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Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 343 records · Page 19Linked to original sources
PubMed1988

Analysis of gene expression using episomal mouse dihydrofolate reductase minigenes.

We have constructed a plasmid encoding a mouse dihydrofolate reductase (dhfr) minigene which produces dhfr transcripts with all of the 5' and 3' ends observed from the chromosomal mouse dhfr gene. The minigene contains 5' flanking regions, all dhfr coding sequences, one intervening sequence, 11.5 kb of 3' flanking regions beyond the termination codon, an E. coli plasmid origin of replication and antibiotic resistance, and an SV40 minimal origin of replication; the total size is 17.2 kb. When transfected into cells constitutively producing a temperature sensitive SV40 T antigen, the plasmid minigene replicates at the permissive temperature, but fails to replicate at the nonpermissive temperature. Therefore, transcription can be observed in the presence or absence of minigene replication. In addition, a stable divergently transcribed RNA is produced from the dhfr minigene promoter region, with the same 5' ends that are seen in the chromosomal divergently transcribed gene. We show that deletion of the sole remaining intron of the dhfr minigene significantly lowers the amount of dhfr transcript produced but does not affect the amount of divergent transcript. The promoter region for these transcripts contains four 48 bp repeats; reducing the number of these repeats lowers the amount of both dhfr and divergent transcripts produced from the minigene.

Animals↗
PubMed1988

Percutaneous transluminal angioplasty in patients with prior myocardial revascularization surgery.

Direct myocardial revascularization surgery using either the saphenous vein or internal mammary artery has become the definitive surgical treatment for coronary artery occlusive disease. Certain patients who have undergone these procedures, however, have recurrent myocardial ischemia due to progression of disease in unbypassed vessels, to obstruction in the arteries distal to the insertion of the bypass conduit, or to disease of the conduit itself. Balloon angioplasty may be used to relieve myocardial ischemia in these situations; however, initial studies suggested a low primary success rate coupled with excessive mortality and morbidity. Improvements in patient selection, equipment and technical expertise now allow angioplasty to be performed in this patient population with results comparable to that in the general coronary angioplasty population. Of the 3,016 angioplasty procedures performed between September 1980 and June 1987, 236 patients had previously undergone revascularization surgery. The primary success rate was 93% (390 of 419 stenoses successfully dilated). Overall, clinical restenosis was observed in 39%, including a 43% restenosis rate in patients undergoing only saphenous vein graft angioplasty. This did not differ appreciably from the restenosis rate in postbypass patients undergoing angioplasty of only native vessels (37%) or internal mammary arteries (42%). Emergency revascularization surgery was required in 7 of 236 patients (3%), each of whom had myocardial infarction. One of 236 patients (0.4%) died. Thus, angioplasty may be used to relieve recurrent myocardial ischemia in patients with prior direct myocardial revascularization procedures with a high initial success rate and acceptable risk. Early (less than 6 months) restenosis is not infrequent and remains the largest obstacle to a satisfactory clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed1988

Morphological lesions in the brain preceding the development of postischemic seizures.

This study explores how hyperglycemia and enhanced tissue lactic acidosis influence the density and distribution of ischemic brain damage. Ischemia of 10-min duration was produced in glucose-infused rats by bilateral carotid clamping combined with hypotension, and the brains were perfusion-fixed with formaldehyde following recirculation of 3, 6, 12 and 18 h. After about 24 h the hyperglycemic animals developed seizures, and at that time two groups were added, one fixed prior to, and one after the onset of seizures. Similar experiments were made on normoglycemic animals with recirculation times of 1.5 to 96 h. After fixation the brains were embedded in paraffin, subserially sectioned and stained with celestine blue/acid fuchsin. In both normo- and hyperglycemic animals, neurons in the dentate hilus of the hippocampal formation and in the thalamic lateral reticular nucleus showed early and dense neuronal necrosis. In neocortex, hippocampal CA1 sector and caudoputamen, hyperglycemia shortened the delay before damage occurred and markedly enhanced the damage. Specific for the hyperglycemic animals was damage of the substantia nigra, pars reticulata (SNPR), manifest already at the earliest recovery periods studied; this finding is discussed in relationship to the role SNPR is assumed to play in preventing spread of seizure discharge.

