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Biomedical subjects

A D Smith

Publications and source records attributed to A D Smith.

At least 19 recordsLinked to original sources
PubMed1992

Detection in life of confirmed Alzheimer's disease using a simple measurement of medial temporal lobe atrophy by computed tomography.

The medial temporal lobe of the brain is important for normal cognitive function, notably for memory, and is the region with the most extensive pathological change in Alzheimer's disease (AD). We wanted to find out if atrophy of the medial temporal lobe could be detected in life in patients in whom a diagnosis of AD was subsequently established histopathologically. The minimum width of the medial temporal lobe, measured by temporal-lobe-oriented computed tomography (CT) about one year before death, in 44 patients with a histopathological diagnosis of AD (cases) was nearly half (0.56 of the median) that in 75 controls of the same age with no clinical evidence of dementia (95% confidence interval 0.51-0.61). There was little overlap between the distributions of measurements in cases and controls. A cut-off (< 0.79 MoM) selected to yield a 5% false-positive rate gave an expected detection rate of 92%. A cut-off selected to yield a false-positive rate of 1% (< 0.70 MoM) yielded a 79% detection rate. 20 of the 44 patients with histopathologically diagnosed AD had been scanned more than once before death, and the test (cut-off < 0.79 MoM) was positive in all 20 more than a year before and in 9/10 more than 2 years before death. In 10 subjects with dementia but with histopathology excluding AD, the mean minimum width of the medial temporal lobe was significantly greater than that in the cases with AD, but was not significantly different from that in controls. Medial temporal lobe CT is a non-invasive, rapid, simple and effective test for AD which could have immediate application firstly in improving the accuracy of prevalence and incidence studies and, secondly, for the identification of groups of high-risk patients in the evaluation of novel treatments for AD. In the future, it could be applied as a screening test.

Aged↗
PubMed1992

Epitopic regions recognized by monoclonal antibodies against rat brain hexokinase: association with catalytic and regulatory function.

Using direct and competitive epitope mapping methods, 23 monoclonal antibodies (Mabs) against rat brain hexokinase (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) were divided into nine groups, each recognizing epitopes within defined surface regions of the N- or C-terminal domains; the latter have been associated with regulatory or catalytic functions, respectively. Reactivity of Mabs with the isolated domains was also studied. Based on the effect of various ligands on immunoreactivity, specific regions involved in ligand-induced conformational changes were identified. Adjacent epitopic regions, designated Regions F and G and located in the N- and C-terminal domains, respectively, were selectively affected by inhibitory hexose 6-phosphates (or analogs), marking these regions as being involved in transmission of the conformational signal from the regulatory N-terminal domain to the catalytic C-terminal domain. Consistent with this, the Ki for inhibition of the enzyme by the glucose 6-phosphate analog, 1,5-anhydroglucitol-6-phosphate, was markedly increased by Mabs binding in these regions, but unaffected by Mabs binding elsewhere in the molecule. Reactivity with Mabs recognizing conformationally sensitive epitopes in Region H of the C-terminal domain was greatly decreased by binding of substrate hexoses that induce closure of a cleft in the catalytic domain; selective recognition of the "open cleft" conformation, thereby preventing closure of the cleft required for progression of the catalytic cycle, can account for the marked decrease in Vmax that results from binding of these Mabs. Reactivity with Mabs binding to Region H was also decreased in the presence of inhibitory hexose 6-phosphates, implying that cleft closure was also induced by the latter; this is consistent with the suggestion that limitation of access to the C-terminal ATP binding site, resulting from cleft closure, is a factor in inhibition of the enzyme.

Amino Acid Sequence↗
PubMed1992

Percutaneous pyeloplasty (endopyelotomy) for congenital ureteropelvic junction obstruction.

Endopyelotomy was performed in 30 patients with congenital primary ureteropelvic junction obstruction; 4 patients had high insertion of the ureter and 8 patients had caliceal stones. Clinical and radiologic success was achieved in 25 patients. There were five failures, all of whom subsequently had successful open pyeloplasty. The theoretical and experimental foundations of the procedure and fine points of the operative technique are presented. Endopyelotomy appears to be valuable for primary ureteropelvic junction obstruction just as it is for secondary obstruction.

Adolescent↗
PubMed1992

RP-30A: new tracer for detection of changes in testicular blood flow in rat torsion model.

