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Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders.
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PMID:Neuroprotection by the metabolic antioxidant alpha-lipoic acid. 895 63

In the last two decades, a tremendous amount of knowledge has been accumulated in various fields of biomedical research that discloses mechanisms of platelet/leukocyte/endothelium interactions. Occupying a strategically important location between circulating blood and underlying tissues, the endothelium effectively modulates both the functional state of the blood cells and the tone of vascular smooth muscle by generating or metabolizing a host of humoral substances. Under normal conditions, the endothelium releases agents with predominantly vasodilator and antiaggregant/anticoagulant activity that prevent thrombotic and angiospastic disorders. However, a variety of pathophysiological stimuli may trigger endothelial reorganization with the expression of different prothrombotic factors and activation of platelets and leukocytes that, combined, leads to blood cell adhesion to the endothelial monolayer, aggregation as thrombi, and the formation of numerous spasmogenic substances. Activation of the blood cells in the vicinity of the endothelium may induce endothelial dysfunction/injury, resulting in impairment of normal endothelial antispasmodic control. Within the microcirculatory bed, intravascular activation of the blood cells leads to scattered microvessel plugging, increased vascular permeability, edema formation, and cytotoxic actions of blood cell-released agents on the underlying tissue. A growing body of evidence suggests that these processes may be involved in pathophysiological cerebrovascular reactions including symptomatic angiospasm following subarachnoid hemorrhage, segmental occlusive constriction in atherosclerotic cerebral arteries, and constrictive vasomotion in microvessels. A perturbation in the delicate equilibrium between blood cells and endothelium in the microcirculation seems to be a factor aggravating ischemic brain damage or even primarily causing focal cerebral ischemia and scattered microinfarctions. Increased predisposition to these pathophysiologic events might influence unfavorably the effects of risk factors such as hypercholesterolemia, hypertension, and diabetes on cerebrovascular morbidity and mortality. Although the importance of blood cell/endothelium imbalance appears to be clear, its pharmacologic regulation is not sufficiently established. Some drugs have been demonstrated to limit platelet and/or leukocyte activity and protect the endothelial defense mechanisms, but the optimal therapeutic strategy has yet to be elaborated.
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PMID:Cerebrovascular reactivity: role of endothelium/platelet/leukocyte interactions. 905 80

Nonvalvular atrial fibrillation is associated with an overall risk of stroke of 4.5% per year. Advancing age, prior stroke or transcient cerebral ischemia, diabetes and hypertension are known risk factors. Ischemic stroke in patients with atrial fibrillation are generally more severe than ischemic stroke in patients with sinus rhythm. Warfarin is effective for primary and secondary prevention of ischemic stroke, reducing the risk by 68%. The effect of aspirin is still controversial, reducing the risk by 18-44%. Recent clinical trials have investigated the effect of warfarin given at a very low intensity either alone or combined with aspirin. The results from the SPAF III study demonstrated that a combination of mini-intensity warfarin plus aspirin was insufficient for stroke prevention in atrial fibrillation. Other trials now indicate, that oral anticoagulation at INR-values below 2.0 is not effective for stroke prevention in these patients. It is recommended that patients at high risk of stroke are treated with warfarin at an intensity of INR 2.0-3.0. Patients younger than 65 without other risk factors can be given aspirin 325 mg/day. The present clinical challenge is to ensure effective and safe oral anticoagulation to patients with atrial fibrillation at high risk of stroke.
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PMID:Prevention of thromboembolic events in atrial fibrillation. 919 82

