Biomedical subjects

G Alexander West

Publications and source records attributed to G Alexander West.

9 recordsLinked to original sources

PubMed2006

Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.

Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC(Ca-ATP) channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC(Ca-ATP) but not K(ATP) channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC(Ca-ATP) channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.

ATP-Binding Cassette Transporters↗

PubMed2006

Fine spatiotemporal structure of phase in human intracranial EEG.

OBJECTIVE: To transfer to the clinic for humans the technology and theory for high-resolution EEG analysis that have been developed in the laboratory with animals. METHODS: EEGs were recorded at high spatial resolution from a 1 x 1 cm 8 x 8 electrode array on the right inferior temporal gyrus of a patient undergoing preoperative monitoring for epilepsy surgery. Cosines were fitted to EEG segments to measure frequency and phase and compute location, size, latency, phase velocity, duration, and recurrence rate of radially symmetric spatial patterns called phase cones. The Hilbert transform was also used to get high temporal resolution. RESULTS: In the awake state, the power spectral density (PSD) showed power-law decrease in log power with log frequency at 1/falpha, alpha approximately 2, but with peaks in the standard empirical ranges. The phase in beta and gamma ranges had spatial gradients in conic form. Resetting of these stable spatial patterns of phase cones was spatially coincident at intermittent discontinuities ('phase slip') recurring at theta rates. Cones had half power diameters from 2 to 50+ mm; their durations had power-law distributions with values ranging from 6 to 300+ ms depending on length of the analysis window. In slow wave sleep PSD decreased at 1/falpha, alpha approximately 3,with loss of beta-gamma spectral peaks and diminished or absent oscillations and spatiotemporal phase structure. CONCLUSIONS: Spatiotemporal structures in awake human and rabbit EEG showed striking similarities. The only clear differences were ascribable to differing scales of measurement. These fine spatiotemporal structures of EEG were diminished or lost in slow wave sleep. SIGNIFICANCE: The fine structure indicates that neocortical stability is sustained at self-organized criticality; that synaptic input in the awake state drives neocortex away from criticality causing beta-gamma oscillations in re-stabilizing 'neural avalanches'; and that diminished input in slow wave sleep allows return toward criticality but with some added risk of instability and seizure.

Adult↗

PubMed2006

Self-inflicted nail-gun injury with 12 cranial penetrations and associated cerebral trauma. Case report and review of the literature.

In this case report, the authors describe a 33-year-old man who presented with headache due to the presence of 12 nail-gun nails impacted in his cranium and cerebral parenchyma. The authors also review the relevant literature regarding penetrating brain injury. The patient's physical examination revealed a Glasgow Coma Scale score of 15 and impairment of abduction of the right eye and abduction of the jaw producing dysarthria; the remaining results of the neurological examination were normal. Both x-ray films and computerized tomography (CT) scans of the head revealed the presence of 12 nails, the majority of which were located intracranially. A scattering artifact limited the ability of CT scanning to demonstrate any intracranial hemorrhage. Angiography did not demonstrate any evidence of traumatic vascular injury. After general anesthesia had been induced in the patient, the nails were removed in the operating room. Following removal of the final nail, a small left temporal craniotomy was performed to control hemorrhage from a tear in the left middle meningeal artery. Despite the development of a postoperative insular hematoma, the patient was discharged home with minimal deficits. This patient is the only known survivor of the largest number of foreign objects (12) to penetrate the skull intentionally. Overall, self-inflicted nail-gun injuries are less common than accidental discharges. A review of the literature, however, suggests that for penetrating brain injury, self-infliction is the more common mechanism. For those patients who survive such an injury, clinical decision making must focus on preventing further cortical or vascular damage. A rational management strategy should permit these patients to be discharged with no additional injury.

Adult↗

PubMed2006

Diagnosis and treatment of craniocervical dislocation in a series of 17 consecutive survivors during an 8-year period.

OBJECT: Craniocervical dissociation (CCD) is a highly unstable and usually fatal injury resulting from osseoligamentous disruption between the occiput and C-2. The purpose of this study was to elucidate systematic factors associated with delays in diagnosing and treating this life-threatening condition and to introduce an injury-severity classification with therapeutic implications. METHODS: In a retrospective evaluation of institutional databases, the authors reviewed medical records and original images obtained in 17 consecutive surviving patients with CCD treated between 1994 and 2002. Images and clinical results of treatment were evaluated, emphasizing the timing of diagnosis, clinical effect of delayed diagnosis, potential clinical or imaging warning signs, and response to treatment. Craniocervical dissociation was identified or suspected on the initial lateral cervical spine radiograph acquired in two patients (12%) and was diagnosed based on screening computerized tomography findings in two additional patients (12%). A retrospective review of initial lateral x-ray films showed an abnormal dens-basion interval in 16 patients (94%). The 2-day average delay in diagnosis was associated with profound neurological deterioration in five patients (29%). Neurological status declined in one patient after a fixation procedure was performed. There were no cases of craniocervical pseudarthrosis or hardware failure during a mean 26-month follow-up period. The mean American Spinal Injury Association (ASIA) motor score of 50 improved to 79, and the number of patients with useful motor function (ASIA Grade D or E) increased from seven (41%) preoperatively to 13 (76%) postoperatively. CONCLUSIONS: The diagnosis of CCD was frequently delayed, and the delay was associated with an increased likelihood of neurological deterioration. Early diagnosis and spinal stabilization protected against worsening spinal cord injury.

