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Biomedical subjects

R J Dempsey

Publications and source records attributed to R J Dempsey.

At least 73 records · Page 4Linked to original sources
PubMed1996

Enhanced accumulation of free fatty acids in experimental focal cerebral ischemia.

Cerebral ischemia is well known to cause an increase in the level of free fatty acids (FFAs) in rodent species. Such FFA accumulations may signal regional lipid membrane damage and are postulated to participate in the pathogenesis of progressive infarction after cerebral ischemia. In this study we have examined the regional levels of FFAS in the cortices of cats after 8 h of middle cerebral artery occlusion. The levels of specific FFAs (palmitic, stearic, and oleic acids) were 1.5 and 2.0 times higher in the penumbral and dense ischemic regions, respectively, than those in the non-ischemic contralateral region. Although no significant differences were found between the penumbra and dense ischemic regions in the levels of arachidonic acid, the levels of docosahexaenoic acid in both of these regions were significantly higher than those in the contralateral region (P < 0.05). These results suggest that enhanced accumulation of FFAs are regionally distributed after focal ischemia and may contribute to neuronal damage after focal cerebral ischemia in non-rodent species.

Animals↗
PubMed1996

Effect of hyperglycemia on reperfusion-associated recovery of intracellular pH and high energy phosphates after transient cerebral ischemia in gerbils.

Hyperglycemia increases cerebral damage after transient cerebral ischemia. This study used in vivo 31P nuclear magnetic resonance spectroscopy to determine the relationship of intracellular tissue acidosis and delayed recovery of brain high-energy phosphates to increased damage during the reperfusion period. Mongolian gerbils were subjected to transient bilateral carotid ischemia for 20 min with 2 h reperfusion. All gerbils were pretreated intraperitoneally with equivalent volumes in saline of 0.003 units per kilogram of insulin or vehicle, or with 4 grams of glucose per kilogram. The gerbils were then scanned in a 4.7 Tesla Magnetic Resonance Imager-Spectrometer to determine levels of intracellular pH, inorganic phosphate, adenosine triphosphate, and phosphocreatine. In each group, intracellular pH decreased with ischemia, but most significantly in hyperglycemic animals (6.45 +/- 0.15), in which it had not recovered to preischemic levels by the end of the reperfusion period (6.8 +/- 0.1 vs 7.04 +/- 0.1, p < 0.05). High-energy phosphates phosphocreatine-inorganic phosphate and phosphocreatine-adenosine triphosphate showed partial recovery in all groups throughout the reperfusion period; the recovery was not significantly altered by glucose status. Hyperglycemia worsened pH but not the recovery of high-energy phosphates in animals reperfused after 20 min of transient cerebral ischemia. This sustained acidosis may be a primary event in transient damage in hyperglycemic animals.

Adenosine Triphosphate↗
PubMed1996

Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury.

Sixty-eight patients were entered into a randomized, prospective, double-blinded controlled trial of supplemental zinc versus standard zinc therapy to study the effects of zinc supplementation on neurologic recovery and nutritional/metabolic status after severe closed head injury. One month after injury, the mortality rates in the standard zinc group and the zinc-supplemented group were 26 and 12%, respectively. Glasgow Coma Scale (GCS) scores of the zinc-supplemented group exceeded the adjusted mean GCS score of the standard group at day 28 (p = 0.03). Mean motor GCS score levels of the zinc-supplemented group were significantly higher on days 15 and 21 than those of the control group (p = 0.005, p = 0.02). This trend continued on day 28 of the study (p = 0.09). The groups did not differ in serum zinc concentration, weight, energy expenditure, or total urinary nitrogen excretion after hospital admission. Mean 24-h urine zinc levels were significantly higher in the zinc-supplemented group at days 2 (p = 0.0001) and 10 (p = 0.01) after injury. Mean serum prealbumin concentrations were significantly higher in the zinc-supplemented group (p = 0.003) at 3 weeks after injury. A similar pattern was found for mean serum retinol binding protein level (p = 0.01). A significantly larger number of patients in the standard zinc group had craniotomies for evacuation of hematoma; thus a bias may have been present. The results of this study indicate that zinc supplementation during the immediate postinjury period is associated with improved rate of neurologic recovery and visceral protein concentrations for patients with severe closed head injury.

Adolescent↗
PubMed1996

Effect of difluoromethylornithine treatment on regional ornithine decarboxylase activity and edema formation after experimental brain injury.

