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Biomedical subjects

J McCulloch

Publications and source records attributed to J McCulloch.

At least 199 records · Page 11Linked to original sources
PubMed1985

Phase II study of vincristine infusion in refractory small cell carcinoma of the lung.

Fifteen patients with extensive refractory small cell carcinoma of the lung received prolonged intravenous infusion of vincristine. All but one patient had previously been given vincristine by conventional bolus injection. Treatment consisted of a 0.5-mg bolus injection followed immediately by 0.25 mg/m2/day infusion which was continued for 5 days. Toxicity in general was minimal, but rapidly progressive disease precluded adequate assessment in the majority of patients. No objective responses were observed. Infusion of vincristine does not appear to be an efficacious salvage treatment for this disease.

Adult↗
PubMed1985

Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists.

The vasomotor responses of individual cerebral pial arterioles on the convexity of the cerebral cortex to subarachnoid perivascular micro-injections of dopamine and the putative dopamine receptor agonists, apomorphine, SKF 38393 and LY 141865, have been examined in 38 anaesthetized cats. The perivascular microapplication of dopamine (10(-9)-10(-3)M) effected dose-dependent reductions in pial arteriolar calibre, with the maximum reductions in calibre (22 +/- 2% from preinjection levels: mean +/- s.e.) being observed at 10(-3)M. The cerebrovascular constriction produced by dopamine (10(-5)M) could be significantly attenuated by the concomitant perivascular administration of phentolamine (10(-6)M) or methysergide (10(-6)M). The perivascular microapplication of apomorphine (10(-8)-10(-4)M) effected dose-dependent increases in arteriolar calibre, with the maximum increase (31 +/- 6%) being observed with apomorphine (10(-5)M). The perivascular administration of the putative dopamine D1-receptor agonist, SKF 38393 (10(-9)-10(-4)M) increased arteriolar calibre, with the maximum response (24 +/- 3%) being observed with injection of 10(-7)M. The putative dopamine D2-receptor agonist, LY 141865, also increased cerebral arteriolar calibre, but only at high concentrations (maximum calibre increase 25 +/- 6.1 with 10(-4)M). The cerebrovascular dilatations elicited by apomorphine and by SKF 38393 were markedly attenuated by the concomitant perivascular microapplication of the putative dopamine D1-receptor antagonist, SCH 23390 (10(-8)M). The perivascular administration of SCH 23390 (10(-9)-10(-5)M) per se did not alter arteriolar calibre nor the arteriolar dilatation provoked by microinjections of acidic cerebrospinal fluid. These results point to the presence on cat cerebral arterioles of dopamine receptors (probably of D1 subtype) mediating dilation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema.

A new model for establishing a successful and consistent arterial recirculation has been devised following middle cerebral artery (MCA) occlusion in the rat. A snare ligature was introduced at the stem of the MCA just distal to the lenticulostriate branches, and occlusion and recirculation were performed by pulling and releasing the thread. This method had an advantage over the use of a small clip which caused damage to the artery without good recirculation. Study of local cerebral blood flow using carbon-14 (14C)-iodoantipyrine, of cerebrovascular permeability using 14C-aminoisobutyric acid, and of brain-water content using the microgravimetric technique was performed upon recirculation following various periods of occlusion and compared with the results in permanent ischemia. A reactive hyperemia was noted within the previously ischemic area immediately upon recirculation following either a 30-minute or a 2-hour ischemic period. One or 2 hours later, delayed hypoperfusion developed in this region, but the circulation over the periphery of the ischemic area recovered well. Cerebrovascular permeability was not, however, altered during the time courses studied. Topographic changes in tissue specific gravity were compared between permanent and transient ischemia in the corresponding time-courses. Although there was a greater decrease in tissue specific gravity following recirculation when the ischemic period was maintained longer, edema formation was resolved by recirculation. Further study is required to determine thresholds of ischemic brain damage and edema formation at recirculation following focal cerebral ischemia.

Aminoisobutyric Acids↗
PubMed1985

Chemonucleolysis for herniated nucleus pulposus in adolescents.

