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Biomedical subjects

A D Smith

Publications and source records attributed to A D Smith.

At least 253 records · Page 14Linked to original sources
PubMed1992

Association of atrophy of the medial temporal lobe with reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer's disease.

A combination of medial temporal lobe atrophy, shown by computed tomography, and reduced blood flow in the parietotemporal cortex, shown by single photon emission tomography, was found in 86% (44/51) of patients with a clinical diagnosis of senile dementia of the Alzheimer type (SDAT). The same combination of changes was found in four out of 10 patients with other clinical types of dementia and in two out of 18 with no evidence of cognitive deficit. Of the 12 patients who died, 10 fulfilled histopathological criteria for Alzheimer's disease, nine of them having a clinical diagnosis of SDAT, and one a clinical diagnosis of multi-infarct dementia. All 10 patients with histopathologically diagnosed Alzheimer's disease had shown a combination of hippocampal atrophy and reduced parietotemporal blood flow in life. In 10 patients (nine with SDAT) out of 12 in whom the hippocampal atrophy was more noticeable on one side of the brain than on the other the parietotemporal perfusion deficit was also asymmetrical, being greater on the side showing more hippocampal atrophy. These results suggest that the combination of atrophy of the hippocampal formation and reduced blood flow in the parietotemporal region is a feature of dementia of the Alzheimer type and that the functional change in the parietotemporal region might be related to the loss of the projection neurons in the parahippocampal gyrus that innervate this region of the neocortex.

Aged↗
PubMed1992

Differential effects of captopril and enalapril on tissue renin-angiotensin systems in experimental heart failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitor therapy elicits beneficial responses from patients with heart failure. We hypothesized that a major site of action of these drugs is tissue ACE and that ACE inhibitors might differ in their ability to inhibit tissue ACE. To test this hypothesis, we assessed the effects of captopril and enalapril on blood pressure and renal function and on serum and tissue ACE activities in sham-operated rats and rats with heart failure induced by coronary artery ligation. METHODS AND RESULTS: During short-term (1-week) treatment, captopril (200 mg.kg-1.day-1) and enalapril (25 mg.kg-1.day-1) elicited equipotent effects on blood pressure and inhibition of serum ACE activity (85%). The effects of long-term treatment (47 days) were then studied beginning 45 +/- 5 days after coronary ligation in four treatment groups: sham-operated, vehicle (n = 14); heart failure, vehicle (n = 10); heart failure, captopril (n = 8); and heart failure, enalapril rats (n = 7). During long-term treatment, captopril and enalapril caused comparable falls of 12-18 mm Hg in blood pressure (p < 0.01 compared with vehicle treatment). There was no change in urine volume or sodium or potassium excretion in vehicle- or captopril-treated heart failure rats; in contrast, enalapril-treated heart failure rats demonstrated 83% and 10% increases in urine volume and daily sodium excretion, respectively, compared with vehicle-treated rats (both p < or = 0.01). No significant changes in blood urea nitrogen or creatinine were observed with either treatment. Enalapril but not captopril elicited a significant decrease in serum and lung ACE activities. Captopril but not enalapril inhibited aortic ACE activity. Both agents caused a comparable inhibition of renal ACE activity. The magnitude of inhibition of renal ACE activity but not serum and vascular (aortic) ACE activities correlated with the long-term blood pressure response. Enalapril but not captopril normalized renal angiotensinogen expression; the magnitude of this effect correlated with the increase in daily urinary sodium excretion (r = -0.43; p < or = 0.005). CONCLUSIONS: These data suggest that chronic treatment with these two agents elicits differential effects on tissue ACE activities and renal angiotensinogen regulation. The differential renal effects of these agents may be important in the treatment of heart failure.

Angiotensinogen↗
PubMed1992

When and how to treat caliceal stones.

Currently, there are no guidelines for the selection of patients for caliceal stone removal, although there is no doubt that urologists are taking a more aggressive approach now that treatments with low morbidity are available. We discuss when and how to treat patients with symptomatic and asymptomatic caliceal stones.

Humans↗
PubMed1992

Gangrene and Fournier's gangrene.