This study examined the effect of difluoromethylornithine (DFMO) on regional activities of ornithine decarboxylase (ODC) and edema formation in bilateral cerebral cortex and hippocampus after a unilateral controlled cortical-impact (CCI) injury in rats. To measure the activity of ODC, the brains of injured and control rats were frozen in situ at 30 min, 3, 6, and 24 h after CCI brain injury of moderate severity. The specific gravity, an indicator of edema formation, was examined in decapitated animals at corresponding time points. Brain injury induced significant increases of ODC in the ipsilateral hippocampus, adjacent and injury-site cortices, and in the contralateral cortex and hippocampus at 3 and 6 h after injury. No significant edema formation was found in any brain region at 30 min after injury. A significant edema formation was first found only in the injury-site cortex at 3 h after injury. At 6 and 24 h after injury, significant edema was found in all regions ipsilateral to the injury-site. At 24 h after injury, significant but less severe edema was also found in the contralateral cortex and hippocampus. DFMO, an irreversible inhibitor of ODC, abolished the increase in ODC in all regions. It also attenuated edema formation in the adjacent cortex and in the contralateral cortex and hippocampus. These findings indicate that polyamines may play a role in posttraumatic brain edema formation, particularly in important brain regions remote from the injury-site.

Animals↗
PubMed1996

Regional activity of ornithine decarboxylase and edema formation after traumatic brain injury.

This study examined ornithine decarboxylase (ODC) activity and edema formation bilaterally in brain cortices and hippocampi after lateral controlled cortical-impact injury in rats. To measure the activity of ODC, the brains of injured and control rats were frozen in situ at 30 minutes and at 6, 24, and 72 hours after controlled cortical-impact injury of moderate severity. The specific gravity of these regions was examined in decapitated animals at corresponding time points as an indicator of edema formation. Thirty minutes after injury, ODC activity did not increase in the injury-site cortex and ipsilateral hippocampus. At 6 hours after injury, ODC activity had increased by nine times that of the control in the injury-site cortex, by five times in the adjacent cortex, and by five and one-half times in the ipsilateral hippocampus. Twenty-four hours after injury, ODC activity had increased by three times that of the control in the injury-site cortex and two times in the ipsilateral hippocampus. Seventy-two hours after injury, activity had returned to control levels. ODC activity increased significantly in the contralateral cortex and hippocampus only at 6 and 24 hours. The injury-site and adjacent cortices and the ipsilateral hippocampus showed significant edema at 6, 24, and 72 hours but not at 30 minutes after injury. These findings indicate that polyamine metabolism is significantly altered in traumatic brain injury. The temporal association between ODC activity and edema formation indicates that polyamines might be a contributing factor in edema formation after traumatic brain injury. The delayed induction of ODC after brain injury suggests a potential therapeutic window for future pharmacological intervention to decrease posttraumatic secondary cerebral injury.

Animals↗
PubMed1996

An analysis of perioperative surgical mortality and morbidity in the asymptomatic carotid atherosclerosis study. ACAS Investigators. Asymptomatic Carotid Atherosclerosis Study.

BACKGROUND AND PURPOSE: Our aim was to determine the perioperative morbidity and mortality rates of patients in the surgical arm of the multi-institutional, prospective, randomized Asymptomatic Carotid Atherosclerosis Study (ACAS). METHODS: Of 828 patients with carotid stenosis of 60% or more randomized to the surgical arm of ACAS, 721 underwent carotid endarterectomy (CEA). To qualify for participation, surgeons were required to have performed at least 12 CEAs per year with a combined neurological morbidity and mortality rate no greater than 3% for asymptomatic patients and 5% for symptomatic patients. Clinical centers had to demonstrate arteriographic morbidity less than 1% and mortality less than 0.1% per year. Primary events were stroke and death in the period between randomization and 30 days after surgery; secondary events were transient ischemic attack and myocardial infarction occurring in the same period. RESULTS: Of the 721 patients who underwent CEA, 1 died and 10 others had strokes within 30 days (1.5%). Of the 415 who underwent arteriography after randomization but before CEA, 5 (1.2%) suffered transient ischemic attack or stroke caused by arteriography. Thus, a nearly equal risk of stroke was associated with both CEA and carotid arteriography. In addition, 6 transient ischemic attacks and 3 myocardial infarctions could be directly linked to CEA, for a total CEA event rate of 2.6%. CONCLUSIONS: Patients with asymptomatic internal carotid artery stenosis exceeding 60% reduction in diameter who are acceptable candidates for elective operation may be considered for CEA if the combined arteriographic and surgical complication rates are 3% or less.

Anesthesia↗
PubMed1996

Protective effect of the 5-lipoxygenase inhibitor AA-861 on cerebral edema after transient ischemia.

