomly assigned to receive either subcutaneous nadroparin calcium 3800 anti-factor Xa IU/0·4 mL twice daily or oral aspirin 160 mg daily for 10 days, and then all received aspirin 80–300 mg once daily for 6 months. This study is registered at www.strokecenter.org/trials (number 493).

Findings
Among 603 patients recruited, 353 (180 LMWH, 173 aspirin) had LAOD (300 had intracranial LAOD only, 42 had both intracranial and extracranial disease, and 11 had extracranial disease only). The proportion of patients with good outcomes at 6 months (Barthel index ≥85) was 73% in the LMWH group and 69% in the aspirin group (absolute risk reduction 4%; 95% CI −5 to 13). Analysis of prespecified secondary outcome measures showed a benefit in outcome for LMWH versus aspirin on the modified Rankin scale dichotomised at 0–1 (odds ratio 1·55, 95% CI 1·02–2·35). Haemorrhagic transformation of infarct and severe adverse events were similar in both groups. Post-hoc analyses of patients without LAOD, and all treated patients, showed similar proportions with a good outcome in aspirin and LMWH groups (78% vs 79% and 73% vs 75%, respectively).

Interpretation
Overall, the results do not support a significant benefit of LMWH over aspirin in patients with LAOD. The benefits indicated in most outcome measures warrant further investigation into the use of anticoagulation for acute stroke in patients with large artery atherosclerosis, particularly in intracranial atherosclerosis.

lancet neurology

A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release

Mar Matarín PhDa, ‡, W Mark Brown MAh, ‡, Sonja Scholz MDg, ‡, Javier Simón-Sánchez BSa, d, ‡, Hon-Chung Fung MDc, e, f, ‡, Dena Hernandez MSa, J Raphael Gibbs BSb, g, Fabienne Wavrant De Vrieze PhDc, Cynthia Crewsc, Angela Britton MSa, Carl D Langefeld PhDh, Thomas G Brott MDi, Robert D Brown, Jr MDj, Bradford B Worrall MDk, Michael Frankel MDl, Scott Silliman MDm, L Douglas Case PhDh, Dr Andrew Singleton PhDa, , , John A Hardy PhDc, g, Stephen S Rich PhDh and James F Meschia MDi

aMolecular Genetics Unit, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
bComputational Biology Core, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
cLaboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
dUnitat de Genética Molecular, Departamento de Genómica y Proteómica, Instituto de Biomedicina de Valencia-CSIC, Valencia, Spain
eDepartment of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan
fReta Lila Weston Institute of Neurological Studies, University College London, London, UK
gDepartment of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK
hDivision of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
iDepartment of Neurology, Mayo Clinic, Jacksonville, FL, USA
jDepartment of Neurology, Mayo Clinic, Rochester, MN, USA
kDepartments of Neurology and Public Health Sciences, University of Virginia, VA, USA
lDepartment of Neurology, Emory University School of Medicine, GA, USA
mDepartment of Neurology, University of Florida College of Medicine, Jacksonville, FL, USA

Summary
Background
Despite evidence of a genetic role in stroke, the identification of common genetic risk factors for this devastating disorder remains problematic. We aimed to identify any common genetic variability exerting a moderate to large effect on risk of ischaemic stroke, and to generate publicly available genome-wide genotype data to facilitate others doing the same.

Methods
We applied a genome-wide high-density single-nucleotide-polymorphism (SNP) genotyping approach to a cohort of samples with and without ischaemic stroke (n=278 and 275, respectively), and did an association analysis adjusted for known confounders in a final cohort of 249 cases and 268 controls. More than 400 000 unique SNPs were assayed.

Findings
We produced more than 200 million genotypes in 553 unique participants. The raw genotypes of all the controls have been posted publicly in a previous study of Parkinson's disease. From this effort, results of genotype and allele association tests have been publicly posted for 88% of stroke patients who provided proper consent for public release. Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke.

Interpretation
The data generated here comprise the first phase of a genome-wide association analysis in patients with stroke. Release of phase I results generated in these publicly available samples from each consenting individual makes this dataset a valuable resource for data-mining and augmentation.

lancet neurology

Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study
低分子肝素与阿斯匹林在治疗亚洲人急性缺血性中风伴大动脉闭塞性疾病中的一项随机性对比研究
Prof Ka Sing Wong FRCPa, , , Christopher Chen FRCPb, Ping Wing Ng FRCPc, Tak Hong Tsoi FRCPd, Ho Lun Li MRCPe, Wing Chi Fong MRCPf, Jonas Yeung FRCPg, Chi Keung Wong FRCPh, Kin Keung Yip MRCPi, Hong Gao MDj, Hwee Bee Wong MScj and for the FISS-tris Study Investigators‡

aDepartments of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China
bDepartment of Neurology, Singapore General Hospital, Singapore
cDepartment of Medicine, United Christian Hospital, Hong Kong
dDepartment of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong
eDepartment of Medicine, Princess Margaret Hospital, Hong Kong
fDepartment of Medicine, Queen Elizabeth Hospital, Hong Kong
gDepartment of Medicine, Alice Ho Nethersole Hospital, Hong Kong
hDepartment of Medicine, North District Hospital, Hong Kong
iDepartment of Medicine, Ruttonjee Hospital, Hong Kong SAR, China
jClinical Trials and Epidemiology Research Unit, Singapore
作者及机构从略
Summary摘要
Background背景
Acute stroke patients with large artery occlusive disease (LAOD) have a distinct pathophysiology and may respond differently to anticoagulation treatments. We compared the efficacy of a low-molecular-weight heparin (LMWH), nadroparin calcium, with aspirin in Asian acute stroke patients with LAOD.
LAOD,即伴大动脉闭塞疾病的急性中风具有特殊的病理生理机制,因此对抗凝治疗可能存在不同反应.我们对亚洲LAOD患者进行了低分子肝素LMWH,那屈肝素钙与阿斯匹林疗效的对比研究.
Methods方法
Acute ischaemic stroke patients with onset of symptoms less than 48 h and LAOD (diagnosed by transcranial doppler imaging, carotid duplex scan, or magnetic resonance angiography) were recruited. Patients were randomly assigned to receive either subcutaneous nadroparin calcium 3800 anti-factor Xa IU/0·4 mL twice daily or oral aspirin 160 mg daily for 10 days, and then all received aspirin 80–300 mg once daily for 6 months. This study is registered at www.strokecenter.org/trials (number 493).
收集发病48h内急性中风和LAOD患者病例.通过经颅多普勒超声显像,颈动脉双重扫描,或磁共振动脉成像检查确定LAOD病例.病人被随机给予皮下注射那屈肝素钙(抗活性第10凝血因子)3800 IU/0·4 mL ,一日2次或口服阿斯匹林160 mg/日,共10天,之后都给予阿斯匹林80–300 mg /日,连用6个月.这项研究在www.strokecenter.org/trials (number 493)上进行了注册.
Findings结果
Among 603 patients recruited, 353 (180 LMWH, 173 aspirin) had LAOD (300 had intracranial LAOD only, 42 had both intracranial and extracranial disease, and 11 had extracranial disease only). The proportion of patients with good outcomes at 6 months (Barthel index ≥85) was 73% in the LMWH group and 69% in the aspirin group (absolute risk reduction 4%; 95% CI −5 to 13). Analysis of prespecified secondary outcome measures showed a benefit in outcome for LMWH versus aspirin on the modified Rankin scale dichotomised at 0–1 (odds ratio 1·55, 95% CI 1·02–2·35). Haemorrhagic transformation of infarct and severe adverse events were similar in both groups. Post-hoc analyses of patients without LAOD, and all treated patients, showed similar proportions with a good outcome in aspirin and LMWH groups (78% vs 79% and 73% vs 75%, respectively).
在全部603例患者中,353例(180例接受了低分子量肝素,173例接受了阿斯匹林)患LAOD(300例为仅伴颅内大动脉疾病,42例同时伴颅内和颅外大动脉疾病,11例仅存在颅外大动脉病变).6个月良好预后的比例(Barthel指数 ≥85)低分子量肝素组占73%,阿斯匹林组占69%(绝对风险下降4%;95%有效区间 -5到13).进一步详细的中等预后检测分析显示低分子量肝素优于阿斯匹林,改良Rankin二分量表为0-1(优势比 1·55, 95%有效区间1·02–2·35).两组梗死出血性转化和严重并发症出现率无差别.实验后分析显示,无LAOD的急性中风患者,阿斯匹林和低分子量肝素两种治疗的良好预后比率相似(分别为78% 和79% ,73% 和75%).
Interpretation讨论
Overall, the results do not support a significant benefit of LMWH over aspirin in patients with LAOD. The benefits indicated in most outcome measures warrant further investigation into the use of anticoagulation for acute stroke in patients with large artery atherosclerosis, particularly in intracranial atherosclerosis.
总之,研究结果显示,在LAOD病人中,低分子量肝素治疗并不明显优于阿斯匹林.多数预后评价认为,在伴大动脉病变,特别是颅内大动脉病变的急性中风患者中使用抗凝治疗是有效的,进一步的研究是必要的.
lancet neurology

Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK)
用葡萄糖-钾-胰岛素注射液（GKI）治疗卒中后发生的高血糖：英国有关卒中后血糖胰岛素试验（GIST-UK）

作者及机构等从略

Summary
摘要

Background
背景
Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death. We sought to determine whether treatment with glucose-potassium-insulin (GKI) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days.
急性卒中后发生高血糖是一种常见现象，（这种高血糖）也增加了患者死亡的风险。我们正尝试着确定，在急性卒中发生后，立即应用GKI注射液来保持血糖正常值是否可以减低90天内的死亡率。

Methods
方法
Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6•0–17•0 mmol/L were randomly assigned to receive variable-dose-insulin GKI (intervention) or saline (control) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4–7 mmol/L, with no glucose intervention in the control group. The primary outcome was death at 90 days, and the secondary endpoint was avoidance of death or severe disability at 90 days. Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery. The trial was powered to detect a mortality difference of 6% (sample size 2355), with 83% power, at the 5% two-sided significance level. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN 31118803)
患者均为24小时内发生卒中，血糖在6•0–17•0 mmol/L之间。这些患者被随机的应用不定剂量的GKI（干预组）或者盐溶液（对照组）持续24小时静点。GKI注射液的目的是将血糖维持在4–7 mmol/L，对照组没有血糖干预。我们关心的首要结果是90天内的死亡率，第二是如何避免90天内发生重残或死亡。另外我们还预期分析并试着确定残疾和神经功能恢复的差异性。试验的死亡率差异为6％（样本量2355），检验效力83％，双向有效指标5％。本研究已注册为国际标准化随机对照试验（编号ISRCTN 31118803）。

Findings
结果
The trial was stopped due to slow enrolment after 933 patients were recruited. For the intention-to-treat data, there was no significant reduction in mortality at 90 days (GKI vs control: odds ratio 1•14, 95% CI 0•86–1•51, p=0•37). There were no significant differences for secondary outcomes. In the GKI group, overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group (mean difference in glucose 0•57 mmol/L, p<0•001; mean difference in blood pressure 9•0 mmHg, p<0•0001).

933名患者加入了本试验，后来由于加入者越来越少，试验停止。对治疗数据进行分析，发现两组的90天内死亡率没有明显的差异性（GKI组与对照组：优势比为 1•14， 95% CI 0•86–1•51, p=0•37）。第二项结果也没有明显的差异性。在GKI组中，所有的血糖平均值和收缩压的平均值都要明显的低于对照组（血糖平均差为0•57 mmol/L， p<0•00；血压平均差为9•0 mmHg，p<0•0001）。

Interpretation
解析
GKI infusions significantly reduced plasma glucose concentrations and blood pressure. Treatment within the trial protocol was not associated with significant clinical benefit, although the study was underpowered and alternative results cannot be excluded.
GKI注射液明显的减低了血糖浓度和血压。本试验的治疗研究数据并没有体现明显的临床优势，但即便如此，这种治疗方案不应该被排斥。

lancet neurology
柳叶刀神经病学

A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release
缺血性脑卒中患者的广基因组基因分型的研究：最初的分析和数据发布

作者等从略

Summary
摘要

Background
背景
Despite evidence of a genetic role in stroke, the identification of common genetic risk factors for this devastating disorder remains problematic. We aimed to identify any common genetic variability exerting a moderate to large effect on risk of ischaemic stroke, and to generate publicly available genome-wide genotype data to facilitate others doing the same.
尽管有证据显示遗传性物质在卒中发生中扮演着重要角色，但导致这种破坏性功能障碍（卒中）的普遍基因风险因素还不明了。我们的目的是识别任何在缺血性脑卒中中发挥一定的乃至巨大作用的普遍的基因变异性，同时也为致力于此研究的其他同道提供公用的（共享的）广基因组基因型数据（库）。

Methods
方法
We applied a genome-wide high-density single-nucleotide-polymorphism (SNP) genotyping approach to a cohort of samples with and without ischaemic stroke (n=278 and 275, respectively), and did an association analysis adjusted for known confounders in a final cohort of 249 cases and 268 controls. More than 400 000 unique SNPs were assayed.
我们用广基因组的高密度、单核苷酸多形性（SNP）基因分型去处理一组队列样本，这些样本有或者没有缺血性脑卒中（分别为n=278 、275），然后对校正过的最终队列样本（试验组即有卒中：249例；对照组即无卒中：268例）进行关联分析。分析测定了超过400 000个独立的SNP。

Findings
结果
We produced more than 200 million genotypes in 553 unique participants. The raw genotypes of all the controls have been posted publicly in a previous study of Parkinson's disease. From this effort, results of genotype and allele association tests have been publicly posted for 88% of stroke patients who provided proper consent for public release. Preliminary analysis of these data did not reveal any single locus conferring a large effect on risk for ischaemic stroke.
我们在533个独立的试验对象上得到了超过200万个基因型。对照组的未经任何处理的基因型已经在前一阶段的一个有关帕金森疾病的研究中公开发布。有88％的卒中患者完全授权同意公开发布自己的试验信息，（他们的）这些基因型和等位基因关联试验的结果已经公开发布。对这些数据的初步分析并没有显示有任何单一的基因座在缺血性脑卒中中发挥巨大作用。

Interpretation
解读
The data generated here comprise the first phase of a genome-wide association analysis in patients with stroke. Release of phase I results generated in these publicly available samples from each consenting individual makes this dataset a valuable resource for data-mining and augmentation.
这里（发布）的资料包含了对缺血性脑卒中患者广基因组关联研究的最初阶段。这些均被试验对象授权同意公开发布的第一阶段的研究成果，为数据的采集和扩大提供了极有价值的数据库资源。

lancet neurology
柳叶刀神经病学

Deep Gray Matter Perfusion in Multiple Sclerosis
Dynamic Susceptibility Contrast Perfusion Magnetic Resonance Imaging at 3 T
多发性硬化的脑深部灰质灌注三维动态敏感对照磁共振灌注成像
Matilde Inglese, MD, PhD; Sun-Jung Park, MS; Glyn Johnson, PhD; James S. Babb, PhD; Laura Miles, PhD;Hina Jaggi, MS; Joseph Herbert, MD; Robert I. Grossman, MD

Objectives: To assess the presence of perfusion abnormalities in the deep gray matter of patients with relapsingremitting and primary progressive multiple sclerosis (MS) in comparison with healthy controls and to investigate the impact of perfusion impairment on clinical disability and fatigue.
目的：评价缓解复发型和原发进展型多发性硬化与健康对照病例存在的脑深部白质灌注异常，研究灌注损伤对临床残疾和疲劳症状的影响。
Design: Survey.
设计：测量
Setting: Research-oriented hospital.
机构：研究定点医院
Patients: Twenty-two patients with MS and 11 age- and sex-matched healthy volunteers.
患者：22名MS患者，11名年龄、性别匹配的健康志愿受试者。
Intervention: Absolute cerebral blood flow, cerebral blood volume, and mean transit time were measured in the thalamus, putamen, and caudate nuclei.
干预：检测了丘脑、苍白球、尾状核的绝对脑血流量，脑血容量，平均通过时间。
Main Outcome Measures: Decrease of cerebral blood flow in the deep gray matter of patients with MS and correlation between perfusion impairment and the severity of fatigue.
总结果的评价：评价MS患者脑深部白质血流量下降程度及灌注减少与无力严重度的关系。
Results: The cerebral blood flow value averaged over the thalamus, putamen, and caudate nuclei was significantly lower in patients with primary progressive MS (P<.001) and in patients with relapsing-remitting MS (P=.01) compared with controls, and there was a trend for patients with primary progressive MS to have lower average cerebral blood flow than patients with relapsingremitting MS (P=.06). With respect to cerebral blood volume, there was a significant difference between patients with primary progressive MS and controls (P<.001) and between the 2 groups of patients (P=.03) but not between patients with relapsing-remitting MS and controls (P>.30). The fatigue score was significantly correlated with cerebral blood flow (r=0.4; P<.001) and cerebral blood volume (r=0.5; P=.004).
结果：与健康对照组相比，丘脑、苍白球、尾状核的脑血流量平均值在原发进展 (P<.001)及缓解复发型MS患者(P=.01)显著降低，原发进展型MS患者存在比缓解复发型平均脑血流量更低的一种趋势(P=.06)。在脑血容量方面，原发进展型与对照组MS患者存在显著差异(P=.03)，而缓解复发型与健康对照之间就不存在显著差异(P>.30)。疲劳指数与脑血流量 (r=0.4; P<.001)，脑血容量 (r=0.5; P=.004) 显著相关。
Conclusion: The decrease of tissue perfusion in the deep gray matter of patients with MS is associated with the severity of fatigue.
结论：MS患者深部脑白质组织灌注下降与疲劳严重度有关。
Arch Neurol. 2007;64:196-202
神经病学档案

