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Biomedical subjects

D M Turner

Publications and source records attributed to D M Turner.

At least 19 recordsLinked to original sources
PubMed1992

Simple assays of retinoid activity as potential screens for compounds that may be useful in treatment of psoriasis.

Human epidermal cell cultures were used to study the effects of retinoids on keratinocyte differentiation. Keratin profiles were studied by quantitative gel electrophoresis of culture extracts, whereas the extent of envelope formation was assessed in an enzyme-linked immunosorbent assay (ELISA) using an antibody that specifically recognizes keratinocyte envelopes. Exposure of cultures to a variety of different retinoids produced both dose-dependent decreases in keratin 16 with consequent increases in the keratin 14: keratin 16 ratio, and a decrease in envelope formation. The order of activity in both assays was similar: arotinoid ethyl ester (Ro 13-6298) greater than or equal to arotinoid acid (Ro 13-7410) much greater than all trans retinoic acid (Ro 1-5488) greater than acitretin (Ro 10-1670) greater than or equal to etretinate (Ro 10-9359), the only difference being that acitretin was slightly more active than etretinate in the keratin assay whereas these retinoids were equi-active in the envelope assay. Analysis of the lesional keratins of psoriasis patients showed that etretinate caused a reduction in keratin 16 and an increase in the keratin 14:keratin 16 ratio, although the magnitude of these changes and their correlation with clinical improvement was variable. As the in vitro assays reported here are simple and quick, they allow rapid screening of compounds for retinoid-like activity.

3T3 Cells↗
PubMed1992

Regional variation in steroid anesthetic modulation of [35S]TBPS binding to gamma-aminobutyric acidA receptors in rat brain.

Steroids that enhance gamma-aminobutyric acid (GABA)A receptor function in the central nervous system allosterically modulate the binding of the convulsant chloride channel ligand [35S]-t-butyl bicyclophosphorothionate. When assayed in membrane homogenates and in tissue sections by autoradiography, concentration-dependence curves vary with respect to both brain region and the nature of the steroid. Alphaxalone and endogenous steroid hormone metabolites inhibit the binding of [35S]-t-butyl bicyclophosphorothionate in some regions, enhance it in others and give biphasic concentration-dependence in others, apparently the result of algebraic summation of two effects involving regional-dependent enhancement or inhibition. The alphaxalone effect is additive with that produced by adding GABA to the binding assays in some regions, but synergistic in other areas. Likewise, the effect of GABA is inhibited completely by saturating concentrations of the antagonist bicuculline methochloride in some areas but only partially in others, and completely or partially reversed by the convulsant benzodiazepine Ro5-4864, depending on region. The granule cell and molecular layers of cerebellum are particularly different in these allosteric interactions. The heterogeneity of binding behavior is consistent with the presence of multiple GABAA receptor subtypes in the brain. Regional variation in subunit gene expression apparently produces a family of hetero-oligomeric GABAA receptors with different biological and pharmacological properties, including qualitative and quantitative differences in modulation by neuroactive steroids.

Anesthetics↗
PubMed1991

The benzodiazepine/alcohol antagonist Ro 15-4513: binding to a GABAA receptor subtype that is insensitive to diazepam.

The imidazobenzodiazepinone Ro 15-4513 has been shown previously to bind to central benzodiazepine receptors as well as to a second, uncharacterized class of sites that do not bind diazepam, differentiating them from the normal benzodiazepine-binding site on the gamma-aminobutyric acid (GABA)-A (GABAA) receptor. This study describes the characterization of these unique diazepam-insensitive (DZ-IS) sites. Ro 15-4513 binding to DZ-IS sites was abundant in cerebellum from cow, rat and human and detectable in cortex, hippocampus and striatum by autoradiography on rat brain sections. These sites represented approximately 20% of the total binding in bovine cerebellar membranes, but only 2 to 3% of the total in cortex. Ro 15-4513 binds with the same affinity (Kd approximately 4.5 nM) to both diazepam-sensitive and DZ-IS sites in the cerebellum. A number of compounds which bind to the classical benzodiazepine receptors also bind to the DZ-IS sites. These compounds include: the pyrazoloquinoline CGS 8216, the beta-carbolines methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, ZK 95962, ZK 94326 and ZK 93126, as well as the classical benzodiazepine receptor antagonist, Ro 15-1788. Besides binding diazepam poorly, the DZ-IS sites demonstrate a very low affinity for other benzodiazepines. Ligands which bind to the various drug receptor sites on the GABA receptor complex do not directly modulate the binding of Ro 15-4513 to DZ-IS sites nor does ethanol. However, antagonism of Ro 15-4513 binding to the DZ-IS sites by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate and by CGS 8216 is modulated by the presence of GABA.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1990