Animals↗
PubMed1988

Estimation of frequency of occurrence of abstract designs after frontal or temporal lobectomy.

Patients with unilateral frontal- or temporal-lobe excisions and normal control subjects were shown a series of abstract designs. Within the series, the designs differed in the number of times that they appeared. The frontal-lobe groups (right more so than left) were impaired in recalling the frequency of occurrence of the designs. Recognition deficits were found only in the patients with right temporal-lobe lesions. The impairment in frequency estimation may reflect a disorderly search process in memory, or a deficit in cognitive estimation, or both.

Form Perception↗
PubMed1988

Effect of changes in cardiac autonomic balance on blood pressure regulation in man.

The role of cardiac autonomic balance in fitness-related differences in blood pressure regulation was evaluated by comparing the cardiovascular responses to lower body negative pressure (LBNP) in 10 trained and 10 untrained men. Cardiac autonomic balance was quantified as the ratio of resting heart rate to intrinsic heart rate, and was significantly lower in the trained subjects (0.68 +/- 0.03) than the untrained subjects (0.81 +/- 0.03) indicating a greater parasympathetic dominance at rest in the trained subjects. Arterial pressure decreased significantly more during LBNP in the trained subjects and was due to lower chronotropic and vasoconstrictor responses in these trained subjects. 'Cardiac autonomic balance' was equilibrated between the groups by partial parasympathetic blockade with atropine sulfate in the trained subjects and partial sympathetic blockade with metoprolol tartrate in the untrained subjects. Equilibration of cardiac autonomic balance eliminated the group differences in blood pressure maintenance, and chronotropic and vasoconstrictor responsiveness during LBNP. It was hypothesized that the elevated tone of parasympathetic control of the heart rate of the trained subjects resulted in an attenuation of blood pressure regulation.

Adult↗
PubMed1988

Recall of spatial location by the amnesic patient H.M.

The amnesic patient H.M. was tested for immediate recall of the location of objects in an array. Three array-sizes were used: 16, 7, or 4 objects. With 16 objects, H.M.'s performance was at chance level; with the smaller arrays, his performance was above chance, but still well below the levels achieved by age-matched control subjects. The ability to recall location by H.M. did not differ under incidental and intentional learning conditions, thus failing to support the notion that automatic encoding skills may be selectively disrupted in amnesia.

Amnesia↗
PubMed1988

Pathogenesis of substantia nigra lesions following hyperglycemic ischemia: changes in energy metabolites, cerebral blood flow, and morphology of pars reticulata in a rat model of ischemia.

A spectacular spongiotic lesion, symmetrical in distribution and restricted to the pars reticulata of the substantia nigra (SNPR) has recently been described in hyperglycemic rats surviving 1-18 h after a brief period of transient ischemia. The purpose of this study was to clarify the pathogenesis of the lesion. In order to study whether the lesion was due to changes occurring during ischemia, local cerebral blood flow (l-CBF) and energy metabolites were measured in the substantia nigra (SN) and in other brain areas. Furthermore, brains were examined by light and electron microscopy immediately after ischemia and in the early recirculation period. Autoradiographic CBF measurements showed ischemia flow levels in the SN of 30-40% of control, similar in normo- and hyperglycemic rats. Thus, although ischemic, this structure had a considerable amount of residual flow. There was also a corresponding partial preservation of the adenylate energy charge. However, lactate levels were high, and in hyperglycemic subjects they rose to values previously described during status epilepticus (about 25 mumol/g). In hyperglycemic animals, neuronal alterations were consistently present in SNPR by the end of the 10-min period of ischemia. They included clumping of nuclear chromatin and subplasmalemmal clearing of the perikaryon. Some mitochondrial swelling was present in neuronal perikarya and in dendrites. The normal alignment of microtubules in the dendrites was disturbed, but there was no or only slight swelling of the dendrites. Aggregation of synaptic vesicles was a conspicuous finding in axonal terminals, which were also slightly swollen. Otherwise, the axons appeared largely spared. Microvessels looked quite intact. Similar cellular changes were observed in the early recovery period. Dendrites, however, started to swell, and their expansion finally caused the spongiotic appearance of the pars reticulata. The appearance of the dendritic lesions is strongly suggestive of transmitter-mediated ("excitotoxic") damage. However, it seems likely that the marked acidosis is injurious as well. We tentatively conclude that both mechanisms interact to give the final lesion. The results, and those previously obtained in epileptic seizures, suggest that mitochondria of SN neurons and neuronal processes are particularly prone to damage.