Cerebrospinal Fluid tau/_-Amyloid42 Ratio as a Prediction of Cognitive Decline
in Nondemented Older Adults
脑脊液tau蛋白/Aβ42比率对非痴呆老年人认知功能下降的预测
Anne M. Fagan, PhD; Catherine M. Roe, PhD; Chengjie Xiong, PhD; Mark A. Mintun, MD;John C. Morris, MD; David M. Holtzman, MD
Objectives: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/ absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals.
目的：研究脑脊液和血浆检测法对从非痴呆老年人中辨别出早期AD（通过临床标准和脑内是否存在淀粉样蛋白来确定）的效率，同时评估这些生物标记预测认知正常个体将来发展为痴呆可能性的能力。
Design: Evaluation of CSF β-amyloid40 (Aβ40), Aβ42, tau, phosphorylated tau181, and plasma Aβ40 and Aβ42 and longitudinal clinical follow-up (from 1 to 8 years).
设计：评价脑脊液淀粉样蛋白Aβ40, Aβ42，tau蛋白，磷酸化的tau蛋白，血浆Aβ40 、 Aβ42和临床纵向跟踪观察(1—8 年)结果。
Setting: Longitudinal studies of healthy aging and dementia through an AD research center.
研究机构：一个AD研究中心来源的几个健康老年人和痴呆纵向调查
Participants: Community-dwelling volunteers (n=139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia.
研究对象（参加者）：社区居民志愿者139例，60—91岁不等，临床判断为认知正常（临床痴呆指数CDR=0），或非常轻微（CDR=0.5），或轻度（CDR=1）AD痴呆。
Results: Individuals with very mild or mild AD have reduced mean levels of CSF Aβ42 and increased levels of CSF tau and phosphorylated tau181. Cerebrospinal fluid Aβ42 level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound in demented and nondemented individuals. The CSF tau/Aβ42 ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau181/Aβ42 ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0.
结果：非常轻微或轻度AD个体CSF的Aβ42水平低于平均值，tau蛋白、磷酸化tau蛋白水平升高，非痴呆和痴呆病人CSFAβ42水平完全依赖于脑PIB成像是否存在淀粉样蛋白，CSF tau/Aβ42比率（校正危害比，5.21；95%可信区间1.58-17.22）和磷酸化tau/Aβ42比率（校正危害比，4.39；95%可信区间1.62-11.86）预示临床痴呆发生率CDR值从0到大于0。
Conclusions: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Aβ42, when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Aβ42 ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.
结论：AD最轻症状阶段与成熟阶段表现同样的CSF生物标记表现型。另外，当CSF的Aβ42水平与淀粉样蛋白成像检查相结合时，更有利于临床确定脑中存在淀粉样蛋白的个体是否存在痴呆。重要的是，CSF tau/Aβ42比率是预示认知功能正常老年人症状前痴呆的强烈生物指标。
Arch Neurol. 2007;64:343-349

Immediate Anticoagulation for Acute Stroke in Atrial Fibrillation Yes
有房颤的急性卒中患者是否早期应用抗凝剂是
Ángel Chamorro, MD, PhD

(Stroke. 2006;37:3052-3053.)

正文
Meta-analyses contest the value of “immediate” anticoagulation in acute stroke1 although the trials included in these analyses referred to patients treated protractedly and the anticoagulants examined had significant pharmacological differences.2 Post hoc analyses of some of these trials extend the overall negative effects of anticoagulation to patients with stroke secondary to atrial fibrillation (AF).3 The value of immediate anticoagulation in patients with acute stroke secondary to AF, alike its role in any other stroke subtype, has not been adequately explored. Thus, I agree that “delayed” anticoagulation is not beneficial for stroke attributable to AF, although I defend that to bring
down the value of “immediate” anticoagulation is premature. Absence of evidence is not equal to evidence of absence.
Observational data suggest that full anticoagulation with unfractionated heparin (UH) started within 6 hours from clinical onset is better than delayed anticoagulation.4 The
Rapid Anticoagulation Prevents Ischemic Damage (RAPID) trial is the closest randomized approach to immediate anticoagulation, with a mean treatment delay of 6.9 hours.5 Other trials delayed treatment for 24 (Trial of Org 10172 in Acute Stroke Treatment [TOAST], Fraxiparin in Stroke Study Bis [FISS bis]), 30 (Heparin in Acute Embolic Stroke Trial [HAEST]) or 48 hours (FISS, Tinzaparin in Acute Ischemic Stroke Trial [TAIST], International Stroke Trial [IST]), and some of them are also limited by unblinding of treatment, ill-timed use of CT, or ambiguous definitions of end points (ie, recurrent stroke). The RAPID trial confirmed the higher risk of bleeding by excessive anticoagulation.5 Therefore, the omission of monitoring of biological effects is especially worrisome in previous UH trials. Endocrinologists might have also suspected the safety of insulin if the agent had been explored in trials ignoring serum glucose levels.
RAPID was an academic effort to reconcile science and simplicity, but insufficient funding dissuaded many investigators to participate.5 The main rationale of the study implied that UH is an anticoagulant with time-dependent antiinflammatory properties. Unfortunately, a hopeless recruitment rate led to the premature termination of the study when only 67 patients had been included. Nevertheless, RAPID was able to show a trend toward more effective prevention of stroke recurrence with UH (0%) than aspirin (8.6%; P0.09) and without an increment in serious bleeding (8.6% for aspirin, 6.3% for UH; P0.71).
Delaying anticoagulation in stroke secondary to AF was advocated in the late 80s for the fear of facilitating early hemorrhagic transformation. However, since the mid 90s we
know that carefully monitored UH is safe, even in patients with large infarcts attributable to AF.7 But the urgency of full anticoagulation is mainly justified in light of the molecular mechanisms of brain ischemia.8 Predictably, during the crucial hours that went before patients reached adequate anticoagulation in previous trials, excitatory amino acids, cytokines, calcium, and free radicals peaked to high levels that dwindled
the extent of salvageable brain tissue. Treatment delay for 1 or 2 days is trivial if our primary aim is to decrease the risk of early stroke recurrence (HAEST trial). However, treatment delay may be of vital relevance if we aim primarily to improve functional outcome and reduce mortality (as did all other anticoagulation trials). Only an (unrealistic) extremely large reduction of recurrent strokes would translate into improved functional outcome at follow-up. But this approach is early secondary stroke prevention rather than acute stroke therapy.
Stroke secondary to AF has triggered special concerns because it was thought to represent a situation of higher risk of early stroke recurrence although more recent information opposes this concept. Then, a more liberal anticoagulation attitude for the fear of early recurrence is unwarranted. Rather, the central issue that calls for a serious testing of immediate anticoagulation in stroke secondary to AF is what I would define
as the tissue factor (TF) link. Briefly, TF follows the release of cytokines after stroke and is the primary cellular initiator of the coagulation cascade in vivo. TF behaves as a hemostatic envelope diffusely expressed in the adventitia of cerebral vessels, but
there is also prominent TF expression in the human cortex. Accordingly, any acute embolic stroke, including that secondary to AF, is a TF-mediated prothrombotic state that could theoretically be opposed with adequate anticoagulation. Therefore, the TF link emphasizes the consequences rather than the causes of stroke for treatment decisions. Given that UH achieves faster anticoagulation levels than any other regimen, I recommend this therapy for many of my patients if there are not contraindications.
Calibration of activated partial thromboplastin time ratios to their corresponding heparin levels (0.3 to 0.5 U/mL), careful monitoring, and frequent dose adjustments are essential safety measures.5 However, I strongly believe that Peter Sandercock, my contestant in this controversy and good friend in less controversial issues, shares with me that a well-funded RAPID II trial is urgently needed.