This study examined the effect of AA-861, a specific 5-lipoxygenase inhibitor, on brain levels of leukotriene C4 (LTC4) and correlated any changes with changes in edema formation and cerebral blood flow (CBF) after transient ischemia in gerbils. Brain levels of LTC4 were observed to be increased at 1, 2, and 6 hours of reperfusion following 20 minutes of occlusion. At 2 hours of reperfusion, a pretreatment dose of 1000 mg/kg of AA-861 was required to inhibit more than 90% of the reperfusion-induced increases in brain LTC4. At this dose, inhibition of LTC4 production was observed at 2 and 6 hours of reperfusion. The specific gravity of both the cortex and subcortex was decreased at 6 hours of reperfusion after 20 minutes of occlusion. At 2 hours of reperfusion, no significant difference was observed in the specific gravity of the cortex and subcortex regions of gerbils pretreated with AA-861 or with vehicle, but at 6 hours of reperfusion significant positive differences were observed. Cerebral blood flow decreased to approximately 10% of preocclusion values during occlusion and returned to near-preocclusion values after 10 minutes of reperfusion. No significant differences were observed in regional CBF in the AA-861- and vehicle-pretreated gerbils during reperfusion. These findings indicate that LTC4 production after transient cerebral ischemia may be an important contributor to the development of cerebral edema and that CBF does not mediate the LTC4-involved development of edema.

Animals↗
PubMed1995

Activation of phosphatidylinositol bisphosphate signal transduction pathway after experimental brain injury: a lipid study.

Regional levels of phosphatidylinositol 4,5-bisphosphate (PIP2), diacylglycerol (DG) and free fatty acids (FFA), involved in the signal transduction pathway of the excitatory neurotransmitter system, were measured after lateral fluid percussion (FP) brain injury in rats. At 5 min postinjury, tissue PIP2 concentrations were significantly reduced in the cortices and hippocampi of both ipsilateral and contralateral hemispheres. Only levels of stearic and arachidonic acids were substantially decreased in PIP2 in these regions of the brain. At the same time after injury, both DG and FFA were significantly increased in the cortices and hippocampi of both hemispheres. As was true for PIP2, only levels of stearic and arachidonic acids markedly changed in both DG and FFA in these regions of the brain. At 20 min postinjury, a significant decrease in PIP2 concentration and significant increases in levels of DG and FFA were observed only in the injured left cortex. In addition to the increases in stearic and arachidonic acids in FFA, increased amounts of palmitic and oleic acids were also found in the injured left cortex at 20 min after injury. These results suggest that the PIP2 signal transduction pathway is activated in the cortex and hippocampus at the onset of lateral FP brain injury and that the enhanced phospholipase C-catalyzed phosphodiestric breakdown of PIP2 is a major mechanism of liberation of FFA in these sites immediately after such injury.

Analysis of Variance↗
PubMed1995

Structural alterations in synaptosomal membrane-associated proteins and lipids by transient middle cerebral artery occlusion in the cat.

We have previously reported that ischemia reperfusion injury results from free radical generation following transient global ischemia, and that this radical induced damage is evident in the synaptosomal membrane of the gerbil. [Hall et al, (1995) Neuroscience 64: 81-89]. In the present study we have extended these observations to transient focal ischemia in the cat. We prepared synaptosomal membranes from frontal, parietal-temporal, and occipital regions of the cat cerebral cortex with reperfusion times of 1 and 3 hours following 1 hour right middle cerebral artery occlusion. The membranes were selectively labeled with protein and lipid specific paramagnetic spin labels and analyzed using electron paramagnetic resonance spectrometry. There were significant motional changes of both the protein and lipid specific spin labels in the parietal-temporal and occipital regions with 1 hour reperfusion; but, both parameters returned to control values by 3 hours reperfusion. No significant changes were observed in the normally perfused frontal pole at either reperfusion time. These results support the argument that free radicals play a critical role in cell damage at early reperfusion times following ischemia.

Animals↗
PubMed1995

Factors leading to early recurrence of carotid plaque after carotid endarterectomy.

BACKGROUND: Carotid endarterectomy to remove atherosclerotic plaque restores blood flow and reduces the risk of cerebral ischemia. In some patients, however, postoperative plaque recurrence reduces the clinical benefit of carotid endarterectomy. METHODS: Using duplex ultrasound scanning, we evaluated carotid artery restenosis in 63 endarterectomy patients followed for an average of 26.6 months after surgery. RESULTS: During follow-up, two-thirds of the patients showed some observable vessel wall thickening. A negative correlation was found between years since smoking cessation and recurrence of carotid plaque. Maximum benefit was seen when smoking cessation occurred at least 1 year before endarterectomy. The least benefit was seen when smoking continued or when cessation occurred within 1 year of endarterectomy. CONCLUSIONS: Smoking status was the only cardiovascular risk factor independently and significantly associated with recurrent plaque thickness.

