Search PubMed⌕ Search

Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 199 records · Page 11Linked to original sources
PubMed1994

The influence of plasma glucose concentrations on ischemic brain damage is a threshold function.

To investigate whether aggravation of damage in hyperglycemic subjects is a continuous function of changes in intra- and extracellular pH during ischemia or whether there is a threshold value, preischemic plasma glucose was varied from 8.3-20.0 mM. 10 min forebrain ischemia was induced. The results showed that no animal with plasma glucose of < 13 mM developed seizures, and that all animals with glucose of > 16 mM died in status epilepticus. Half of the animals with plasma glucose in the range of 13-16 mM showed seizures and 50% of these died. In surviving animals, histological brain damage occurred in the hippocampal CA3 sector, cingulate cortex, thalamic nuclei and substantia nigra, structures normally not injured by 10 min ischemia. The data demonstrate that there is a glucose threshold of 10-13 mM, above which seizures develop and additional damage appears, and another one (> 16 mM), above which seizures are invariably fatal.

Animals↗
PubMed1994

Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament.

The present experiments were designed to study under what circumstances middle cerebral artery (MCA) occlusion by an intraluminal filament technique leads to hyperthermia and what the mechanisms are. We found that permanent MCA occlusion by this technique lead to a rise in body (core) temperature to 39.0-39.5 degrees C during the first 2-4 h, and to sustained hyperthermia thereafter (38.5-39.0 degrees C). After 2 h of transient MCA occlusion hyperthermia could only be avoided if anesthesia (with control of temperature) was maintained for 2 h of ischemia and 1 h of recirculation or, in unanesthetized animals, if external cooling was maintained for 2 h of ischemia and 2 h of recirculation. Control of temperature only during ischemia did not prevent a postischemic rise in temperature. One hour of MCA occlusion had less effect on body temperature. Results are presented which suggest that the hyperthermia observed is due to an interference, by the intraluminal filament, of circulation to hypothalamic centers regulating body temperature. It is speculated that the hyperthermia induced may blunt or obliterate the effect of drugs, normally considered to ameliorate brain damage due to focal ischemia.

Animals↗
PubMed1994

Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters.

The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5'-exons linked to separate promoters and one 3'-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n = 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.

Animals↗
PubMed1994

Mechanisms of vasovagal syncope: relevance to postflight orthostatic intolerance.

Orthostatic intolerance can present a very serious limitation to astronauts attempting any functions requiring the upright position. Vasovagal syncope is a common cause of fainting characterized by paradoxic bradycardia and vasodilation in the presence of decreasing arterial pressure. Several mechanisms have been proposed to mediate vasovagal syncope and it seems likely that redundant mechanisms exist both centrally and peripherally which can mediate these responses. Spaceflight alters reflex control of cardiovascular function in several ways which may influence susceptibility to vasovagal syncope provoked by the Bezold-Jarisch reflex.

Bradycardia↗
PubMed1994

Role of retinoblastoma gene product in p53-mediated DNA damage response.

The cellular response to DNA-damaging agents involves the activation of cell cycle checkpoints. Checkpoints provide a transient delay in cell cycle progression, presumably to allow time for the cell to repair the damage. A most important checkpoint, active in the G1 phase of the cell cycle, is mediated by the p53 tumor suppressor gene product. To investigate the role of downstream components of the cell cycle machinery in p53-mediated G1 arrest, the possible involvement of the RB gene product was examined. Rb and p53 proteins were studied by immunoprecipitation and Western blotting experiments in the presence and absence of DNA-damaging treatment. The phosphorylation status of Rb was altered following DNA damage in p53 wild-type cell lines, but was not altered in p53 mutant cell lines, nor in cell lines where p53 function was abrogated by viral gene products. These findings indicate that Rb probably plays a role in the activation of the p53-mediated checkpoint.

Cell Cycle↗
PubMed1994

Calbindin-D28k immunoreactivity within the cholinergic and GABAergic projection neurons of the basal forebrain.

The purpose of this study was to determine whether the calcium binding protein calbindin-D28k was present within the cortically projecting basal forebrain neurons of various rodent species not previously examined. Double-label immunocytochemistry was performed using antibodies against calbindin-D28k and choline acetyltransferase (ChAT) to detect the presence of the calcium binding protein within the cholinergic basal forebrain neurons of various species (i.e., humans, rats, mice, gerbils, guinea pigs). Antibodies against calbindin-D28k, ChAT, and glutamic acid decarboxylase (GAD) were also used in combination with a cortically injected retrograde tracer (Fluoro-Gold) to determine whether calbindin-D28k immunoreactive (IR) neurons within the basal forebrain projected to the frontoparietal cortex. The nucleus basalis of rats was examined for the presence of calbindin-D27k IR within the GABAergic basal forebrain neurons. All species examined had cholinergic, GABAergic, and calbindinergic neurons within the basal forebrain; however, only the cholinergic neurons within the human nucleus basalis of Meynert were also immunoreactive for calbindin-D28k. Although all rodent species had both cholinergic and GABAergic basal forebrain neurons that contained the Fluoro-Gold dye, none of the calbindin-D28k IR neurons, detected using monoclonal and polyclonal antibodies, were found to contain the retrograde tracer. These results indicate that the cortically projecting cholinergic and GABAergic basal forebrain neurons within these rodent species do not contain calbindin-D28k. Therefore, age- and disease-related loss of nucleus basalis projection neurons may not be mediated by alterations in calbindin-D28k.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Hyperthermia aggravates and hypothermia ameliorates epileptic brain damage.