译文：

系统评价还在争论卒中后早期抗凝的价值1，尽管纳入系统评价的试验提到病人应用抗凝剂的时间较迟，以及不同抗凝剂有不同的药理学作用2。对这些试验分析发现抗凝剂对房颤继发的卒中无益处。正如其他类型的卒中一样，继发于房颤的卒中应用抗凝剂还没有得到充分的研究3。因此，我认同延迟抗凝对房颤继发的卒中没有益处，虽然我认为早期抗凝是令人失望的观点是不成熟的。缺乏证据不等于没有证据。
观察性研究显示，发病后6小时应用足剂量的普通肝素效果好于延迟用药4。快速抗凝预防缺血性损害（The Rapid Anticoagulation Prevents Ischemic Damage，RAPID）试验是最近一个研究发病后早期应用抗凝剂的随机试验，平均用药时间为6.9小时5。Trial of Org 10172 in Acute Stroke Treatment （TOAST）和Fraxiparin in Stroke Study Bis（FISS bis）为病后24小时用抗凝剂，急性栓塞型卒中应用肝素试验(Heparin in Acute Embolic Stroke Trial （HAEST）为30小时， FISS, Tinzaparin in Acute Ischemic Stroke Trial （TAIST）和 International Stroke Trial （IST) 为30小时。其中有些试验限制为非盲法治疗，头颅CT检查较随意，或终点指标不明确。RAPID试验发现过度抗凝发生出血的危险性较高5。因此，忽视监测生化指标是以前普通肝素试验的缺陷。如果不监测血糖水平应用胰岛素，内分泌学家也曾经怀疑该药的安全性。
RAPID是一个学术上平衡科学和简单化的试验，但仍因资金不足导致许多研究者放弃5。这个试验主要的原理是肝素具有时间依赖性的抗炎性质6。可惜因较低的纳入率而中止，仅纳入67例。虽然如此，但RAPID可观察出一种趋势，即对于预防卒中复发，肝素比阿司匹林更有效(8.6%；P＝0.09)且没有增加严重出血的比例(阿司匹林，8.6%；普通肝素，6.3%；P＝0.71)5
在80年代后期，由于担心房颤继发卒中早期发生出血转化，肝素应用较迟。然而，自90年代中期后，我们都知道，应用普通肝素时严密的监测是安全的，甚至对于房颤继发大面积梗塞7。应用足剂量肝素的理论依据是脑缺血的分子学机制8。可以预测的是，以前试验方法是在达到充分肝素化之前，病人最严重的时期已过，活性氨基酸、细胞因子、钙离子和自由基水平已达到高峰，进而导致可挽救的脑组织减少。如果我们的主要目的是降低卒中早期复发风险，延迟1～2天用肝素也不会影响结果，如HAEST试验。但是，如果我们的主要目的是改善功能和降低死亡率，延迟用肝素就可能会影响预后。只有大幅度的降低卒中复发率（不现实的）才可能提高预后。但这种治疗方式是用于早期继发卒中预防，不是用于急性卒中治疗。
房颤继发卒中是一种特殊类型，被认为是一种早期卒中复发的高危险状态，尽管最近的资料反对这种观点。然而，还没有发现一种作用更安全的抗凝药预防早期卒中复发。早期应用抗凝剂治疗房颤继发卒中的监测项目的主要问题是我们要确定凝血激酶的环节。简而言之，凝血激酶是在卒中后细胞因子释放后发生，是体内主要的凝血连锁细胞启动因子。凝血激酶作为一种止血膜弥散的分布在脑血管外膜上，其在人类大脑皮质上表达也较丰富9。任何急性栓塞型卒中，包括继发于房颤的卒中，都是一种凝血激酶介导的血栓前状态。理论上讲，这种状态与充分抗凝是对立的。因此，凝血激酶环节强调结局而不是卒中治疗决策的原因。如果普通肝素能较其他药物更快的达到抗凝水平，如果没有禁忌症，我推荐我治疗的病人使用普通肝素5。校准活化部分凝血激酶时间与其相对应的肝素水平，严密的监测和调整剂量是保证安全的重要措施。我深信我的辩论对手和好朋友Peter Sandercock也会认为，有充足资金资助的RAPIDⅡ期试验是迫切需要的。

虽然文献是去年的，但还是比较新的，也是当前卒中治疗的争论热点。我会陆续把反方的评述也翻译出来，希望对大家有用。也请版主谅解。

Immediate Anticoagulation for Acute Stroke in Atrial Fibrillation No
Peter Sandercock, MA, DM, FRCPE
有房颤的急性卒中患者是否早期应用抗凝剂不
(Stroke. 2006;37:3054-3055.)

正文：
“No benefit of heparin has been demonstrated for acute stroke patients with AF [atrial fibrillation]; whether selected subgroups would respond differently remains to be proven. Aspirin followed by early initiation of warfarin for long-term secondary prevention is reasonable antithrombotic management.” The quote above is the conclusion of a careful review of the randomized trial evidence that was available in 2002, yet it is clear that many physicians and neurologists still cling to the nonevidence-based habit of giving intravenous heparin for acute ischemic stroke associated with AF.2–5 While some
dispute the validity of the trial evidence,5,6 there are others who accept that there is no evidence of net benefit from heparin in this setting.1,3,7 Indeed the American Stroke Association/ American Academy of Neurology scientific statement on the subject concludes, “IV, unfractionated heparin or high-dose LMW heparin/heparinoids are not recommended for any specific subgroup of patients with acute ischemic stroke that is based on any presumed stroke mechanism or location (eg, cardioembolic, large vessel atherosclerotic, vertebrobasilar, or ‘progressing’ stroke) because data are insufficient
(Grade U).”
Because this high-quality practice guideline concludes there is no reliable evidence to support immediate anticoagulation, it is worth examining the determinants of current
clinical practice. A survey of 36 US academic medical centers showed that 29% of a sample of 497 patients with acute ischemic stroke were treated with intravenous heparin, but the proportion-treated varied enormously between centers; from “not at all” in 7 centers to 88% in 1 center.2 A survey of opinion among 280 neurologists from the US and 270 neurologists from Canada showed, despite the publication of clinical trials, which have not shown any long-term benefit from heparin for patients with acute stroke, both US and Canadian neurologists would use IV heparin in large numbers for this condition.3 US neurologists were significantly more likely than Canadian neurologists to use IV heparin. US neurologists more often cited medicolegal factors as a potential
influence on the decision-making process than Canadian neurologists.3 Similarly, a survey of 180 neurologists in Michigan showed the vast majority of neurologists in Michigan would use IV heparin for patients with AF-related stroke (91% of those with a defined opinion). Medicolegal factors influenced the selection of heparin as a therapy for 41% of physicians. In summary, it appears the medicolegal system in US has a very powerful effect that tends to retain this nonevidence-based treatment!
The situation in Germany is similar in that there is frequent but variable use of IV heparin; full anticoagulation with heparin (“full dose”) was performed on selected patients in 32/33 stroke units (97%). The selection criteria and thus the frequency of high-dose heparin use varied widely among the different centers.5 The variation was attributed to “individualisation of the therapy in every case”; ie, the selection criteria were based on physiological principles rather than evidence from randomized trials. In the UK, IV heparin was hardly used at all in acute ischemic stroke of any type. Such enormous variations in clinical practice are hard to justify. Variation between countries and between centers within the same country in the use of a particular treatment often indicates that there is no reliable evidence on which to base treatment decisions. This certainly appears true for this particular controversy. Unfortunately, I suspect there are not
enough clinicians with sufficient equipoise who would be prepared to recruit patients to a randomized trial comparing full dose IV heparin with control in patients with acute
ischemic stroke and AF. Furthermore, it would require a governmental funding agency such as the National Institutes of Health (NIH) or United Kingdom Medical Research
Council (UK MRC) to support an appropriately-sized trial (because IV heparin is a generic drug with no major commercial potential). However, an IV heparin trial would be
competing with other, much more promising stroke interventions for government funding. A trial of IV heparin is not enough of a “burning question” that it would be likely to win in a competition for funding.
So what to advise? Generally, don’t choose IV heparin just because that’s what everyone else does or because you fear litigation. Stick to the evidence and be reasonable (ie, avoid heparin). Start aspirin immediately, because it is effective, safe, simple, needs no complex monitoring and can be used in even the most resource-poor health systems. When the period of highest risk of intracranial bleeding/hemorrhagic conversion
of the infarct has passed, start oral anticoagulants and stop the aspirin.

译文：
“已经证明肝素治疗有房颤的急性卒中患者是无益的，用肝素治疗其他卒中亚型是否有益，还没有结论。应用阿司匹林后再用华法令进行长期的二级预防是合理的抗凝措施”1。
上述评论是源于2002年一个随机对照试验的系统评价，但是，还有很多内科和神经科医生仍然采用无证据支持的治疗方式，给予有房颤的急性卒中患者静脉应用肝素2－5。然而，一些学者争论这些证据的可靠性5，6，也有学者认为肝素的有效性是没有证据的1，3，7。美国卒中协会指出：基于缺血性卒中的可能机制和分类（心源型，大动脉硬化型，基底动脉型和进展性卒中），不推荐任何类型的缺血性卒中静脉应用普通肝素或大剂量低分子肝素，因为目前证据不足（U级证据）8。
这些高质量的实践指南认为，没有可靠的证据支持卒中后早期应用抗凝剂，所以值得在实践中检验这一结论。调查了美国36个学院医学中心，发现497个急性卒中病人有29％的静脉应用肝素。但各个中心应用情况明显不同，7个中心没有应用，1个中心有88％的病人在用8。调查了美国的280个和加拿大的270个神经科医生，发现两国医生均在临床中大量的应用了肝素，尽管公布的四个临床试验结果显示，肝素对急性卒中患者的长期效果没有益处3。而且美国医生较加拿大的更喜欢应用肝素。美国医生比加拿大医生更喜欢的引用法医学的证据作为决策的依据3。同样的，调查了密西根州的180个神经科医生，发现大部分医生应用肝素治疗有房颤的卒中患者（91％的医生有此观点）。法医学的证据影响41％的内科医生选择用肝素治疗卒中。总之，法医学派在美国很强势，影响着这种无证据支持的治疗方式。
这种情况在德国也是相同的，应用肝素也很频繁但有所不同。有97％的卒中单位（32/33）给有房颤的卒中病人足剂量的肝素，但这些中心的选择标准不同，因而应用足剂量肝素的比例也不同5。这种不同可能源于“个体化治疗”，例如，选择标准是以生理学理论为基础，而不是以随机试验的证据。但在英国，各类型的急性缺血性卒中很少静脉应用肝素9。
如此巨大的差异很难确定哪种治疗方式是正确的。国家间和同一国家不同中心间在应用某一治疗措施的差异，表明这种治疗措施尚没有可靠的证据。因此，争论是必要的。不幸的是，我怀疑临床医生，在做静脉应用肝素治疗有房颤的卒中病人的随机对照试验时，不能将纳入的病例充分均衡的分组。而且，因为肝素为普通药物，没有很大的商业利润，可能需要像美国国家卫生研究院或英国医学研究委员会这样的政府资助，才能做这个试验。然而，肝素试验可能还需要和政府资助的其他有前景的卒中干预试验竞争。况且，这个试验也不是热点问题，不一定就能赢得政府的资助。
我想建议什么呢？不要应用肝素，仅仅是因为可能被起诉。坚持以证据和合理性为基础（如：不用肝素）。早期应用阿司匹林，因为它有效、简单、不需要复杂的监测，甚至可用于最穷的人群。当颅内出血或出血转化的高风险时期过后，开始口服抗凝剂并停用阿司匹林。

Immediate Anticoagulation for Acute Stroke in Atrial Fibrillation No, but . . . .
Stephen M. Davis, MD, FRACP; Geoffrey A. Donnan, MD, FRACP
有房颤的急性卒中患者是否早期应用抗凝剂不，但是……
(Stroke. 2006;37:3056.)