A 65-year-old man who had a history of diabetes mellitus visited a hospital for recent memory disturbance. MR angiography showed stenoses of the main trunks of the intracranial arteries. He was admitted to our hospital, and angiography revealed occlusion of the left cervical internal carotid and right middle cerebral arteries, and stenoses of the right internal carotid, right anterior cerebral, left vertebral, and right posterior cerebral arteries. There was collateral circulation formed from the left external carotid and left posterior cerebral arteries. Basal moyamoya vessels were also observed. 123I-IMP SPECT showed low perfusion of the right cerebral hemisphere, and response to acetazolamide was poor. Based on the angiographical findings and the presence of diabetes mellitus, the patient was diagnosed as having quasi-moyamoya disease. Vascular reconstructive surgery was indicated. Since there was no recipient artery adequate for STA-MCA anastomosis, encephalo-duro-arterio-synangiosis was performed on the right side. Postoperatively, the patient's recent memory improved gradually, and angiography performed 7 months after the operation revealed neovascularization from the superficial and deep temporal arteries. Although indirect bypass surgery has been applied mainly to child moyamoya disease, its effectiveness for cerebral ischemia in adult patients has also been reported, particularly in cases with misery perfusion. Neovascularization with indirect bypass surgery can be expected if the patient is under misery perfusion, even in elderly patients.
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PMID:[Neovascularization after encephalo-duro-arterio-synangiosis in elderly quasi-moyamoya disease: a case report]. 930 Apr 48

In the general population, peripheral atherosclerosis is a strong predictor of cardiovascular disease and death. In patients with known coronary artery disease, it is unclear whether the presence of additional noncoronary atherosclerosis is of further prognostic value. In the Bypass Angioplasty Revascularization Investigation, 5-year outcome was compared between patients with and without clinically evident noncoronary atherosclerosis. Within the subgroup with noncoronary atherosclerosis, surgery, and angioplasty treatment strategies were compared. Noncoronary atherosclerosis was defined as claudication, peripheral vascular surgery, abdominal aortic aneurysm, history of cerebral ischemia, or carotid disease. Among 1,816 patients, 303 (17%) had noncoronary atherosclerosis. These patients were more likely to have a history of congestive heart failure, diabetes, and hypertension, and were more likely to smoke. Coronary angiographic variables were similar between the 2 groups. Five-year survival was 75.8% for patients with noncoronary atherosclerosis and 90.2% for those without (p < 0.001). The adjusted relative risk of death was 1.7 for any noncoronary atherosclerosis, 1.5 for lower extremity disease alone, 1.7 for cerebral disease alone, and 2.3 for both conditions. Among the 303 patients with noncoronary atherosclerosis, the adjusted relative risk of death for surgery versus angioplasty was 0.87 (p = 0.40). However, the study has limited power to detect a treatment effect in this small subgroup. Thus, patients with combined coronary and clinically evident noncoronary atherosclerosis are a high-risk group with significantly worse long-term outcome compared patients with isolated coronary disease.
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PMID:Long-term prognostic value of clinically evident noncoronary vascular disease in patients undergoing coronary revascularization in the Bypass Angioplasty Revascularization Investigation (BARI). 948 22

The factor II G20210A mutation is a recently identified congenital risk factor for venous thrombosis. Its role in artery disease is still undefined. We investigated 72 patients (35 male and 37 female) with documented ischemic stroke occurred before 50 years of age and without risk factors such as diabetes, hypertension, and hyperlipidemia; 198 thrombosis-free individuals were investigated as the control group. We found 7 heterozygotes (9.7%) and 2 homozygotes (2.7%) for the mutant factor II allele among the patients and 5 heterozygotes (2.5%) among the controls; the mutant factor II allele frequency in the patient group (7.6%, 95% confidence interval [CI], 3.3 to 11.9) was significantly higher than in the controls (1.2%; 95% CI, 0.1 to 2.3; P = .0001). The prevalence of other investigated mutant alleles (factor V G1691A, methylenetetrahydrofolate reductase C677T) did not significantly differ between the two groups. The odds ratio for ischemic stroke associated with the carriership of the mutant factor II allele (both heterozygous and homozygous genotypes) was 5.1 (95% CI, 1.6 to 16.3). Heterozygous genotype was associated with a 3.8-fold increased risk for cerebral ischemia (95% CI, 1.1 to 13.1); in particular, assuming an expected prevalence of homozygotes in the general population of 1.6 to 10,000 according to the Hardy-Weinberg equilibrium, the risk associated with the homozygous genotype was estimated exceedingly high, being increased 208-fold.
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PMID:Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. 957 89

