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Biomedical subjects

D I Graham

Publications and source records attributed to D I Graham.

338 records · Page 19Linked to original sources
PubMedDate not supplied

Cerebral ischemia induces alterations in tau and ubiquitin proteins.

Excessive stimulation of glutamate receptors and elevation of intracellular calcium levels initiate the neurodegenerative process resulting from cerebral ischemia. However, the subsequent cascade of molecular changes which are of pathogenic significance is less well understood. Breakdown of the cytoskeleton may be involved in the progression from compromise of neuronal viability to irreversible damage. Alteration of the microtubule-associated protein tau, as reflected by increased Alz-50 immunoreactivity, was induced by permanent focal cerebral ischemia in vivo but only in a proportion of neurones. Alz-50 immunoreactive neurones did not exhibit the characteristics of irreversible ischemic cell damage. Increased immunoreactivity to the stress response protein ubiquitin was also induced by ischemia in a proportion of neurones. Both proteins are components of neurofibrillary tangles in Alzheimer's disease. Alterations of the microtubule-associated protein tau may be a feature of the early stages of the ischemia-induced degeneration and the ubiquitin response may be an attempt by compromised neurones to deal with the presence of abnormal proteins.

Animals↗
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Effects of hemorrhagic hypotension on the cerebral circulation. II. Electrocortical function.

The effects of graded hemorrhagic hypotension on electrocortical function was investigated in 12 cats anesthetized with alpha-chloralose. Cerebral function was assessed both in terms of spontaneous activity (EEG) and the somatosensory evoked response. No significant changes in the EEG trace or in the amplitude of the positive/negative waves of the primary evoked response were observed at mean arterial pressures of between 120 mm Hg and 40 mm Hg. At levels of systemic arterial pressure of less than 40 mm Hg cortical rhythms became slower as pressure was decreased and an isoelectric EEG was recorded in the pressure range 10--30 mm Hg. The earliest sign of any change in the amplitude of the primary evoked responses was observed at arterial pressures of approximately 35--40 mm Hg. Below this value the amplitude decreased with decreasing systemic pressure and became zero in the pressure range 15--25 mm Hg.

Animals↗
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Effects of hemorrhagic hypotension on the cerebral circulation. III. Neuropathology.

A neuropathological examination was made of 15 cats anesthetized with alpha-chloralose, subjected to a stepwise reduction in mean arterial pressure by graded hemorrhagic hypotension. Five animals were sacrificed by perfusion-fixation at a mean arterial pressure of 75 mm Hg, 5 at a mean pressure of 35 mm Hg and 5 at 25 mm Hg. Ischemic brain damage was seen in only 5 animals, one sacrificed at a mean arterial pressure of 35 mm Hg and 4 at a pressure of 25 mm Hg. It was maximal in the selectively vulnerable areas and included the boundary zones between the major arteries of the cerebral hemispheres, the Ammon's horn and the thalamus.

Animals↗
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Cerebral blood flow in rats during physiological and humoral stimuli.

The technique for estimating cerebral blood flow (CBF) in anesthetized rats by injecting 133Xe into the internal carotid artery represents a potentially useful and inexpensive model for screening cerebral vascular responses to pathophysiological and pharmacological stimuli. We have examined associated neuropathology, the validity and the reproducibility of the method, and made comparisons of initial slope estimates of CBF with those obtained by stochastic analysis. Initial slope estimates (CBF = 1.62 +/- 0.04 ml min-1g-1, X +/- SE, N = 38) were linearly related to stochastic measurements (CBF = 1.42 +/- 0.09 ml min-1g-1, N = 6), and overestimated mean CBF by about 15%. A reactivity to CO2 of 0.05 ml min-1g-1 per mm Hg, and an auto-regulation range of 70 to 180 mm Hg were found. CBF responses to the intra-arterial infusion of aminergic drugs were determined before and after opening of the blood-brain barrier with hypertonic urea. Serotonin reduced CBF after, but not before, the administration of urea. Acetylcholine increased CBF when the barrier was intact, the effect being augmented when the barrier was disrupted; these responses were reduced by atropine. Histamine increased CBF only after barrier opening, and this response was attenuated by the H2-receptor antagonist, metiamide. These studies indicate that initial slope estimates of CBF derived in rats from intracarotid 133Xe injection, which represents an inexpensive and simplified approach for screening cerebral circulatory adjustments, may facilitate the characterization of stimuli affecting CBF.

Acetylcholine↗
PubMedDate not supplied

Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats.

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.

Animals↗
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Chronic antihypertensive treatment in the rat reverses hypertension-induced changes in cerebral blood flow autoregulation.