Fifty-five adolescents between the ages of thirteen and nineteen years underwent chemonucleolysis for one or more herniated lumbar discs at St. Michael's Hospital, Toronto, Ontario. The surgery was done by the senior one of us (J.M.) between 1972 and 1982. The duration of symptoms ranged from two months to three years. Pain in the lower limb was the predominant symptom in forty-eight patients. Reduction of the amount of straight leg-raising by 50 per cent or more, with or without pain in the ipsilateral hip when the asymptomatic limb was lifted (cross-over pain) and with or without pain radiating up or down the lower limb when the tibial nerve was pressed in the popliteal fossa (bowstring discomfort), was considered evidence of tension on or irritation of the nerve root and was present in all patients. Chemonucleolysis was considered as an alternative to discectomy and was performed only after the patient failed to respond to conservative management. An anaphylactic reaction occurred in one patient and was treated successfully. The most common symptom after injection was increased back pain, and it was controlled with medication. One patient had transient weakness of the extensor hallucis longus after injection. The length of follow-up ranged from two to twelve years (average, four years and six months), excluding one patient who was killed in an accident six months after injection. Chemonucleolysis did not relieve the symptoms in eleven of the fifty-five patients. These eleven patients all subsequently had surgical excision of the disc, and in them the chemonucleolysis was considered to have failed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Functional consequences of unilateral lesion of the locus coeruleus: a quantitative [14C]2-deoxyglucose investigation.

The functional consequences, as reflected in local rates of glucose utilization, of ablation of the locus coeruleus (the nucleus from which a major portion of the ascending noradrenergic fibres arise) have been examined in conscious rats with the quantitative autoradiographic [14C]2-deoxyglucose technique. Measurements of glucose utilization were made 72 h after histologically verified unilateral electrolytic lesions of the locus coeruleus. In the overwhelming majority of the 35 grey matter regions examined, the rate of glucose utilization was unaltered by lesions of the locus coeruleus, and in the limited number of CNS regions in which significant alterations were observed, the magnitude of the changes was invariably modest (less than 20% different from sham-operated control animals). Reductions in glucose use were observed in ipsilateral ventral (by 14%) and lateral thalamic nuclei (by 17%), and rates of glucose utilization in most regions of cerebral cortex were significantly lower (about 10%) in the ipsilateral hemisphere relative to the hemisphere contralateral to the lesion. In one region, the median raphe nucleus, glucose utilization was significantly elevated (by 19%) following lesions of the locus coeruleus. Attempts to accentuate the effects of locus coeruleus lesions by pharmacological manipulation of CNS adrenoreceptors by means of the systemic administration of phenoxybenzamine (30 mg/kg, 40 min prior to measurement of glucose use) in animals bearing unilateral locus coeruleus lesions were unsuccessful; the modest alterations in glucose utilization observed following locus coeruleus lesion alone were even less pronounced in lesioned animals receiving phenoxybenzamine. The alterations in local glucose utilization provoked by phenoxybenzamine were similar in sham-lesioned and locus coeruleus-lesioned animals. It would appear that the functional consequences, in terms of glucose utilization, are much less pronounced when a single neurotransmitter system (in the present studies, noradrenergic neurones) is lesioned than when a multiple neurotransmitter, functionally integrated pathway (such as the visual system) is disrupted.

Animals↗
PubMed1984

Extrastriatal circuits activated by intrastriatal muscimol: a [14C]2-deoxyglucose investigation.