正文：
We all accept that full anticoagulation is highly effective, proven therapy for the great majority of patients with atrial fibrillation (AF) for the prevention of recurrent stroke. This controversy relates chiefly to the timing of anticoagulation in the acute stroke setting, the agent and mode of administration.
It is useful to track the path of the use of heparin over the past 25 years. Many of us based a practice of acute intravenous heparin in AF patients on the trial of the Cerebral
Embolism Study Group (1983),1 which concluded that the immediate anticoagulation of embolic stroke was effective and apparently safe, yet based on only 45 randomized
patients. Clearly, conclusions based on such small numbers would not be reached a quarter of a century later, where trial methodology is so much more sophisticated.
Two major influences then led to guidelines that immediate anticoagulation is not warranted. First, Sandercock and others, in much larger randomized trials, showed that there was a substantially lower risk of early recurrent embolism than previously thought.2,3,4 Second, these trials did show an overall benefit for a policy of acute anticoagulation. However, none of these trials used a monitored anticoagulation protocol. Interestingly, in an earlier heparin controversy in our series, we pointed out that there had been no adequate trial of APTT-monitored intravenous heparin in acute ischemic
stroke. Sadly, as indicated by Chamorro, this remains the case. Furthermore, we are not convinced that there is bioequivalence between different anticoagulation agents and mode of administration.
So, what do we do in this evidence-light zone? In the great majority of patients with AF, we do not use full anticoagulation in any form in the acute stroke setting and would
generally commence warfarin within a few days of symptom onset. In exceptional circumstances, such as recurrent embolism or echocardiographic evidence of left atrial or ventricular thrombus, we would immediately anticoagulate. Our final word: the reality is that heparin is still widely used around the world in this setting. We don’t believe that this controversy will die without an adequately powered trial of monitored anticoagulation in high-risk patients with AF and acute stroke.

译文：
我们都知道，足剂量的抗凝剂对预防大部分房颤病人发生卒中是有效的。目前争论的焦点是在急性卒中时抗凝剂使用的时间、药物类型和给药方式。
追踪过去25年应用肝素的历史是有益的。我们给房颤病人应用肝素是基于1983年脑栓塞研究1，该试验结论是栓塞型卒中发病后早期应用肝素是有效和安全的，但该结论仅仅基于45个的随机病人。基于如此少的病例得出的结论难以满足25年后的要求，现在的试验方法相当复杂。
两个主要事件得出指南，认为早期抗凝有效性的结论是不一定正确的。首先，Sandercock和其他人基于大样本随机试验表明，有房颤的卒中早期复发栓塞的的风险很小，与以前的结论不同2，3，4。其次，这些试验表明急性期抗凝是有效的。但这些试验均没有抗凝监测协议。本杂志以前也讨论过这个题目，发现静脉应用肝素治疗急性缺血性卒中时，没有充分的监测活化部分凝血激酶时间。正如Chamorro指出，这是实际情况5。而且，我们也不能确定不同的抗凝剂和用药方式生物学效价是否相等。
我们该怎么对待这种证据缺乏的情况呢？在急性卒中中心，对于大部分房颤病人，我们没有应用任何形式的抗凝剂，在病程后几天开始应用华法令。但在特殊情况下，如栓塞复发或超声心动图显示左房和左室内有血栓，我们会早期用抗凝剂。
总之，目前世界上在这领域内，肝素还在广泛的使用。我们确信不可能通过这次辩论，而没有强有力的抗凝治疗有房颤的急性卒中的试验支持，就会能得出确定结论。

请翻译2007年的文章，谢谢支持！

Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study

Prof Seibu Mochizuki MDa, , , Björn Dahlöf MDc, Prof Mitsuyuki Shimizu MDa, Katsunori Ikewaki MDa, Makoto Yoshikawa MDa, Ikuo Taniguchi MDa, Makoto Ohta MDa, Taku Yamada MDa, Kazuhiko Ogawa MDa, Kiyoshi Kanae MDa, Makoto Kawai MDa, Shingo Seki MDa, Fumiko Okazaki MDa, Masayuki Taniguchi MDa, Satoru Yoshida MDa, Prof Naoko Tajima MDb and for the Jikei Heart Study group‡
aDivision of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
bDivision of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
cInstitute of Medicine, Department of Emergency and Cardiovascular Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

Summary

Background

Drugs that inhibit the renin–angiotensin–aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease.

Methods

We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20–79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40–160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328.

Findings

After a median follow-up of 3·1 years (range 1–3·9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21·3 vs 34·5 per 1000 patient years; hazard ratio 0·61, 95% CI 0·47–0·79, p=0·0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0·60, 0·38–0·95, p=0·028), angina pectoris (19 vs 53; 0·35, 0·20–0·58, p<0·0001), and heart failure (19 vs 36; 0·53, 0·31–0·94, p=0·029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups.

Interpretation

The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

the lancet

The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison

Prof David G Sherman MDa, , , Prof Gregory W Albers MDb, Prof Christopher Bladin MDc, Prof Cesare Fieschi MDd, Prof Alberto A Gabbai MDe, Prof Carlos S Kase MDf, William O'Riordan MDg, Prof Graham F Pineo MDh and on behalf of the PREVAIL Investigators‡
aDepartment of Medicine (Neurology), University of Texas Health Science Center, San Antonio, TX, USA
bDepartment of Neurology and Neurological Sciences, Stanford University Medical Center, Palo Alto, CA, USA
cBox Hill Hospital (Monash University), Melbourne, Australia
dUniversity “La Sapienza”, Rome, Italy
eUNIFESP–Disciplina de Neurologia, Sao Paulo, Brazil
fDepartment of Neurology, Boston University School of Medicine, Boston, MA, USA
gParadise Valley Hospital, National City, CA, USA
hUniversity of Calgary, Calgary, Alberta, Canada

Summary

Background

Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke.

Methods

1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6–14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke ≥14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805.

Findings

In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10·5 days (SD 3·2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0·57, 95% CI 0·44–0·76, p=0·0001; difference −7·9%, −11·6 to −4·2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0·0036) or less than 14 (42 [8%] vs 69 [14%]; p=0·0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0·83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0·23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0·55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0·015).

Interpretation

Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.

the lancet

Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study
Valsartan（缬沙坦）在患高血压和其它心血管疾病的日本人群中的作用（来自Jikei即东京慈会大学的心脏研究）：一个以发病率和死亡率为终点指标的随机、非盲研究

作者及研究机构等从略

Summary
摘要

Background
背景

Drugs that inhibit the renin–angiotensin–aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease.
能抑制肾素－血管紧张素－醛固酮系统的药物在预防和治疗心血管疾病方面都是很有益处的。然而，在亚裔人口中，有关这种（良性）影响的证据是缺乏的。我们的目的是研究针对患有心血管疾病的日本人，在常规心血管治疗的基础上，辅以血管紧张素受体阻滞剂（ARB）是否能更有疗效。

Methods
方法

We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20–79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40–160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328.
我们选定了3081名日本人来作为多中心的、前瞻性的、随机对照试验的试验对象，他们的年龄在20－79岁之间（平均年龄65[SD 10]岁），均患有高血压、冠心病（冠状动脉粥样硬化性心脏病）、心力衰竭或者合并这些功能障碍，并且均接受常规的治疗。作为常规治疗的附加方案，这些病人被指定接受valsartan（每天40－160mg）或者其它没有血管紧张素受体阻滞剂参与的治疗方案。我们首要的终点指标包括心血管疾病的发生率和死亡率。通过疗效进行分析。本研究在clintrials.gov（官方临床试验）上注册，证号为NCT00133328。

Findings
结果

After a median follow-up of 3•1 years (range 1–3•9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21•3 vs 34•5 per 1000 patient years; hazard ratio 0•61, 95% CI 0•47–0•79, p=0•0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0•60, 0•38–0•95, p=0•028), angina pectoris (19 vs 53; 0•35, 0•20–0•58, p<0•0001), and heart failure (19 vs 36; 0•53, 0•31–0•94, p=0•029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups.
经过平均为3.1年（范围：1－3.9年）的随访，首要的终点指标（心血管疾病的发生率和死亡率）应用valsartan组要明显少于对照组（92对149；绝对风险：每年、每1000人中21.3对34.5；危害比0.61，95% CI 0.47－0.79， p=0.0002）。这种不同主要应归因于应用valsartan组比对照组的卒中和短暂的缺血性卒中发作的几率更低（29对48；0.60，0.38－0.95，p=0.028），心绞痛的发生率更低（19对53；0.35，0.20－0.58，p<0.0001），以及心衰的发生率更低（19对36；0.53，0.31－0.94, p=0.029。死亡率和耐受性在两组中并没有区别。