Fournier's gangrene is an aggressive disease affecting the perineum. Clearly, it can no longer by considered idiopathic in its origin, as most infection can be localized to a cutaneous, urethral, or rectal source. It presents in a broad age range and can have an indolent onset, thus requiring a high index of suspicion. It may be fulminant and progressive in the case of immunocompromise and underlying debilitating illnesses. Despite aggressive antibiotic therapy and debridement, it is associated with a high mortality rate. This rate has been higher in older patients, those with a rectal focus, and diabetics. Hyperbaric oxygen therapy has shown some promise in shortening hospital stays, increasing wound healing, and decreasing the gangrenous spread when used in conjunction with surgical debridement and antibiotics. New reconstructive efforts, such as medial thigh myocutaneous flaps, have improved the cosmetic aftermath of the extensive debridement. Fournier's gangrene remains a true urologic emergency, which mandates aggressive initial care by means of early recognition, early hemodynamic stabilization, and the institution of parenteral broad-spectrum antibiotics. This is followed by multiple debridements and in some cases urinary or rectal diversion. The concomitant use of hyperbaric oxygen therapy in selected cases followed by meticulous reconstructive surgery and salvage has further reduced the mortality rate and improved the cosmetic outcome.

Gangrene↗
PubMed1991

Effect of ligand binding on the tryptic digestion pattern of rat brain hexokinase: relationship of ligand-induced conformational changes to catalytic and regulatory functions.

The Type I isozyme of rat hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) is comprised of N- and C-terminal domains, associated with regulatory and catalytic functions, respectively. Extensive sequence similarity between the domains is consistent with evolution of the enzyme by gene duplication and fusion. Cleavage at tryptic sites located in the C-terminal domain is markedly sensitive to ligands present during digestion, while analogous sites in the N-terminal domain are either resistant to trypsin or unaffected by the presence of ligands. These results imply a lack of structural equivalence between the N- and C-terminal domains, with the overall structure of the N-terminal domain being "tighter" and with a major component of ligand-induced conformational changes being focused in the C-terminal domain. Based on a previously proposed structure for brain hexokinase, protection by substrate hexoses is attributed to substrate-induced closing of a cleft in the C-terminal domain. Similar protection at C-terminal cleavage sites results from binding of inhibitory hexose-6-phosphates to the N-terminal domain. In addition, hexose-6-phosphates evoke cleavage at a site, T5, located in a region that has been associated with binding of ATP to the C-terminal domain. Thus, alterations in this region, coupled with reduced accessibility resulting from cleft closure, may account for the mutually exclusive binding of inhibitory hexose-6-phosphates and substrate ATP. In the absence of Mg2+, all nucleoside triphosphates examined (ATP, UTP, CTP, and GTP) protected against digestion by trypsin. In contrast, ATP-Mg2+ stabilized the C-terminal domain but destabilized the N-terminal domain, while the chelated forms of the other nucleoside triphosphates were similar to the unchelated forms in their effect on proteolysis; the unique response to ATP-Mg2+ reflects the specificity for ATP as a substrate.

Adenosine Triphosphate↗
PubMed1991

Bradykinin stimulates DNA synthesis in competent Balb/c 3T3 cells and enhances inositol phosphate formation induced by platelet-derived growth factor.

Both platelet-derived growth factor (PDGF) and bradykinin were found to induce a growth response in Balb/c 3T3 cells. However, whereas PDGF brought about a five-fold increase in the incorporation of [3H]thymidine into DNA, the response to bradykinin was never more than 50%. When bradykinin was present simultaneously with sub-optimal concentrations of PDGF the response was about 15% greater than with PDGF alone. In contrast, if the cells were made competent by a 5 hr preincubation with PDGF which was then washed away, subsequent addition of bradykinin induced a more than two-fold increase in incorporation of [3H]thymidine into DNA compared with competent cells subsequently incubated with serum-free medium alone. Bradykinin also acted synergistically with insulin when the two agents were added simultaneously to competent cells. PDGF induced marked increases in the concentration of inositol phosphates at 30 min after stimulation, but by this time point any effect of bradykinin had disappeared. However, the simultaneous presence of PDGF and bradykinin induced increases at 30 min that were 50-100% greater than with PDGF alone. It is concluded that the pathways by which PDGF and bradykinin initiate a growth response in BALB/c 3T3 cells only partly overlap. Their actions on the synthesis of inositol phosphates exhibit distinctive temporal characteristics, but can be co-operative at 30 min and at earlier time intervals. This effect was found to be time-dependent, and developed over the first 5 min.