The quantitative autoradiographic [14C]2-deoxyglucose technique has been employed in conscious, lightly restrained rats to investigate the functional consequences (which are reflected as alterations in local rates of glucose utilization) of unilateral intrastriatal administration of the GABAergic agonist, muscimol. Intrastriatal injections of muscimol (500 ng) effect a widespread, homogeneous reduction (by 33%) in glucose utilization throughout the ipsilateral striatum. Increased glucose utilization following intrastriatal muscimol injection was observed in each region to which the principal striatal efferent projections are directed (ipsilateral globus pallidus increased by 29%; ipsilateral entopeduncular nucleus increased by 33%; ipsilateral pars reticulata increased by 46%). Significant focal alterations in glucose utilization occurred in a number of other regions ipsilateral to the injection, including lateral habenular nucleus (increased by 16%), pars compacta of the substantia nigra (increased by 28%), ventrolateral nucleus of the thalamus (decreased by 40%), sensory-motor cortex (decreased by 47%), deep layer of the superior colliculus (decreased by 18%), and subthalamic nucleus (decreased by 18%). In the overwhelming majority of brain regions examined, glucose utilization was unaltered by intrastriatal administration of muscimol. All regions which displayed significant alterations in glucose use with intrastriatal muscimol are known to have direct connections with the striatum (e.g. pallidus and nigra), or to be anatomical components in polysynaptic striatal outflow pathways (e.g. striatal-pallidal-ventral thalamic-neocortical circuit). The present results indicate that activity within striatal efferent circuits can be differentially modified by the effects of the GABAergic agonist, muscimol, within the caudate nucleus.

Animals↗
PubMed1984

Focal cerebral ischemia in the rat: topography of hemodynamic and histopathological changes.

We studied local cerebral blood flow, as measured by autoradiography with digital image processing and by tissue morphology, in six rats 4 hours after occlusion of the proximal middle cerebral artery. A consistent, three-dimensional pattern of graded reductions in local cerebral blood flow involved the affected hemisphere, with a densely ischemic zone (local cerebral blood flow less than 3 ml/100 gm/min) in the dorsolateral caudate putamen and the adjacent frontoparietal cortex. In the frontoparietal cortex, the normal laminar pattern of local cerebral blood flow was disrupted, and there was a transcortical gradient in flow, with pronounced ischemia in deeper layers and relatively preserved superficial flow. Comparisons of autoradiographic findings with histopathological abnormalities in adjacent frozen sections showed that the region of ischemic damage corresponded closely with the area of greatest reduction in blood flow. Although around this region local cerebral blood flow increased centrifugally, a striking finding was that flow density changed abruptly (a tenfold variation in flow within a 1 to 2 mm interval) at the edge of the pathological lesion. Penumbral conditions may therefore exist in only a very narrow zone 4 hours after onset of focal ischemia. After occlusion of a major cerebral artery, the pattern of local cerebral blood flow changes appears to depend on interactions among vascular architecture, reductions in perfusion pressure, alterations in metabolic demands, and variations in local vascular resistance.

Animals↗
PubMed1984

Effect of the calcium antagonist nimodipine on local cerebral blood flow: relationship to arterial blood pressure.

The effect of the calcium antagonist nimodipine on local CBF in 31 regions of the CNS was studied with the [14C]iodoantipyrine autoradiographic technique in lightly anaesthetised, mechanically ventilated rats. Continuous intravenous infusion of nimodipine (1, 2, or 4 micrograms kg-1 min-1) produced a dose-dependent reduction in MABP (reduced by 26 +/- 2% after 30 min of nimodipine, 4 micrograms kg-1 min-1) and a significant elevation in plasma glucose concentration (increased by 44 +/- 2% after 30 min of nimodipine, 4 micrograms kg-1 min-1). Local CBF was increased significantly during infusions of nimodipine (1 microgram kg-1 min-1) in 9 of the 31 regions examined (including the cerebral cortex, hippocampus, hypothalamus, and most thalamic nuclei). In contrast to the increases in CBF observed in forebrain regions, no significant increases in CBF were observed during nimodipine infusions in regions of the lower brainstem, cerebellum, and pons or in myelinated fibre tracts. The proportionately greatest increases in local CBF were observed during infusions of the lowest dosage of nimodipine (1 microgram kg-1 min-1), suggesting either that this dosage provokes maximum cerebrovascular relaxation or that effects of increasing concentrations are counteracted by the concomitant systemic hypotension.

Animals↗
PubMed1984

Effects of cholecystokinin octapeptide on pial arteriolar diameter.

