Acute and chronic effects of oxyhemoglobin on voltage-dependent ion channels in cerebral arteries.

Voltage-dependent potassium (Kv) and calcium (VDCC) channels play an important role in the regulation of membrane potential and intracellular calcium concentration in cerebral artery myocytes. Recent evidence suggests VDCC activity is increased and Kv channel activity is decreased in cerebral arteries following subarachnoid hemorrhage (SAH), promoting enhanced constriction. We have examined the impact of the blood component oxyhemoglobin on Kv and VDCC function in small (100-200 microm) diameter cerebral arteries. Acute (10 min) exposure of oxyhemoglobin caused cerebral artery constriction and Kv current suppression that was abolished by tyrosine kinase inhibitors and a Kv channel blocker. Although short-term oxyhemoglobin application did not directly alter VDCC activity, five-day exposure to oxyhemoglobin was associated with enhanced expression of voltage-dependent calcium channels. This work suggests that acute and chronic effects of oxyhemoglobin act synergistically to promote membrane depolarization and increased VDCC activity in cerebral arteries. These actions of oxyhemoglobin may contribute to the development of cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat.

Tamoxifen (TAM), a widely used non-steroidal anti-estrogen, has recently been shown to be neuroprotective in a rat model of reversible middle cerebral artery occlusion (rMCAo). Tamoxifen has several potential mechanisms of action including inhibition of the release of excitatory amino acids (EAA) and nitric oxide synthase (NOS) activity. The question addressed in this study was whether TAM reduces ischemia-induced production of nitrotyrosine, considered as a footprint of the product of nitric oxide and superoxide, peroxynitrite. In rat brain, 2 h rMCAo produced a time-dependent increase in nitrotyrosine content in the cerebral cortex, as measured by Western blot analysis. Compared with vehicle, TAM significantly reduced nitrotyrosine levels in the ischemic cortex at 24 h. The neuronal (n)NOS inhibitor, 7-nitroindazole also tended to reduce nitrotyrosine, but this reduction was not statistically significant. Immunostaining for nitrotyrosine was seen in cortical neurons in the MCA territory and this immunostaining was reduced by TAM. In vitro, TAM and the calmodulin inhibitor trifluoperazine inhibited, with similar EC(50) values, the activity of recombinant nNOS as well as NOS activity in brain homogenates, measured by conversion of [(3)H]arginine to [(3)H]citrulline. There was marginal inhibition of recombinant inducible (i)NOS activity up to 100 microM TAM. These data suggest that TAM is an effective inhibitor of Ca(2+)/calmodulin-dependent NOS and the derived peroxynitrite production in transient focal cerebral ischemia and this may be one mechanism for its neuroprotective effect following rMCAo.

Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion.

Inhibitors of cell-swelling-activated anion channels, including the antiestrogenic compound tamoxifen (TAM), have been shown to attenuate the increase in excitatory amino acids (EAA) during ischemia. Since TAM enters the CNS we tested whether it provides protection from damage due to reversible middle cerebral artery occlusion (rMCAo) in rats. TAM (5 mg/kg, i.v.) infused 25 min before ischemia, potently reduced the total volume of the infarct from 328 +/- 34 mm3 to 41 +/- 21 mm3, a reduction of 87%, as measured by TTC staining. It was equally effective when infused starting at 1 h after reperfusion, i.e. 3 h after initiation of rMCAo. Protection of neurons was also found histologically. TAM had no effect on CBF as measured by hydrogen clearance. This appears to be the first report of a marked neuroprotective effect of TAM. Further studies are needed to determine whether its effects are due to inhibition of EAA release and/or other potential neuroprotective sites of action.

Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker.

BACKGROUND AND PURPOSE: Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum. METHODS: Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS), administered separately or together through the dialysis probe. RESULTS: In control striata during ischemia, glutamate and aspartate concentrations increased 44+/-13 (mean+/-SEM) times and 19+/-5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9. 6+/-1.7 versus control, 15.4+/-2.6 pmol/ microL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8+/-1.1 versus control, 10.1+/-0.7 pmol/ microL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7+/-0.7 versus control, 10.9+/-1.2 pmol/ microL). CONCLUSIONS: These findings support the hypothesis that both cell swelling-induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.

