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Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 271 records · Page 15Linked to original sources
PubMed1991

Heme-protein fission under nondenaturing conditions.

Slow heme transfer from horseradish peroxidases C2 and A2, cytochrome c peroxidase, chloroperoxidase, and leghemoglobins to a heme acceptor protein, apomyoglobin, has been studied under mild conditions. The reaction is best described as heme release into water followed by quick engulfment by apomyoglobin. The energetics of the activated process are large and interpreted as connected to both polypeptide motions during release and the ordering of water around the heme during solvation. The free energy required to break the iron(III)-ligand 5 (L5) bond is a minor but crucial portion of the activation free energy. Donor-acceptor protein interactions are not involved in the transfer. Fast heme release from inactive protein has also been observed. Apoprotein recombination with porphyrins and hemes suggest that this lack of activity is a result of Fe-L5 bond breaking.

Apoproteins↗
PubMed1991

Pastoral care representation on the hospital ethics committee.

A recommendation for pastoral care representation on hospital ethics committees (HEC) is commonplace in the literature, but the rationale for this recommendation (and the actual practice) often is assumed or unarticulated. The authors propose a holistic anthropology which acknowledges the bodily, psychological, and spiritual aspects of all persons as a starting point for discussing the reasons for pastoral care representation. The spiritual aspect of the human person is described together with the role of the clinical chaplain on the HEC. The qualifications, skills, and training required for the HEC representative are also provided.

Clergy↗
PubMed1991

Influence of moderate hypothermia on ischemic brain damage incurred under hyperglycemic conditions.

Preischemic hyperglycemia aggravates brain damage following transient ischemia, and adds some special features to the damage incurred, notably a high frequency of postischemic seizures, cellular edema, and affectation of additional brain structures, such as the substanta nigra pars reticulata (SNPR). We raised the question whether mild intra-ischemic hypothermia (32-33 degrees C), known to reduce selective neuronal vulnerability in normoglycemic subjects, also ameliorates the characteristic damage observed in hyperglycemic animals. To that end, two series of experiments were performed. In the first, normo- and hypothermic animals were subjected to 10 min of ischemia during hyperglycemic conditions (plasma glucose 20-25 mmol.l-1), and allowed either 15 h or 1 week of recovery. In the second, both normo- and hyperglycemic animals were subjected to 15 min of ischemia (at normal or reduced temperature) and surviving animals were studied after 1 week of recovery. All normothermic, hyperglycemic animals developed postischemic seizures and died within the first 24 h. Mild hypothermia afforded substantial protection. Thus, 6/7 hypothermic animals subjected to 10 min of ischemia survived 1 week of recovery and none developed post-ischemic seizures. Of the hypothermic animals subjected to 15 min of ischemia 6/11 survived for 1 week, only one of which developed seizures. Protection by hypothermia was also shown by the histopathological analysis. Experiments with 10 min of ischemia and 15 h of recovery showed the expected damage in normothermic, hyperglycemic subjects. Hypothermia markedly reduced damage in all vulnerable structures, including the cingulate cortex and SNPR. The protection was most pronounced in the caudoputamen, where no affected neurons were seen in the hypothermic subjects. The experiments with 15 min of ischemia confirmed previous findings that mild hypothermia protects normoglycemic animals against the insult. The results also showed that hypothermia prevented most of the exaggeration of damage caused by hyperglycemia. However, under hypothermic conditions hyperglycemia still augmented damage in the cingulate cortex, medial and lateral venteroposterior thalamic nuclei, and SNPR, structures specifically damaged under hyperglycemic, normothermic conditions. This suggests that hypothermia has less of a protective effect on mechanisms causing such damage than on neuronal damage in the classic selectively vulnerable regions, particularly the caudoputamen.

Animals↗
PubMed1991

The effect of a dihydropyridine calcium antagonist (isradipine) on selective neuronal necrosis.