Anticardiolipin antibodies (aCL) are a risk factor for cerebral ischemia. In migraine, the association is controversial, with widely varying results in different small series. The controversy in part may be due to the inherent difficulty in distinguishing the transient focal neurologic events (TFNE) of migraine from TIA. To assess the frequency of aCL in migraine, we prospectively evaluated consecutive adults under 60 years of age with migraine without aura and with recent TFNE (<24-hour duration) clinically suggestive of either migraine with aura or TIA. We concomitantly enrolled persons with no CNS disease. Each person was interviewed and had blood drawn for solid-phase ELISA with IgG and IgM aCL isotyping. Neuroradiologic studies were reviewed. Patients with TFNE were followed every 6 months for the duration of the 3-year study. The frequency of aCL positivity (IgG >20, IgG >40, IgM >7.5) for the 645 patients with TFNE (8.8, 3.1, 4.2%), the 518 persons in the TFNE subgroup with migraine with aura (8.9, 3.3, 4.1%), the 497 persons with migraine without aura (7.0, 2.0, 3.6%), and the 366 control subjects (9.3, 3.6, 3.9%) did not differ significantly between groups. In TFNE patients with elevated aCL titer, the association was positive with diabetes mellitus, TFNE duration <15 minutes, and diplopia and was negative with hemiparesis, tinnitus, and family history of stroke. Findings on imaging consistent with cerebral ischemia were more frequent in aCL-positive persons. The short-term risk of stroke was uniformly low. In young persons, aCL is not associated with migraine or with TFNE, although diabetes mellitus, negative family history of stroke, and brief duration of symptoms (including diplopia) may predict immunoreactivity. Imaging studies suggest an ischemic etiology of TFNE in this cohort.
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PMID:Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events: a prospective study. 1010 49

A matched case-control study (1:1) was carried out among 122 hospitalized patients with Binswanger's leukoencephalopathy to explore the possible risk factors of BE. Data collected were processed with conditional logistic regression analysis. Individual logistic analysis showed that family history of vascular dementia, history of hypertension, diabetes, coronary heart disease, transient cerebral ischemic attacks (TIAs), cerebral ischemia, cerebral hemorrhage, renal disfunction, alcohol intake smoking were risk factors while healthy life style played protective effect. Body weight index, average family income, education level and type A behavior scores did not show close relations with BE. Multiple regression analysis showed that hypertension, TIAs, coronary heart disease, diabetes and family history of vascular dementia were independent risk factors.
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PMID:[A study on the risk factors of Binswanger's leukoencephalopathy (BE)]. 981 23

The purpose of this study was to determine the prevalence, clinical significance, and embolic potential of thoracic aortic plaque in patients with cerebral ischemia and to further study the correlation of aortic plaque with carotid or heart disease. We used transesophageal echography (TEE) to evaluate potential source of emboli in aortic arch and heart, and duplex in carotid artery. A atherosclerotic lesion of aortic arch was defined as normal (0), mild plaque (1), moderate plaque (2) and protruding plaque or mobile plaque (3). 75 of 100 patients were found to have atherosclerotic lesion in aortic arch. 16 of 75 patients over degree 2 exhibited no pathologic finding of heart or carotid and 4 of 16 patients were classified as degree 3. The pathologic findings of heart and carotid were significantly correlated with aortic plaque. Age, diabetes, CAD were also significantly correlated with aortic plaque. Aortic atherosclerosis was common in cerebral ischemia. Aortic plaque might be responsible for not only some unexplained embolic events, but also for some of the embolic stroke in patient who have carotid artery or heart disease. Age, diabetes, CAD might be important risk factors in the development of atherosclerotic lesion in the aortic arch.
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PMID:Aortic plaque as a potential cause for cerebral ischemia. 981 73

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. Excessive activation of PARP, however, can deplete tissue stores of nicotinamide adenine dinucleotide (NAD), the PARP substrate which, with the resultant depletion of ATP, leads to cell death. In many cases of CNS damage, for example vascular stroke, nitric oxide release is a key stimulus to DNA damage and PARP activation. In conditions as diverse as focal cerebral ischaemia, myocardial infarction and toxin-induced diabetes, PARP inhibitors and PARP gene deletion afford dramatic protection from tissue damage. Accordingly, PARP inhibitors could provide novel therapeutic approaches in a wide range of clinical disorders.
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PMID:Poly (ADP-ribose) polymerase, nitric oxide and cell death. 1032 3


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