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Biomedical subjects

B Hughes

Publications and source records attributed to B Hughes.

At least 55 records · Page 3Linked to original sources
PubMed1992

Problems measuring contrast sensitivity in children.

A preliminary study measured the contrast sensitivity function (CSF) in 30 children (aged 3 months-5 years). Preferential looking techniques were used to assess CSF to sine wave gratings displayed on one of two screens. To find a meaningful contrast sensitivity procedure we compared the results with a shorter procedure using an edge stimulus. The following problems were encountered: measuring the contrasts required to detect four or five different spatial frequencies took time, resulting in boredom and loss of attention in our subjects; there was poor correlation between CSF and edge detection; an interesting artefact resulted in a plateau rather than a low frequency fall-off in the CSF of five of the children greater than 30 months old. This artefact may have resulted from peripheral rather than central retinal responses and/or motion artefacts in the stimulus onset. A follow up study with 41 additional children aged 3-36 months limited the contrast testing to that of the spatial frequency corresponding to the peak of the CSF. The shortened procedure, plus a lot of encouragement, resulted in higher contrast sensitivities in all but the oldest age group and successful monocular contrast measurements. In order to avoid artefacts arising from peripheral vision, children were encouraged to look at each screen before responding.

Child, Preschool↗
PubMed1992

Involvement of beta 2-adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats.

1. Bradykinin can release neuronal calcitonin gene-related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg-1, i.v.) were assessed in the same chronically-instrumented, conscious, Long Evans rats in the absence and in the presence of human alpha-CGRP [8-37] or ICI 118551, antagonists of CGRP1-receptors and beta 2-adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human alpha-CGRP and beta 2-adrenoceptor agonists, respectively. 2. Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed. 3. Human alpha-CGRP [8-37] had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551. 4. In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg-1 min-1) elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained. 5. The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of beta 2-adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin-induced increase in mesenteric blood flow does not depend on this mechanism.

Adrenal Medulla↗
PubMed1992

The effect of monoclonal antibodies to calcitonin gene-related peptide (CGRP) on CGRP-induced vasodilatation in pig coronary artery rings.

1. The modification of the vasodilator effect of calcitonin gene-related peptide (CGRP) by a panel of monoclonal antibodies (MAbs), which map to discrete epitopes on the CGRP molecule, was investigated in pig coronary artery rings (PCA). The preparations were pre-constricted with acetylcholine (3 x 10(-7) M) and concentration-response curves to CGRP (2 x 10(-10)-2.56 x 10(-8) M) were obtained in the presence or absence of each MAb. 2. CGRP caused a concentration-dependent relaxation of PCAs which reached a maximum (98.2 +/- 4.8%, n = 25) at 1.28 x 10(-8) M and gave an EC50 of 3.8 +/- 0.8 x 10(-9) M. 3. Two MAbs which map to the N-terminal, CN1 and CRA3, did not affect the CGRP response whilst a third, CRA5, significantly inhibited its effect. 4. The C-terminal MAb, CRA2, did not modify the CGRP response whilst, in contrast, CB3 (C-terminal) potentiated its effect. A similar augmentation of the CGRP-induced vasodilatation was seen in the presence of the middle-region MAb, CRA8. 5. These results suggest that regional specific MAbs can modify the vasodilator effect of CGRP causing either inhibition (CRA5, N-terminal) or potentiation (CB3, C-terminal; CRA8, middle region).

Analysis of Variance↗
PubMed1992

A metabolic assessment of the beta 1 selectivity of bisoprolol.

Twelve healthy volunteers were given single oral doses of bisoprolol 5 mg, 10 mg and 20 mg and atenolol 50 mg and 100 mg in a randomised, placebo-controlled study. The effects of these drugs on beta 2-stimulated hypokalaemia and hyperglycaemia (produced by intravenous terbutaline infusion) were studied. Comparable beta-blockade was achieved with bisoprolol 20 mg, and atenolol 50 mg and 100 mg as measured by attenuation of exercise heart rate. Measurements of areas under or over the curve (AUC and AOC) of hypokalaemic or hyperglycaemic response to terbutaline infusion showed that bisoprolol (10 mg and 20 mg) and atenolol (50 mg and 100 mg) were significantly less beta 1 selective than 5 mg bisoprolol. Furthermore, there was a trend towards decreasing beta 1 selectivity with increasing doses of bisoprolol. Bisoprolol, an effective once daily antihypertensive and antianginal treatment, has comparable beta 1 selectivity to atenolol as measured by metabolic response. At a dose of 5 mg, bisoprolol has a measurable impact on beta 1 receptors but minimal effect on beta 2 receptors.

Adrenergic beta-Antagonists↗
PubMed1991

Differential vasodilator profile of calcitonin gene-related peptide in porcine large and small diameter coronary artery rings.

