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Biomedical subjects

D I Graham

Publications and source records attributed to D I Graham.

At least 109 records · Page 6Linked to original sources
PubMed1996

Is beta-APP a marker of axonal damage in short-surviving head injury?

beta-Amyloid precursor protein (beta-APP), a normal constituent of neurons which is conveyed by fast axonal transport, has been found to be a useful marker for axonal damage in cases of fatal head injury. Immunocytochemistry for beta-APP is a more sensitive technique for identifying axonal injury than conventional silver impregnation. This study was designed to determine how quickly evidence of axonal damage and bulb formation appears. Using this method a variety of brain areas were studied from 55 patients who died within 24 h of a head injury. Immunocytochemical evidence of axonal injury was first detected after 2 h survival, axonal bulbs were first identified after 3 h survival, and the amount of axonal damage and axonal bulb formation increased the longer the survival time.

Adolescent↗
PubMed1996

The neuronal cytoskeleton: an insight for neurosurgeons.

The cytoskeleton is important in the structure and function of the neuron. Disruption of the cytoskeletal proteins occurs in a variety of forms of acute brain injury including cerebral ischaemia and diffuse anonal injury. The final common pathway mediating neuronal cell death involves loss of the integrity of the cytoskeleton and these disturbances may have a key role in the progression of events following acute brain injury. This review aims to provide an insight into the neuronal cytoskeleton in the normal state and in disorders encountered in neurosurgical practice.

Axons↗
PubMed1996

Depletion of choline acetyltransferase activity but preservation of M1 and M2 muscarinic receptor binding sites in temporal cortex following head injury: a preliminary human postmortem study.

Abnormalities of cholinergic neurotransmission have been implicated in the memory deficits that result from head injury on the basis of results obtained from experimental animal models and cholinergic agonist treatment in head-injured survivors. The purpose of the present study was to make a preliminary investigation of pre- and postsynaptic markers of cholinergic transmission in human postmortem brain from patients who died as a result of head injury and age matched controls. Choline acetyltransferase activity, M1 and M2 receptor binding sites were assayed in the inferior temporal gyrus from 7 head-injured patients and 7 controls. The mean value of choline acetyltransferase activity was reduced by approximately 50% in the head-injured group compared to the control, although in 2 head-injured cases enzyme activity was similar to that of controls. In contrast to the reduction in choline acetyltransferase activity, there was no difference between the head-injured and control groups in the levels of either M1 or M2 receptor binding. These preliminary results indicate that there is a significant presynaptic abnormality of cholinergic neurotransmission in postmortem human brain following head injury but that muscarinic receptor binding sites are unaltered.

Aged↗
PubMed1996

Endothelin receptor antagonist increases cerebral perfusion and reduces ischaemic damage in feline focal cerebral ischaemia.

These investigations characterised the cerebrovascular effects of an endothelin ETA-receptor antagonist PD156707 in normal and ischaemic cat brain. A dose of PD156707 that inhibited the effects of exogenous endothelin-1 was established in nonischaemic cerebral resistance arterioles. Perivascular microapplication of the endothelin-receptor antagonist PD156707 (0.03-3 microM) had a minimal effect on nonischaemic pial resistance arterioles. The perivascular co-application of PD156707 and ET-1 (10 nM) effected a dose-dependent attenuation of the ET-1 vasoconstrictive response (IC50 = 0.1 microM). Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion) attenuated the vasoconstriction elicited by perivascular ET-1 (10 nM) in normal pial arterioles (ET-1 vasoconstriction: -37 +/- 13% from preinjection baseline; after intravenous PD156707: 6 +/- 10% from preinjection baseline). In the focal ischaemia studies, cerebral perfusion was measured in the suprasylvian and ectosylvian gyri (by laser Doppler flowmetry). Occlusion of the middle cerebral artery reduced cerebral perfusion in the suprasylvian and ectosylvian gyri by approximately 50%. Intravenous administration of PD156707 (3 mumol/kg bolus + 5 mumol/kg/h infusion), initiated 30 min after middle cerebral artery occlusion, effected a progressive increase in cerebral perfusion up to preocclusion baseline levels, whereas cerebral perfusion in vehicle-treated animals did not vary from its postocclusion level. In these animals, the intravenous administration of PD156707 reduced the hemispheric volume of ischaemic damage by 45% (vehicle: 2,376 +/- 1,107 mm3; PD156707: 1,307 +/- 548 mm3; p < 0.05). Our investigations indicate that endothelin receptor antagonism may be a new therapeutic strategy for the amelioration of focal ischaemic damage.

