Biomedical subjects

Gregory J Zipfel

Publications and source records attributed to Gregory J Zipfel.

8 recordsLinked to original sources

PubMed2006

Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway.

Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn(2+) is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn(2+) depended on entry, elevation in intracellular free Zn(2+) ([Zn(2+)](i)), a reduction in NAD(+) and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD(+). NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn(2+) neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn(2+) neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD(+) levels in Zn(2+) neurotoxicity.

Aldehydes↗

PubMed2006

Clinical features and outcome in North American adults with moyamoya phenomenon.

BACKGROUND AND PURPOSE: To describe baseline clinical features and outcomes of adults with moyamoya phenomenon treated at a single North American institution. METHODS: We identified 34 adults with moyamoya phenomenon by review of angiographic records. Clinical presentation and baseline stroke risk factors were obtained by chart review. Follow-up was obtained prospectively. A 5-year Kaplan-Meier stroke risk was calculated. RESULTS: The median age was 42 (range 20 to 79) years. Twenty-five were women. The initial symptom was ischemia, hemorrhage, or asymptomatic in 24, 7, and 3 patients, respectively. Twenty-two had bilateral involvement and 12 had unilateral moyamoya vessels. Baseline stroke risk factors were similar between groups. The median follow-up in 31 living patients was 5.1 (range 0.2 to 19.6) years. Fourteen patients were treated with surgical revascularization (20 total hemispheres). In medically treated symptomatic hemispheres, the 5-year risk of recurrent ipsilateral stroke was 65% after the initial symptom and 27% after angiographic diagnosis. Patients with bilateral involvement presenting with ischemic symptoms were at the highest risk of subsequent stroke (n=17, 5-year risk of stroke with medical treatment after first symptom of 82%). In surgically treated hemispheres, the 5-year risk of perioperative or subsequent ipsilateral stroke or death was 17%. This was significantly different compared with medical treatment after first symptom (P=0.02) but not after angiographic diagnosis. CONCLUSIONS: Moyamoya phenomenon in North American adults is associated with a high risk of recurrent stroke, particularly those with bilateral involvement and ischemic symptoms. These data suggest a potential benefit with surgery if diagnosis could be made earlier.

Adult↗

PubMed2006

Current status of manpower needs for management of cerebrovascular disease.

The cerebrovascular discipline has undergone dramatic changes in recent years. The advent, development, and now widespread application of endovascular therapy for various cerebrovascular diseases has been the predominant influence behind many of these changes, but other factors (some scientific, others less so) have also contributed significantly. As our discipline evolves, it is critical to periodically examine how such changes have altered our manner of practice and to determine what impact such changes might have on manpower allocation and training for the future. This article is our attempt at providing such an assessment. First, we will critically review recent trends within the fields of intracranial aneurysms, arteriovenous malformations, carotid atherosclerotic occlusive disease, and ischemic stroke and how these trends have impacted our profession. Thereafter, we will provide a perspective on what the cerebrovascular manpower needs of the future might be and by whom these needs will be met. Finally, we will examine how the new generation of cerebrovascular specialists, including neurosurgeons, neuroradiologists, and some neurologists, will attain their requisite surgical or endovascular training and attempt to determine which careers, pathways, and opportunities will be available to these individuals in the future.

Career Mobility↗

PubMed2005

Moyamoya disease in adults: the role of cerebral revascularization.

Moyamoya disease is a disorder characterized by bilateral progressive steno-occlusion of the terminal internal carotid arteries with associated development of a fragile network of basal collateral vessels. It most commonly presents in children, but is also frequently seen in adults, especially in the third or fourth decade of life. Adults afflicted with this disease have very different clinical characteristics as compared with children. For example, adults more commonly present with hemorrhage than cerebral ischemia, while children present with cerebral ischemia nearly 75% of the time and very rarely present with hemorrhage. This significantly impacts treatment considerations for the adult-onset moyamoya patient, as cerebral revascularization, though well accepted in the context of cerebral ischemia, is relatively controversial for the prevention of rehemorrhage. The purpose of this article is to review the pertinent general features of moyamoya disease, examine the clinical characteristics associated with the adult-onset form of this disease, and provide a detailed discussion regarding the indications, operative techniques, and outcomes of direct and indirect revascularization surgical procedures.

Journal Article↗

PubMed2004

Update on the management of unruptured intracranial aneurysms.