Aged↗
PubMed1995

Ornithine decarboxylase activity and edema formation in cerebral ischemia of conscious gerbils.

General anesthetic agents often affect the biochemical and physiologic changes triggered by cerebral ischemia. This study examined the regional activities of ornithine decarboxylase (ODC) in gerbils subjected to 5 min of bilateral carotid occlusion without anesthesia. At 2, 4, and 6 h of reperfusion, significant ODC activity was observed in both the cortex and the hippocampus. Pretreatment with alpha-difluoromethylornithine (DFMO) significantly blocked the ODC activity at 2, 4, and 6 h. Significant edema formation was found at 2, 4, and 6 h. At 2 h, edema formation was unaffected by administration of DFMO. However, DFMO treatment reduced later edema formation at 4 and 6 h. These results demonstrate that ODC activity and edema formation are delayed in gerbils after the induction of transient ischemia even with the removal of anesthetic agents and their potentially protective effects. These findings suggest that ODC activity and its induction of delayed cerebral edema are specific to cerebral ischemia and not to an anesthetic effect. DFMO treatment reduced both the ODC activity and edema formation, indicating a role for polyamines in postischemic edema formation.

Animals↗
PubMed1995

Regional concentrations of cyclic nucleotides after experimental brain injury.

Regional concentrations of lactate, glucose, cAMP, and cGMP were measured after lateral fluid percussion brain injury in rats. At 5 min after injury, while tissue concentrations of lactate were elevated in the cortices and hippocampi of both the ipsilateral and contralateral hemispheres, those of glucose were decreased in these brain regions. By 20 min after injury, increases of lactate concentrations and decreases of glucose concentrations were observed only in the cortices and in the hippocampus of the ipsilateral hemisphere. Whereas the cAMP concentrations were unchanged in the cortices and hippocampi of the ipsilateral and contralateral hemispheres at 5 min after injury, decreases were found in the injured cortex and ipsilateral hippocampus at 20 min after injury. The tissue concentrations of cGMP were found to be elevated only in the ipsilateral hippocampus at 5 min after injury. The present observation that tissue glucose decreases in the injured cortex and the ipsilateral hippocampus are consistent with the published findings of increased hyperglycolysis and oxidative metabolism in brain immediately after injury. The present findings that the concentrations of cAMP and cGMP change in the cortex and hippocampus provide biochemical evidence for the neurotransmitter's surge after brain injury.

Animals↗
PubMed1994

Blockade of ornithine decarboxylase enzyme protects against ischemic brain damage.

Polyamines are derived from ornithine by the actions of ornithine decarboxylase (ODC), which is the rate-limiting step in this pathway. Polyamines play a role in cell growth, neoplasia, differentiation, and response to injury. We have shown that transient cerebral ischemia gives rise to increased ODC mRNA and enzyme activity in the gerbil brain. ODC and polyamines are thought to be important in the generation of edema and the neuronal cell loss associated with cerebral ischemia. To test this theory, we examined the ODC activity, putrescine levels, and neuronal density in the CA1 region of the hippocampus following ischemia and reperfusion injury in the absence and presence of an inhibitor of ODC activity, alpha-difluoromethylornithine (DFMO). Pretreatment of animals with DFMO resulted in attenuation of the ODC activity following 5 min of ischemia and 4 h of reperfusion. In addition, DFMO prevented the increase in polyamine levels, as determined by measurement of putrescine in the ischemic brain. These alterations were not due to changes in ODC mRNA level. Further analysis revealed that DFMO treatment blocked the delayed neuronal cell death in the CA1 region of the hippocampus that accompanies ischemia and reperfusion injury. Administration of DFMO resulted in a dose-dependent beneficial effect upon neuronal cell survival. These results suggest that ODC enzyme activity and the production of polyamines play a significant role in the response of the brain to ischemic injury.

Animals↗
PubMed1994

Enhanced phosphodiestric breakdown of phosphatidylinositol bisphosphate after experimental brain injury.