Animals↗
PubMed1991

GABA-like immunoreactivity in different cellular populations of cerebellar cortex of rats before and after treatment with amino-oxyacetic acid.

The postembedding immunogold procedure was used to detect changes in the levels of gamma-aminobutyric acid (GABA)-like immunoreactivity at the ultrastructural level in the cerebellar cortex of control rats and rats treated with the GABA transaminase inhibitor, amino-oxyacetic acid (AOAA), in order to increase the levels of GABA. GABA-immunoreactive structures were labelled using an antiserum directed against GABA coupled to bovine serum albumin and a secondary antibody conjugated to colloidal gold. The density of gold particles per square micron of tissue was taken as a measure of GABA-like immunoreactivity. In separate groups of control and AOAA-treated animals, the levels of GABA were assessed biochemically in the cerebellum, the cortex, the ventral mesencephalon and the striatum. Six hours after treatment with AOAA the GABA levels in the cerebellum, the cortex, the ventral mesencephalon and the striatum. Six hours after treatment with GABA immunoreactivity of the Golgi and basket cell terminals was significantly greater than that of mossy fibres, granule cell dendrites and perikarya and glial cells. The value obtained for Golgi terminals was the highest of all the structures examined and was twice that of their perikarya. Six hours after treatment with AOAA the GABA immunoreactivity in Golgi and basket cell terminals and in glial cells was greatly enhanced. The drug treatment slightly enhanced the immunoreactivity in mossy fibres and granule cell dendrites but induced no change in granule cell bodies. Thus, in both control and treated rats, the highest GABA immunoreactivity was present in the terminals of GABAergic cells, and the lowest in putative glutamatergic cells. The results demonstrate that there is a high degree of selectivity in the changes in GABA levels following the inhibition of GABA transaminase in the cerebellum. They also confirm the potential of the use of postembedding methods for the quantification of endogenous amino acid at cellular and subcellular levels, in relative and possibly also absolute terms.

4-Aminobutyrate Transaminase↗
PubMed1991

Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease.

The possibility that the different molecular forms of acetylcholinesterase (AChE) in cerebrospinal fluid (CSF) which can be revealed by isoelectric focusing may reflect changes in AChE in pathologically affected neurons in Alzheimer's disease was tested in a retrospective study. CSF samples obtained at necropsy from 33 patients with clinically diagnosed dementia, 9 with possible dementia, and 19 without a diagnosis of dementia were examined by isoelectric focusing. An additional band indicating an anomalous molecular form of AChE was present in CSF from 19 of 23 patients with a histological diagnosis of Alzheimer's disease and no other central nervous system disorder but in none of the 19 non-demented patients (without a histological diagnosis of Alzheimer's disease). The band was also present in 2 of 8 patients with histologically defined Alzheimer's disease plus other neurological disorders and in 4 of 8 patients with possible dementia who did not meet histopathological criteria for Alzheimer's disease. The absence of the anomalous form of AChE from the CSF of non-demented patients and its presence in the CSF of the majority of patients with Alzheimer's disease has implications for our understanding of the biological basis of the disease and might form the basis of an antemortem diagnostic test.

Acetylcholinesterase↗
PubMed1991

Coexistence of GABA and glutamate in mossy fiber terminals of the primate hippocampus: an ultrastructural study.