The effects of the perivascular microapplication of sulphated cholecystokinin octapeptide (CCK-8) on pial arteriolar calibre have been examined in anaesthetised cats using a video-display image-splitting technique. The microinjection of CCK-8 (10(-7) M) in the injectate did not modify the constriction or dilatation of pial arterioles provoked by the perivascular microinjection of alkalotic (pH 7.45) or acidic (pH 6.8) artificial CSFs, respectively. Thus, although CCK-8-immunoreactive neuronal processes are known to be associated with cortical blood vessels, CCK-8 appears to have minimal vasomotor effects on pial vessels.

Animals↗
PubMed1984

Intracranial haemorrhage induced at arterial pressure in the rat. Part 2: Short term changes in local cerebral blood flow measured by autoradiography.

The regional distribution of blood flow following intracranial haemorrhage at arterial pressure was measured with the 14C-iodoantipyrine autoradiographic technique in Sprague Dawley Rats. With uncontained haemorrhage, there was a bilateral reduction in cerebral blood flow, associated with a fall in cerebral perfusion pressure. With contained intracerebral haemorrhage there was a profound ipsilateral reduction in flow in the hemisphere adjacent to the haematoma. This study indicates that extensive cerebral ischaemia occurs immediately after an intracerebral haemorrhage, and that this may be the result of compression of the microcirculation.

Animals↗
PubMed1984

Neuropeptide Y: immunocytochemical localization to and effect upon feline pial arteries and veins in vitro and in situ.

Plexuses of nerve fibres containing neuropeptide Y (NPY)-like immunoreactivity invest pial arteries belonging to the circle of Willis, pial arterioles, occasionally penetrating arterioles and large veins. A more sparse supply of NPY-like fibres were observed around pial veins and venules. The NPY-immunoreactive fibres are located within the adventitia or at the adventitia-media border. Only occasional fibres are present in cerebral vessels of animals in which the superior cervical ganglion has been removed one week previously. Administration of NPY resulted in strong, concentration-dependent contractions of isolated feline middle cerebral arteries whereas administration of avian pancreatic polypeptide (APP) elicited weak contractions. In chloraloseanaesthetized cats, perivascular microapplication of NPY in situ resulted in marked concentration-dependent contractions of cerebral pial arterioles (34.7 +/- 6.6%; maximum decrease in calibre with NPY. Perivascular administration of NPY resulted in the constriction of pial veins but the magnitude of the venous calibre reductions was smaller than the response of arterioles at each reductions was smaller than the response of arterioles at each concentration examined. APP did not elicit contraction of pial arterioles or veins during in situ conditions. The pharmacological and immunocytochemical results strongly indicate the existence of a novel perivascular neuronal system containing NPY, which mediates contraction of cerebral blood vessels and NPY is colocalized with NA in sympathetic nerves.

Animals↗
PubMed1984

Urinary thiamine excretion after oral physiological doses of the vitamin.

Urinary thiamine excretion has been measured in healthy subjects after oral physiological doses of the vitamin. There was a highly significant correlation between the oral dose and the urinary excretion. However, there was considerable overlap between the baseline values and the urinary excretion following doses up to 1000 micrograms. It is recommended that repeated daily measurements are made to differentiate baseline excretion from that recorded after oral physiological doses. This study may have relevance to the monitoring of dietary fortification programmes with thiamine.

Adult↗
PubMed1983

Neuropeptide Y: cerebrovascular innervation and vasomotor effects in the cat.

Avian pancreatic polypeptide (APP) has been proposed to be a neurotransmitter in a subpopulation of sympathetic nerves. Here, we present immunocytochemical and pharmacological evidence that the structurally related peptide, neuropeptide Y (NPY), is likely to be the biologically active material in these nerves. Cerebral arteries from cats are invested with a dense network of NPY-containing nerve fibres, as demonstrated by immunocytochemistry. This immunoreaction is abolished by prior removal of the superior cervical ganglion. NPY causes strong contractions of cerebral arteries in vitro whereas APP has small effects on the vasomotor reactivity. The NPY-induced contractions were not inhibited by the alpha 2-adrenoceptor antagonist rauwolscine (10(-7) M) or the 5-hydroxytryptamine antagonist ketanserin (10(-7) M). The contractions were, however, sensitive to calcium removal or to the calcium antagonist diltiazem (10(-4) M).