The influence of hyperthermia and hypothermia on epileptic brain damage was studied in rats, in which status epilepticus was induced by flurothyl. Histopathological changes were examined by light microscopy after 1 or 7 days of recovery. Two series of animals were studied. In the first, short periods of seizures (20 and 25 min) were employed to examine whether moderate hyperthermia (39.5 degrees C) would aggravate epileptic brain damage, and a longer period (45 min) was used to investigate whether moderate hypothermia (32.5 degrees C) would ameliorate the damage. The second series investigated whether brief periods of status epilepticus (10 min) would cause brain damage if hyperthermia were high or excessive. For this series, animals with body temperatures of 37.0, 39.0, and 41.0 degrees C were studied. Data from normothermic animals (37.5 degrees C) confirmed previously described neuronal damage. Although hyperthermic animals failed to show increased damage in the CA1 sector, or in the hilar region of the dentate gyrus, they showed enhanced damage in the neocortex and globus pallidus (GP). In substantia nigra pars reticulata (SNPR) four out of five hyperthermic animals had bilateral infarcts after 20 min of status epilepticus, whereas no normothermic animal showed such damage. Hypothermia seemed to ameliorate epileptic brain damage in the neocortex (n.s.) and GP (P < 0.05) following status epilepticus for 45 min. Three out of seven hypothermic animals had mild SNPR involvement compared to severe infarction of the nucleus in five out of six normothermic animals (P < 0.05). Thus, hyperthermia aggravated and hypothermia ameliorated epileptic brain damage both in regions showing selective neuronal necrosis (neocortex) and in regions developing pan-necrosis (GP and SNPR). The second series displayed an unexpected result of excessive hyperthermia. Animals subjected to only 10 min of status epilepticus at a temperature of 41 degrees C showed not only neocortical lesions, but also moderate to extensive damage to the hippocampus (CA1, subiculum, and dentate gyrus). It is concluded that at high body and brain temperature, brief periods of status epilepticus can yield extensive brain damage, primarily affecting the hippocampus.

Animals↗
PubMed1994

Mitochondrial DNAs of the fungus Armillaria ostoyae: restriction map and length variation.

A restriction-enzyme-site map is presented for the 147-kb mtDNA of North American Armillaria ostoyae. The locations of five structural genes, atp6, atp8, coxI, coxIII, and cob, along with the location and orientation of the large and small ribosomal RNA genes, were determined through Southern hybridizations with cloned genes from other fungal mtDNAs. Based on this map, the variation in mtDNA suggested geographic structure at two different levels. On a large geographic scale, 17 mtDNA types from North America were distinct, with respect to both size and restriction maps, from three mtDNA types from Europe. At the local scale, identical mtDNA types were evident among several different genetic individuals located no more than 1 km apart at a site in Michigan. No mtDNA type occurred more than once among genetic individuals from different regions of North America, although the occurrence of similar mtDNAs in isolates from distant regions suggested that this may occur at a low frequency with large sample sizes. Among the North American mtDNA types, analysis of discrete length variants was inconsistent with the hypothesis that the mtDNA of A. ostoyae evolves as a clonal lineage in which each length mutation represents a unique event. The two remaining hypotheses, that similar mutational events have occurred independently and that genetic exchange and recombination occurs among mtDNAs in natural populations of this species, remain to be tested.

Agaricales↗
PubMed1994

Rapid adaptation of vagal baroreflexes in humans.

We evaluated the time course of carotid baroreflex adaptation to arterial pressure elevations induced by phenylephrine infusion (1 microgram/kg per min) in 13 normotensive volunteers. Vagally-mediated carotid baroreceptor-cardiac reflex responses were assessed serially with a staircase pressure/suction sequence delivered to a neck chamber. Carotid baroreflex stimulus-response relations shifted up the response (R-R interval) axis and to the right on the stimulus (pressure) axis (determined as the carotid distending pressure at saturation) within 90-120 s (time between measurements) during the first 10 min. The shifts in position of the reflex relation were sustained throughout the infusion. The position of operational point pressure, relative to carotid distending pressure at saturation, was unchanged throughout the infusion period. These data suggest that human carotid baroreceptor reflex relations change within minutes to retain beat-to-beat pressure regulation as the prevailing pressure increases.