Animals↗
PubMed1996

A new experimental model of contusion in the rat. Histopathological analysis and temporal patterns of cerebral blood flow disturbances.

The authors have devised a simple reproducible rodent model of focal cortical injury that uses a mechanical suction force applied through intact dura. The time course and pattern of changes in neurons, glia, and microvasculature were investigated using this model. Early traumatic disruption of the blood-brain barrier and hemorrhage do not occur in this model; however, many of the features of human contusion seen with light and electron microscopy are closely reproduced. At the site of injury, early swelling and lucency of neural dendritic processes have been shown to precede an astrocyte response. In the absence of perivascular hemorrhage, delayed perivascular protein leakage and polymorphonuclear infiltration of the damaged cortex occurs, which is suggestive of an acute inflammatory response. Cerebral blood flow (CBF) has been measured using 14C-iodoantipyrine autoradiography at 30 minutes, 4 hours, and 24 hours after induction of negative-pressure injury in rats anesthetized with halothane and in time-matched sham-operated controls. A significant reduction in blood flow in the sensorimotor cortex at the site of the injury was present at 30 minutes, 4 hours, and 24 hours after induction of the lesion, compared to the contralateral cortex (superficial lamina, ipsilateral 50 +/- 7 ml/100 g/minute, contralateral 112 +/- 26 ml/100 g/minute). The CBF was significantly reduced at the ipsilateral entorhinal cortex at 30 minutes postinjury but no significant reduction was demonstrated at later time points. Although marked alterations in CBF occurred in this cortical injury model, the magnitude and duration of the reduction in CBF are not consistent with those necessary for production of ischemic cell damage. These data indicate that this model of cortical injury can be used to examine biomechanical aspects of contusion without domination by ischemic pathophysiology.

Animals↗
PubMed1996

Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms.

Brain injury is the leading cause of death among individuals under the age of 45 years in the United States and Europe. Recently, the neuropathologic classification of posttraumatic brain damage has provided insight into the specific mechanisms underlying traumatically induced neuronal damage and death. Studies regarding the biomechanics of brain trauma have also provided great insight into the pathophysiologic mechanisms underlying specific patterns of posttraumatic cellular death. Based upon recent clinical evaluations and biomechanical studies, laboratory models of human brain injury have been developed that faithfully reproduce a number of important features of clinical brain trauma. Biomechanical models have been used to study both the acute sequelae of brain injury and the role of neurochemical alterations in contributing to the development of secondary or delayed cellular death and damage. This report reviews and integrates the laboratory investigations linking experimental models of brain injury to clinical diagnosis and treatment.

Animals↗
PubMed1995

The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat.

The neuroprotective efficacy of the hydroperoxide scavenger ebselen was assessed in a model of transient focal ischaemia that utilises the potent vasoconstrictor peptide endothelin-1 to induce temporary occlusion of the middle cerebral artery (MCA). Pretreatment with ebselen (10 or 30 mg/kg p.o., 40 min pre-MCA occlusion) dose dependently reduced the volume of ischaemic damage assessed 4 h post-endothelin-1 application in the anesthetised rat. The lower dose of ebselen (10 mg/kg) resulted in a non-significant 35% reduction in the total volume of ischaemic damage compared with the vehicle control. In contrast the higher dose of ebselen (30 mg/kg) significantly reduced the volume of ischaemic damage in the cerebral hemisphere and cerebral cortex by 48% and 53%, respectively. The marked reduction in brain damage achieved with ebselen cannot be attributed to drug-induced alterations in blood pressure, body temperature or arterial blood gases since these physiological variables were closely monitored and were not significantly altered by ebselen treatment. Thus ebselen is an effective neuroprotective agent against acute focal ischaemic-reperfusion injury.

Animals↗
PubMed1995

Axonal injury: a universal consequence of fatal closed head injury?

beta-Amyloid precursor protein immunostaining has recently been shown to be a reliable method for detecting the damage to axons associated with fatal head injury. In an attempt to compare the efficacy of this technique with conventional histological detection of axonal damage, we have reanalysed sections from a large well-characterised series of head-injured and control patients. The results indicate that the frequency of axonal injury has been vastly underestimated using conventional silver techniques, and that axonal injury may in fact be an almost universal consequence of fatal head injury.

Adolescent↗
PubMed1995

Cytochemical evidence for redistribution of membrane pump calcium-ATPase and ecto-Ca-ATPase activity, and calcium influx in myelinated nerve fibres of the optic nerve after stretch injury.