Animals↗
PubMed1988

Lack of complementation in somatic cell hybrids between fibroblasts from patients with different forms of cystinosis.

Cystinosis is an autosomal recessive disease in which three clinical forms are recognized: infantile nephropathic, with renal tubular damage by 1 year of age and progressive glomerular insufficiency; intermediate, with tubular and glomerular insufficiency beginning at a later age; benign, with no kidney damage. Skin fibroblasts cultured from patients with all types of cystinosis show increased intralysosomal free (nonprotein) cystine; however, fibroblasts from heterozygotes have normal free-cystine values. To determine whether genetic complementation occurs between the different forms, somatic cell hybrids were constructed between cells from a patient with infantile nephropathic cystinosis and cells from patients with other types of cystinosis. If complementation occurred, the hybrids would be expected to have normal cystine levels. To construct hybrid cells, a "universal parent" cell type (TG1-neo), which was hypoxanthine/aminopterin/thymidine (HAT) sensitive and G418 resistant was constructed from an infantile nephropathic cystinosis fibroblast strain. Polyethylene glycol fusion of TG1-neo with other cells that are not HAT sensitive or G418 resistant allowed for selection of hybrid cells in a medium containing HAT and the aminoglycoside G418. As indicated by elevated cystine levels, complementation did not occur between TG1-neo and two different benign cystinosis strains, an intermediate cystinosis strain, or another nephropathic cystinosis cell strain. When a normal fibroblast strain was fused with TG1-neo, all 15 hybrid clones studied contained normal amounts of intracellular free cystine.

Cells, Cultured↗
PubMed1988

Failure of pre-ischemic lidocaine administration to ameliorate global ischemic brain damage in the rat.

The cerebral protective effects of lidocaine were evaluated using a rat model of severe (near-complete) global ischemia produced by 10 min of bilateral carotid artery occlusion combined with systemic hypotension (MAP 45-55 mmHg). Prior to the induction of ischemia, 16 rats were given incremental doses of lidocaine intravenously until EEG slowing with sharp wave activity became evident. An equal number of rats (controls) received saline prior to the ischemic insult. Normoxia, normocapnia, and normothermia were maintained at all times. Following ischemia, the animals were allowed to recover. At 1.5 h post-ischemia, eight rats from each treatment group were reanesthetized, and regional brain water content was assessed gravimetrically. Brain specific gravity was significantly reduced from normal values in both treatment groups, and was unaltered by pre-ischemic lidocaine administration. Seven days post-ischemia, the remaining animals were reanesthetized; the brains were formalin fixed and processed for identification of irreversibly injured neurons in the hippocampus, neocortex, and caudate nucleus. Saline-treated rats displayed 75 +/- 4% (mean +/- SD) dead cells in the hippocampus (CA1); lidocaine-treated rats had similar injury (78 +/- 7%). In the neocortex and caudate nucleus, injury was graded as moderate, and no difference in severity could be distinguished between the treatment groups. The authors conclude that pre-ischemic treatment with maximal sub-epileptogenic doses of lidocaine had no effect on either early post-ischemic cerebral edema or delayed neuronal necrosis in this rat model of near-complete global ischemia.

Animals↗
PubMed1988

Baroreflex function in endurance- and static exercise-trained men.