Adolescent↗

PubMed2005

Effect of caffeine on cerebral blood flow response to somatosensory stimulation.

Despite caffeine's wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine on neurovascular coupling. In the present study, we evaluated the effects of caffeine, an adenosine receptor antagonist, on intracerebral arterioles in vitro and subsequently, on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50 micromol/L) on adenosine-induced vasodilatation. At the lower concentration, caffeine was without effect, but at the higher concentration, caffeine produced significant attenuation. In our in vivo studies, we determined the cerebrospinal fluid (CSF) caffeine concentrations at 15, 30, and 60 mins after intravenous administration of 5, 10 and 40 mg/kg. At the latter two concentrations, CSF levels exceeded 10 micromol/L. We then evaluated the pial arteriolar response during cortical activation caused by contralateral SNS after administering caffeine intravenously (0, 5, 10, 20 30, and 40 mg/kg). The pial circulation was observed through a closed cranial window in chloralose-anesthetized Sprague-Dawley rats. The contralateral sciatic nerve was isolated, positioned on silver electrodes and stimulated for 20 secs (0.20 V, 0.5 ms, and 5 Hz). Arteriolar diameter was quantified using an automated video dimension analyzer. Contralateral SNS resulted in a 23.8% +/-3.9% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose studied (5 mg/kg) had no effect on either resting arteriolar diameter or SNS-induced vasodilatation. However, at higher doses (10, 20, 30, and 40 mg/kg, intravenously), caffeine significantly (P < 0.05; n = 6) attenuated both resting diameter and cerebral blood flow (CBF) responses to somatosensory stimulation. Intravenous administration of theophylline (10, 20, and 40 mg/kg), another adenosine receptor antagonist, also significantly reduced SNS-induced vasodilatation in a dose-dependent manner. Hypercarbic vasodilatation was unaffected by either caffeine or theophylline. The results of the present study show that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Adenosine↗

PubMed2005

Cocaine- and amphetamine-regulated transcript (CART) peptide: a vasoactive role in the cerebral circulation.

Cocaine- and amphetamine-regulated transcript (CART) peptides are known to be involved in the stress response and have been implicated in the regulation of the cardiovascular system. We evaluated the direct vasoactive properties of CART in the cerebral circulation and its potential mechanisms of action. Penetrating cerebral arterioles, isolated from male Sprague-Dawley rats, were cannulated using a concentric micropipette setup, pressurized and perfused. The vascular response to intraluminal and extraluminal CART peptide was characterized. The endothelium dependence of this response was assessed by means of the endothelial light-dye injury model. The nonspecific endothelin receptor antagonist PD-145065, the ET(A)-specific antagonist BQ-123, the ET(B)-specific antagonist BQ-788, and the inhibitor of endothelin-converting enzyme phosphoramidon were used to characterize the involvement of the endothelin pathway in the vascular response to CART peptide. Extraluminal and intraluminal application of CART peptide (0.1 nm to 1 micromol/L) evoked a long-lasting dose-dependent constriction of isolated penetrating cerebral arterioles to approximately 80% of resting myogenic tone. Disruption of the endothelium by the endothelial light/dye injury model resulted in the abolition of this response (P<0.05). Extraluminal administration of PD-145065, BQ-123, and phosphoramidon blocked the constriction response to CART peptide (P<0.01). The ET(B) antagonist, BQ-788, did not alter the constriction response to CART peptide. Cocaine- and amphetamine-regulated transcript peptide is a potent vasoconstrictor in the cerebral circulation. Its direct vasoactive properties are endothelium-dependent and are mediated by ET(A), not ET(B), endothelin receptors.

Animals↗

PubMed2003

The ISAT trial.

Explore the source record for details and available documents.

Angioplasty↗

PubMed2003

cGMP-dependent and not cAMP-dependent kinase is required for adenosine-induced dilation of intracerebral arterioles.

