Biomedical subjects
Publications and source records attributed to S H Graham.
The dose-response curve and time window of efficacy for dextrorphan in permanent focal brain ischemia leading to infarction was studied in the rat. With pretreatment, the maximum effective dose of 20 mg/kg reduced the eventual infarct volume by greater than 50%. Delayed drug administration, up to 45 min following permanent middle cerebral artery occlusion, significantly reduced infarct size.
Explore the source record for details and available documents.
The time-course of changes in extracellular glutamate and energy metabolism during 30 or 60 min of complete cerebral ischemia and 60-90 min of reperfusion was investigated by microdialysis and magnetic resonance spectroscopy in parallel groups of rats. During the first 10 min of ischemia, adenosine triphosphate (ATP) was completely depleted, and lactate increased 10-fold; after 30 min, intracellular pH had decreased to 6.33 +/- 0.11. ATP and lactate did not change further between 30 and 60 min of ischemia. Glutamate increased 30-fold between 10 and 30 min of ischemia and continued to increase in the 60-min ischemia group. After 30 min of reperfusion, glutamate had returned to pre-ischemic levels in both groups. The cellular energy state recovered within 50-60 min after 30 min of ischemia but never returned to more than 60% of baseline values after 60 min of ischemia. The continued increase in extracellular glutamate after total depletion of ATP suggests that glutamate release during ischemia is not entirely energy dependent. Ca(2+)-independent glutamate release and failure of energy-dependent glutamate re-uptake mechanisms may result in continued increase in extracellular glutamate. The rapid normalization of extracellular glutamate after 30 and 60 min of ischemia despite differences in the recovery of energy metabolism suggests that the glutamate levels were reduced by an energy-independent mechanism, such as diffusion into the restored circulation.
Specific probes were obtained using PCR cloning from rat brain for the 78 kDa glucose regulated (grp78), inducible 72 kDa (hsp70) as well as constitutive 73 kDa (hsc73) heat shock mRNAs. Grp78 and hsc73 were expressed in normal rat brain whereas hsp70 was not. Subcutaneous injection kainic acid (10 mg/kg) produced seizures and induced all three mRNAs. The induction of grp78 and hsp70 mRNAs occurred within 2 h, peaked between 6-8 h, persisted for 48 h, and returned to control levels by 72 h. Expression of the grp78 and hsp70 mRNAs after focal ischemia progressively increased with occlusion durations from 15-120 min in the cerebral cortex. Though grp78 and hsp70 mRNAs were induced modestly in the striatum by 15 min of ischemia, longer durations of ischemia were characterized by little change in the grp78 mRNA levels and relatively lower levels of hsp70 expression. This result indicates that progressive increases in the duration of ischemia in brain, prior to infarction, may produce proportional increases in transcription of the heat shock genes. However, once the duration of ischemia is long enough to produce infarction, this severely limits the availability of ATP which blocks transcription of the heat shock genes. In conclusion, concurrent induction of the heat shock genes suggests that kainic acid seizures and focal ischemia induce several different stress responses in brain cells caused by denaturation of proteins, changes of protein synthesis, and changes of protein glycosylation.
Excitatory amino acids (EAAs) are important mediators of ischemic injury in stroke. N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to be very effective neuroprotective agents in animal models of stroke, but may have unacceptable toxicity for human use. An alternative approach is to inhibit the release of EAAs during stroke. BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine], a drug that inhibits veratrine-induced release of the EAA glutamate in vitro, was tested in a rat model of proximal middle cerebral artery (MCA) occlusion. BW1003C87 significantly decreased ischemia-induced glutamate release in brain when given either 5 min before or 15 min following permanent MCA occlusion. Pretreated and posttreated rats had smaller infarct volumes and preserved glucose metabolism in the ischemic cortex at 24 h after MCA occlusion. BW1003C87 did not induce heat shock protein in the cingulate or retrosplenial cortex, suggesting that it does not injure neurons in these regions as do NMDA antagonists. These results demonstrate that drugs that inhibit glutamate release in ischemia may be nontoxic and show promise for the treatment of stroke.
The efficacy of GM1 ganglioside treatment in stroke was studied in a permanent middle cerebral artery occlusion model in the rat. A dose-dependent attenuation of infarct size at 24 hr was documented with the maximum effective dose halving the volume of the experimental stroke. Delayed administration at 5 min, but not 15 min, after vessel occlusion was as effective as preocclusion drug administration. Morphologic sparing was confined to the cortical penumbra; no protection in the ischemic core was found. Morphologically salvaged cortex was also metabolically preserved as demonstrated by quantitative measurement of glucose utilization. In vivo microdialysis demonstrated an attenuation of ischemic-induced glutamate release in the cortex with GM1 administration but no effect was found in the caudate. Hypotension did not occur even with doubling of the maximally effective dose of GM1. Accordingly, GM1 may be a safe and effective treatment for stroke.