RP-30A is a radioactive tracer being evaluated for the detection of regional myocardial blood flow. This study compares RP-30A to technetium 99m pertechnetate as radioactive tracers for the detection of testicular blood flow changes in early testicular torsion. The left testis of adult male Sprague-Dawley rats was subjected to either thirty or sixty minutes of 720 degrees torsion. Injections of RP-30A or 99mTc-pertechnetate followed by sacrifice and scintillation counting of the testes was performed. No significant difference was detected between the torted testes and the right control testes in both groups receiving 99mTc-pertechnetate and the thirty-minute group receiving RP-30A. The torted testes of the sixty-minute group receiving RP-30A revealed a significant difference (decrease) in uptake indicating that RP-30A may be a more sensitive tracer in detecting testicular blood flow changes in early testicular torsion.

Animals↗
PubMed1992

Quantitative microdialysis of dopamine in the striatum: effect of circadian variation.

Two quantitative microdialysis methods were used to determine the concentration of extracellular dopamine in the anterior striatum of the rat. In the first method, the slow perfusion flow rate method, perfusion was at 57 nl/min and dialysate samples were collected every 90 min for 18 h and assayed for dopamine (DA), DOPAC (3,4-dihydroxy-phenylacetic acid), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA). There was a significant increase in the concentration of dopamine during the dark cycle compared with the light cycle (14.7 +/- 1 nM vs. 9.3 +/- 0.7 nM; mean +/- SEM; P less than 0.0001), indicating possible circadian variations in the extracellular concentration of DA. There was a steady decrease in the level of DOPAC and HVA, and no change in the level of 5-HIAA. For the point of no-net-flux method, animals were perfused with 4 concentrations of DA or DOPAC, bracketing the extracellular concentrations. The extracellular concentrations of DA and DOPAC using this method were 10.2 +/- 1.7 nM and 17.4 +/- 2.6 microM, respectively. The in vivo recoveries for DA and DOPAC as derived from the slope of the linear regression curves were 72 +/- 3% and 43 +/- 5%. These values were shown to be significantly different (P less than 0.001). Both methods gave similar results for the level of DA in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

A neuroleptic-like effect of ceronapril on latent inhibition.

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1992

Synaptic organization of GABAergic inputs from the striatum and the globus pallidus onto neurons in the substantia nigra and retrorubral field which project to the medullary reticular formation.

Anatomical tract-tracing and immunohistochemical techniques involving correlated light and electron microscopy were used to determine whether the descending striatal and pallidal afferents to the substantia nigra pars reticulata converge onto individual neurons projecting to the pontomedullary and medullary reticular formation in the rat. Injections of biocytin into the ventrolateral region of the striatum and Phaseolus vulgaris-leucoagglutinin into the ventrolateral and caudal regions of the globus pallidus led to overlapping anterogradely labelled terminal fields within the dorsolateral substantia nigra pars reticulata. These terminal fields were punctuated by neurons which had been retrogradely labelled following injections of wheatgerm agglutinin conjugated to horseradish peroxidase into the lateral pontomedullary reticular formation. The anterogradely labelled striatal and pallidal terminals displayed different morphological characteristics; the striatal terminals were small and diffusely distributed throughout the neuropil without any particular neuronal association whereas the pallidal terminals were large and formed pericellular baskets around the perikarya of retrogradely and non-retrogradely labelled nigral neurons. In areas of the substantia nigra where there was an overlap between the two terminal fields, individual retrogradely labelled nigroreticular neurons were found to be apposed by both sets of anterogradely labelled terminals. Electron microscopic analysis revealed that the striatonigral and pallidonigral terminals displayed different ultrastructural features, the striatal terminals were small, contained few mitochondria and formed symmetric synaptic contacts predominantly with the distal dendrites of nigroreticular neurons whereas the pallidal terminals were large, contained numerous mitochondria and formed symmetric synaptic contacts preferentially with perikarya and proximal dendrites of nigroreticular neurons. Post-embedding immunohistochemical staining revealed that both striatonigral and pallidonigral terminals, some which formed synaptic contact with nigroreticular neurons, displayed GABA immunoreactivity. Examination of twelve retrogradely labelled neurons in the electron microscope revealed that all received synaptic inputs from both sets of anterogradely labelled terminals. In addition to the substantia nigra pars reticulata, neurons of the retrorubral field were also retrogradely labelled following injections of wheatgerm agglutinin conjugated to horseradish peroxidase into pontomedullary reticular formation. These retrorubroreticular neurons were part of a continuum of labelled cells which extended from the dorsolateral substantia nigra pars reticulata caudally into the retrorubral field. When combined with anterograde tracing methods it was found that the retrorubroreticular neurons received synaptic inputs from pallidal terminals which were morphologically similar to the pallidonigral terminals and formed symmetric synapses with the neuronal somata and proximal dendrites. In contrast to nigroreticular neurons, the stratonigral terminals were not seen in contact with retrorubroreticular cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Transmembrane oxalate exchange: its relationship to idiopathic calcium oxalate nephrolithiasis.