One of the links in the trisynaptic circuit of the hippocampus is the synapse between the mossy fibre terminals of dentate granule cells and CA3 pyramidal cells of Ammon's horn. This synapse has been physiologically characterized as excitatory, and there is pharmacological and immunohistochemical evidence that mossy fibre terminals utilize glutamate as a neurotransmitter. This study demonstrates the presence of GABA-immunoreactivity in mossy fibre axons and terminals of the monkey at the electron microscopic level. We combined Golgi impregnation to identify CA3 pyramidal neurones, with postembedding immunocytochemistry to characterize the inputs to the identified cells. GABA immunoreactivity was present in mossy fibre terminals that made synaptic contact with complex embedded spines of identified Golgi-impregnated CA3 pyramidal neurones. GABA immunoreactivity could be demonstrated in serial sections of the same mossy fibre terminals by using 3 different antisera raised against GABA. In serial sections, the mossy fibre terminals were shown to be immunoreactive for both glutamate and GABA. In contrast, glutamate immunoreactivity but not GABA immunoreactivity was found in other terminals that did not have the morphological characteristics of mossy fibre terminals. GABA immunoreactivity in mossy fibre terminals was also demonstrated in a human surgical specimen of hippocampus. The coexistence of an "excitatory" amino acid and of an "inhibitory" amino acid in the same "excitatory" nerve terminal raises the possibility of corelease of the two transmitters, suggesting that the control of hippocampal neural activity is more complex than hitherto suspected.

Adolescent↗
PubMed1991

Basal extracellular dopamine is decreased in the rat nucleus accumbens during abstinence from chronic cocaine.

Rats were treated for 10 days with cocaine (20 mg/kg, i.p.) followed by either 1 or 10 days of abstinence. On the test day a microdialysis method was performed in which dopamine (DA) was added to the perfusate at concentrations above and below the expected extracellular concentration (0, 2.5, 5, and 10 nM) to generate a series of points that can be interpolated to determine the concentration of no net flux, which represents the extracellular DA concentration. The slope of the line generated by this method is the in vivo recovery of the dialysis probe. After 1 day of abstinence, there was no significant difference in basal DA levels in the nucleus accumbens (N ACC) between cocaine treated (4.1 +/- 0.3 nM; mean +/- SEM) and saline-treated (3.9 +/- 0.2 nM) groups. However, there was a significant increase in the slope of the cocaine-treated group (0.91 +/- 0.04 vs. 0.67 +/- 0.08; P greater than 0.03). After 10 days of abstinence, there were reduced basal extracellular levels of DA in the N ACC of the cocaine-treated group as compared with saline-treated controls (P less than 0.002). The basal extracellular DA concentration in the N ACC was 2.1 +/- 0.3 nM for the cocaine group and 3.9 +/- 0.2 nM for the control group. The slopes of the curves were not significantly different for the cocaine (0.63 +/- 0.07) and saline (0.64 +/- 0.09) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1991

Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine.

The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.

Animals↗
PubMed1991

The acute and chronic toxicity of ten chlorinated organic compounds to the American flagfish (Jordanella floridae).

The acute toxicity (96-hr median lethal concentrations (LC50s) of ten chlorinated isomers of benzene, phenol, ethane, and ethylene to the American flagfish (Jordanella floridae) were determined in both static and flow-through systems. Chronic toxicity to embryo-larval fish was also estimated from hatching success and post-hatch survival as well as fry growth rates and survival. Maximum acceptable toxicant concentrations (MATC) were estimated where possible. In general, for both acute and chronic toxicity tests, the order of increasing relative toxicity based on the water-borne exposure concentrations was: chloroethanes, chloroethylenes, chlorobenzenes, and chlorophenols. Within groups, more highly chlorinated isomers were usually more toxic. The presence of suspended or colloidal 1,2,4,5-tetrachlorobenzene was observed in acute toxicity testing and affected toxicity estimates.

Animals↗
PubMed1991

Disposition of mitochondrially bound hexokinase at the membrane surface, deduced from reactivity with monoclonal antibodies recognizing epitopes of defined location.