The experiments were designed to test the possibility that calcium influx into neurons via voltage sensitive calcium channels (VSCCs) contribute to brain damage in two conditions in which any amelioration of neuronal necrosis may be assumed not to occur through an improvement of blood flow, viz., hypoglycemic coma and brief transient ischemia. Hypoglycemic coma is thought to lead to neuronal necrosis by release of glutamate and cellular influx of calcium during the insult, while damage due to brief transient ischemia may, at least in part, result from increased calcium cycling across cell membranes in the postinsult period. The insults were delivered to anesthetized rats, and the localization and density of neuronal necrosis were evaluated by histopathology following 1 week of recovery. One dihydropyridine calcium antagonist (isradipine), given in doses which have been reported to ameliorate ischemic damage due to stroke, failed to reduce damage incurred by 30 min of hypoglycemic coma, or 15 min of transient forebrain ischemia. Provided that it can be assumed that isradipine in the doses employed reduced calcium influx via VSCCs, the results support the notion that calcium influx through VSCCs plays only a minor pathogenetic role in global/forebrain ischemia or in hypoglycemia, and they suggest that the effect of blockers of VSCCs in stroke, if any, is due to both blockade of VSCCs and increase in blood flow.

Animals↗
PubMed1991

Grief resolution among the bereaved in hospice and hospital wards.

As a study of grief resolution, 71 surviving spouses of patients who had died in a hospice or a hospital acute care oncology ward were interviewed in their homes 6 and 12 months following the death of their mate. It was hypothesized that hospice survivors would score significantly lower on measures of depression and anxiety, would be more involved socially, would be more involved in constructive social action, and would be less likely to use tranquilizers than hospital survivors. At 6 months there is only partial support for the hypotheses. At 12 months there is strong support for the hypotheses. Interpretations of these findings and comparisons with similar studies are discussed.

Acute Disease↗
PubMed1991

Sympathetic neural responses to induced ventricular tachycardia.

Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.

Aged↗
PubMed1991

Free radical production and ischemic brain damage: influence of postischemic oxygen tension.

It is now becoming increasingly clear that free radicals contribute to brain damage in several conditions, such as hyperoxia and trauma. It has been more difficult to prove that free radical production mediates ischemic brain damage, but it has often been suggested that it may be a major contributor to reperfusion damage, observed following transient ischemia. Recent results demonstrate that cerebral ischemia of long duration, particularly when followed by reperfusion, leads to enhanced production of partially reduced oxygen species, notably hydrogen peroxide (H2O2). It has also been suggested that postischemic hyperoxia, e.g. an increased oxygen tension during the recirculation period, adversely affects recovery following transient ischemia. Other data support the notion that brain damage caused by permanent ischemia (stroke) is significantly influenced by production of free radicals. The present study, however, fails to show that recirculation following brief periods of ischemia (15 min) leads to an enhanced H2O2 production, and that hyperoxia aggravates the ischemic damage. This study was undertaken to reveal whether variations in oxygen supply in the postischemic period following forebrain ischemia in rats affect free radical production and the brain damage incurred. To that end, rats ventilated on N2O/O2 (70:30) were subjected to 15 min of transient ischemia. Normoxic animals were ventilated with the N2O/O2 mixture, hyperoxic animals with 100% O2, and hypoxic ones with about 10% O2 (balance either N2O/N2 or N2) during the recirculation. At the end of this period, the animals were decapitated for assessment of H2O2 production with the aminotriazole/catalase method. This method is based on the notion that aminotriazole interacts with H2O2 to inactivate catalase; thus, the rate of inactivation of catalase in aminotriazole treated animals reflects H2O2 production. In a parallel series, animals ventilated with one of the three gas mixtures in the early recirculation period, respectively, were allowed to recover for 7 days, with subsequent perfusion-fixation of brain tissues and light microscopical evaluation of the brain damage. Animals given aminotriazole, whether rendered ischemic or not, showed a reduced tissue catalase activity, reflecting H2O2 production in the brain. Hyperoxic animals failed to show increased tissue H2O2 production, while hypoxic ones showed a tendency towards decreased production. However, all three groups (hypo, normo- and hyperoxic) had similar density and distribution of neuronal damage. These results suggest that although postischemic oxygen tensions may determine the rates of H2O2 production, variations in oxygen tensions do not influence the final brain damage incurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Amitrole↗
PubMed1991

Acidosis-induced ischemic brain damage: are free radicals involved?

Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is delocalization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of alpha-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or alpha-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.

Acidosis↗
PubMed1991

Expression of p53 mutant protein(s) in diethylnitrosamine-induced foci of enzyme-altered hepatocytes in male Fischer-344 rats.

Several types of human and animal tumors have been shown to carry mutations in the p53 gene. While the translation product of the wild type gene has tumor suppressor properties, mutant alleles of the gene produce proteins that can cooperate with other oncogene products in transforming cells. In this paper, evidence is presented indicating that a p53 gene mutation(s) occurs in foci of enzyme-altered hepatocytes induced by diethylnitrosamine in male Fisher-344 rats. The evidence was obtained by means of immunohistochemical and immunoblotting techniques, using antibodies directed against mutant forms of the p53 protein.

Animals↗
PubMed1991

Phenytoin treatment and folate supplementation affect folate concentrations and methylation capacity in rats.

Phenytoin (PHT) has long been known to cause folate depletion with chronic use. In animal models PHT has been shown to interfere with folate-dependent one-carbon metabolism. Folic acid supplementation in humans has been shown to restore blood levels of folates to normal, but the effects of folic acid supplementation on the PHT-induced effects on one-carbon metabolism have not been addressed. In the present study rats were treated for 8 wk with 1) PHT, 2) folic acid, 3) PHT plus folic acid or 4) vehicle (propylene glycol). Phenytoin treatment caused a decrease in weight gain over the 8 wk of treatment. This effect on weight gain was reversed by folic acid supplementation, but the decrease in brain folate concentration caused by PHT was not reversed by folic acid supplementation, which by itself apparently caused a decrease in brain folate concentration. Phenytoin treatment tended to increase methylation capacity (S-adenosylmethionine:S-adenosylhomocysteine ratio) in the brain and decrease methylation capacity in the liver. Folate supplementation by itself increased methylation capacity in the liver but had no effect in the brain. Folic acid and PHT apparently had independent but opposite effects in the liver, leading to a normalization of methylation capacity. These data suggest that folic acid supplementation in PHT therapy may be effective in reversing the peripheral effects of chronic PHT treatment on one-carbon metabolism but not the central effects.

Animals↗
PubMed1991

Arterial oxygen saturation in patients undergoing perfusion lung scanning with 99Tcm-labelled macroaggregates of human serum albumin.

Radionuclide imaging of the lungs with 99Tcm-labelled macroaggregates of human serum albumin (99Tcm-MAA) is a safe, reliable and non-invasive method of diagnosing pulmonary embolism. It has been suggested that following intravenous injection of 99Tcm-MAA, arterial oxygen saturation falls significantly. Oxygen saturation was measured in 101 patients who had received an intravenous injection of 99Tcm-MAA prior to a perfusion lung scan. Readings were taken using a pulse oximeter at rest, immediately following injection, 10, 30 and 60 min post-injection. Twenty-five normal volunteers who were not injected acted as controls. Forty patients showed no change in oxygen saturation throughout the study. A fall of 1% was seen in 32 patients and 2-3% in 26 patients. Of the three patients who demonstrated a reduction in saturation of 6, 7 and 13%, two had chronic airways disease and one had left ventricular failure. Twenty out of 25 normal controls showed no change in saturation over the period of observation. Five showed a fluctuation of 1-2% between the measurements. All patients and controls remained asymptomatic with almost all readings returning to the initial values after 1 h. It was the patients with chest or heart disease who showed a fall in saturation. The study shows that the majority of patients undergoing a perfusion scan with 99Tcm-MAA show no significant fall in oxygen saturation. If a fall occurs, it may be related to the underlying disease process rather than to 99Tcm-MAA.