Interpretation
解读

The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.
在常规治疗的基础上辅以valsartan比其它额外的常规治疗更能预防心血管事件的发生。这些益处并不能完全用血压控制的差异性来解释。

the lancet
柳叶刀

The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison
克塞和普通肝素在预防急性缺血性脑卒中后静脉血栓发生中的有效性和安全性的对比（优势研究）：一个非盲的随机对照试验

作者及研究机构等从略

Summary
摘要

Background
背景

Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke.
在预防静脉血栓中，低分子量肝素和普通肝素均被推荐使用，但（我们）还不能确定哪一种疗法是最适合的。我们的目的是比较卒中患者应用依诺肝素和普通肝素的有效性和安全性。

Methods
方法

1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6–14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe stroke ≥14, less severe stroke <14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805.
我们选定1762名不能独立行走的急性缺血性卒中的患者，并在48小时内随机给予40mg依诺肝素，每日一次皮下注射，或者给予5000U普通肝素，每12小时皮下注射，平均用药时间为10天（范围6－14天）。应用国家卫生研究所卒中等级（NIHSS）的评分来对患者进行评估（严重卒中≥14，次重卒中<14）。有效性的首要终点指标包括有症状或者无症状的深静脉血栓，有症状的肺栓塞，或致死性肺栓塞。安全性的首要终点指标是有症状的颅内出血，较多的颅外出血和所有的致死原因。本研究在ClinicalTrials.gov（官方临床试验）上注册，证号为NCT00077805。

Findings
结果

In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10•5 days (SD 3•2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0•57, 95% CI 0•44–0•76, p=0•0001; difference −7•9%, −11•6 to −4•2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0•0036) or less than 14 (42 [8%] vs 69 [14%]; p=0•0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0•83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0•23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0•55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0•015).
在有效性方面（接受1次或更多的剂量，存在深静脉血栓或者肺栓塞，再或者被判定有静脉血栓发生），依诺肝素（n=666）和普通肝素（n=669）被应用10.5天（SD 3.2）。依诺肝素与普通肝素相比，降低了43％的静脉血栓风险（68[10%]对121[18%]；相对风险 0.57，95% CI 0.44–0.76，p=0.0001；差分−7.9%, −11.6到−4.2）；这种（风险的）降低与患者的NIHSS评分是一致的，即14分或者更高分为26 [16%]对52 [30%]，p=0.0036，小于14分为42 [8%] 对69 [14%]，p=0.0044。任何形式的出血的发生率是相似的，依诺肝素为69 [8%]，普通肝素为71 [8%]，p=0.83。有症状的颅内出血合并较多的颅外出血出现频率很小，并且应用依诺肝素和普通肝素得到的结果非常相近，依诺肝素为11 [1%]，普通肝素为6 [1%]，p=0.23。我们的记录表明有症状的颅内出血在两者中无明显差别，依诺肝素为4 [1%]，普通肝素为6 [1%]，p=0.55。较多颅外出血的发生率上，依诺肝素要高于普通肝素（7 [1%]对0，p=0.015）。

Interpretation
解读

Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.
我们的结果提示：考虑到临床上的风险比率和日一次的便利给药方式，我们认为在预防急性缺血性脑卒中患者发生静脉血栓中，克塞比普通肝素更加合适。

依诺肝素就是克塞。

the lancet

柳叶刀

新的卒中2007guideline。
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大家可以直接去阅读。由于翻译量过大，就不登出来了。感兴趣的战友可以将黑体字部分翻译出来供大家学习。
以下为节选。请大家重点看。

Class I Recommendation

The oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients (Class I, Level of Evidence A). This recommendation has changed in that a dose of aspirin is now included.

Class III Recommendations

Aspirin should not be considered a substitute for other acute interventions for treatment of stroke, including the intravenous administration of rtPA (Class III, Level of Evidence . These recommendations have not changed from previous statements.

The administration of aspirin as an adjunctive therapy within 24 hours of thrombolytic therapy is not recommended (Class III, Level of Evidence A). This recommendation has not changed.

The administration of clopidogrel alone or in combination with aspirin is not recommended for the treatment of acute ischemic stroke (Class III, Level of Evidence C). This recommendation was not included in the previous statement. The panel supports research testing the usefulness of emergency administration of clopidogrel in the treatment of patients with acute stroke.
Outside the setting of clinical trials, the intravenous administration of antiplatelet agents that inhibit the glycoprotein IIb/IIIa receptor is not recommended (Class III, Level of Evidence . This recommendation has been added since the last guideline was published.

Class I Recommendations

Imaging of the brain is recommended before initiating any specific therapy to treat acute ischemic stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.

In most instances, CT will provide the information to make decisions about emergency management (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.

The brain imaging study should be interpreted by a physician with expertise in reading CT or MRI studies of the brain (Class I, Level of Evidence C). This recommendation has been added since the previous guideline.

Some findings on CT, including the presence of a dense artery sign, are associated with poor outcomes after stroke (Class I, Level of Evidence A). This recommendation has not changed from the previous guideline.

Multimodal CT and MRI may provide additional information that will improve diagnosis of ischemic stroke (Class I, Level of Evidence A). This recommendation has been added since the previous guideline.

Class II Recommendations

Nevertheless, data are insufficient to state that, with the exception of hemorrhage, any specific CT finding (including evidence of ischemia affecting more than one third of a cerebral hemisphere) should preclude treatment with rtPA within 3 hours of onset of stroke (Class IIb, Level of Evidence A). This recommendation has not changed from the previous guideline.
Vascular imaging is necessary as a preliminary step for intra-arterial administration of pharmacological agents, surgical procedures, or endovascular interventions (Class IIa, Level of Evidence . This recommendation has not changed from the previous guideline.

Class III Recommendations

Emergency treatment of stroke should not be delayed in order to obtain multimodal imaging studies (Class III, Level of Evidence C). This recommendation has been added since the previous guideline.

Vascular imaging should not delay treatment of patients whose symptoms started <3 hours ago and who have acute ischemic stroke (Class III, Level of Evidence . This recommendation has been added since the previous guideline。

I级推荐

推荐在急性脑卒中进行任何特殊治疗前行脑的影像学检查(Class I, Level of Evidence A)。此推荐与既往指南比没有改变。

绝大部分情况下，CT可以提供制定急诊处理决策的信息(Class I, Level of Evidence A)。此推荐与既往指南比没有改变。

应由对脑CT或MRI阅片有经验的医师解释脑的影像学检查 (Class I, Level of Evidence C)。此推荐与既往指南比是新增加的。

CT上的一些发现，包括动脉高密度征，与脑卒中后转归不良相关(Class I, Level of Evidence A)。此推荐与既往指南比没有改变。

多模态CT和MRI可提供额外的信息从而改善缺血性卒中的诊断(Class I, Level of Evidence A)。此推荐与既往指南比是新增加的。

II级推荐

尽管如此，除非是出血，ＣＴ上其他任何的特异发现（包括大于大脑半球1/3区域缺血的证据），用以排除起病3小时内的脑卒中的rtPA治疗，资料是不充分的 (Class IIb, Level of Evidence A)。此推荐与既往指南比没有改变。

血管影像学检查作为动脉内给予药物，手术操作或血管内治疗的初步步骤是必要的(Class IIa, Level of Evidence )。此推荐与既往指南比没有改变。