There has been controversy for some time as to whether a posttraumatic influx of calcium ions occurs in stretch/nondisruptively injured axons within the central nervous system in both human diffuse axonal injury and a variety of models of such injury. We have used the oxalate/pyroantimonate technique to provide cytochemical evidence in support of such an ionic influx after focal axonal injury to normoxic guinea pig optic nerve axons, a model for human diffuse axonal injury. We present evidence for morphological changes within 15 min of injury where aggregates of pyroantimonate precipitate occur in nodal blebs at nodes of Ranvier, in focal swellings within axonal mitochondria, and at localized sites of separation of myelin lamellae. In parallel with these studies, we have used cytochemical techniques for localization of membrane pump Ca(2+)-ATPase and ecto-Ca-ATPase activity. There is loss of labelling for membrane pump Ca(2+)-ATPase activity on the nodal axolemma, together with loss of ecto-Ca-ATPase from the external aspect of the myelin sheath at sites of focal separation of myelin lamellae. Disruption of myelin lamellae and loss of ecto-Ca-ATPase activity becomes widespread between 1 and 4 h after injury. This is correlated with both infolding and retraction of the axolemma from the internal aspect of the myelin sheath to form periaxonal spaces which are characterized by aggregates of pyroantimonate precipitate, and the development of myelin intrusions into invaginations of the axolemma such that the regular profile of the axon is lost. There is novel labelling of membrane pump Ca(2+)-ATPase on the cytoplasmic aspect of the internodal axolemma between 1 and 4 h after injury. There is loss of an organized axonal cytoskeleton in a proportion of nerve fibres by 4-6 h after injury. We suggest that these changes demonstrate a progressive pathology linked to calcium ion influx after stretch (non-disruptive) axonal injury to optic nerve myelinated fibres. We posit that calcium influx, linked to or correlated with changes in Ca(2+)-ATPase activities, results in dissolution of the axonal cytoskeleton and axotomy between 4 and 6 h after the initial insult to axons.

Adenosine Triphosphatases↗
PubMed1995

Quantification of beta APP immunoreactive pre-alpha cells in the entorhinal cortex using image analysis.

The neuropathological diagnosis of Alzheimer's disease requires an assessment of the quantity of pathology present. Advances in molecular biology have highlighted the role of beta-amyloid precursor protein (beta APP) in the pathogenesis of the disease. This protein is found in neurons and other cells and many neuropathological studies would benefit from a method which generates reliable data on the numbers of cells containing significant amounts of the protein. Classically, generation of such data would have involved laborious manual counting. This particular approach carries low levels of inter- and intra-rater reliability and is much dependent on the skill and experience of the operator. We have used immunocytochemistry to specifically define a single cell population, pre-alpha cells, containing beta APP, and have developed a computerized cell counting programme that can reliably quantify these cells in human post-mortem brain samples. We have obtained a high level of accuracy (> 95%) and efficiency in identifying and quantifying target cells and have demonstrated that our protocol can be used effectively by both novice and expert. This method could be easily configured to provide quantitative data for a wide range of immunocytochemically defined cell populations.

Adolescent↗
PubMed1995

Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury.

Deposition of amyloid beta-protein (A beta) in the brain plays a key role in the pathogenesis of Alzheimer's disease. Apolipoprotein E epsilon 4 allele (apo E-epsilon 4) is a strong risk factor for Alzheimer's disease, and there is in vitro evidence that apo E is directly involved in A beta deposition. Head injury is an epidemiological risk factor for Alzheimer's disease and deposition of A beta occurs in approximately one-third of individuals dying after a severe head injury. We report here that the frequency of apo E-epsilon 4 in those individuals with A beta deposition following head injury (0.52) is higher than in most studies of Alzheimer's disease, while in those head-injured individuals without A beta deposition the apo E-epsilon 4 frequency (0.16) is similar to controls without Alzheimer's disease (P < 0.00001). This finding provides further evidence linking apo E-epsilon 4 with A beta deposition in vivo and suggests that known environmental and genetic risk factors for Alzheimer's disease may act additively. In addition our finding indicates a genetic susceptibility to the effects of a head injury.

Adolescent↗
PubMed1995

Distribution of beta-amyloid protein in the brain following severe head injury.