Induced hypervolemia and inotropic support for acute cerebral arterial insufficiency: an underused therapy.

BACKGROUND: Hypervolemia and induced systemic hypertension are generally considered the standard approach to the treatment of vasospasm. Despite evidence in favor of its efficacy, this therapy is used rarely in acute cerebrovascular occlusion. We present a case supporting this treatment paradigm. CASE DESCRIPTION: A patient developed aphasia and hemiplegia 8 h after carotid endarterectomy caused by embolic occlusion of the middle cerebral artery. Hyperdynamic/hypervolemic therapy was instituted. Serial angiograms filmed over the next 8 h demonstrated reperfusion of the hemisphere, through collateral flow. The patient's symptoms resolved. CONCLUSIONS: We believe this case demonstrates the effectiveness of hypervolemia and inotropic support in the treatment of acute embolic stroke by inducing dilatation of the leptomeningeal collateral circulation.

Anterolateral dynamized instrumentation and fusion for unstable thoracolumbar and lumbar burst fractures.

STUDY DESIGN: A retrospective chart review of 36 patients treated with dynamized anterolateral instrumentation and fusion after decompression for thoracolumbar and lumbar burst fractures is presented. OBJECTIVES: To evaluate a device that allows continual bone graft vertebral endplate compression and determine its potential for healing in patients with thoracolumbar and lumbar burst fractures. SUMMARY OF BACKGROUND DATA: Anterior spinal surgery has led to implant adaptations. Such implants have undergone an evolution in hopes of improving the rate of healing and avoiding neurovascular catastrophes. METHODS: Thirty-six patients underwent anterior decompression dynamized instrumentation and fusion for thoracolumbar and lumbar burst fractures. This involved a dual-rod, quadrilateral, cross-linked frame that allows for continual compression but deters rotation and shear stresses. RESULTS: All patients healed solidly without instrumentation failure. An average recovery of 1.3 Frankel grades was recorded. Subsidence of bone graft vertebral endplate was less than in those placed in a trough. CONCLUSIONS: Dynamized load-sharing anterolateral Cotrel-Dubousset instrumentation led to solid bone graft healing without implant failure by allowing continual compression while deterring shear and rotational stresses.

Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia.

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.

Aortic arch interruption associated with ruptured cerebral aneurysm.

The authors present a case of aortic arch interruption in an adult, an anomaly that was discovered coincidentally during angiography for ruptured cerebral aneurysm. The presentation in adulthood with rupture of the aneurysm and the successful surgical treatment of both abnormalities are unusual.

Interrupted arterial occlusion reduces ischemic damage in a focal cerebral ischemia model of rats.

It is generally thought by neurosurgeons that when temporary clipping of a major cerebral vessel is necessary during aneurysm surgery, repeated short periods of cerebral ischemia are safer for the brain than a single long episode. This study was performed to investigate whether repetitive short episodes of cerebral ischemia would alter the resulting brain injury as compared with a single long period of ischemia in a rat model for focal cerebral ischemia. Middle cerebral artery occlusion and reperfusion were performed by the intraluminal thread technique. The experimental design consisted of a single 90-minute occlusion period in the continuous ischemia group versus three 30-minute occlusion periods with 15-minute reperfusion periods in the repetitive group. Local cerebral blood flow was measured by the hydrogen clearance technique. During the ischemic period, local cerebral blood flow values significantly decreased in both the continuous and the repetitive groups. Cerebral blood flow restoration was demonstrated after each episode of reperfusion in both groups. The neurological status scores 2 hours after surgery in the rats subjected to repetitive insults were significantly better compared with those in the rats of the continuous ischemia group. However, the scores on Days 1, 3, and 7 did not show a significantly better difference. The animals were killed 7 days after the induction of ischemia for the measurement of the infarction area under the microscope. The total area of infarction was significantly reduced (4.05 +/- 4.56 versus 47.2 +/- 37.3 mm2, P < 0.001) by interruption of the ischemic time period.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous thrombosis of an unruptured anterior communicating artery aneurysm. An unusual cause of ischemic stroke.