The effect of exercise training mode on reflex cardiovascular control was studied in a cross-sectional design. We examined the cardiovascular responses to progressive incremental phenylephrine (PE) infusion to maximal rates of 120 micrograms/min and the delta heart rate/delta blood pressure responses to lower body negative pressure (LBNP) to -50 Torr in 30 men who were either endurance exercise trained (ET), untrained (UT), or weight trained (WT). During PE infusion, measures of blood pressures, forearm blood flow, heart rate and cardiac output, and calculations of forearm vascular resistance, stroke volume, and peripheral vascular resistance were made at each infusion rate when steady-state blood pressure was attained. No significant differences (P less than 0.05) in forearm blood flow or resistance were observed between the groups at any dose of PE, suggesting that the vasoconstrictor response was similar among the groups. Regression analyses of heart rate against mean blood pressure during the PE infusion were performed to evaluate baroreflex function. A linear model was used and correlation coefficients ranging from 0.82 to 0.96 were obtained (P less than 0.05). The slope of the line of best fit for the ET subjects (-0.57) was significantly less (P less than 0.05) than the slopes obtained for either the UT (-0.91) or WT (-0.88) subjects. In addition, the delta heart rate/delta blood pressure measurements obtained during LBNP reflected a similarly significant attenuation of reflex chronotropic control in the ET subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Blood pressure regulation during cardiac autonomic blockade: effect of fitness.

The purpose of this study was to determine the role of the autonomic nervous system's control of the heart in fitness-related differences in blood pressure regulation. The cardiovascular responses to progressive lower-body negative pressure (LBNP) were studied during unblocked (control) and full blockade (experimental) conditions in 10 endurance-trained (T) and 10 untrained (UT) men, aged 20-31 yr. The experimental conditions included beta 1-adrenergic blockade (metoprolol tartrate), parasympathetic blockade (atropine sulfate), or complete blockade (metoprolol and atropine). Heart rate, blood pressure, forearm blood flow, and cardiac output were measured at rest and -16 and -40 Torr LBNP. Forearm vascular resistance, peripheral vascular resistance, and stroke volume were calculated from these measurements at each stage of LBNP. Blood pressure was maintained, primarily by augmented vasoconstriction, equally in T and UT subjects during complete and atropine blockade. The fall in systolic and mean pressure from 0 to -40 Torr was greater (P less than 0.05) in the T subjects during the unblocked and metoprolol blockade conditions. This reduced blood pressure control during unblocked condition was attributable to attenuated vaso-constrictor and chronotropic responses in the T subjects. We hypothesize that an autonomic imbalance (elevated base-line parasympathetic activity) in highly trained subjects restricts reflex cardiac responses, which accompanied by an attenuated vasoconstrictor response, results in attenuated blood pressure control during a steady-state hypotensive stress.

Adult↗
PubMed1988

Appearances on computed tomography following thoracoplasty for pulmonary tuberculosis.

Thoracic computed tomography was performed in 32 patients who had undergone thoracoplasty as part of their treatment for pulmonary tuberculosis. Pleural thickening and the prevalence of bronchiectasis were more marked in the operated hemithorax. Bullae were more prevalent in the operated hemithorax but the difference was not statistically significant. In all but one patient, scoliosis was present. Illustrative examples are presented to demonstrate the range of appearances following this operation.

Bronchiectasis↗
PubMed1988

Chronic primidone treatment in the rat: an animal model of primidone therapy.

A continuously protective, nontoxic, oral model of chronic treatment with primidone was developed in the rat. Rats were treated with primidone (100 mg/kg) by gastric gavage twice daily for up to 8 weeks. This treatment was continuously protective as measured by seizures induced by hexafluorodiethyl ether and minimally toxic as measured by weight gain. Plasma primidone concentration reached a peak (13 micrograms/ml) 2 hours after gavage and was almost undetectable by 12 hours. Plasma phenobarbital concentration peaked (52 micrograms/ml) at 6 hours postgavage after reaching a minimum (19 micrograms/ml) at one hour postgavage. Phenobarbital concentrations measured in plasma, brain and liver after 8 weeks of chronic treatment correlated significantly between each tissue and plasma.