Cerebral blood flow (CBF) autoregulation was studied in renal hypertensive rats receiving chronic antihypertensive treatment. Young Wistar Kyoto rats (WKY) were made hypertensive by the Loomis procedure i.e. partial infarction of one kidney with contralateral nephrectomy. Systolic tail blood pressure was measured at 2-week intervals throughout the study. After two months, by which time the rats had been severely hypertensive for 5-6 weeks, antihypertensive treatment was begun; reserpine, dihydralazine and hydrochlorothiazide were administered in the drinking water. Blood pressure fell rapidly to normotensive levels and remained so. Following two months of antihypertensive treatment, the lower blood pressure limit of CBF autoregulation was studied during controlled bleeding. In age-matched untreated renal hypertensive WKY, the lower limit of autoregulation was in the mean arterial pressure range 90-109 mm Hg, as compared to 50-69 mm Hg in age-matched normotensive WKY. In contradistinction to the untreated rats, the treated rats had a normal lower limit of autoregulation, i.e. 50-69 mm Hg. It was inferred that the reversal of the functional change in CBF autoregulation reflected reversal of hypertension-induced cerebrovascular hypertrophy/hyperplasia.

Animals↗
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The distribution of ischaemic damage and cerebral blood flow after unilateral carotid occlusion and hypotension in the rat.

We have developed a model of haemodynamic cerebral ischaemia by inducing haemorrhagic hypotension (40-50 mmHg mean blood pressure) following unilateral common carotid occlusion, with external carotid ligation, in anaesthetised rats. The neuropathological pattern of ischaemic brain damage was correlated with the distribution of change in cerebral blood flow using the 14C-iodoantypyrine autoradiographic technique. Whereas hypotension alone (40-50 mmHg) resulted in neither ischaemic brain damage nor significant alterations in cerebral blood flow, the combination of this degree of hypotension with unilateral carotid occlusion produced predominantly unilateral ischaemic brain damage which correlated with regions of reduced cerebral blood flow. With this type of haemodynamically induced oligaemia, the most vulnerable areas were the lateral neocortex, the caudate nucleus, the hippocampus and the thalamus. Within the cortex, the greatest reductions in blood flow occurred in the deeper cortical layers, and this was the most frequent site of ischaemic cell change. These data support the concept of a haemodynamic mechanism in the pathogenesis of some transient cerebral ischaemic attacks in man.

Animals↗
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Alterations in behavior, brain electrical activity, cerebral blood flow, and intracranial pressure produced by triethyl tin sulfate induced cerebral edema.

The interrelationships between cerebral edema, intracranial pressure (ICP), and cerebral blood flow (CBF) were studied in acute and chronic triethyl tin sulfate treated rats. Prior to pentobarbital anesthesia behavioral observations were made. ICP and regional CBF were measured under steady state conditions and brain water content was determined by vacuum drying of the right cerebral hemisphere. Control and chronic animals were neurologically normal. There were two distinct acute groups: (1) acute low pressure (ALP) animals - alert but tetraperetic, and (2) acute high pressure (AHP) animals - deeply stuporous, with minimal pain response and gross EEG slowing. ICP was significantly elevated only in AHP animals. Hemispheric CBF was significantly reduced in AHP and chronic animals. The interaction of increased pressure and edema (AHP) produced the greatest decrease in CBF, although deep white flows were significantly affected in all experimental groups. Chronic animals had significantly lower flow in four of seven regions compared to ALP animals despite no significant difference in ICP. Water content was significantly increased in all experimental groups with the greatest increase in the chronic animals. In the absence of any significant increase in ICP, cerebral edema appears to cause a significant reduction in cerebral blood flow and this reduction corresponds with the magnitude and location of the edema.

Acute Disease↗
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Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization.

Sequences resembling those of human enterovirus type B sequences have been associated with motor neurone disease/amyotrophic lateral sclerosis. In a previous study we detected enteroviral sequences in spinal cord/brain stem from cases of motor neurone disease/amyotrophic lateral sclerosis, but not controls. Adjacent tissue sections to two of those strongly positive for these sequences by reverse-transcriptase polymerase chain reaction were analyzed by in situ hybridization with digoxigenin-labelled virus-specific antisense riboprobes. In one case, a female aged 83 showing 12 month rapid progressive disease, signal was specifically localized to cells identifiable as motor neurones of the anterior horn. In another case, a male aged 63 with a 60-month history of progressive muscle weakness, dysarthia, dyspnoea and increased tendon reflexes, signal was located to neurones in the gracile/cuneate nuclei of the brain stem tissue block that had been analyzed. This case showed loss of neurones in the anterior horn of the spinal cord by histopathologic examination which would account for clinical signs of motor neurone disease/amyotrophic lateral sclerosis. Dysfunction of the gracile/cuneate nuclei might have been masked by the paralytic disease. These structures are adjacent to the hypoglossal nuclei, and suggest either localised dissemination from hypoglossal nuclei or a possible route of dissemination of infection through the brainstem to the hypoglossal nuclei. These findings provide further evidence for the possible involvement of enteroviruses in motor neurone disease/amyotrophic lateral sclerosis.

5' Untranslated Regions↗
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TUNEL-positive staining in white and grey matter after fatal head injury in man.

