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Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 109 records · Page 6Linked to original sources
PubMed1993

Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences.

The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 microliters of 10(-7)-10(-4) M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10(-5) M of 9 +/- 11 ml 100 g-1 min-1 compared to 104 +/- 22 ml 100 g-1 min-1 with vehicle, p < 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 +/- 34 mm3 at 10(-5) M compared to 0.22 +/- 0.57 mm3 for vehicle, p < 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.

Animals↗
PubMed1993

Thermography as a diagnostic aid in sciatica.

Thermography has been proposed as a diagnostic aid in patients with sciatica. Supporters of thermography state that: (a) normal patients have normal thermograms of their lower extremities, and (b) abnormal patients (with disk ruptures causing sciatica) have abnormal thermograms. To test these two hypotheses, 56 patients with clinically documented acute sciatica, with a supporting diagnostic study [computed tomography (CT), CT/myelography, and/or magnetic resonance imaging] showing a ruptured disk, had presurgical thermograms. One year after surgical intervention, they had to have had a documented success to surgical treatment intervention to stay in the study. These 56 patients were then matched with 56 control (normal) patients who had electronic thermograms. The 112 thermograms were then interpreted blindly by two thermographers. The sensitivity and specificity of thermography as a diagnostic aid in sciatica were statistically analyzed. The sensitivity of thermography (its ability to be positive when sciatica was clinically obvious) was 60% and 50% for the two thermographic readers. The specificity of thermography (its ability to be negative in asymptomatic patients) was 45% and 48% for the two thermographers. Our conclusions are no different than those published in 1985: thermography is not useful as a diagnostic aid in sciatica.

Adult↗
PubMed1993

Rheumatoid arthritis: how well do the theories fit the evidence?

In this brief review, inspired partly by a symposium at the autumn meeting of the British Society for Immunology, 1992, varying hypotheses concerning the etiopathogenesis of rheumatoid arthritis (RA) are explored and tested against current evidence. Immunogenetic considerations, whilst of interest, have not aided our understanding of the development of this disease. The association with restricted HLA-DR beta chain hypervariable sequences does not hold true with all cases of RA (but may be related to disease severity) and studies of T cell receptor (TCR) beta chain usage fail to show consistent oligoclonality of infiltrating T cells in the synovial compartment. Etiologies based on triggering by bacteria are also considered: homologies between the 'shared epitope' sequences of HLA-DR1 and DR4 beta chains, Escherichia coli dnaJ and Proteus haemolysin do not indicate any feasible mechanisms for the development of RA, and cannot explain the many cases in which such DR sequences do not occur, though new data from man and animals enhance interest in the role of bowel flora. Finally, the striking parallels between slow bacterial infections and RA, in terms of immunogenetics, pathology, IgG glycosylation abnormalities and autoimmune manifestations, are put forward as circumstantial evidence that such bacterial infections may underly, or trigger, this serious disease.

Arthritis, Rheumatoid↗
PubMed1993

Abnormalities in rCBF and computed tomography in patients with Alzheimer's disease and in controls.

The pattern of abnormal distribution of the single photon emission computed tomography (SPECT) cerebral blood flow tracer 99m-technetium-hexamethylpropyleneamine oxime (99Tcm-HMPAO) was investigated in 14 patients with clinically diagnosed Alzheimer's disease (AD) who subsequently had post-mortem confirmation of the disease and also in 14 elderly control subjects. These abnormalities were compared with computed tomography (CT) scans to investigate the degree to which the focal SPECT deficits were due to atrophy. The results show that SPECT imaging with 99Tcm-HMPAO and CT scanning both have a higher incidence of abnormality in AD patients than in controls and that the difference between patients and controls is greater with SPECT than with CT. Frontal SPECT and CT abnormalities in moderate/severe Alzheimer's disease occur as frequently as temporal/occipital abnormalities but the latter are rare in control subjects. Around 50% of the SPECT deficits occur in CT normal brain regions, showing that atrophy is not the sole cause of SPECT deficits.

Aged↗
PubMed1992

Efficacy of D-CPPene, a competitive N-methyl-D-aspartate antagonist in focal cerebral ischemia in the rat.