The vasodilator profile of calcitonin gene-related peptide (CGRP) was compared in large diameter (3-4 mm outer diameter) and small diameter (less than 1 mm outer diameter) rings from porcine left anterior descending coronary arteries (LAD). CGRP relaxed both sized rings in an endothelium-independent manner but was 10 X more potent in small compared to large diameter rings. Repeated administration of CGRP to small diameter rings did not cause the development of tolerance to its effects, whereas in the large diameter rings marked tolerance developed. Pretreatment with the CGRP peptide fragment, CGRP-(8-37) antagonised the vasodilator effects of CGRP in a concentration-dependent manner, but in large diameter rings, the antagonistic potency of CGRP-(8-37) was 10 X less than that seen in the small diameter rings. This differing vasodilator profile of CGRP in small and large diameter rings of pig LADs may be related to a differential CGRP receptor distribution along their length.

Acetylcholine↗
PubMed1991

Human alpha-calcitonin gene-related peptide (CGRP)-(8-37), but not -(28-37), inhibits carotid vasodilator effects of human alpha-CGRP in vivo.

Human alpha-calcitonin gene-related peptide-(8-37) alone (up to doses of 30 nmol kg-1 min-1) had no significant effects on blood pressure, heart rate or common or internal carotid haemodynamics, although it caused significant, reversible, inhibition of the hypotensive, tachycardic, and common and internal carotid vasodilator effects of human alpha-CGRP (0.03 nmol kg-1 min-1) in conscious, Long Evans rats. Human alpha-CGRP-(28-37) up to doses of 300 nmol kg-1 min-1 had no cardiovascular effects itself and did not influence responses to human alpha-CGRP. These results are consistent with the carotid haemodynamic effects of human alpha-CGRP being due largely to activation of the CGRP1-receptor subtype.

Animals↗
PubMed1991

Purification of a hybrid plasminogen activator protein.

Recombinant DNA technology has been employed to produce a hybrid gene in which the kringle and serine protease domains of tissue plasminogen activator are linked to the heavy-chain Fd region of a fibrin-specific antibody. The hybrid gene is co-expressed with antibody light chains. This communication describes a purification procedure for the hybrid protein, involving affinity and ion-exchange chromatography. The purified hybrid protein has been used in vivo and in vitro clot lysis experiments and has been shown to be effective at clot dissolution.

Animals↗
PubMed1991

Different effects of reoxygenation on the electrical activity of ventricular muscle.

Response of a hypoxic and acidotic (HA, with exogenous lactate) ventricular muscle tissue to subsequent reoxygenation in the absence of substrate (0 mM dextrose) was different from that of a Purkinje fiber. The K+ concentration in this solution (4.6 mM) was slightly higher than that in Tyrode solution (2.7 mM). The observed effects of reoxygenation of such a ventricular tissue were also variable. The ventricular muscle tissue exhibited the following different responses on reoxygenation after hypoxia and acidosis: (1) arrhythmias, without much depolarization of the membrane potential, (2) oscillatory after-potentials (OAPs) during the late diastole, which lessened in amplitude as the time of reoxygenation increased, but no arrhythmias, or (3) a pronounced slowed phase of repolarization (hump), but no arrhythmias. These different effects of reoxygenation did not occur if concentration of K+ in HA was very much higher than 4.6 mM. Common to these three different responses was the prolongation of the action potential durations during reoxygenation at the 50% and 90% levels of repolarization (APD50 and APD90) and a slight increase in the resting tension after 30-40 minutes of reoxygenation. Some of the observed responses of ventricular muscles were well mimicked by increasing extracellular calcium, but the different and variable effects of arrhythmias, OAPs, and prolonged APD require further analysis.

Acidosis, Lactic↗
PubMed1991

Amantadine toxicity presenting with complex ventricular ectopy and hallucinations.

Amantadine hydrochloride is a commonly prescribed drug with a narrow therapeutic-to-toxic range. Toxicity is related to the anticholinergic properties of the drug and primarily affects the cardiovascular, central nervous, and respiratory systems. We report the case of an adolescent who ingested 1.3 grams of amantadine and developed complex ventricular arrhythmias and altered mental status. The arrhythmias were completely suppressed with intravenous lidocaine. This case supports the hypothesis that lidocaine is effective for treatment of ventricular arrhythmias secondary to amantadine toxicity.

Adolescent↗
PubMed1991

Differential effects of (+/-)-dobutamine and human alpha-CGRP on cardiac and on regional haemodynamics in conscious Long Evans rats.