Potency of rapidly acting barbiturates in dogs, using inhibition of the laryngeal reflex as the end point.

Thiopental, thiamylal, and methohexital were administered to 30 dogs to determine equipotent doses necessary to inhibit laryngeal reflexes. The doses studied were 7.1, 10.0, 14.1, 20.0, and 28.3 mg of thiopental/kg of body weight; 5.7, 8.0, 11.3, 16.0, and 22.6 mg of thiamylal/kg; and 3.5, 5.0, 7.1, 10.0, and 14.1 mg of methohexital/kg. At 1, 2.5, 5, and 10 minutes after injection, the presence or absence of the laryngoscopic reflex, pedal reflex, and jaw tone were recorded. The times for return of each reflex, as well as the ability to walk 10 steps without assistance, were also recorded. Using the method of least squares, a probit analysis was performed on the quantal responses at 1 minute. The effective dose in 50% of the population for the laryngoscopic reflex was chosen as the end point for intubation, and the computed doses necessary to achieve this end point were 19.4 mg of thiopental/kg, 18.4 mg of thiamylal/kg, and 9.7 mg of methohexital/kg. When potencies of the drugs were compared with that of thiopental (1), thiamylal was found to be equipotent (1.06) and methohexital twice as potent (2.0). At the accepted clinical dose, recovery times for thiopental (71.1 +/- 7.2 minutes) and thiamylal (75.3 +/- 7.7 minutes) were similar, and twice that for methohexital (33.9 +/- 4.6 minutes).

Animals↗
PubMed1990

Cardiovascular and respiratory effects of three rapidly acting barbiturates in dogs.

The cardiovascular and respiratory effects of 3 rapidly acting barbiturates, thiopental sodium, thiamylal sodium, and methohexital sodium, were studied in dogs from completion of injection until 12.5 minutes after injection. The doses administered were 19.4 mg of thiopental/kg of body weight, 18.4 mg of thiamylal/kg, and 9.7 mg of methohexital/kg, which were chosen as equipotent doses necessary to inhibit the laryngoscopic reflex in 50% of the population. To determine the cardiovascular and respiratory effects for each drug, the values at each measurement time following injection were compared with baseline values (T0). At the 15- and 30-second measurement times following thiopental administration, stroke volume (SV) decreased; heart rate (HR), left atrial pressure, and mean pulmonary arterial pressure increased; and cardiac index (CI), myocardial contractility, and systemic and pulmonary vascular resistances were not different from baseline values. Mean arterial pressure (MAP) was not different from the baseline value at 15 seconds, but was increased from 30 seconds to 2 minutes. All values except HR had returned to baseline values by 7.5 minutes. At all measurement times, arterial oxygen tension and arterial pH were decreased, and arterial carbon dioxide tension increased from baseline values. Although the cardiovascular and respiratory changes following administration of thiamylal and methohexital were similar to those described for thiopental, some differences were found. Following thiamylal administration, systemic vascular resistance increased at 1 minute, pulmonary vascular resistance increased at 1 and 2 minutes, and myocardial contractility increased at 1 and 2 minutes. Following methohexital administration, MAP decreased at 15 seconds, and SV decreased at all measurement times.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Keratin gene expression during the resolution of psoriatic plaques: effect of dithranol, PUVA, etretinate and hydroxyurea regimens.