BW 1003C87, 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid, has been tested for its in vitro and in vivo effects on glutamate release in rat brain tissue, and for its cerebro-protective action in two rodent models of cerebral ischemia. In rat brain slices the release of glutamate evoked by veratrine is inhibited by BW 1003C87 (IC50 = 1.6 microM). In anaesthetised rats with microdialysis probes implanted in the dorsal hippocampus the increase in extracellular glutamate evoked by veratrine is markedly reduced by co-infusion of BW 1003C87, 100 microM. In anaesthetised rats with microdialysis probes implanted in the cortex and the caudate nucleus ipsilateral to a middle cerebral artery (MCA) occlusion the increase in dialysate glutamate concentration seen in the first 2 h following MCA occlusion is markedly attenuated by the prior administration of BW 1003C87, 20 mg/kg i.v. In rats subjected to 10 min of bilateral common carotid artery occlusion the loss of CA1 pyramidal neurons (assessed 7 days later) is reduced by administration of BW 1003C87 (20 mg/kg i.v., at the time of ischemia and 4 h later). The volume of cortex showing infarction 72 h after unilateral MCA occlusion is reduced by treatment with BW 1003C87 (20 mg/kg, i.v., beginning 5 min after occlusion). Inhibition of glutamate release may provide a therapeutic approach in cerebral ischemia as well as in epilepsy.
The non-competitive NMDA receptor antagonists, PCP (phencyclidine), MK801, and ketamine produce psychosis in humans and abnormal vacuoles in posterior cingulate and retrosplenial rat cortical neurons. We show that PCP (> or = 5 mg/kg), MK801 (> or = 0.1 mg/kg), and ketamine (> 20 mg/kg) induce hsp70 mRNA and HSP70 heat shock protein in these vacuolated, injured neurons, and PCP also induces hsp70 in injured neocortical, piriform, and amygdala neurons. The PCP, MK801, and ketamine drug induced injury occurs in 30 day and older rats, but not in 0-20 day old rats, and is prevented by prior administration of the antipsychotic drugs haloperidol and rimcazole. Since haloperidol and rimcazole block dopamine and sigma receptors, and since M1 muscarinic cholinergic receptor antagonists also prevent the injury produced by PCP, MK801, and ketamine, future studies will be needed to determine whether dopamine, sigma, M1, or other receptors mediate the injury.
Excitatory amino acids (EAAs) have been implicated in the pathophysiology of cellular injury after brain ischemia. Changes in extracellular levels of amino acids in rat cerebral cortex after permanent proximal middle cerebral artery (MCA) occlusion were examined using microdialysis. Significant increases were found in dialysate concentrations of glutamate, aspartate and gamma-aminobutyric acid (GABA) from the ischemic cortex during the first 90 min after MCA occlusion compared to pre-ischemic concentrations and contralateral hemispheric controls. Total tissue levels of these amino acids in the infarcted hemisphere 90 min after onset of ischemia were not different from the contralateral hemisphere. These results are consistent with the hypothesis that the release of EAAs may contribute to tissue damage in focal cerebral ischemia.
Two patients with caudal pontine lesions had diminished intraoral sensation for all modalities sparing facial sensation. A third patient with lateral medullary infarction developed diminished facial pain and temperature sensation sparing intraoral structures. This segregation of intraoral sensation within the brainstem is consistent with animal studies which show that the rostral spinal trigeminal nuclei in the caudal half of the pons play an important role in intraoral and dental sensation.
Patients who are homosexual, intravenous drug abusers, or have received multiple blood transfusions are at greater risk to contract the immunosuppressive disorders of acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). These persons also have a greater chance of developing serious neurologic complications after an episode of Herpes zoster. We present two cases which emphasize the serious complications of Herpes zoster ophthalmicus in such patients. Since systemically administered acyclovir may shorten the disease course and reduce the complications of Herpes zoster in immunocompromised individuals, the authors favor treatment of all such patients who have Herpes zoster ophthalmicus with a seven-day course of high-dose (30 mg/kg/day) intravenous acyclovir. To minimize serious neurologic complications in such patients, treatment should be instituted immediately before the results of human immunodeficiency virus (HIV) testing are known.