The effect of a novel and potent competitive N-methyl-D-aspartate (NMDA) antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPPene) upon ischemic brain damage has been examined in a rat model of focal cerebral ischemia. Focal cerebral ischemia was produced by permanent occlusion of the left middle cerebral artery (MCA). The animals were sacrificed 24 h after MCA occlusion and the amount of ischemic brain damage was assessed at 8 predetermined coronal planes. Pretreatment with D-CPPene (1.5, 4.5 or 15 mg/kg, i.v.), initiated 15 min prior to MCA occlusion (followed by constant infusion at 1, 3 or 10 mg/kg/h), produced dose-dependent reductions in the volumes of infarction; the dose of 4.5 mg/kg being the most effective (reduced by 37%; P < 0.01). These results indicate that systemic administration of the competitive NMDA antagonist D-CPPene has neuroprotective effects in a model of focal cerebral ischemia and define the dose dependency of its neuroprotective effects.

Animals↗
PubMed1992

A correlative study of calcium channel antagonist binding and local neuropathological features in the hippocampus in Alzheimer's disease.

[3H]PN200-110 binding sites were studied by means of quantitative autoradiography in hippocampal sections of patients with Alzheimer's disease and age-matched control subjects. Choline acetyltransferase activity, plaque, tangle and cell densities were also determined in the same tissue samples used for autoradiographic studies. Quantitative autoradiographic analysis of [3H]PN200-110 binding in control hippocampus revealed a heterogeneous pattern similar to that described in rodents, being particularly high in the dentate gyrus. In Alzheimer's disease, [3H]PN200-110 binding was markedly reduced in the subiculum (control = 9.85 +/- 1.41 pmol/g; Alzheimer = 3.41 +/- 0.54 pmol/g, mean +/- S.E.M., P less than 0.001). In the subiculum there was a disproportionate reduction of [3H]PN200-110 binding in comparison to cell loss in Alzheimer's disease. The activity of choline acetyltransferase in the hippocampus was markedly reduced in Alzheimer's disease (controls 6.9 +/- 1.0; Alzheimer 2.7 +/- 0.9 nmol/h/mg protein, mean +/- S.E.M., P less than 0.01). There was a strong correlation between choline acetyltransferase activity and [3H]PN200-110 binding in the subiculum. [3H]PN200-110 binding did not correlate with plaque density in the subiculum. The discrete reduction and preservation of [3H]PN200-110 binding in the present study is consistent with the pattern of selective cellular vulnerability in the hippocampal region in Alzheimer's disease.

Aged↗
PubMed1992

Inhibition of nitric oxide synthesis does not reduce infarct volume in a rat model of focal cerebral ischaemia.

The effect of the nitric oxide (NO) synthesis inhibitor Ng-nitro-L-arginine methylester (L-NAME) on ischaemic brain damage was determined in a rat model of focal cerebral ischaemia. Ischaemia was induced by permanent occlusion of the left middle cerebral artery (MCA) and infarction assessed 4 h post-occlusion by quantitative histopathology. L-NAME (30 mg/kg s.c.), administered 30 min pre- and 30 min post-MCA occlusion, did not significantly alter the volume of ischaemic damage in the cerebral hemisphere, neocortex or caudate nucleus compared with saline controls. This result provides no support for the view that NO generation is a key component in the post-ischaemic cascade leading to acute neuronal death.

Animals↗
PubMed1992

Autoradiographic evaluation of forskolin and D1 dopamine receptor binding in a rat model of focal cerebral ischaemia.

Post-ischaemic changes in forskolin and D1 dopamine receptor (labelled with SCH23390) binding sites were evaluated in a rat unilateral middle cerebral artery occlusion (MCA) model. The changes in binding were assessed acutely (2 h post-MCA occlusion) in relation to local cerebral blood flow (lCBF) and chronically (24 h post-MCA occlusion) in relation to histopathological alterations. Two hours following occlusion lCBF was significantly reduced throughout the territory of the MCA. Despite the widespread hypoperfusion, significant reductions in binding were only observed in the dorsolateral caudate nucleus--the region with the most profound reduction in blood flow (6% of the control contralateral lCBF value). Forskolin binding sites were reduced to 40% of the contralateral value while D1 binding sites were reduced to 80% of the contralateral value. Analysis of the relationship between forskolin binding and CBF in the caudate nucleus revealed that the ischaemic threshold for alteration in forskolin binding sites 2 h after MCA occlusion was approximately 34 ml/100 g/min. Twenty-four h post-occlusion forskolin binding sites were further reduced in the dorsolateral caudate nucleus (to 6% of contralateral) while D1 binding showed minimal reduction from that observed at 2 h. The areas of reduced binding corresponded to the area of histopathological change in the caudate nucleus and rostral neocortex. In conclusion, reduction in forskolin binding progresses further than reduction in D1 binding within the first 24 h following focal cerebral ischaemia. For both forskolin and D1 binding sites, the areas of reduced binding 24 h post-MCA occlusion predicted the area of histopathological change.