Animals↗
PubMed1983

Differential effects of locus coeruleus lesions upon metabolic activity in CNS nuclei involved in cardiovascular regulation.

The alterations of local cerebral glucose utilization in 5 medullary and 6 supramedullary regions involved in cardiovascular regulation, which result from unilateral electrolytic lesions of the locus coeruleus, have been examined in conscious rats, using the quantitative autoradiographic [14C]2-deoxyglucose technique. Unilateral lesions of the locus coeruleus (72 h prior to study) did not result in any significant alteration in glucose utilization in any of medullary (e.g. nucleus of the tractus solitarius, dorsal motor nucleus of the vagus) or diencephalic (e.g. periventricular and paraventricular hypothalamic nuclei, lateral habenular nucleus) regions which were examined. However, the increased glucose utilization which occurred in some medullary nuclei (e.g. nucleus of the solitary tract, dorsal motor nucleus of the vagus) following administration of the alpha-receptor antagonist, phenoxybenzamine (30 mg/kg, i.v.), was significantly attenuated by lesions of the locus coeruleus, whereas the increased glucose utilization elicited in hypothalamic nuclei by the drug was unaffected by locus coeruleus lesions. In contrast, glucose utilization in the lateral habenular nucleus was elevated significantly following phenoxybenzamine only in animals bearing unilateral locus coeruleus lesion; the drug being without effect in this region in sham-lesioned rats. These differential consequences of locus coeruleus lesions upon glucose utilization in nuclei involved in cardiovascular regulation emphasize the complex nature of the influence of the locus coeruleus upon blood pressure control.

Animals↗
PubMed1983

A critical appraisal of semi-quantitative analysis of 2-deoxyglucose autoradiograms.

Semi-quantitative analysis (e.g. optical density ratios) of [14C]2-deoxyglucose autoradiograms is widely used in neuroscience research. We demonstrate that a fixed ratio of 14C-concentrations in the CNS does not yield a constant optical density ratio but is dependent upon the exposure time in the preparation of the autoradiograms and the absolute amounts of 14C from which the concentration ratio is derived. The failure of a fixed glucose utilization ratio to result in a constant optical density ratio represents a major interpretative difficulty in investigations where only semi-quantitative analysis of [14C]2-deoxyglucose autoradiograms is undertaken.

Animals↗
PubMed1983

A potential error in modifications of the [14C]2-deoxyglucose technique.

Although the technique developed by Sokoloff et al. employing [14C]2-deoxyglucose as tracer, provides measurements of local cerebral glucose utilization, various modifications of the original technique are presently in widespread use. We have examined the validity of a crucial simplifying assumption which is an integral feature of many of these modifications; namely, that all the radioisotope in the CNS at the moment of sacrifice is present as 2-deoxyglucose-6-phosphate. By employing the kinetic model developed by Sokoloff et al. and arterial plasma [14C]2-deoxyglucose and glucose histories, the proportion of total radioactivity present in the CNS as unphosphorylated 2-deoxyglucose was calculated and found to vary from 5 to 50% of the total amount of isotope present in the CNS under different experimental conditions. It can be shown to be dependent upon (a) the rate of cerebral glucose utilization, (b) the time which elapses from administration of the radioisotope until the sacrifice, (c) the route by which the isotope is administered, and (d) arterial plasma glucose levels. Thus, modifications of the original 2-deoxyglucose technique have introduced a potential source of error which is not a feature of the approach of Sokoloff and his associates.

Animals↗
PubMed1983

The effects of the GABAergic agonist muscimol upon the relationship between local cerebral blood flow and glucose utilization.

The relationship between cerebral blood flow and glucose utilization was studied in conscious rats using the [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiographic techniques respectively. Both blood flow and glucose use decreased in parallel in the 38 areas of the brain analyzed following administration of the GABA agonist muscimol, thus maintaining the relationship observed in control rats. The present study offers no evidence for a direct vasodilatatory action for muscimol in the conscious rat, but points to underlying regional metabolic activity as the primary determinant of cerebral blood flow.

Animals↗