Paraffin sections from the hippocampus, the cingulate gyrus and the insula of 18 head-injured patients who survived between 5 hours and 10 days, and 18 age-matched controls, were stained by the terminal deoxynucleotidyl transferase mediated biotinylated deoxyuridine triphosphate nick end labelling (TUNEL) technique for evidence of in situ DNA fragmentation. Additional staining techniques (HE, combined LFB/CV and immunohistochemistry for GFAP and CD68) were used to characterize any lesions and their time course. Only the occasional TUNEL+ cell per area was seen in the control brains. TUNEL+ cells were identified in both grey and white matter of the head-injured material and their numbers peaked between 24 and 48 hours and were still present at 10 days. Within the hippocampus, fewer TUNEL+ cells were seen in grey (between 3-5 per area) than in the white matter, (up to 51+ per area) whereas in the cingulate gyrus and in the insula, the number of TUNEL+ cells was always greater in the cortex (between 11-20 per area) than in white matter (6-10 per area). In the grey matter, most TUNEL+ cells had the morphology of necrosis. However, the histological appearances of some of the neurons (2-3%), and of oligodendroglia and macrophages in white matter (about 5%) were those of apoptosis.

Adult↗
PubMedDate not supplied

Age does not influence DNA fragmentation in the hippocampus after fatal traumatic brain injury in young and aged humans compared with controls.

Paraffin sections from the hippocampus of 12 head-injured patients (Group A, aged between 4 and 12 years n = 6 and Group B, aged between 64 and 89 years n = 6) and associated age-matched controls were stained by the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) technique for evidence of in-situ DNA fragmentation. TUNEL+ cells were of 2 Types: I (non-apoptotic) and II (apoptotic). In addition sections stained H&E, combined Luxol Fast Blue/Cresyl Violet and by immunohistochemistry for astrocytes (GFAP) and macrophages (CD68) were used to characterize the lesions. Small numbers of Type I TUNEL+ cells were seen in all sectors of the hippocampus except CA2 of both Groups A and B. Type II TUNEL+ cells were mainly found in the white matter. They constituted less than 1% of all TUNEL+ cells. There were similar or fewer TUNEL+ cells in the corresponding areas in the controls compared with the head-injured patients. However, in the dentate fascia and the CA4 sector of the Group B cases, larger numbers of TUNEL+ cells were seen in controls than after trauma. In the grey matter most TUNEL+ cells had the morphology ofnecrosis that corresponded with foci of selective neuronal damage. Only a few TUNEL+ cells were seen in white matter. The occasional Type I TUNEL+ cells were seen in grey matter. It is concluded that the amount and distribution of DNA fragmentation in children and adults is similar and therefore at least in the hippocampus does not provide an explanation for age as an independent variable of outcome after traumatic brain injury in childhood.

Age Factors↗
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No evidence for the presence of apolipoprotein epsilon4, interleukin-lalpha allele 2 and interleukin-1beta allele 2 cause an increase in programmed cell death following traumatic brain injury in humans.

BACKGROUND: Brain injury after trauma is an important cause of mortality and morbidity in society. There is evidence in both man and laboratory animals that in addition to necrosis, cell loss may occur as a result of programmed cell death (PCD). The cellular and molecular responses after head injury are partly influenced by genetic polymorphisms of apolipoprotein E and the pro-inflammatory cytokine IL-I. AIM: The principal aim of this study was to determine whether the presence of the ApoE epsilon4, IL- 1 alpha2 or IL- 1beta2 allele types influenced the amounts of PCD after head injury compared with controls. METHODS: Paraffin sections from the hippocampus of 38 patients (32 M : 6 F, aged 15 - 75, mean 38 years, survival 7- 576 hours; mean 36 hours) who died after a head injury were stained by Tunel histochemistry and quantified, and genotyping was undertaken by PCR "blind" to clinical detail. RESULTS: There were more Tunel+ cells (neurons and glia) after head injury than in controls with statistically increased numbers in all sectors of the hippocampus including the dentate fascia. However, there was no correlation between ApoEepsilon4, IL- 1 alpha allele 2 and IL- 1beta allele 2 and the amount of Tunel positivity. CONCLUSION: Given that both the ApoE and IL-1 influence outcome after various forms of acute brain injury, further work will be required to determine the mechanism underlying this relationship.

Adolescent↗
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Fatal non-missile head injury: a cohort study of patients with and without an intracranial hematoma.

Brain damage in fatal non-missile head injury is outlined in 100 cases with and in 100 cases without an intracranial hematoma. The patients with intracranial hematomas were significantly older, and had a higher incidence of lucid interval and of unilateral diffuse brain swelling but a lower incidence of ischemic lesions in the cerebral cortex and of bilateral diffuse brain swelling than the patients with no hematoma. Cases with unilateral hematomas and cases with unilateral diffuse brain swelling had significantly more severe ipsilateral cerebral contusions.

Adolescent↗