Pathogenetic Role of Endothelial Dysfunction in Idiopathic Vestibulopathy.

Comparative analysis of the groups of patients with idiopathic bilateral vestibular hypofunction and a group of vestibulopathy patients with vertebrobasilar insufficiency demonstrated identity of the basic and additional diagnostic parameters in these syndromes as well as similarity in clinical diagnostic and anamnesis data. In all cases, functional assessment of endothelium-dependent vasodilation and selected biochemical marker sICAM-1 revealed endothelial dysfunction. Drug correction of endothelial dysfunction positively affected the manifestations of major and minor features of the syndrome, which confirmed the contribution of endothelial functional disturbances to the pathogenesis of bilateral vestibular hypofunction.

The effects of resveratrol on vasospasm after experimental subarachnoidal hemorrhage in rats.

BACKGROUND: Cerebral vasospasm remains a major cause of morbidity and mortality in patients with SAH. Although many pharmacologic agents and chemicals have been used to prevent and treat CV, the pathogenesis of that condition has not been established. We investigated the efficacy of resveratrol, a stilbene polyphenol and tyrosine kinase inhibitor that occurs naturally in grapes and red wine, in a murine basilar artery vasospasm model. METHODS: Forty-two Wistar albino rats were used in this study. The rats were divided into 3 groups of 14 animals each: the sham-operated control group (group 1), the vasospasm group (group 2), and the treatment group (group 3). In groups 2 and 3, autologous blood (0.3 mL) was injected into the cisterna magna. After that injection, the rats in group 3 received an intravenous injection of resveratrol (10 mg/kg) for 72 hours. The evaluation of the response to both the injection of autologous blood and treatment was based on biochemical markers in tissue and serum and on light microscopic findings from the basilar artery, which were collected at different intervals after experimental SAH. RESULTS: Endothelin-1 levels in brain tissue and serum were higher in the vasospasm group than in the control group (P < .05). In group 3 rats, the administration of resveratrol resulted in significantly lower ET-1 values than those in group 2. Brain and serum lipid peroxidation levels were markedly elevated in group 2 rats but decreased significantly after resveratrol treatment in group 3 rats (P < .05). Superoxide dismutase expression in brain tissue and serum was lower in group 2 rats than in sham-operated controls, and a significant increase in the SOD level was associated with resveratrol treatment. On examination via light microscopy 72 hours after SAH, the mean perimeters of the arterial lumen in groups 1, 2, and 3 were 719 +/- 16, 411.6 +/- 9, and 590.1 +/- 5.6 microm, respectively. The mean thickness of the arterial wall was as follows: in group 1, 11.1 +/- 0.8 microm; in group 2, 16.1 +/- 1.2 microm; and (after resveratrol treatment) in group 3, 13.4 +/- 0.6 microm. CONCLUSIONS: The results of our study showed that resveratrol induced the relaxation of smooth muscle in the wall of the basilar artery and may be provided with neuroprotection against cerebral ischemia in a rat model. These effects may be associated with the antioxidant and vasodilatory effects of resveratrol, which could prove to be an agent prophylactic against CV and to be therapeutic for individuals who experience that event.

Quantitative Blood Flow Assessment by Multiparameter Analysis of Indocyanine Green Video Angiography.

BACKGROUND: Measurements of quantitative blood flow are crucial during brain vascular surgery. Indocyanine green video angiography (ICG-VAG) is an accepted method of blood flow visualization; however, quantitative techniques have not yet been established. Thus, the aim of this study was to further develop ICG analysis for visualizing intraoperative flow changes. METHODS: We conducted basic experiments and clinical investigations to establish a relationship between ICG-VAG and measured blood flow. We evaluated several parameters and identified optimal indicators that precisely reflect blood (or fluid) flow. Both in vitro and in vivo studies were performed to calculate the interval between baseline and the intensity peak (Grad) and to measure actual flow rate. RESULTS: Grad and actual flow rate showed good exponential correlation, with R2 values of 0.90 in vitro and 0.82 in vivo. In a representative patient (case 3), we performed intraoperative flow analysis using FlowInsight, which identified a marked elevation in Grad on the brain surface. Because this observation is predictive of brain hyperperfusion, we used these data to carefully manage blood pressure postoperatively. CONCLUSIONS: Grad is the optimum parameter for estimating flow conditions. Although ICG-VAG provides only visual profiles of blood circulation in the brain, this procedure has the potential to be widely used in clinical situations. ICG-based flow measurement can be used to identify normal and abnormal blood flow conditions, such as graft flow and vascular pathology. The novelty of this technique is that the fluorescence intensity of Grad enables surgeons to quantitatively measure real blood flow.