The crown area (MCBA) and cusp areas of mandibular molars of Homo sapiens (M-1 = 131; M-2 = 71), Gorilla (M-1 = 25) and Pongo (M-1 = 24) were studied to determine whether the relative size of the mesial and distal cusps are related to overall crown size. Allometric trends were assessed by examining the correlation between relative cusp areas and MCBA and by calculating the slope of the regression line of log cusp area and log MCBA. With the exception of the metaconid in the Homo sapiens M-2S, the results of the intraspecific analyses provide little evidence of an allometric trend for relative reduction of the mesial cusps with increasing crown size. None of the samples provide consistent or reliable evidence of such a trend for the protoconid, nor do the M-1 samples provide evidence for such a trend for the metaconid. The evidence from the distal cusps is also mixed: positive allometry for the entoconid for the Homo sapiens M-2S and for the hypoconulid for the Homo sapiens M-1S, with no departure from isometry in either Gorilla or Pongo. The interspecific data provide no evidence of any trend for the mesial cusps to decrease or the distal cusps to increase in importance in larger teeth. If one accepts the proposition that the static allometric trends observed in this study are reasonable analogues for any allometric relationships within, or between, fossil hominid taxa, then the evidence presented above does not support the hypothesis that the reduction of the trigonid, which is observed in the "robust" australopithecines, is an allometric phenomenon.
Accurate measurements of the absolute and relative size of individual cusps, the arrangement of the primary fissure system and the shape of coronal cross sections of the tooth crown have been used to investigate the pattern of variation in Plio-Pleistocene hominid mandibular molar teeth. Teeth were either grouped into one of six taxonomic categories or considered as individual cases. Univariate analysis of relative cusp areas shows that the two taxonomic categories of 'robust' hominids from East and Southern Africa have relatively small mesial cusps, but a relatively large entoconid and hypoconulid and Principal Component plots of the data show that the 'robust' categories can be distinguished on the basis of relative cusp size. Other evidence suggests that these differences are not likely to be the result of allometric phenomena. Fissure pattern was analysed using the X/Y coordinates of defined reference points. Patterns were compared by Procrustes analysis and the relationships between teeth contained in the resulting similarity matrix were portrayed using Principal Coordinates plots and a nearest neighbours table. The positions of the posterior fovea and the mesial longitudinal fissure were important for distinguishing taxonomic categories. The shape of the coronal profiles proved difficult to quantify, but there were consistent and distinct differences between the South African 'robust' sample and teeth included within the East African Homo category. When these results are combined with those of a previous study of overall crown size and the distribution of extra cusps, they allow the affinities of isolated teeth or contentious specimens to be assessed. For example, our results show that KNM-ER 1506 and 1802 are more similar to the East African Homo group than any other category, and they indicate that though SK 1587 and 1588 are small teeth, they nonetheless are closest to the South African 'robust' category in terms of relative cusp size, fissure pattern and crown profile shape. The closest affinities of the Taung First mandibular molars are also with the South African 'robust' sample.
Eight-seven consecutive children with head injury were evaluated within two hours of injury by clinical examination, by computed tomographic brain images, and for systemic blood clotting disorders. All were treated by a standard regimen and survival rates calculated according to the initial neurologic abnormalities and pathology of the injury. Patients with the more severe neurologic abnormalities and those with more brain tissue destruction had poorer survival rates. However, 71% of all patients had one or more abnormal clotting tests and 32% had the disseminated intravascular coagulation and fibrinolysis syndrome by laboratory criteria. The mortality was over four times greater in those patients with DIC compared to those with normal clotting values. Our findings indicate that minor hemostatic abnormalities are the rule in head-injured children, that DIC occurs in nearly one-third of cases, and that DIC is associated with a marked increase in the mortality after brain injury: DIC may be a treatable secondary effect of head trauma that could decrease the mortality.
Serum levels of creatine kinase (CK) and its myocardial isoenzyme (CK-MB) were measured and serial ECG recorded in 24 male and 6 female patients with severe head trauma. All patients were comatose, but no patient sustained a spinal or chest injury. Total CK activity was elevated in at least one sample in each patient. Elevated CK-MB activity was found in 28 patients. The serial CK-MB data did not follow the same pattern as that of patients suffering from myocardial infarctions. The mean CK-MB remained elevated for at least 3 days after injury, although individual patterns were variable. ECG abnormalities included prolonged corrected QT interval (QTc) in 90% and a variety of nonspecific ST segment and T wave changes in 53%. These ECG findings are consistent with other clinical studies of severe neurological disorders, particularly cerebrovascular accidents. The elevated CK-MB activity indicates that ongoing myocardial damage occurs in patients with severe head injury. Although the underlying mechanism is not entirely clear, an excessive release of catecholamines is the most likely mechanism accounting for diffuse myocardial damage, prolonged elevated CK-MB values and the observed ECG abnormalities.