Adult↗
PubMed1991

Cutaneous manifestations of acquired immunodeficiency syndrome in children.

Cutaneous disorders are among the most common manifestations of HIV infection in both children and adults. Because of the obvious visibility of the integument, these lesions are often the presenting manifestation of HIV-related disease. The cutaneous afflictions are frequently related to the sequelae of impaired immunity and include opportunistic infections and neoplasms as well as dramatic exacerbations and/or the development of rapidly progressive and severe manifestations in pre-existing, normally benign dermatoses. In many cases of AIDS, iatrogenic cutaneous disorders associated with toxic or allergic drug reactions are seen. With the increasing incidence of pediatric HIV infection and with therapeutic prolongation of survival, certain cutaneous manifestations (especially drug reactions) are likely to become more common. Kaposi sarcoma and other neoplasms may be recognized with increased frequency in HIV-infected children. New or previously unrecognized cutaneous manifestations of pediatric AIDS are likely to emerge. Familiarity with the various dermatologic presentations of pediatric AIDS can result in the earlier diagnosis and treatment of the disease and, hopefully, the prolongation of the patient's life.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Neurocytotoxicity: pharmacological implications.

Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.

Amino Acids↗
PubMed1991

Intestinal vitamin D-dependent calbindin-D9k and alkaline phosphatase in spontaneously hypertensive rats.

Intestinal Ca2+ malabsorption has been described in spontaneously hypertensive rats (SHRs), but the molecular basis for this defect is unknown. In this study, we measured intestinal alkaline phosphatase and vitamin D-dependent Ca(2+)-binding protein (calbindin-D9k), two proteins implicated in the active pathway of intestinal Ca2+ absorption. Both proteins were measured in the small intestines of SHRs and their normotensive controls, Wistar-Kyoto rats, before, during, and after development of hypertension (4, 9, 14, 18, and 28 wk of age). At all ages, alkaline phosphatase activity in duodenum (0-6 cm) was decreased by 30-57% (P less than 0.001) and by 47-75% in the 2nd intestinal segment (6-12 cm) (P less than 0.001-0.05). Calbindin-D9k was decreased similarly. The decreases of calbindin were statistically significant (P less than 0.001-0.05) in the duodena at 4, 14, 18, and 28 wk (9-30% decreases) and in the 2nd segment at 4, 14, and 18 wk (38-69% decreases; P less than 0.001-0.005). Decreased calbindin in SHRs was documented in animals from two suppliers. The deficiencies of calbindin-D9k and alkaline phosphatase could not be attributed to malnutrition or to a generalized brush-border defect as indicated by body weights and the intestinal marker enzyme sucrase. Although calbindin-D9k was decreased in young SHRs, the serum 1,25-dihydroxycholecalciferol [1,25(OH)2D3] was increased by 59 and 129% in 4- and 9-wk-old SHRs (P less than 0.001), respectively; by contrast, serum 1,25(OH)2D3 was unchanged or decreased in older SHRs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1991

Differential baroreflex modulation of human vagal and sympathetic activity.

We compared baroreflex modulation of human vagal-cardiac and sympathetic muscle activity in healthy volunteers by measuring R-R interval and peroneal nerve responses to a profile of positive and negative (40-65 mmHg) R-wave-triggered neck pressure steps during held expiration. R-R interval responses were sigmoid. Sympathetic activity increased abruptly with 40 mmHg pressure but returned to baseline levels as this pressure was maintained. The first decremental pressure step reduced sympathetic activity to below baseline, and the next three steps inhibited activity. During the final three steps, sympathetic activity increased to baseline, and after the return of neck pressure to ambient levels sympathetic activity increased to the highest levels recorded. Our results suggest that on a second-by-second basis human vagal-cardiac responses are determined simply by the net level of baroreceptor stimulation. Sympathetic muscle responses are determined complexly by the direction of changes (rising or falling) more than absolute arterial pressure levels and importantly by inputs from both carotid and aortic baroreceptors.

Adult↗