Animals↗
PubMed1992

The effect of the kappa-opioid receptor agonist CI-977 in a rat model of focal cerebral ischaemia.

The effect of a novel, highly potent and selective kappa-opioid receptor agonist CI-977 upon ischaemic brain damage and brain swelling has been examined in a rat model of focal cerebral ischaemia. Focal ischaemia was produced by the permanent occlusion of the left middle cerebral artery (MCA) during a brief period of halothane anaesthesia. The animals were sacrificed 24 h after MCA occlusion and the amount of ischaemic brain damage and swelling was assessed in coronal sections at 8 predetermined stereotactic planes. Treatment with CI-977 (0.03, 0.3 or 3 mg/kg), initiated 30 min prior to MCA occlusion (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling, with the most marked reductions being noted with CI-977 (0.3 mg/kg) in both infarction (reduced by 38% from controls; P less than 0.02) and swelling (reduced by 31%; P less than 0.002). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar with saline-treated and CI-977-treated animals (overall correlation coefficient r = 0.896). These results indicate that CI-977 is effective in reducing infarction in a model of focal cerebral ischaemia, and that the reduction in brain swelling occurs in parallel with the reduction in ischaemic damage.

Animals↗
PubMed1992

The development of monoclonal antibodies to the human mitochondrial 60-kd heat-shock protein, and their use in studying the expression of the protein in rheumatoid arthritis.

OBJECTIVE: To assess the claim that the human 60-kd heat-shock protein (HSP) is highly expressed in the joints of patients with rheumatoid arthritis (RA), but is not readily detected in normal tissues. METHODS: Monoclonal antibodies were raised against the human 60-kd mitochondrial heat-shock protein (P1 protein; hsp60), and their specificity was established. They were then applied to synovial tissue. RESULTS: HSP was expressed similarly in normal, osteoarthritic, and RA synovium. Low levels of hsp60 were detected in synovial fluid by immunoprecipitation. CONCLUSION: Minor differences in the distribution of hsp60 in synovium from RA joints were attributable to increased cellularity and to the disorganization of the tissue architecture.

Animals↗
PubMed1992

Flash and pattern reversal visual evoked responses in normal and demented elderly.

P1 and P2 components of visual evoked responses (VERs) to flash stimuli were compared between patients diagnosed as suffering from Senile Dementia of the Alzheimer Type (AD) and elderly controls. Additionally the P100 component of the VER to pattern reversal stimuli at high and low contrast and using large and small check patterns was compared. Significant differences between moderate AD patients and the normal elderly were found for the P2 component of the flash stimulus and for the P100 component of the high spatial frequency pattern reversal stimuli at low contrast. These findings suggest a deficit in primary visual processing and a selective deficit in secondary visual processing in moderate cases of dementia. This indicates that visual processing capacities of AD patients decline as the disease progresses in line with the continual degeneration of neuronal populations involved with vision.

Aged↗
PubMed1992

Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.

1. A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2. The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3. The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4. NMDA receptor antagonists have marked effects on brain function in normal animals. The balance between these potential adverse effects and the anti-ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5. The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.

Amino Acids↗
PubMed1992

On the stability of messenger RNA and ribosomal RNA in the brains of control human subjects and patients with Alzheimer's disease.

The levels of the mRNAs encoding the G protein subunits GS alpha, G beta 1, and G beta 2 were measured by northern blotting in the frontal cortex and hippocampus of control subjects and of patients with a clinical and histopathological diagnosis of dementia of the Alzheimer type (DAT). There was no significant difference, in either brain region, between the control and DAT groups for any of the G protein mRNAs measured. The degree of intersubject variability was very high, e.g., GS alpha mRNA in the frontal cortex (mean optical density +/- SD) was 405 +/- 342 in the control group versus 305 +/- 207 in the DAT group. The extent of generalised RNA degradation was assessed by detecting the breakdown products of 28S rRNA. RNA degradation was present in tissue samples from every human subject studied. The extent of 28S rRNA degradation in each subject was found to be related to the levels of G protein mRNA detected. The degree of RNA degradation in human subjects was found to be very variable and unaffected by the presence of DAT. RNA degradation correlated poorly with postmortem interval and this was confirmed by a controlled study of postmortem degradation in rat tissue. The possibility that the relative hypoxia and ischaemia in patients immediately before death could influence RNA degradation is discussed. The variable extent of RNA degradation means that great care must be taken to ensure the validity of RNA analyses undertaken in human postmortem brain, particularly when techniques are employed (such as in situ hybridisation) that themselves give no indication of RNA integrity.