Quantitative changes in the levels of keratin polypeptides extracted from keratotome shavings from psoriatic epidermis were measured by using one-dimensional SDS-PAGE, followed by scanning densitometry. Values obtained were compared with results for non-lesional epidermis and from epidermis from normal individuals. Patients on four different treatment regimens were investigated by repeated sampling over 3-4 months starting before therapy commenced. The levels of four keratins changed significantly: keratins I (70 kd) and 2 (66 kd) tended to rise to normal levels, while keratins 16 (50 kd) and 18 (44 kd) fell to normal levels. There were differential effects as well as differences in the rates of normalization depending upon the treatment regimen. The most rapid normalization of the levels of all four keratins was observed with topical dithranol (anthralin) treatment (five patients) with plaque resolution and keratin level normalization after 7-9 weeks. Oral hydroxyurea (three patients) had similar effects, but over a longer time scale (20 weeks). In contrast, oral etretinate (four patients) caused a normalization of all except keratin 2 (66 kd) over a period of 20-28 weeks, and keratin I (70 kd) levels tended to 'overshoot' the normal level. PUVA (five patients) caused rapid normalization (in 9-12 weeks) of keratins 2 (66 kd) and 18 (44 kd), but had much weaker effects on keratins I (70 kd) and 10 (57 kd). These results suggest that resolution of lesions as judged by clinical criteria can occur without normalization of the keratin electrophoretic profile. Possibly the most reliable marker of clinical resolution was the reduction in keratin 16 (50 kd), since treatment effects on the differentiation of keratins I (70 kd) and 2 (66 kd) were different.

Anthralin↗
PubMed1989

Steroid anesthetics and naturally occurring analogs modulate the gamma-aminobutyric acid receptor complex at a site distinct from barbiturates.

The steroid anesthetic alphaxalone and a series of naturally occurring analogs were compared in potency and efficacy with each other and the hypnotic barbiturate pentobarbital for interaction with gamma-aminobutyric acid (GABA) receptors:binding sites in rat brain membranes and functional activity in 36Cl- flux measurements with rat hippocampal slices. The steroids enhanced [3H]muscimol binding to GABA receptor sites, enhanced [3H] flunitrazepam binding to benzodiazepine receptors and inhibited [35S]t-butyl bicyclophosphorothionate binding to picrotoxin/convulsant binding sites on the GABA receptor-chloride channel complex. The same steroids that were active in modulating the binding of ligands to the various receptor sites on the GABA receptor complex at micromolar concentrations enhanced muscimol-stimulated 36Cl- flux in rat hippocampal slices. The steroids, like the barbiturates, increased the maximal response to muscimol but produced little or no potentiation of basal 36Cl- flux in the absence of GABA agonist. Although the effects of steroids and barbiturates were similar, separate sites of action were demonstrated conclusively by the observation that the two classes of compounds, when included together, gave additive or synergistic effects on binding, as well as on 36Cl- flux in the absence of GABA agonist. Structure-activity studies showed that the synthetic steroid anesthetic alphaxalone was the most potent compound tested, followed by the naturally occurring steroids tetrahydro-deoxycorticosterone, allo-tetrahydrocorticosterone, cis-androsterone and 5 alpha-androstan-17 beta-ol-3-one. The ability of several naturally occurring steroids to enhance GABA-mediated inhibition in the brain suggests the possibility of an endogenous steroid modulator of neuronal function.

Anesthetics↗
PubMed1989

The faculty fellowship program: uniting service and education.

The outcomes of the pilot year for this project met the goals of increased faculty clinical skills, increased nursing personnel at the unit level and the completion of specified projects based on identified clinical needs. Continued development of the Faculty Fellowship Program will yield further opportunity to study benefits, such as increased student performance in the acute care setting, increased recruitment of graduate nurses and improved integration of nursing education and service in addressing health care issues.

Fellowships and Scholarships↗
PubMed1988

Infestation in the dog by the paralysis tick, Ixodes holocyclus. 4. Cardiovascular effects.

