Katalin Sas

Aspirin resistance in stroke: 2004

Aspirin is a well-established medication in the treatment of atherothrombotic vascular disease. However, despite aspirin treatment a substantial number of patients experience recurring ischaemic episodes. Aspirin resistance denotes those situations when it is unable to protect individuals from thrombotic complications, or when it fails to produce an anticipated effect in laboratory tests of platelet function. There are various laboratory techniques with which to evaluate the effectiveness of aspirin and other antiplatelet drugs. It has been estimated that in 5-60% of patients, aspirin does not achieve adequate efficacy in various measures of platelet activity. Some studies have revealed that vascular patients shown by laboratory tests to be aspirin-resistant are at an increased risk of major vascular events. The suggested mechanisms of aspirin resistance, among others, include genetic polymorphisms, alternate pathways of platelet activation, aspirin-insensitive thromboxane biosynthesis, drug interactions, or low aspirin dose. An increase in the dosage of aspirin or conversion to clopidogrel or clopidogrel plus aspirin might be beneficial in the management of those patients who are aspirin resistant. Additional work is required to improve and validate laboratory tests of platelet function, so that they may become useful tools for selecting the most appropriate antiplatelet therapy for an individual patient. Improvements in antiplatelet treatment strategies in the future should lead to a reduction in premature vascular events.

Kynurenine diminishes the ischemia-induced histological and electrophysiological deficits in the rat hippocampus

The neuroprotective effect of L-kynurenine sulfate (KYN), a precursor of kynurenic acid (KYNA, a selective N-methyl-D-aspartate receptor antagonist), was studied. KYN (300 mg/kg i.p., applied daily for 5 days) appreciably decreased the number of injured pyramidal cells from 1850+/-100/mm(2) to 1000+/-300/mm(2) (p<0.001) in the CA1 region of the hippocampus in the four-vessel occlusion (4VO)-induced ischemic adult rat brain. A parallel increase in the number of intact, surviving neurons was demonstrated. Post-treatment with KYN (applied immediately right after reperfusion) proved to be much less effective. In parallel with the histology, a protective effect of KYN on the functioning of the CA1 region was observed: long-term potentiation was abolished in the 4VO animals, but its level and duration were restored by pretreatment with KYN. It is concluded that the administration of KYN elevates the KYNA concentration in the brain to neuroprotective levels, suggesting its potential clinical usefulness for the prevention of neuronal loss in neurodegenerative diseases.

Favorable Early Outcome of Carotid Artery Stenting Without Protection Devices

Background and Purpose— Protection devices are increasingly used in carotid artery stenting. However, no randomized trial has been conducted to evaluate the efficacy of such devices, and arguments have also been formulated against their routine use. We set out to investigate the complication rates associated with carotid artery stenting performed without protection devices. Applicability of covered stents in the carotid system was also evaluated. Methods— Between January 2001 and July 2003, 245 consecutive patients (260 hemispheres) underwent carotid artery stenting. No protection devices were applied. Covered stents were implanted in 31 (12.1%) cases. The incidence of complications during the intervention and the subsequent 30-day follow-up period was recorded. Results— The technical success rate was 98.8%. One postprocedural nonneurological death (0.4%) occurred. Neurological complications (inclusive of transient ischemic attacks) were observed in 14 cases (5.4%). The rate of major complications (death, major stroke, and myocardial infarction) was 1.6% among the symptomatic and 1.5% among the asymptomatic cases. The rate of minor strokes was 3.2% in the symptomatic and 1.5% in the asymptomatic group. Of the neurological complications, 64.3% occurred postprocedurally. No ipsilateral neurological complications were detected in the subgroup treated with covered stents. Conclusions— Carotid artery stenting without protection devices appears to be safe. Most of the neurological complications could not have been prevented with protection devices, because they occurred after the intervention. The application of covered stents may reduce the rate of embolization-related complications in the periprocedural period.

Neuroprotection achieved in the ischaemic rat cortex with l-kynurenine sulphate

L-kynurenine is a metabolic precursor of kynurenic acid, which is one of the few known endogenous N-methyl-D-aspartate receptor inhibitors. In contrast with kynurenic acid, L-kynurenine is transported across the blood-brain barrier, and it may therefore come into consideration as a therapeutic agent in certain neurobiological disorders, e.g. ischaemia-induced events. The present study evaluated the effect of L-kynurenine administration (300 mg/kg i.p.) on the global ischaemic brain cortex both pre- and post-ischemic intervention. The statistical evaluation revealed that L-kynurenine administration beneficially decreased the number of neurones injured per mm(2) in the cortex, not only in the pre-treated animals, but also in those which received L-kynurenine after the ischaemic insult. It is concluded that even the post-traumatic administration of L-kynurenine may be of substantial therapeutic benefit in the treatment of global brain ischaemia. This is the first histological proof of the neuroprotective effect achieved by the post-traumatic administration of L-kynurenine in the global ischaemic cortex.

Hippocampal (CA1) activities in Wistar rats from different vendors Fundamental differences in acute ischemia

Two-vessel occlusion, a frequently used model of global cerebral ischemia in rats, results in a dysfunction predominantly within the CA1 field of the hippocampus; it induces many processes with different time-scales. However, the great divergence in the results of the studies reported in the literature suggests valuable differences in response to hypoperfusion-induced ischemia among the laboratory rats used in these studies. In the present work, the acute effects of two-carotid occlusion-induced global ischemia (2VO) on the CA3 stimulation-evoked population spike activity in the CA1 region of Wistar rats from different suppliers (Charles-River and Harlan) were compared. In the acute electrophysiological experiments, the hippocampal CA1 responses revealed that the Charles-River rats immediately compensated the 2VO much better than did the Harlan rats. However, 3 days later, no difference could be observed between the CA1 activities of these rats. The presented data show that the Wistar rats from different vendors represent an important source of variability in the results of acute experiments on the hippocampal ischemia. These observations draw attention to the importance of the careful choice of the laboratory rats (both strains and breeds) used in such experiments.