Aged↗
PubMed1992

Autoradiographic analysis of 3H-MK-801 (dizocilpine) in vivo uptake and in vitro binding after focal cerebral ischemia in the rat.

The clinical utility of N-methyl-D-aspartate (NMDA) receptor antagonists is now being assessed in ischemic brain injury in humans. The uptake and retention of NMDA receptor antagonists in ischemic tissue will influence the design of clinical trials. The effects of permanent occlusion of the middle cerebral artery, induced 15 minutes prior to isotope administration, on the uptake of 3H-MK-801 (dizocilpine) have been assessed in the rat with quantitative autoradiography. In a group of three rats at 15 minutes after the intravenous administration of 3H-MK-801, the level (mean +/- standard error of the mean) of isotopic tracer in the ischemic cortex and striatum was markedly less than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 22 +/- 4 vs. 84 +/- 11 pmol/gm, p less than 0.01). In contrast, in a group of five rats at 60 minutes after the intravenous administration of 3H-MK-801, the level of isotopic tracer in the ischemic cortex and striatum was greater than that in the contralateral hemisphere (ipsilateral vs. contralateral caudate nucleus: 52 +/- 8 vs. 32 +/- 4 pmol/gm, p less than 0.05). There were no significant alterations in the specific binding of 3H-MK-801 in vitro in ischemic tissue at equivalent times. The early uptake of 3H-MK-801 into the central nervous system is dominated by the level of cerebral blood flow, whereas at later times after administration enhancement of MK-801 binding by elevated extracellular glutamate concentrations appears to be more important in determining the level of the drug in ischemic tissue.

Animals↗
PubMed1992

Transient glucose hypermetabolism after acute subdural hematoma in the rat.

Ischemic brain damage occurs in most patients with acute subdural hematoma, yet many aspects of the distribution and extent of this damage remain unexplained. Previous studies in rat model, which produces a region of infarction under the hematoma, have implicated an "excitotoxic" mechanism, suggesting that high concentrations of excitatory amino acids may exacerbate ischemic damage. A study is described in which local glucose utilization is measured 2 or 4 hours after induction of acute subdural hematoma in the rat. These changes are compared to those produced by introducing the same volume of inert silicone gel into the subdural space. Massive increases (up to 142%) in glucose utilization occurred throughout both hippocampi and in a variable zone around the ischemic core, but these had normalized by 4 hours after blood injection. Hippocampal hypermetabolism was not seen after introduction of the silicone mass, suggesting that diffusible substances from the clotted blood may be responsible for these changes. This transient hypermetabolism accords with an excitotoxic process, which may amplify brain damage after acute subdural hematoma.

Acute Disease↗
PubMed1991

Preservation of [125I]galanin binding sites despite loss of cholinergic neurones to the hippocampus in Alzheimer's disease.

[125I]Galanin binding sites were examined in the hippocampal region of patients with Alzheimer's disease (AD) and age-matched control subjects using quantitative autoradiography. In control subjects, [125I]galanin binding sites were highly concentrated in the presubicular parvopyramidal layer (5.60 +/- 0.74 pmol/g), while other hippocampal regions had considerably lower levels of binding (0.56-1.73 pmol/g). In the majority of hippocampal regions, [125I]galanin binding was similar in AD patients to that in controls with a significant reduction being observed only in the deep layers of the parahippocampal gyrus. The activity of choline acetyltransferase, determined in the same tissue samples used for autoradiographic studies, was markedly reduced in AD (controls 6.8 +/- 0.6; AD 2.7 +/- 0.6 nmol/h/mg protein, mean +/- S.E.M.). These data are not consistent with a presynaptic location on cholinergic terminals of galanin binding sites in the human hippocampus unless upregulation has occurred.

Aged↗