Adaptation, Physiological↗
PubMed1994

Fitting of low-intensity wide-line spectra dominated by chemical shift anisotropy.

How experimental parameters affect the appearance, and consequently the fitting, of signals having very wide lines is discussed. As these spectra usually have very low intensities, pulse sequences that remove acoustic ringing and other experimental artefacts have to be used. These pulse sequences introduce further spectral distortions. A FORTRAN 77 program was developed that accounts for these effects. The fitting of these broad spectra is demonstrated by application to 207Pb solid-state nuclear magnetic resonance (NMR) spectra.

Anisotropy↗
PubMed1994

Acidosis induced by hypercapnia exaggerates ischemic brain damage.

Although preischemic hyperglycemia is known to aggravate damage due to transient ischemia, it is a matter of controversy whether or not this is a result of the exaggerated acidosis. It has recently been reported that although tissue acidosis of a comparable severity could be induced in normoglycemic dogs by an excessive rise in arterial CO2 tension, short-term functional recovery was improved, rather than compromised. In the present experiments we induced excessive hypercapnia (PaCO2, approximately 300 mm Hg) in normoglycemic rats before inducing forebrain ischemia of 10-min duration. This reduced the brain extracellular pH to values normally encountered in hyperglycemic rats subjected to ischemia. The events induced by hypercapnia clearly enhanced ischemic brain damage, as assessed histologically after 7 days of recovery. We hypothesize that the decisive event was an exaggerated decrease in extra- and intracellular pH and that the results thus demonstrate an adverse effect of acidosis. However, since postischemic seizures did not occur in the hypercapnic ischemic rats, the results also demonstrate that changes in intra-extracellular pH and bicarbonate concentrations modulated ischemic damage in an unexpected way.

Acidosis↗
PubMed1994

Preischemic hyperglycemia leads to delayed postischemic hyperthermia.

BACKGROUND AND PURPOSE: Temperature alterations are known to influence the outcome of transient ischemia, even when instituted in the postischemic period. Since preischemic hyperglycemia aggravates ischemic brain damage, the question of whether hyperglycemic animals become hyperthermic arose. To explore this possibility, we measured body temperature telemetrically in normoglycemic and hyperglycemic rats subjected to 10 minutes of forebrain ischemia at a body (and brain) temperature of 37 degrees C. METHODS: Isoflurane-anesthetized animals were subjected to 10 minutes of forebrain ischemia under normoglycemic or hyperglycemic conditions. Temperature changes after ischemia were measured by means of a telemetric temperature coil. RESULTS: In normoglycemic animals, temperature decreased to 35.6 +/- 1.1 degrees C (mean +/- SD) during the first 4 hours of recovery, after which it gradually increased to normal values (38 degrees C). Hyperglycemic animals behaved differently in that they remained normothermic for approximately 10 hours during recovery and later became hyperthermic, with core temperatures rising above 39 degrees C. The rise in temperature was not due to the osmotic load of the glucose administered because infusion of mannitol, which gave a comparable increase in plasma osmolality, failed to cause delayed postischemic hyperthermia. Excessive hypercapnia during ischemia in normoglycemic animals, which produces cerebral acidosis of a magnitude similar to that of hyperglycemia and is known to aggravate ischemic lesions, likewise failed to induce hyperthermia. When post-ischemic seizures ensued in hyperglycemic subjects, temperature was 39.8 +/- 0.6 degrees C. Animals with seizures invariably died. To evaluate the influence of postischemic hyperthermia on the outcome, an additional series of experiments was performed in which delayed hyperthermia was avoided by gentle cooling (n = 6) or by acetaminophen administration (n = 5). Although these procedures prevented delayed hyperthermia, they neither blocked seizure induction nor affected the fatal outcome. Postischemic seizures developed when the core temperatures of animals were 37.9 +/- 0.1 degrees C and 37.8 +/- 0.2 degrees C in the cooled and acetaminophen-treated groups, respectively. CONCLUSIONS: The results suggest that both delayed hyperthermia and delayed seizures in hyperglycemic animals are caused by the aggravated damage incurred by these animals during or immediately after the ischemic insult.

Acetaminophen↗
PubMed1994

The future of healthcare ethics committees.

Ethics committees are fairly common in healthcare institutions in the United States. Comprised of a multidisciplinary membership, including physicians, their functions within institutions are generally threefold: policy recommendation, ethics education and case consultation. The number of such committees will grow as a result of "Patient Rights" standards established by the Joint Commission on Accreditation of Healthcare Organizations (1992 Manual). The author projects and discusses five areas of development and change in the future of healthcare ethics committees. These five areas are: 1) renewed efforts to educate healthcare professionals, 2) cooperation and collaboration among ethics committees, 3) networking with community-based ethics groups, 4) clearer delineation of responsibilities and limitations, and 5) continuous quality improvement. The ability of ethics committees to address successfully these areas of change will determine their future usefulness.

Bioethical Issues↗