Red blood cell oxalate flux rates were measured in various populations of stone patients and controls. Idiopathic and normocalciuric stone patients and post-prostatectomy patients exhibited rates significantly greater than the nonstone controls. The fact that this abnormality was not limited to patients with calcium oxalate nephrolithiasis suggests that this cellular defect is not universal nor an important etiological factor for calcium oxalate nephrolithiasis.

Adult↗
PubMed1992

Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis.

A total of 15 patients with unilateral nephrostomy tubes after extracorporeal shock wave lithotripsy received either 0 (placebo), 100, 500, 1,000 or 2,000 mg. ascorbic acid on days 2 and 3 postoperatively. Before and after administration, successive 6-hour urine specimens were collected from the nephrostomy tube and from the contralateral kidney directly into a preservative to stabilize ascorbic acid and oxalate. In 1 patient in each group preservative was omitted from the collection pouch. Urinary oxalate was then measured enzymatically after removal of ascorbic acid with sodium nitrite. Preservatives proved necessary for full recovery of analyte. At doses of 500 mg. or more of ascorbic acid there was a statistically significant increase in urinary oxalate equivalent to 1.2 to 1.8% of the millimoles of ascorbate administered. This represented an increase in urinary oxalate excretion of 6 to 13 mg. per day per 1,000 mg. ascorbic acid supplement. This amount would increase the risk of calcium oxalate urolithiasis.

Adult↗
PubMed1992

Laparoscopic needles and trocars: an overview of designs and complications.

Although the gynecologist has utilized the laparoscope both diagnostically and therapeutically for several decades, laparoscopic surgery has only recently gained great acceptance in the general surgical and urologic community. However, the enthusiasm for this new technology for minimally invasive surgery must be dampened by the small incidence of complications, most of which occur during the creation of the initial pneumoperitoneum and, in particular, during the insertion of the Veress needle and the principal trocar. The purpose of this paper is to review needle and trocar designs, to describe the complications of their use, and to identify factors that may contribute to injury and those that will minimize the risk.

Catheterization↗
PubMed1992

11-Methylbenzo[a]pyrene: bay region distortions.

Substitution of a methyl group in the 11-position of benzo[a]pyrene (B[a]P) enhances its carcinogenicity. An X-ray crystallographic determination of the three-dimensional structure of 11-methylbenzo[a]pyrene (11-MeB[a]P) shows that steric overcrowding in the bay region is relieved somewhat by distortions of the bay-region bond angles in the plane of the ring system. A comparison with the structure of 7,12-dimethylbenz[a]anthracene (DMBA), which shows out-of-plane distortions to relieve such strain, shows that, in general, H...H intramolecular interactions between neighboring rings in a polycyclic aromatic hydrocarbon are the primary determinants of the nature of the molecular distortions as a result of steric overcrowding (mainly in-plane for 11-MeB[a]P and mainly out-of-plane for DMBA). The 11-MeB[a]P molecule exhibits considerable flexibility as evidenced by slightly different conformations in the two molecules found in the asymmetric unit of the crystal. One molecule is fairly flat with bond angle distortions in the bay region, while the other is slightly buckled as a result of some twist (15 degrees) in the bay region. Computer modeling indicates that steric overcrowding as a result of the bay-region 11-methyl group may affect the conformation of the ring that bears the diol and epoxide groups in the anti-diolepoxide. The nature of this distortion may, in turn, provide a clue to the reason for the greater carcinogenicity of B[a]P when methylated at the 11-position in the non-benzo bay region site. In addition, the 11-methyl group, because of its bulk, may affect the orientation of the polycyclic hydrocarbon as it lies between the nucleic-acid bases when covalently bound to DNA.

Benzopyrenes↗
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↗