To determine the extent and significance of changes in heart rate and rhythm noticed previously in dogs paralysed with Ixodes holocyclus, two studies were undertaken. In one the electrocardiogram was recorded at stages throughout the disease and the traces analysed for changes, while in the second a detailed study of the effect of Ixodes holocyclus on the cardiovascular system was undertaken. The electrocardiographic changes were extremely variable between stages and between dogs. Generally, if a dysrhythmia occurred in stages 1, 2 or 3 it tended to be sinus tachycardia, ventricular tachycardia or sinus arrest. In stage 4 sinus arrest, sinus bradycardia, or sinus or ventricular tachycardia were the prominent dysrhythmias, whereas in stage 5 sinus bradycardia predominated. Cardiovascular measurements indicated an increase in peripheral vascular resistance leading to a significant elevation in mean arterial pressure at all stages of the disease. Cardiac output was decreased significantly only at stage 2, although it was below the control measurements at all stages. Pulmonary arterial pressure was significantly elevated at stages 2, 3 and 4 due most probably to an increase in pulmonary vascular resistance. Myocardial contractility was not significantly changed throughout the disease. The changes observed in the electrocardiogram and the cardiovascular system in stages 1, 2 and 3 are unlikely to be due to hypoxia and could represent dysfunction of the autonomic nervous system. During stages 4 and 5 oxygen levels were below normal and the bradycardia seen terminally is almost certainly due to hypoxaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Infestation in the dog by the paralysis tick, Ixodes holocyclus. 5. Treatment.

In this study the value of drugs administered with hyperimmune serum in the treatment of advanced disease produced by Ixodes holocyclus was compared under controlled conditions. All control dogs died rapidly whereas one dog survived and 3 dogs died after receiving hyperimmune serum alone. When promethazine hydrochloride was administered with hyperimmune serum 2 dogs recovered rapidly while the remaining 2 died. Administration of dexamethasone and hyperimmune serum allowed 3 dogs to survive while administration of phenoxybenzamine hydrochloride in conjunction with hyperimmune serum allowed rapid recovery of all 4 dogs. Phenoxybenzamine hydrochloride, an alpha-adrenergic blocking drug, was chosen because of its potential to attenuate the arterial hypertension previously reported (Ilkiw et al 1988). The survival of all dogs together with the rapid return to normality indicated that this drug was beneficial in the treatment of dogs with advanced signs of tick paralysis.

Animals↗
PubMed1987

Enhanced ability of skeletal muscle containing cyclocreatine phosphate to sustain ATP levels during ischemia following beta-adrenergic stimulation.

Breast muscle of young chicks fed chow diets containing the creatine analog 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine) accumulated up to 40 mumol/g wet weight of the synthetic phosphagen 1-carboxymethyl-2-imino-3-phosphonoimidazolidine (cyclocreatine-P2-). ATP levels were sustained at high values substantially longer in breast muscle of cyclocreatine-fed chicks, compared to control-fed chicks, during total ischemia initiated 2 h after injection of both groups with the beta-adrenergic agonist isoproterenol (5 mg/kg subcutaneous). For example, in chicks fed 0.5% cyclocreatine for 10-19 days ATP levels in isoproterenol-stimulated breast muscles after 1 h of ischemia at 37 degrees C were 6.1 mumol/g, compared to 1.9 mumol/g for the control-fed group, and after 2 h of ischemia were 3.5 mumol/g compared to 0.6 mumol/g for controls. Creatine-P reserves in isoproterenol-stimulated breast muscles of all dietary groups were essentially exhausted within the first hour of ischemia. In contrast, breast muscle of chicks fed either 1 or 0.5% cyclocreatine still contained 28 and 19 mumol/g of cyclocreatine-P, respectively, after 1 h of ischemia; after 2 h of ischemia, the respective cyclocreatine-P values were 20 and 13 mumol/g. Isoproterenol-stimulated chick breast muscle provides the first skeletal muscle model system for studying the molecular mechanisms by which dietary cyclocreatine helps sustain ATP levels during ischemia. Although adaptive factors are also involved, it is suggested that a significant portion of the ATP-sustaining activity of dietary cyclocreatine in ischemic breast muscle can be attributed to the unique thermodynamic properties of the accumulated cyclocreatine-P. These properties enable cyclocreatine-P to continue to thermodynamically buffer the adenylate system and transport high energy phosphate throughout the long muscle fibers at cytosolic pH values and phosphorylation potentials well below the range where the creatine-P system can function effectively. Synergism between glycolysis and this long-acting synthetic phosphagen might well help delay depletion of ATP levels in skeletal muscles during ischemia. Cyclocreatine feeding provides a unique experimental tool for quantitative evaluation of the proposed protective role of ATP against irreversible cellular damage in skeletal and cardiac muscles during ischemic episodes.