III级推荐

不应为了多模态影像学检查而延误脑卒中的急诊治疗(Class III, Level of Evidence C)。此推荐与既往指南比是新增加的。

起病3小时内的急性缺血性脑卒中患者，血管影像学检查不应延误其治疗(Class III, Level of Evidence C)。此推荐与既往指南比是新增加的。

Association of Low Plasma Aβ42/Aβ40 Ratios With Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease
血浆Aβ42/40低水平与轻度认知障碍、阿尔茨海默病风险增加的关系
Neill R. Graff-Radford, M***h, FRCP; Julia E. Crook, PhD; John Lucas, PhD; Bradley F. Boeve, MD;David S. Knopman, MD; Robert J. Ivnik, PhD; Glenn E. Smith, PhD; Linda H. Younkin, PhD; Ronald C. Petersen, MD, PhD; Steven G. Younkin, MD, PhD
Background: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease.
背景：为了发展AD预防性治疗, 必须发展(应用)AD相关生物标记来确定个体的AD风险,这与(应用)胆固醇水平确定个体的心脏病风险是一样的.
Objective: To determine whether plasma levels of amyloidβprotein (Aβ40 and Aβ42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD.
目的：明确认知功能正常白种老年人血浆β淀粉样蛋白(Aβ40/Aβ42)水平升高是否可用于判断轻度认知障碍和AD患病风险增高。
Design: Using well-established sandwich enzymelinked immunosorbent assays, plasma Aβ40 and Aβ42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD.
设计：这是一项对老年白种人群的前瞻性研究, 随访2-12年(平均3.7年)。应用成型的夹心酶联免疫吸附测定分析法, 在基线水平上分析检测血浆Aβ40/ Aβ42比值, 以检出MCI或AD偶发病例。
Setting: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry.
机构：从初级护理机构以社区为基础招募认知功能正常的白种人志愿者, 进入Mayo Rochester的AD患者登记处。
Patients: We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Aβ levels.
患者：我们随访了563例认知功能正常白种老年人志愿者(平均年龄78岁,62%女性),在检测血浆Aβ基线水平后至少有1次随访记录.
Main Outcome Measures: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart.
主要研究方法：主要输出结果（检测指标）是发展为MCI或AD所需的时间。其次是年认知功能改变率，这些患者均有3-7年间隔不等的Mattis痴呆评定量表评估值。
Results: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Aβ42/Aβ40 ratios in the lower quartiles showed significantly greater risk of MCI orAD(P=.04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Aβ42/Aβ40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Aβ42/Aβ40 ratios had greater cognitive decline (P=.02).
结果：在随访中，53例患者发展为MCI或AD。血浆Aβ42/Aβ40比值在下四分位数者，MCI或AD的患病风险明显增高(P=0.04, 按年龄和载脂蛋白E基因型进行校正)。对比在最低与最高四分位数间的血浆Aβ42/Aβ40比值，得出相对风险为3.1（95%可信区间1.1-8.3）。在按年龄和载脂蛋白E基因型校正后，应用痴呆评定量表数值的年变化率为输出变量作回归分析，结果显示低血浆Aβ42/Aβ40比值者有更高的认知功能下降(P=.02)。
Conclusion: The plasma Aβ42/Aβ40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.
结论：血浆Aβ42/Aβ40比值可能对判断认知功能正常的白种老年人发展为MCI或AD风险升高是一种有用的发病前生物标记.
Arch Neurol. 2007;64:354-362

Class I Recommendations

Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class I, Level of Evidence A). Physicians should review the criteria outlined in Table 11 (which are modeled on those used in the NINDS trial) to determine the eligibility of the patient. A recommended regimen for observation and treatment of the patient is described in Table 12. This recommendation has not changed from previous statements.

Besides bleeding complications, physicians should be aware of the potential side effect of angioedema that may cause partial airway obstruction (Class I, Level of Evidence C). This recommendation has been added since the previous guidelines.

I级推荐
推荐在经过选择的发病3小时内的缺血性卒中患者静脉给予推荐rtPA (0.9 mg/kg, 最大剂量 90 mg) (Class I, Level of Evidence A)。医生应根据表11列出的标准（根据NINDS试验所用的标准修改）来确定合格的患者。表12描述了对患者观察和治疗的推荐方案。此推荐与既往指南比没有改变。

除了出血并发症外，医生亦应该知道潜在的血管性水肿副作用，这可导致气道部分阻塞 (Class I, Level of Evidence C)。此推荐与既往指南比是新增加的。

Class II Recommendations

A patient whose blood pressure can be lowered safely with antihypertensive agents may be eligible for treatment, and the physician should assess the stability of the blood pressure before starting rtPA (Class IIa, Level of Evidence . An elevated blood pressure that requires a continuous infusion of sodium nitroprusside may not be sufficiently stable for the patient to receive rtPA. However, because time is limited, most patients with markedly elevated blood pressure cannot be managed adequately and still meet the 3-hour requirement. This recommendation has not changed from previous guidelines.

A patient with a seizure at the time of onset of stroke may be eligible for treatment as long as the physician is convinced that residual impairments are secondary to stroke and not a postictal phenomenon (Class IIa, Level of Evidence C). This recommendation differs from the previous statements and represents a broadening of eligibility for treatment with rtPA.

II级推荐

可以通过抗高血压药物将血压安全降低的患者可能是治疗的合适患者，医生在给予rtPA前应评价血压的稳定性(Class IIa, Level of Evidence )。需要持续输注硝普钠来控制增高的血压的患者，其血压对接受rtPA治疗来说是不够稳定的。然而，由于时间有限，大部分血压明显增高的患者，不可能充分的控制血压后还能符合3小时的要求。此推荐与既往指南比没有改变。

脑卒中发病时伴有癫痫发作的患者，只要医生确信残留的功能缺损是由脑卒中引起的，而不是发作后现象，则可能是治疗的合适患者(Class IIa, Level of Evidence C)。此推荐与既往陈述不同，代表了rtPA治疗入选条件的增宽。

Class III Recommendations

The intravenous administration of streptokinase for treatment of stroke is not recommended (Class III, Level of Evidence A). This recommendation has not changed from previous guidelines.

The intravenous administration of ancrod, tenecteplase, reteplase, desmoteplase, urokinase, or other thrombolytic agents outside the setting of a clinical trial is not recommended (Class III, Level of Evidence C). This recommendation is new.

III级推荐

不推荐静脉给予链激酶治疗脑卒中(Class III, Level of Evidence A)。此推荐与既往指南比没有改变。

不推荐临床试验目的外静脉给予安克洛酶、替奈普酶、瑞替普酶、去氨普酶、尿激酶或者其他血栓溶解剂 (Class III, Level of Evidence C)。此推荐是新推荐。

Class I Recommendations

Intra-arterial thrombolysis is an option for treatment of selected patients who have major stroke of <6 hours’ duration due to occlusions of the MCA and who are not otherwise candidates for intravenous rtPA (Class I, Level of Evidence . This recommendation has not changed since previous guidelines.

Treatment requires the patient to be at an experienced stroke center with immediate access to cerebral angiography and qualified interventionalists. Facilities are encouraged to define criteria to credential individuals who can perform intra-arterial thrombolysis (Class I, Level of Evidence C). This recommendation has been added since previous guidelines.

I级推荐

发病6小时内的大脑中动脉闭塞，且不适合静脉rtPA溶栓的大卒中，动脉内溶栓对经过选择的患者是一个选择(Class I, Level of Evidence .。此推荐与既往指南比没有改变。

患者需要在有经验的脑卒中中心，该中心有即时的脑血管造影检查及取得资格的介入学家。鼓励相关机构对可执行动脉内溶栓治疗的人员制定标准（Facilities are encouraged to define criteria to credential individuals who can perform intra-arterial thrombolysis） (Class I, Level of Evidence C)。此推荐是上次指南起增加的。

Class II Recommendation

Intra-arterial thrombolysis is reasonable in patients who have contraindications to use of intravenous thrombolysis, such as recent surgery (Class IIa, Level of Evidence C). This recommendation was not included in the previous guideline.

II级推荐
动脉内溶栓对有静脉溶栓禁忌症（例如近期的手术）的患者是合理的。(Class IIa, Level of Evidence C)。此推荐在既往的指南中未包括在内。

Class III Recommendation

The availability of intra-arterial thrombolysis should generally not preclude the intravenous administration of rtPA in otherwise eligible patients (Class III, Level of Evidence C). This recommendation has not changed from previous guidelines.

III级推荐

动脉内溶栓不能妨碍对合适的患者进行静脉rtPA治疗(Class III, Level of Evidence A)。此推荐与既往指南比没有改变。

Class I Recommendations

The oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients (Class I, Level of Evidence A). This recommendation has changed in that a dose of aspirin is now included.

I级推荐

推荐对大多数的脑卒中患者发病24~48小时内口服阿司匹林治疗（初始剂量325 mg）(Class I, Level of Evidence A)。此推荐有改变，包括了阿司匹林的剂量（This recommendation has changed in that a dose of aspirin is now included）。

Class III Recommendations

Aspirin should not be considered a substitute for other acute interventions for treatment of stroke, including the intravenous administration of rtPA (Class III, Level of Evidence . These recommendations have not changed from previous statements.

The administration of aspirin as an adjunctive therapy within 24 hours of thrombolytic therapy is not recommended (Class III, Level of Evidence A). This recommendation has not changed.

The administration of clopidogrel alone or in combination with aspirin is not recommended for the treatment of acute ischemic stroke (Class III, Level of Evidence C). This recommendation was not included in the previous statement. The panel supports research testing the usefulness of emergency administration of clopidogrel in the treatment of patients with acute stroke.
Outside the setting of clinical trials, the intravenous administration of antiplatelet agents that inhibit the glycoprotein IIb/IIIa receptor is not recommended (Class III, Level of Evidence B. This recommendation has been added since the last guideline was published.

III级推荐

阿司匹林不能作为其他脑卒中急性期干预治疗的替代，包括静脉给予rtPA (Class III, Level of Evidence 。此推荐与既往指南比没有改变。

不推荐溶栓治疗24小时内作为辅助治疗给予阿司匹林(Class III, Level of Evidence A)。此推荐没有改变。

不推荐单用氯吡格雷或与阿司匹林联用治疗急性缺血性卒中 (Class III, Level of Evidence C)。此推荐既往的声明里没有包括。写作小组支持急诊给予氯吡格雷治疗急性脑卒中有效性的研究。

除临床试验外，不推荐静脉给予抑制糖蛋白IIb/IIIa 受体的抗血小板药物(Class III, Level of Evidence . 此推荐于上次指南发布后增加。

Class I Recommendation

In exceptional cases, a physician may prescribe vasopressors to improve cerebral blood flow. If drug-induced hypertension is used, close neurological and cardiac monitoring is recommended (Class I, Level of Evidence C). This recommendation has been added since the previous guideline was published.