Adenosine (ADO) is a potent cerebral vasodilator and has been proposed as a metabolic regulator of cerebral blood flow. However, the signal transduction pathway by which ADO causes vasodilation in cerebral microvessels is currently unknown. The current study was designed to investigate the role of cyclic nucleotides and cyclic nucleotide-dependent protein kinases in ADO-induced dilation of resistance-sized rat cerebral arterioles that develop spontaneous tone. Arterioles were cannulated and perfused intraluminally at constant flow (2 microl/min) and pressure (60 mm Hg). ADO (29.7 +/- 2.0%; 1 microM), CGS-21680 (16 +/- 4%, 1 microM), 8-bromo-cyclic guanosine monophosphate (8 Br-cGMP; 29.9 +/- 3.9%; 100 microM), sodium nitroprusside (SNP; 30.6 +/- 3.3%, 1 microM), cyclic guanine monophosphate-dependent protein kinase activator (Sp-8-pCPT-cGMPS, 25.9 +/- 4.2%; 10 microM), forskolin (30.5 +/- 5.9%; 0.1 microM), and pH 6.8 all produced large dilations. The selective cGMP-dependent protein kinase inhibitor, Rp-8-pCPT-cGMPS (10 microM), had no effect on resting diameter or reactivity to acidic pH, but significantly ( < 0.05) attenuated arteriolar dilations to ADO (59%, n = 8), CGS-21680 (60%, n = 4), SNP (62%, n = 3), 8 Br-cGMP (88%, n = 3), and Sp-8-pCPT-cGMPS (98%, n = 3). H8, the less-selective cyclic nucleotide-dependent protein kinase inhibitor, had similar effects as Rp-8-pCPT-cGMPS. Additionally, the inhibitor of the soluble guanylate cyclase, 1H-[1,24]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), blocked the response to SNP (70% inhibition) and significantly inhibited the ADO response (43% inhibition). In contrast, inhibition of the cyclic ADO monophosphate (cAMP)-dependent protein kinase Rp-8-CPT-cAMPS had no effect on the ADO, SNP, or pH responses, but significantly blocked forskolin-induced vasodilation (53%). It is concluded that ADO-induced vasodilation in cerebral microvessels, at least in part, involves cGMP and cGMP-dependent protein kinase, but not cAMP or cAMP-dependent kinase. Our data therefore provides a new insight into mechanisms by which ADO invokes vasodilation in cerebral microvascular arterioles.

Adenosine↗

PubMed2003

Adenosine-A2a receptor down-regulates cerebral smooth muscle L-type Ca2+ channel activity via protein tyrosine phosphatase, not cAMP-dependent protein kinase.

Adenosine acting via A2a receptors (A2aR) is a potent cerebral vasodilator that relaxes vascular smooth muscle cells (VSMCs) by a mechanism attributed to activation of cAMP-dependent protein kinase (cAK). We examined effects of adenosine and its mechanism of action on L-type Ca2+ channels in native VSMCs from rat basilar artery. Reverse transcription-polymerase chain reaction and immunofluorescence imaging confirmed transcription and expression of A2aR, and in situ hybridization confirmed presence of mRNA for L-type Cav1.2b channels. In patch-clamp experiments, adenosine down-regulated Ca2+ channel currents in a concentration-dependent manner, with receptor-subtype-specific antagonists [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) versus 1,3-dipropyl-8-cyclopentyl-1,3-dipropylxanthine] showing that this was caused by action of A2aR. Down-regulation of channel currents was mimicked by stimulation of cGMP-dependent protein kinase (cGK; 8-Br-cGMP) and by inhibition of tyrosine kinase (AG-18) but not by stimulation of cAK [forskolin and 8-bromo-cAMP (8-Br-AMP)]. Down-regulation of currents by the A2aR agonist 2-[p-(2-carboxyeth yl)phenylethylamino]-5'-N-ethyolcarboxamidoadenosine (CGS-21680) was blocked by inhibiting protein tyrosine phosphatase (PTP; orthovanodate and dephostatin), but not by inhibiting cGK (KT-5823 and H-7). Western blots of lysate or of immunoisolated Ca2+ channels from arterial segments incubated with CGS-21680 showed 1) increased phosphorylation of vasodilator-stimulated phosphoprotein that was blocked by inhibiting cAK (KT-5720), consistent with activation of cAK by A2aR; and 2) decreased tyrosine phosphorylation of immunoisolated alpha1c subunit of the Ca2+ channel. Our data show that cAK, although activated, was not germane to down-regulation of Ca2+ channel activity by A2aR, and they delineate a novel signaling mechanism involving reduced tyrosine phosphorylation of Ca2+ channels by A2aR probably caused by PTP activation.

Animals↗