Deposits of beta-amyloid protein (beta AP) can be found in the brains of 30% of fatally head-injured patients; they have been found in children and after survival times of only 4 h. The principal aims of this study were to map the distribution of beta AP in 14 patients aged 65 years or less in whom it was known that the protein had been deposited, and to correlate its distribution with the pathologies of traumatic brain injury. The results show that beta AP is widely distributed, and that there is no correlation between its presence and cerebral contusions, intracranial haematoma, axonal injury, ischaemic brain damage, brain swelling or the pathology of raised intracranial pressure. These findings suggest that the deposition of beta AP is a consequence of the acute phase response of nerve cells to stress in susceptible individuals. Further studies will be required to establish the possible relationship between the deposition of beta AP following head injury and the molecular neuropathology of Alzheimer's disease.

Adolescent↗
PubMed1995

The nature, distribution and causes of traumatic brain injury.

The identification and interpretation of brain damage resulting from a non-missile head injury is often not easy with the result that the most obvious structural damage identified postmortem may not be the most important in trying to establish clinicopathological correlations. For example patients with a fracture of the skull, quite severe cerebral contusions or a large intracranial haematoma that is successfully treated can make an uneventful and complete recovery if no other types of brain damage are present. However, not infrequently more subtle forms of pathology are present and ones that can only be identified microscopically. A systematic and pragmatic approach through the autopsy is therefore required and one that recognises the need for tissue to be retained in ways that are appropriate for cellular and molecular studies.

Apolipoproteins E↗
PubMed1995

Therapeutic potential of endothelin receptor antagonists in experimental stroke.

This investigation demonstrates an increase in endothelin (ET)-mediated vascular tone in peri-ischemic areas after experimental focal cerebral ischemia (middle cerebral artery occlusion) in the cat. Adventitial application of the butenolide antagonist PD155080 (30 microM), after MCA occlusions resulted in marked increases in caliber of dilated (10.6 +/- 1.6% change from preinjection baseline) and constricted vessels (68.7 +/- 17.5% change from pre-injection baseline). Cerebral blood flow (measured by laser Doppler flowmetry) was reduced after MCA occlusion to 50% of preocclusion levels. Intravenous administration of PD156707 30 min after MCA occlusion restored cerebral blood flow to preocclusion baseline levels at 6 h. The volume of ischemic damage in the cerebral hemisphere after MCA occlusion was significantly reduced (by 45%) after intravenous administration of PD156707.

Animals↗
PubMed1994

Increased numbers of beta APP-immunoreactive neurones in the entorhinal cortex after head injury.

In a previous publication we hypothesized that Alzheimer's disease (AD) can be induced by the age-related increase in expression of beta-amyloid precursor protein (beta APP) in the medial temporal lobe. Head injury has also been identified as a risk factor for AD and as such, similarities should exist between the pathology found after head injury and the earliest stages of pathology in AD. In this study, we have quantified the number of beta APP-immunoreactive neurones in the medial temporal cortex (pre-alpha cells, layer II) of 13 head injured and 17 control patients. Significantly more beta APP immunoreactive neurones were observed in head injury cases (mean 18.4 per cluster) compared with controls (mean 13.4 per cluster, p < 0.05). These data provide a mechanism to explain how an environmental event such as head injury can generate the same molecular pathology (increased neuronal beta APP) as is found in the earliest stages of AD.

Adolescent↗
PubMed1994

Neuroprotective effect of remacemide hydrochloride in focal cerebral ischemia in the cat.

The neuroprotective effects of remacemide hydrochloride ((+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide hydrochloride) have been assessed with permanent occlusion of one middle cerebral artery in chloralose-anesthetized cats in which key physiologic variables have been monitored throughout the post-ischemic period. An infusion of remacemide hydrochloride (278 micrograms/kg/min; total dose 25 mg/kg) initiated 90 min prior to middle cerebral artery occlusion and discontinued at occlusion, reduced significantly (P < 0.02) the volume of ischemic damage (from 2505 +/- 454 mm3 of vehicle-treated cats to 1266 +/- 54 mm3 of remacemide hydrochloride-treated cats).

Acetamides↗
PubMed1994

Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression.

Activated microglia containing IL-1 alpha-immunoreactive (IL-1 alpha +) product were increased 3-fold in number in the acute phase following head injury, a risk factor for later development of Alzheimer's disease, and this increase was correlated with a 7-fold increase in the number of neurons with elevated beta-amyloid precursor protein (beta-APP) levels (R = 0.78; P < 0.05). Furthermore, clusters of beta-APP+ dystrophic neurites present in these patients were invariably associated with activated IL-1 alpha + microglia. These findings suggest that early overexpression of IL-1 alpha and beta-APP is a priming event for later neuropathological changes evident at end stages of Alzheimer's disease.

Adult↗