A panel of monoclonal antibodies against rat brain hexokinase (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) has been employed to investigate the orientation of the mitochondrially bound enzyme on the mitochondrial surface. Based on their ability to immunoprecipitate truncated forms of the protein, obtained by in vitro translation of truncated versions of the mRNA, the epitopes for seven monoclonal antibodies were mapped to regions consisting of 20-50 amino acid residues within the sequence of the N-terminal half of the enzyme. There is extensive sequence similarity between the N- and C-terminal halves of this enzyme, which is thought to have evolved by a process of gene duplication and fusion. However, these antibodies react selectively with epitopes in the N-terminal half, and thus epitopic regions for several of these antibodies could be further defined by eliminating from consideration regions showing substantial sequence similarity with the C-terminal half. The epitope for one of the monoclonal antibodies, designated 4D4, was shown to involve the extreme N-terminus of the enzyme; selective proteolytic modification of this region resulted in loss of immunoreactivity. Relative location of epitopes for three other antibodies, designated 2B, 1C5, and 4C5, within a 20-residue segment was deduced from effects of modifying sulfhydryl residues within this segment on immunoreactivity. Thus, by a combination of sequence analysis and experimental methods, the epitopes for these seven antibodies could be localized to defined regions within the overall sequence. The ability of these antibodies to prevent binding of hexokinase to mitochondria, and their ability to recognize the mitochondrially bound enzyme, provided a basis for assessing the relative proximity of the corresponding epitopes to the mitochondrial surface when the enzyme was bound. The disposition of the bound enzyme on the mitochondrial surface was deduced by relating these results to the proposed structure for brain hexokinase.

Amino Acid Sequence↗
PubMed1991

Interpreting aquatic toxicity QSARs: the significance of toxicant body residues at the pharmacologic endpoint.

Aquatic QSAR investigations employ bioassay data where a biological response is associated with a toxicant concentration in the exposure water. Although convenient this ignores the fundamental principle that the response is more closely related to an amount present in the organism. This problem has been examined using acute toxicity and bioconcentration QSARs employing log Kow as the molecular descriptor. Combining these QSAR relationships enables estimates of the amount of toxicant in organisms to be made. For acute narcosis (50% mortality) the toxicant level in the hydrophobic (lipid) phase of an exposed organism is, as a first approximation, constant at approximately 50 mmol l-1 of lipid. For the acute toxicity of a variety of hydrophobic narcotic organics examined by US EPA-Duluth in tests with fathead minnows, this corresponds to a whole-body residue of about 4 mmol kg-1. Although the level in the hydrophobic phase remains constant, for hydrophilic chemicals (log Kow less than 1.5) the contribution of the hydrophilic (water) phase of the organism dominates and total body residues should be similar to the respective threshold LC50s. This has important implications in simple pharmacokinetic modelling and in interpreting residue levels in organisms collected in environmental monitoring studies.

Animals↗
PubMed1991

Urinary excretion of oxalate by patients with renal hypercalciuric stone disease. Effect of chronic treatment with hydrochlorothiazide.

Hydrochlorothiazide is employed to reduce calcium excretion in patients with urinary stone disease secondary to renal leak hypercalciuria. Because the drug also has been reported to be a competitive inhibitor of oxalate excretion by the renal tubules, we sought to determine whether chronic use indeed affected the amount of oxalate excreted. Patients taking hydrochlorothiazide 50 mg daily did not have a statistically significant reduction in twenty-four-hour urinary oxalate on their customary diets (pretreatment 37 +/- 3 mg/day [mean +/- S.E.M.; N = 22]; at one year 36 +/- 3 mg/day [N = 22]; at two years 37 +/- 3 mg/day [N = 16]). In 12 patients who voluntarily collected twelve-hour urine specimens after dinner on the third day of a low-oxalate diet and again the next day after a 1 g oxalate load, hydrochlorothiazide had no significant effect on oxalate excretion (19 +/- 2.3 mmol oxalate/mol creatinine on hydrochlorothiazide versus 20.6 +/- 2.6 mmol off the drug after low oxalate meal; 50 +/- 7.8 mmol/mol creatinine on hydrochlorothiazide versus 56.2 +/- 7.5 mmol off the drug after an oxalate load). As expected, there was a significant reduction in urinary calcium excretion and thus of calcium oxalate urinary saturation during hydrochlorothiazide administration. Hydrochlorothiazide by itself is not sufficient to reduce oxalate excretion in patients with renal leak hypercalciuria.

Adult↗