BACKGROUND: Stroke caused by spontaneous thrombosis of an unruptured intracranial aneurysm is a rare event. CASE DESCRIPTION: A 66-year-old woman experienced a transient ischemic attack and cerebral infarctions due to spontaneous thrombosis of an unruptured anterior communicating artery aneurysm. Extension of thrombus into both anterior cerebral arteries and the left middle cerebral artery, resulting in ischemic infarction in all three vascular territories, was diagnosed by CT scanning, MRI, and cerebral angiography and confirmed at autopsy. CONCLUSIONS: This case illustrates a rare complication of an unruptured saccular aneurysm with neuroimaging and pathological correlation. Morphological and hemodynamic factors that may have precipitated aneurysm thrombosis are discussed with reference to experimental models.

Insulin reduction of cerebral infarction due to transient focal ischemia.

Insulin has recently been shown to ameliorate damage in models of global brain ischemia. To determine whether insulin is also neuroprotective in focal ischemia, 20 rats were given 2 to 3 IU/kg insulin and 10 did not receive treatment prior to normothermic transient middle cerebral artery occlusion for 2 hours at a blood pressure of 60 mm Hg. To further elucidate whether infarction volume is influenced by variations in blood glucose levels within the physiological range, blood glucose was raised in 10 of the insulin-treated animals to levels comparable with the untreated controls. At 1-week survival, damage was assessed using quantitative neuropathological examination of 25 coronal planes. It was found that preischemic insulin lowered the mean intraischemic blood glucose level from 8.4 +/- 0.2 mM (mu +/- standard error of the mean) in the control group to 3.4 +/- 0.2 mM and reduced total damage (atrophy plus cortical and striatal necrosis), expressed as the percentage of the normal hemisphere, from a control of 28.5% +/- 2.9% to 14.5% +/- 1.6% (p < 0.005). Coadministration of glucose and insulin resulted in a mean intraischemic blood glucose level of 10.1 +/- 0.5 mM, with 27.0% +/- 2.4% total damage (p = 0.96, compared with control). Total ischemic damage showed an independent correlation with blood glucose levels (r = 0.67, p = 0.0018). The findings indicate that insulin benefits transient focal ischemia and that reducing the blood glucose from 8 to 9 mM to the low-normal range of 3 to 4 mM with insulin dramatically reduces subsequent infarction. The data suggest that the neuroprotective mechanism of insulin action in focal middle cerebral artery occlusion is mediated predominantly via alterations in blood glucose levels. In comparison to global ischemia, focal ischemia appears to show only a minor direct central nervous system effect of insulin. In clinical situations in which transient focal ischemia to the hemisphere can be anticipated, insulin-induced hypoglycemia of a mild degree may be beneficial.

Isolated cerebellar lymphomatoid granulomatosis progressing to malignant lymphoma. Case report.

A 60-year-old man presented with progressive and unique neurological symptoms. Investigations identified an isolated cerebellar lesion. This lesion fulfilled the histological criteria for lymphomatoid granulomatosis, and in situ hybridization and deoxyribonucleic acid (DNA) dot blot techniques revealed significant amounts of Epstein-Barr virus DNA within the tumor cells. The patient underwent cranial radiation therapy, and 16 months after the initial presentation the lesion evolved into a malignant lymphoma. He subsequently died secondary to subdural empyema, bacterial meningitis, and bronchopneumonia. The unique clinical and etiological aspects of this case are addressed.

Role of hypervolemic hemodilution in focal cerebral ischemia of rats.

This study was designed to better define a protocol for hypervolemic hemodilution in acute cerebral ischemia and investigate the mechanism of action of this therapy. Anesthetized rats (n = 40) were subjected to 6 h of middle cerebral artery (MCA) occlusion. At 45 min after MCA occlusion, each rat received one of the following treatment modalities: (1) control, (2) isovolemic hemodilution, (3) hypervolemic nonhemodilution (whole blood), (4) hypervolemic hemodilution (normal saline), and (5) hypervolemic hemodilution (hetastarch). Local cerebral blood flow (CBF) was determined with hydrogen clearance technique, and cardiac output was assessed by measuring the descending aorta blood flow (DAF). Infarction volume was estimated by 2,3,5-triphenyltetrazolium chloride staining method. Hetastarch infusion increased both DAF and local CBF more than the other treatments, by 98% and by 89%, respectively. Hetastarch also reduced infarction volume the most to 71 +/- 19 mm3 (p < 0.01 versus control 117 +/- 32 mm3). A significant correlation between percent (%) changes in local CBF and % changes in DAF existed in ischemic brain regions, and the hetastarch infusion improved local CBF more prominently in profoundly ischemic regions in contrast to isovolemic hemodilution. These data demonstrated the superiority of hypervolemic hemodilution with hetastarch as compared to other similar treatment modalities for acute cerebral ischemia, and indicate that cardiac output augmentation may be more responsible than decreased blood viscosity for the beneficial effect of hypervolemic hemodilution on local CBF in profoundly ischemic regions, as such ischemic brain tissue can severely lose its regulatory control of CBF to alterations in cardiac output.