Adenosine Triphosphate↗
PubMed1987

Infestation in the dog by the paralysis tick Ixodes holocyclus. 1. Clinical and histological findings.

Under laboratory conditions 8 dogs were infested with Ixodes holocyclus and the clinical signs and histological findings were recorded. Seven of the dogs developed clinical signs of the disease, died and were subjected to a post-mortem examination, while the eighth dog remained normal. The clinical signs were consistent between animals and enabled the course of the disease to be subdivided into 5 stages to facilitate analysis of data in future experiments. The most prominent feature of the disease was dysfunction of the efferent motor system although some disturbance of the afferent pathways and involvement of the autonomic nervous system did occur. The period elapsing between attachment of the ticks and onset of signs varied from 5.5 to 7 days, while the mean duration of the disease was 23.3 h. The histopathology demonstrated moderate to severe congestion of the liver, kidney and lungs, and in some lung sections pulmonary oedema was present.

Animals↗
PubMed1987

Infestation in the dog by the paralysis tick Ixodes holocyclus. 2. Blood-gas and pH, haematological and biochemical findings.

Arterial blood-gas and pH, haematological and biochemical estimations were carried out on 8 dogs infested with Ixodes holocyclus and 2 uninfested controls. The arterial blood-gas and pH measurements did not change significantly until the dogs were recumbent and unable to lift their heads. When affected dogs became moribund, moderate hypoxaemia with acute ventilatory failure was present. The significant haematological and biochemical abnormalities were difficult to interpret individually, but taken together could reflect sympathetic stimulation of the adrenal cortex or medulla.

Animals↗
PubMed1987

Infestation in the dog by the paralysis tick Ixodes holocyclus. 3. Respiratory effects.

To assess respiratory function in dogs with tick paralysis, respiratory measurements were recorded on 14 dogs experimentally infested with Ixodes holocyclus. There was a progressive fall in respiratory rate with no change in tidal volume, which resulted in a significant fall in minute respiratory volume in the latter stages of the disease. The fall in respiratory rate was possibly central in origin and was accompanied by an increased alveolar-arterial oxygen tension difference, probably caused by pulmonary congestion and oedema. The "grunting" respiration seen in tick paralysis was due to closure of the vocal cords during expiration and could represent an attempt to re-expand collapsed parts of the lung.

Animals↗
PubMed1979

Atherogenesis in the White Carneau pigeon. Further studies of the role of carbon monoxide and dietary cholesterol.

Two experiments are described. In the first, 3 pairs of groups of 20 female White Carneau pigeons were fed on diets containing 0.5%, 1% or 2% cholesterol. Birds in one group from each pair were exposed to 150 ppm carbon monoxide (CO) for 6 h on 5 days of each week for 52 weeks, sufficient to raise their carboxyhaemoglobin (COHb) levels to approximately 10%, while those in the other group were sham-exposed under similar conditions. In the second experiment, 3 groups of 40 female pigeons were each fed on a diet containing 1% cholesterol, one group being exposed to CO to give COHb levels of 20%, one to give COHb levels of 10% and one being sham exposed. In addition, 20 birds in the second experiment were fed on the 1% cholesterol diet but were neither exposed to CO nor sham-exposed. Cholesterol enriched diets caused mean plasma cholesterol values in each group to rise sharply within 4 weeks of starting them, but the levels reached were as high with diets containing 0.5% cholesterol as for diets containing 1% or 2% added cholesterol. Exposure to CO increased plasma and aortic cholesterol levels, though this increase was only statistically significant for aortic levels in the second experiment. In both experiments combined exposure to the 1% cholesterol diet and CO resulted in a significant decrease in aortic triglyceride content. The incidence and severity of coronary artery atherosclerosis was associated with increasing dietary cholesterol. It was also associated with exposure to CO in birds given 0.5% or 1%, but not 2%, dietary cholesterol; the increase in birds given 1% was related to the dose of CO. Possible mechanisms are discussed for this effect of CO, which is not found in normally fed birds.

Animals↗