Regional levels of lactate and inositol 1,4,5-trisphosphate (IP3), a cellular second messenger of the excitatory neurotransmitter system, were measured after lateral fluid percussion (FP) brain injury in rats. At 5 min postinjury, tissue lactate concentrations were significantly elevated in the cortices and hippocampi of both the ipsilateral and contralateral hemispheres. By 20 min postinjury, lactate concentrations were elevated only in the cortices and hippocampus of the ipsilateral hemisphere. Whereas the IP3 concentrations were elevated in the hippocampi of the ipsilateral and contralateral hemisphere and in the cortex of ipsilateral hemisphere at 5 min postinjury, no elevation in these sites was found at 20 min postinjury. Histologic analysis revealed neuronal damage in the cortex and CA3 regions of hippocampus ipsilateral to the injury at 24 h postinjury. The present results suggest activation of the phosphoinositide signal transduction pathway at the onset of injury and of a possible requirement of early persistent metabolic dysfunction (> 20 min) such as the lactate accumulation in the delayed neuronal damage.

Animals↗
PubMed1994

Regional levels of lactate and norepinephrine after experimental brain injury.

The recently developed controlled cortical impact model of brain injury in rats may be an excellent tool by which to attempt to understand the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral controlled cortical impact brain injury of low grade severity; their brains were frozen in situ at various times after injury to measure regional levels of lactate, high energy phosphates, and norepinephrine. Tissue lactate concentration in the injury site left cortex was increased in injured animals by sixfold at 30 min and twofold at 2.5 h and 24 h after injury (p < 0.05). At all postinjury times, lactate concentration was also increased in injured animals by about twofold in the cortex and hippocampus adjacent to the injury site (p < 0.05). No significant changes occurred in the levels of ATP and phosphocreatine in most of the brain regions of injured animals. However, in the primary site of injury (left cortex), phosphocreatine concentration was decreased by 40% in injured animals at 30 min after injury (p < 0.05). The norepinephrine concentration was decreased in the injury site left cortex of injured animals by 38% at 30 min, 29% at 2.5 h, and 30% at 24 h after injury (p < 0.05). The level of norepinephrine was also reduced by approximately 20% in the cortex adjacent to the injury site in injured animals. The present results suggest that controlled cortical impact brain injury produces disorder in the neuronal oxidative and norepinephrine metabolism.

Adenosine Triphosphate↗
PubMed1994

Regional levels of free fatty acids and Evans blue extravasation after experimental brain injury.

The recently developed controlled cortical-impact (CCI) model of brain injury in rats serves as an excellent tool to understand some of the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral CCI brain injury of low-grade severity. Their brains were frozen in situ at various times after injury to measure regional levels of free fatty acids. Tissue total free fatty acids at the injury site within the left cortex were increased at 30 min, 2.5 h, and 24 h postinjury. In injured animals, increases in stearic and arachidonic acids were slightly greater than those in palmitic and oleic acids. The levels of total free fatty acids in the cortex adjacent to the injury site were also increased in injured animals at 2.5 h and 24 h after injury (p < 0.05). Only stearic and arachidonic acids were observed to be significantly increased (p < 0.05) in the adjacent cortex of injured animals at all times after injury. Although no significant increases in total free fatty acids were observed in the left hippocampus adjacent to the injury site, stearate and arachidonate concentrations were increased at 30 min and 2.5 h after injury (p < 0.05). Extravasation of Evans blue was found to be significantly increased in the ipsilateral cortex of injured animals at 30 min and 10 h after brain injury. These results indicate the degradation of membrane phospholipids and blood-brain barrier breakdown in the ipsilateral cortex after lateral CCI brain injury. These results also suggest that arachidonic acid and its metabolites may play a role as a mediator in the blood-brain barrier breakdown associated with cortical impact brain injury in rats.

Animals↗
PubMed1994

A simplified high-performance liquid chromatographic method for direct determination of warfarin enantiomers and their protein binding in stroke patients.

A simplified method for direct determination of warfarin enantiomers by high-pressure liquid chromatography with fluorescence detection has been developed. This method involves solid phase extraction of warfarin in plasma, precolumn derivatization to form diastereoisomeric esters, and post-column reaction to discriminate each enantiomer separately. Ultrafiltration was employed in the separation of unbound warfarin enantiomers. Twelve plasma samples from six stroke patients taking warfarin regularly were analyzed. The average concentration of total warfarin was 0.47 +/- 0.17 mg/L for the S-isomer and 0.69 +/- 0.18 mg/L for the R-isomer. The average protein binding was 99.67 +/- 0.33% for S-warfarin and 99.44 +/- 0.33% for R-warfarin. This methodology provides a quick and reliable technique for determining enantiomeric protein binding of warfarin in clinical settings.

Aged↗