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

Hypothermia reduces glutamate efflux in perilymph following transient cochlear ischemia.

The effect of hypothermia on ischemic injury of the cochlea in gerbils was studied with particular regard to glutamate efflux in the perilymph. Under normothermic conditions interruption of the blood supply to the cochlea for 15 min caused a remarkable elevation of the compound action potential (CAP) threshold, and an increase in perilymphatic glutamate. The CAP threshold recovered to some extent with reperfusion, but not to preischemic levels. CAP thresholds, under hypothermic conditions and with reperfusion, recovered promptly to near pre-ischemic levels, while glutamate concentration did not change. These results, together with electron microscopy studies, suggest that hypothermia prevents hearing loss primarily through reduction of glutamate efflux at the synopses between inner hair cells and primary afferent auditory neurons.

Cerebral blood flow and metabolism following superficial temporal artery to superior cerebellar artery bypass for vertebrobasilar occlusive disease.

In order to clarify the effectiveness of extracranial-intracranial bypass operations in patients with vertebrobasilar occlusive disease, the authors used positron emission tomography to investigate the cerebral blood flow (CBF) and metabolism of eight patients undergoing superficial temporal artery (STA)-superior cerebellar artery (SCA) bypass procedures. In the preoperative studies, CBF in the region of the posterior fossa was low and the oxygen extraction fraction (OEF) was high, the so-called "misery perfusion syndrome." Such changes were evident in both the posterior circulation and the anterior circulation regions. Postoperatively, there was a significant increase in CBF, a significant decrease in the OEF not only in the region of posterior circulation but also over the entire brain, and a disappearance of the uncoupling between CBF and oxygen metabolism. The STA-SCA bypass procedure is effective in improving CBF and metabolism in patients with vertebrobasilar occlusive disease.

Assessment of cerebral blood flow and metabolism in vertebrobasilar insufficiency with 133Xenon and 15O inhalation methods.

Assessment of hemodynamic parameters in patients who had transient basilar symptoms suggesting vertebrobasilar insufficiency requires a systematic and accurate detection of brainstem or cerebellar infarcts. Our aim was to detect with 133Xenon and 15O2 inhalation methods, a low flow state underlying vertebrobasilar insufficiency in a patient who had no impairment of cerebrovascular control related to infarction of brainstem or cerebellum. A woman with intermittent vertebrobasilar symptoms had an angiogram, magnetic resonance imaging and evaluation of hemodynamic parameters with vertebrobasilar circulation with 133Xenon inhalation and 15O inhalation methods MRI failed to show any border-zone or territorial infarcts or degenerative disease. Angiographic study showed significant arterial lesion involving vertebrobasilar vessels. A decrease of blood flow within vertebrobasilar circulation was observed according to 133Xenon and 15O inhalation methods. These preliminary results support the view that significant arterial changes within the vertebrobasilar system might account for a low flow state. 15O2 inhalation method might be in agreement with a previous study performed in vertebrobasilar insufficiency with 133Xenon inhalation method.

Blood-brain barrier permeability derangements in posterior circulation ischemic stroke: frequency and relation to hemorrhagic transformation.

BACKGROUND: Early disruption of the blood-brain barrier (BBB) due to severe ischemia can be detected by MRI T2* permeability imaging. In middle cerebral artery (MCA) infarction, pretreatment T2* permeability derangements have been found in 22% of patients and are powerful predictors of hemorrhagic transformation after revascularization therapy. The frequency, clinical correlates, and relation to hemorrhagic transformation of permeability derangements in posterior circulation have not been previously explored, and may differ as ischemia volume and collateral status are different between vertebrobasilar and MCA infarcts. METHODS: We analyzed clinical and pretreatment MRI data on consecutive patients undergoing recanalization therapy for acute vertebrobasilar ischemia at a medical center November 2001 through September 2009. Pretreatment MRI permeability images were derived from perfusion source imaging acquisitions. Permeability abnormality was detected as persisting increased signal intensity at later time points in perfusion MRI acquisition, indicating local accumulation of contrast caused by BBB leakage. RESULTS: Among the 14 patients meeting study entry criteria, mean age was 71.1 years and median pretreatment NIHSS was 20.5. Permeability imaging abnormality was present in 1 of the 14 patients (7%). Among 14 patients, post-treatment parenchymal hematoma occurred in one and more minor degrees of hemorrhagic transformation in four. The one patient with pretreatment permeability abnormality was the patient to develop post-treatment parenchymal hematoma (Fisher's exact test, P=0.07). CONCLUSION: Pretreatment permeability abnormality, an indicator of BBB derangements, is an infrequent finding in acute posterior circulation ischemic stroke and may be associated with an increased risk of parenchymal hematoma development undergoing recanalization therapy.