I级推荐

在特殊的病例，医生可能给予血管升压药物来改善脑灌注。推荐在应用药物诱导高血压治疗时，监测神经及心脏功能(Class I, Level of Evidence C)。此推荐于上次指南发布后增加。

Class III Recommendation

Drug-induced hypertension, outside the setting of clinical trials, is not recommended for treatment of most patients with acute ischemic stroke (Class III, Level of Evidence . This recommendation has been added since the previous guideline was published.

III级推荐

不推荐药物诱导的高血压用于临床试验以外的大多数急性缺血性脑卒中患者的治疗(Class III, Level of Evidence 。此推荐于上次指南发布后增加。

Class II Recommendations

Although the MERCI device is a reasonable intervention for extraction of intra-arterial thrombi in carefully selected patients, the panel also recognizes that the utility of the device in improving outcomes after stroke is unclear (Class IIb, Level of Evidence . This recommendation has been added since the previous guideline. The panel also recommends that the device be studied in additional clinical trials that will define its role in the emergency management of stroke. This is the first time that a panel has made a recommendation about endovascular treatment of patients with acute ischemic stroke.

The usefulness of other mechanical endovascular treatments is not established (Class IIb, Level of Evidence C). These devices should be used in the setting of clinical trials. This recommendation has not changed from previous guidelines.

II级推荐
虽然MERCI装置在经过仔细选择的患者是动脉内取栓的合理的干预方法，写作小组也认识此装置到对改善卒中后的转归效果并不清楚(Class IIb, Level of Evidence B )。此推荐于上次指南增加。写作小组同时推荐进行另外的临床试验来确定该装置在脑卒中急诊处理中的作用。这是写作小组首次对急性缺血性卒中的血管内治疗进行推荐。

其他血管内机械装置的效用还不确定(Class IIb, Level of Evidence C)。这些装置用于临床试验目的。此推荐较前指南没有改变。

Long-Term Effect of Diabetes and Its Treatment on Cognitive Function

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group*

N Engl J Med 2007;356:1842-52.

Background
Long-standing concern about the effects of type 1 diabetes on cognitive ability has increased with the use of therapies designed to bring glucose levels close to the nondiabetic range and the attendant increased risk of severe hypoglycemia.

Methods
A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests. Glycated hemoglobin levels were measured and the frequency of severe hypoglycemic events leading to coma or seizures was recorded during the follow-up period. We assessed the effects of original DCCT treatment-group assignment, mean glycated hemoglobin values, and frequency of hypoglycemic events on measures of cognitive ability, with adjustment for age at baseline, sex, years of education, length of follow-up, visual acuity, self-reported sensory loss due to peripheral neuropathy, and (to control for the effects of practice) the number of cognitive tests taken in the interval since the start of the DCCT.

Results
Forty percent of the cohort reported having had at least one hypoglycemic coma or seizure. Neither frequency of severe hypoglycemia nor previous treatment-group assignment was associated with decline in any cognitive domain. Higher glycated hemoglobin values were associated with moderate declines in motor speed (P = 0.001) and psychomotor efficiency (P<0.001), but no other cognitive domain was affected.

Conclusions
No evidence of substantial long-term declines in cognitive function was found in a large group of patients with type 1 diabetes who were carefully followed for an average of 18 years, despite relatively high rates of recurrent severe hypoglycemia. (ClinicalTrials.gov number, NCT00360893.)

Long-Term Effect of Diabetes and Its Treatment on Cognitive Function

糖尿病及其治疗对认知功能的长期影响

Background Long-standing concern about the effects of type 1 diabetes on cognitive ability has increased with the use of therapies designed to bring glucose levels close to the nondiabetic range and the attendant increased risk of severe hypoglycemia.

背景：长期以来，人们一直在关注1型糖尿病对认知功能的影响，随着治疗的目标定为将血糖水平降至非糖尿病患者的范围，以及由此而生的严重低血糖风险的增加，人们对此的关注也在增加。

Methods A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests. Glycated hemoglobin levels were measured and the frequency of severe hypoglycemic events leading to coma or seizures was recorded during the follow-up period. We assessed the effects of original DCCT treatment-group assignment, mean glycated hemoglobin values, and frequency of hypoglycemic events on measures of cognitive ability, with adjustment for age at baseline, sex, years of education, length of follow-up, visual acuity, self-reported sensory loss due to peripheral neuropathy, and (to control for the effects of practice) the number of cognitive tests taken in the interval since the start of the DCCT.

方法：DCCT及其随访的EDIC研究入选的1144名1型糖尿病患者，在DCCT研究入组时（平均年龄27岁）及18年后应用相同的成套的综合认知功能测验。随访期间，测量糖化血红蛋白水平并记录导致昏迷或癫痫发作的严重低血糖事件的频度。我们评价了DCCT初始治疗分组、糖化血红蛋白均值及低血糖事件频度对测试的认知功能的影响，调整了基线年龄，性别，受教育年限、随访时间的长短、视力、患者自己汇报的由周围神经病变导致的感觉丧失及（为控制练习的影响）DCCT开始后所做的认知功能测验的数目。

Results Forty percent of the cohort reported having had at least one hypoglycemic coma or seizure. Neither frequency of severe hypoglycemia nor previous treatment-group assignment was associated with decline in any cognitive domain. Higher glycated hemoglobin values were associated with moderate declines in motor speed (P = 0.001) and psychomotor efficiency (P<0.001), but no other cognitive domain was affected.

结果：40％的患者报告了发生过至少一次低血糖导致的昏迷或癫痫发作。严重低血糖的发生频度及之前的治疗分组与任何认知功能域的降低均无关系。高糖化血红蛋白值与运动速度中度下降(P = 0.001) 及精神运动效率(P<0.001)相关，但无其他的认知功能域受影响。

Conclusions No evidence of substantial long-term declines in cognitive function was found in a large group of patients with type 1 diabetes who were carefully followed for an average of 18 years, despite relatively high rates of recurrent severe hypoglycemia. (ClinicalTrials.gov number, NCT00360893.)

结论：一组大宗的1型糖尿病患者严密随访18年的观察发现，尽管存在相对高的严重低血糖复发率，并无重要的认知功能长期下降的证据。(ClinicalTrials.gov number, NCT00360893.)

Targeting Platelets in Acute Experimental Stroke: Impact of Glycoprotein Ib, VI, and IIb/IIIa Blockade on Infarct Size, Functional Outcome, and Intracranial Bleeding
[Original Articles: Stroke]
Kleinschnitz, Christoph MD*; Pozgajova, Miroslava PhD; Pham, Mirko MD; Bendszus, Martin MD; Nieswandt, Bernhard PhD*; Stoll, Guido MD*

Abstract
Background—: Ischemic stroke is a frequent and serious disease with limited treatment options. Platelets can adhere to hypoxic cerebral endothelial cells by binding of their glycoprotein (GP) Ib receptor to von Willebrand factor. Exposure of subendothelial matrix proteins further facilitates firm attachment of platelets to the vessel wall by binding of collagen to their GPVI receptor. In the present study, we addressed the pathogenic role of GPIb, GPVI, and the aggregation receptor GPIIb/IIIa in experimental stroke in mice.

Methods and Results—: Complete blockade of GPIb[alpha] was achieved by intravenous injection of 100 µg Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery occlusion. At 24 hours after transient middle cerebral artery occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining. In mice treated with anti-GPIb[alpha] Fab 1 hour before middle cerebral artery occlusion, ischemic lesions were reduced to [almost equal to]40% compared with controls (28.5±12.7 versus 73.9±17.4 mm3, respectively; P<0.001). Application of anti-GPIb[alpha] Fab 1 hour after middle cerebral artery occlusion likewise reduced brain infarct volumes (24.5±7.7 mm3; P<0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4±19.1 mm3; P<0.05). Importantly, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)2 fragments had no positive effect on stroke size and functional outcome but increased the incidence of intracerebral hemorrhage and mortality after transient middle cerebral artery occlusion in a dose-dependent manner.

Conclusions—: Our data indicate that the selective blockade of key signaling pathways of platelet adhesion and aggregation has a different impact on stroke outcome and bleeding complications. Inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix may offer a novel and safe treatment strategy in acute stroke.

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circulation Volume 115(17), 1 May 2007, pp 2323-2330

Damage to the Insula Disrupts Addiction to Cigarette Smoking
Nasir H. Naqvi,1 David Rudrauf,1,2 Hanna Damasio,3,4 Antoine Bechara1,3,4*
A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.

1 Division of Cognitive Neuroscience, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
2 Laboratory of Computational Neuroimaging, Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
3 Dornsife Cognitive Neuroscience Imaging Center, SGM 501, University of Southern California, Los Angeles, CA 90089, USA.
4 Brain and Creativity Institute, HNB B26, University of Southern California, Los Angeles, CA 90089, USA.

* To whom correspondence should be addressed. E-mail: bechara@usc.edu

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Science 26 January 2007:
Vol. 315. no. 5811, pp. 531 - 534
DOI: 10.1126/science.1135926