Administration, Oral↗
PubMed1987

Cystine exodus from normal leucocytes is stimulated by MgATP.

Cystine exodus from partially purified granular fractions of normal leucocytes is stimulated by MgATP. N-Ethylmaleimide, an inhibitor of the lysosomal H+-translocating ATPase, eliminated the stimulated exodus, but had no effect on basal exodus. As the initial content of cystine was increased, the initial velocity of both the basal and ATP-stimulated egress increased. However, as saturation with substrate was approached, the ATP stimulation disappeared leaving only the N-ethylmaleimide-insensitive basal exodus. The increased initial velocity in the presence of ATP may represent improved binding of cystine to the partially saturated inner transporter as a result of conformational or charge optimization brought about by the action of the H+-translocating ATPase.

Adenosine Triphosphate↗
PubMed1987

Lysosomal cystine transport. Effect of intralysosomal pH and membrane potential.

The regulation of lysosomal cystine transport was studied using cystine dimethyl ester-loaded lysosomes isolated from human diploid fibroblasts. Net efflux from normal fibroblast lysosomes was compared to that from lysosomes of cystinotic fibroblasts, which contain an inherited mutation decreasing lysosomal cystine transport. This exodus of cystine from normal fibroblast lysosomes was greater than from cystinotic fibroblast lysosomes. When lysosomes were incubated with both 5 mM MgCl2 and 2 mM ATP (Mg/ATP), the amount of lysosomal cystine lost from normal lysosomes doubled, but the amount of cystine lost from cystinotic lysosomes remained small. This effect of Mg/ATP on cystine loss from lysosomes isolated from normal fibroblasts was abolished when either carbonyl cyanide m-chlorophenylhydrazone or N-ethylmaleimide was present, suggesting that the effect of Mg/ATP was mediated by the action of a lysosomal proton-translocating ATPase. Addition of KCl, RbCl, or NaCl to normal lysosomes caused smaller increases in cystine exodus. A variety of experimental conditions altered lysosomal pH, membrane potential, and the cystine lost from normal fibroblast lysosomes. These same experimental conditions produced similar alterations in the lysosomal pH and membrane potential of cystinotic fibroblast lysosomes without a comparable alteration in cystine loss. These results have led us to propose a model in which the transport of cystine out of the normal lysosome is regulated by both the lysosomal membrane potential gradient and the transmembrane pH gradient.

Adenosine Triphosphatases↗
PubMed1987

The effect of 1 alpha-hydroxyvitamin D3 on the mineralization defect in disodium etidronate-treated Paget's disease--a double-blind randomized clinical study.

A double-blind randomized study of 29 patients with symptomatic Paget's disease was conducted comparing the clinical, biochemical, and histomorphometric responses to 3-month treatment with placebo (10 patients), low-dose disodium etidronate (EHDP) (5-7 mg/kg/day) (10 patients), and low-dose EHDP plus 1 alpha-hydroxyvitamin D3 (1 alpha D3) 0.5 mcg daily (9 patients). In placebo-treated patients no significant changes were observed in symptoms, biochemistry, or bone histomorphometry. Histologically apparent mineralization defects developed after 3 months of therapy in 90% of patients in the EHDP group, compared with 45% of patients in the EHDP/1 alpha D3 group. In 19% of the patients treated with active medication, the mineralization defects in pagetic bone were accompanied by histological evidence of continued osteoclastic resorption. The development of mineralization defects was not related to serum levels of vitamin D metabolites, alkaline phosphatase, or intestinal calcium absorption but did correlate with the occurrence of hyperphosphatemia during treatment, which was most marked in patients treated with EHDP alone. Although mineralization defects were less frequent in the EHDP/1 alpha D3 group, these patients also responded less well symptomatically, thus limiting the potential usefulness of this drug combination in Paget's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