Dementia, stroke and migraine — Some common pathological mechanisms

Dementia, stroke and migraine are very common neurological disorders affecting a large percentage of the population, and leading to a high degree of disability. Often, adequate therapy is not available. Although the symptoms, the progression and the outcome differ in these disorders, to some extent they may share some common pathophysiological mechanisms. The genetic background, an energy deficit, and excitotoxicity, vascular and thrombotic properties can influence all three disorders, resulting in a neuronal dysfunction, increased cellular vulnerability, neurodegeneration and ultimately cell death. All these cellular events occur in dementias and stroke, moreover recent studies suggest that, besides a dysfunction, neuronal damage may be an issue in migraine too. One of the most central events in the multiple mechanisms involved in the pathogenesis of these disorders is a metabolic disturbance of certain brain cells. As mitochondria provide the cells with energy, realization of the importance of these organelles in the aetiopathogenesis of several disorders has emerged in recent years. This review surveys the most important features of the pathogenesis of dementia, stroke and migraine from the aspect of mitochondrial malfunction highlighting some of the considerable connections between these neurological disorders.

The pentylenetetrazole-induced activity in the hippocampus can be inhibited by the conversion of l-kynurenine to kynurenic acid: An in vitro study

The kynurenine pathway converts tryptophan into various compounds, including L-kynurenine, which in turn can be converted into the excitatory amino acid receptor antagonist kynurenic acid. The ionotropic glutamate receptors have been considered to be attractive targets for new anticonvulsants in neurological disorders such as epileptic seizure. This study was designed to examine the conversion of L-kynurenine to kynurenic acid and to investigate the effects of kynurenic acid on pentylenetetrazole-treated rat brain slices, and in parallel to draw attention to the fact that a well-designed in vitro model has many advantages in pharmacological screening. Schaffer collateral stimulation-evoked field EPSPs were recorded from area CA1 of rat hippocampal slices in vitro; drugs were bath-applied. Pretreatment with the kynurenic acid precursor L-kynurenine led to the elimination of the effect of pentylenetetrazole on hippocampal slices in vitro. N-Omega-nitro-L-arginine, which inhibits kynurenine aminotransferase I and II, abolished this neuroprotective effect. This study has furnished the first in vitro electrophysiological evidence that rat brain slices have the enzymatic capacity to convert exogenously administered L-kynurenine (16 microM) to kynurenic acid in an amount sufficient to protect them against pentylenetetrazole (1 mM)-induced hyperexcitability.

Effect of systemic administration of L-kynurenine on corticocerebral blood flow under normal and ischemic conditions of the brain in conscious rabbits.

&NA; Kynurenic acid, the only known endogenous antagonist of the excitatory amino acid receptors, exerts neuroprotective effect in focal cerebral ischemia. Kynurenic acid poorly while its bioprecursor, l‐kynurenine (L‐KYN) completely crosses the blood‐brain barrier. The aim of our study was to investigate the effect of intravenous l‐KYN (0.3, 1, and 3 mg/kg) on the normal and the unilateral carotid artery occlusion induced ischemic corticocerebral blood flow (cCBF) measured by hydrogen polarography in conscious rabbits. Administration of l‐KYN produced a significant increase in the normal cCBF; the peak values were recorded at the dose of 1 mg/kg (187% at 120 and 150 mins. respectively). The cCBF‐improving effect of l‐KYN was immediate and highly pronounced also in rabbits with carotid occlusion (peak value was 192% at 120 mins. at the dose of 1 mg/kg). Pretreatment with either atropine or N&ohgr;‐nitro‐L‐arginine‐methyl‐ester (L‐NAME) prevented the l‐KYN induced enhancement of the normal and the ischemic cCBF alike. It is suggested that the cCBF‐increasing effect of l‐KYN might be mediated by activation of cholinergic and nitric oxide pathways.

Stroke in essential thrombocythemia

BACKGROUND Our aim was to assess the incidence and the special characteristics of stroke, as a severe complication of patients diagnosed with essential thrombocythemia (ET). METHODS A retrospective analysis was carried out on 102 patients with ET enrolled and analyzed from the period between 1999 and 2012. Patients with one or more strokes were selected. The characteristics of stroke events, the medication, and the median platelet counts were revised. RESULTS One or more stroke events were revealed in 11 cases (4 males and 7 females) with a median age of 67 years [range: 45-82 years]. The median platelet count at hematological diagnosis was 658×10(9)/L [range: 514-1157×10(9)/L], while during the time of stroke it was 450×10(9)/L [range: 320-885×10(9)/L]. The median follow-up of the patients with stroke was 60 months [range: 19-127 months]. At the time of the stroke, almost all the patients (8/11 cases, 73%) were already on anti-platelet therapy, alone or in combination with cytoreductive therapy (e.g. hydroxyurea). Brain imaging modalities in most cases demonstrated periventricular and/or subcortical and/or basal ganglia lacunes or confluent chronic white matter ischemic lesions in all cerebral arterial regions. Most patients (9/11; 82%) presented at least two serious conventional vascular risk factors, which may have influenced both the clinical course and the morphologic alterations. No correlation was found between the platelet count and the occurrence of stroke. CONCLUSION Our findings lead us to suppose that ET may be regarded as a risk factor for stroke (mainly of ischemic, small-vessel type), and the early diagnosis and the personalized management of the patients global vascular risk in the treatment of ET may promote the prevention of further cerebrovascular events.

Neurological complications of pregnancy

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