Central and autonomic nervous system links to the APUD system (and their APUDomas).

The concept of the APUD system and the APUDomas associated with it has evolved significantly since Pearse's description in the 1960s. Part of this evolution has been an understanding of the relationships between the APUD system and the central and autonomic nervous systems. The APUD system now referred to as the diffuse neuroendocrine system, can be linked to the central nervous system and autonomic nervous system by genetics, embryology, cellular characteristics, anatomy, interaction of the systems, and the immune system. Awareness of these relationships may enable clinicians to better understand APUDomas and lead to better methods of detection of these tumours and their treatment.

Hyperdynamic therapy for focal cerebral ischemia of rats: use of colloidal volume expansion and dobutamine.

The effects of hyperdynamic therapy with colloidal volume expansion and pharmacological augmentation of cardiac function with dobutamine on local cerebral blood flow (CBF) and the size of ischemic injury were investigated in rats subjected to 6 h of middle cerebral artery (MCA) occlusion. At 45 min after MCA occlusion, each rat was randomly assigned to one of the following treatment groups: (1) control; (2) hetastarch infusion (HES); and (3) hetastarch plus dobutamine (12 micrograms/kg/min) infusion (HES/DOB). In both the HES and HES/DOB groups, cardiac output and local CBF in ischemic brain markedly increased after treatment and infarction volumes were significantly reduced as compared to the control group. There were, however, no significant differences between both groups apart from a dobutamine-induced tachycardia. Colloidal volume expansion augmented cardiac output, increased CBF in ischemic brain, and substantially modified the extent of ischemic injury. However, the addition of dobutamine did not bring about adjunctive beneficial effects of cardiac performance, CBF, or the degree of ischemic brain damage in the rat focal ischemic model.

Chronic subdural hematoma: the role for craniotomy reevaluated.

The management of chronic subdural hematoma in the adult patient is approached with a variety of different surgical techniques. The trend in recent years has been toward treatment with burr holes or twist-drill holes rather than craniotomy. The rationale for this has been based on the assumption that burr holes and twist-drill holes offer equivalent efficacy and lower morbidity and mortality. This viewpoint is not, however, universally accepted, and many surgeons feel that craniotomy is superior to a burr hole for the management of this condition. In a review of 92 patients presenting over a 3-year period with 112 chronic subdural hematomas, 49 underwent craniotomy and 43 underwent burr-hole treatment. The recurrence of hematomas, requiring another operation, occurred in 8.6%; operative mortality was 2.2% at hospital discharge and 4.4% at follow-up. No patient died as a consequence of the operative procedure. There was no significant difference in the incidence of postoperative complications, hematoma recurrence, or operative mortality among the different surgical groups. Previous reports concerning the superiority of burr holes over craniotomy are not substantiated by this review. Although the issue concerning optimal therapy has not been resolved by this review, at this time, craniotomy remains a valid and safe technique for the management of patients with chronic subdural hematoma.

Nervous system injuries in horseback-riding accidents.

A review of 156 horseback-riding accidents that occurred in southern Alberta over a 6-year period and resulted in nervous system trauma, including 11 deaths, is presented. The majority (81%) of accidents occurred during recreational activity and 81% were associated with falling or being thrown from a horse. Head injury occurred in 92% of patients and accounted for all of the 11 deaths. Spinal injury occurred in 13% of the patients and was associated with head injury in 40%. One peripheral nerve injury was identified. Helmets were used by only two victims. The 11 deaths that occurred as a consequence of severe head injury accounted for 79% of all deaths associated with horseback riding. This profile of neurologic injuries associated with horse-related accidents supports a need for use of protective headgear.