Expression of CD137 in the cerebral artery after experimental subarachnoid hemorrhage in rats: a pilot study.

Inflammation and immunity play a crucial role in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). CD137 is recognized as an independent costimulatory molecule of T cells and activator of monocytes. A growing body of evidence indicates that CD137 is vital for inflammation and immunity. Therefore, this study aimed to investigate the expression of CD137 in the basilar artery in a rat SAH model and to clarify the potential role of CD137 in cerebral vasospasm. A total of 107 rats were randomly divided into four groups: control group; day 3, day 5, and day 7 groups. Day 3, day 5, and day 7 groups were all SAH groups. The animals in SAH groups were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2 and were sacrificed on days 3, 5, and 7, respectively. Cross-sectional area of basilar artery was measured and the CD137 expression was assessed by quantitative real-time PCR, Western blot and immunohistochemistry. The cross-sectional area of basilar artery was found to be 57,944±5581µm(2) in control group, 26,100±2639µm(2) in day 3, 19,723±2412µm(2) in day 5, and 28,800±2980µm(2) in day 7 group, respectively. The basilar artery exhibited vasospasm after SAH and became more severe on day 5. The elevated mRNA and protein of CD137 were detected after SAH and peaked on day 5. CD137 is increasingly expressed in a parallel time course to the development of cerebral vasospasm in a rat experimental model of SAH. These findings indicate the possible role of CD137 in the pathogenesis of cerebral vasospasm after SAH.

Effect of lipid-lowering therapy on the progression of intracranial arterial stenosis.

OBJECTIVES: Intracranial arterial stenosis (IAS) is a severe disease with a high recurrent stroke rate even under the best medical treatment. Statins have been demonstrated to prevent stroke and to slow or halt atherosclerosis progression. This study was performed to observe the effect of atorvastatin on the progression of IAS, explore the factors associated with atherosclerosis regression and the recurrent rate of stroke. METHODS: A hospital-base observation study enrolled 40 stroke patients with middle cerebral artery (MCA) or/and basilar artery (BA) stenosis. All participants had hyperlipidemia and were given atorvastatin 40 mg per day for at least six months. IAS was assessed by magnetic resonance angiogram (MRA) at the time of enrollment and then at least six months later. The primary outcome was the progression of IAS. All patients were also given antiplatelet agents for stroke prevention. RESULTS: At the end of the study, 23 (58 %), 15 (38 %) and 2 (4 %) patients had regressed, stationary and progressed IAS, respectively. Females were likely to have regressed IAS. The recurrent stroke rate was 18 %. Among the 54 stenotic vessels, 29 (54 %) vessels were assessed as improvement in stenosis. CONCLUSION: Compared with other studies, more regressed, stationary IAS and less progressed IAS were found in our study. Female gender was likely to have regressed IAS after statin treatment. Further clinical outcome trials are required to assess the effects of such therapy on morbidity and mortality in this particular group of patients.

Co-expression/co-location of S100 proteins (S100B, S100A1 and S100A2) and protein kinase C (PKC-beta, -eta and -zeta) in a rat model of cerebral basilar artery vasospasm.

OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.

Vascular recanalizing techniques in the hind brain circulation.

Percutaneous transluminal angioplasty (PTA) was performed in 45 patients with a manifest subclavian steal syndrome. Thirty-five of those patients were subjected to follow up examinations over a period of 6 to 18 months. Five patients suffered from severe restenosis and were treated again. Two thirds of the patients benefited from the treatment. PTA of the proximal vertebral artery was performed in 15 patients with bilateral occlusive lesions of the extracranial vertebral arteries. In 13 of these cases the neurological and the vascular states of the patients were regularly reexamined, 8 showed a marked improvement. During the 2 to 25 month observation period (average 15 months post-PTA) reocclusion was observed in only two cases. These showed no recurrent neurological sequelae. Forty-three consecutive patients with acute vertebro-basilar or basilar occlusion received intraarterial fibrinolytic therapy with streptokinase or urokinase. Twenty-three of these had presented severe deficits at the beginning of therapy (e.g. complete tetraplegia, comatous state for more than 6 hours). None of this group survived. By contrast the 20 other patients in this group presented with incomplete fluctuating or progressive motor deficits. None was comatous for more than 6 hours. Fourteen patients (33% in this group) survived. Local intraarterial fibrinolytic therapy is the only therapy successful in the treatment of progressive stroke from vertebro-basilar thrombosis.