Over the past decade, several factors have led to a dramatic change in the manner in which patients with unruptured intracranial aneurysms are diagnosed and treated. These factors include the increased use of noninvasive imaging modalities for the diagnosis of intracranial aneurysms, publication of new natural history data detailing the hemorrhage risks associated with unruptured intracranial aneurysms, and the broad application of endovascular therapy for their treatment. With these new technologies and new natural history data has come considerable uncertainty about the optimal treatment strategy for patients with unruptured intracranial aneurysms. In this light, it seems prudent to review periodically and examine critically all recent data pertaining to the natural history and treatment of unruptured intracranial aneurysms, in an effort to provide a scientific update on which management recommendations can be based. This review article represents the authors' attempt at such an update, and it is their hope that members of the community of neurovascular surgeons might find this information helpful during their continuing efforts to provide optimal care for their patients with unruptured intracranial aneurysms.

Disease Management↗

PubMed2004

Do the morphological characteristics of arteriovenous malformations affect the results of radiosurgery?

OBJECT: The authors sought to determine which morphological features of arteriovenous malformations (AVMs) are statistically predictive of preradiosurgical hemorrhage, postradiosurgical hemorrhage, and neuroimaging-defined failure of radiosurgical treatment. In addition, correlation between computerized tomography (CT) scanning and angiography for the identification of AVM structures was investigated. METHODS: Archived CT dosimetry and available angiographic and clinical data for 268 patients in whom AVMs were treated with linear accelerator radiosurgery were retrospectively reviewed. Many of the morphological features of AVMs, including location, volume, compact or diffuse nidus, neovascularity, ease of nidus identification, number of feeding arteries, location (deep or superficial) of feeding arteries, number of draining veins, deep or superficial venous drainage, venous stenoses, venous ectasias, and the presence of intranidal aneurysms, were analyzed. In addition, a number of patient and treatment factors, including patient age, presenting symptoms, radiation dose, repeated treatment, and radiological outcome, were subjected to multivariate analyses. Two hundred twenty-seven patients were treated with radiosurgery for the first time and 41 patients underwent repeated radiosurgery. Eighty-one patients presented with a history of AVM hemorrhage and 91 patients had AVMs in a periventricular location. Twenty-six patients (10%) experienced a hemorrhage following radiosurgery. Of the 268 patients, 81 (30%) experienced angiographically defined cures, and 37 (14%) experienced MR imaging-defined cures. Eighty-six patients (32%) experienced neuroimaging-defined treatment failure, and 64 underwent insufficiently long follow up. A larger AVM volume (odds ratio [OR] 0.349; p = 0.004) was associated with a decreased rate of pretreatment hemorrhage, whereas periventricular location (OR 6.358; p = 0.000) was associated with an increased rate of pretreatment hemorrhage. None of the analyzed factors was predictive of hemorrhage following radiosurgery. A higher radiosurgical dose was strongly correlated with neuroimaging-defined success (OR 3.743; p = 0.006), whereas a diffuse nidus structure (OR 0.246; p = 0.008) and associated neovascularity (OR 0.428; p = 0.048) were each associated with a lower neuroimaging-defined cure rate. A strong correlation between CT scanning and angiography was noted for both nidus structure (p = 0.000; Fisher exact test) and neovascularity (p = 0.002; Fisher exact test). CONCLUSIONS: Patients presenting with AVMs that are small or periventricular were at higher risk for experiencing hemorrhage. A higher radiosurgical dose correlated strongly with neuroimaging-defined success. Patients in whom the AVM had a diffuse structure or associated neovascularity were at higher risk for neuroimaging-defined failure of radiosurgery. A strong correlation between CT scanning and angiography in the assessment of AVM structure was demonstrated.

Adolescent↗

PubMed2003

Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo.

BACKGROUND AND PURPOSE: In light of recent evidence suggesting that an upregulation of K+ efflux mediated by outward delayed rectifier (I(K)) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of I(K) channels might be neuroprotective against hypoxia/ischemia-induced neuronal death. METHODS: Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K+ channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion. RESULTS: The K+ channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked I(K) without affecting N-methyl-D-aspartate receptor-mediated current or voltage-gated Ca2+ currents. Both TEA and a lipophilic K+ channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo. CONCLUSIONS: These data are consistent with the idea that K+ channel-mediated K+ efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K+ efflux through K+ channels may constitute a therapeutic approach for the treatment of stroke.

Animals↗

PubMed2003

Bone grafting.

In recent years our understanding of spinal fusion biology has improved. This includes the continued elucidation of the step-by-step cellular and molecular events involved in the prototypic bone induction cascade, as well as the identification and characterization of the various critical growth factors governing the process of bone formation and bone graft incorporation. Based on these fundamental principles, growth factor technology has been exploited in an attempt to improve rates of spinal fusion, and promising results have been realized in preclinical animal studies and initial clinical human studies. In this article the authors review the recent advances in the biology of bone fusion and provide a perspective on the future of spinal fusion, a future that will very likely include increased graft fusion rates and improved patient outcome as a result of the successful translation of fundamental bone fusion principles to the bedside.

Animals↗