1. Comparisons were made of the full haemodynamic profiles of the known cardiostimulant, (+/-)-dobutamine, and the putative inotropic peptide, human alpha-calcitonin gene-related peptide (human alpha-CGRP), in conscious, chronically-instrumented Long Evans rats. Both substances were administered continuously i.v. for 60 min at two doses ((+/-)-dobutamine, 2 and 10 mumol kg-1 h-1; human alpha-CGRP, 0.15 and 1.5 nmol kg-1 h-1). 2. In spite of their similar (small) effects on mean arterial blood pressure, the low doses of (+/-)-dobutamine and human alpha-CGRP influenced cardiac haemodynamics differently. Thus, (+/-)-dobutamine caused an increase in cardiac index (due to a tachycardia), accompanied by rises in peak aortic flow, maximum rate of rise of aortic flow (dF/dtmax) and total peripheral conductance. However, the latter waned during the infusion, and after the infusion there was a significant systemic vasoconstriction and reductions in peak aortic flow, dF/dtmax and stroke index. Such 'off' effects following dobutamine infusion have not been described previously. The infusion of the lower dose of human alpha-CGRP caused only a transient fall in central venous pressure. 3. The rise in total peripheral conductance during infusion of the lower dose of (+/-)-dobutamine was associated with increases in hindquarters and common and internal carotid vascular conductances. The fall in total peripheral conductance after infusion was associated with renal vasoconstriction. Although there was no significant change in total peripheral conductance during the infusion of the lower dose of human alpha-CGRP there were hindquarters and carotid vasodilatations together with mesenteric vasoconstriction. 4. Infusion of the higher dose of ( )-dobutamine had greater effects than the lower dose on all cardiac haemodynamic variables and additionally, increased stroke index. However, the negative cardiac haemodynamic effects following the offset of infusion were also enhanced in association with marked renal and mesenteric vasoconstrictions. While infusion of the higher dose of human alpha-CGRP increased cardiac index, peak aortic flow, dF/dtmax and total peripheral conductance, stroke index fell together with central venous pressure. 5. (+/-)-Dobutamine caused greater cardiostimulation and increases in hindquarters blood flow than did human alpha-CGRP. However, the latter at the higher dose caused substantially greater common and internal carotid hyperaemia than did (+/-)-dobutamine, possibly indicating a selective and additional effect of human alpha-CGRP on cranial blood flow. Furthermore, there were no adverse cardiovascular effects following infusion of human alpha-CGRP.

Animals↗
PubMed1991

Regional haemodynamic effects of prolonged infusions of human alpha-calcitonin gene-related peptide in conscious, Long Evans rats.

1. Haemodynamic measurements were made in conscious, Long Evans rats chronically instrumented for the assessment of changes in regional blood flows (renal, mesenteric and hindquarters, or internal and common carotid) and systemic arterial blood pressure and heart rate, before, during and after 3 day infusions of vehicle or human alpha-calcitonin gene-related peptide (CGRP) (1.5 or 15 nmol kg-1 h-1). 2. In animals with renal, mesenteric and hindquarters flow probes (n = 8), during the first day of infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) there was sustained tachycardia and hypotension, a sustained reduction in renal flow, a transient reduction in mesenteric flow and a relatively well-maintained increase in hindquarters flow. All these effects were significantly different from the changes seen in vehicle-infused rats (n = 8), but calculation of vascular conductances showed only the late mesenteric vasodilatation and the sustained hindquarters vasodilatation were different from the changes in vehicle-infused rats. However, by the second day of infusion and thereafter cardiovascular variables in the animals receiving vehicle and those receiving human alpha-CGRP were not different. 3. Nine animals instrumented with probes to monitor changes in internal and common carotid haemodynamics initially received human alpha-CGRP infused at a rate of 1.5 nmol kg-1 h-1. Three of these animals still showed some response to the human alpha-CGRP (tachycardia, hypotension, hyperaemic vasodilatation) throughout the second day of infusion and hence were taken through the 3 day infusion protocol. When the infusion was stopped on the fourth day all these animals showed reversal of the effects of human alpha-CGRP. 4. The results indicate substantial inter-individual variation in the haemodynamic effects of prolonged infusions of human alpha-CGRP in conscious, Long Evans rats. However, since increasing the dose of human alpha-CGRP overcame the desensitization, it is feasible that, in the clinical setting, maintained increases in internal carotid blood flow could be achieved by individually-adjusted infusions of human alpha-CGRP.

Animals↗
PubMed1991

Haemodynamic effects of human alpha-calcitonin gene-related peptide following administration of endothelin-1 or NG-nitro-L-arginine methyl ester in conscious rats.

1 We investigated the peripheral haemodynamic effects of human alpha-calcitonin gene-related peptide (CGRP) following administration of endothelin-1 or NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide production, in conscious, chronically-instrumented, Long Evans rats. 2 Infusion of endothelin-1 (3 nmol kg-1 h-1) caused hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions. Co-infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) reduced the hypertension and abolished the hindquarters vasoconstriction caused by endothelin-1 but the renal and mesenteric vasoconstrictor actions of endothelin-1 were not affected. 3 Infusion of human alpha-CGRP (15 nmol kg-1 h-1) in the presence of endothelin-1 caused hypotension and hyperaemic vasodilatation in the hindquarters; the mesenteric vasoconstrictor effects of endothelin-1 were diminished, but there was only a transient reversal of the renal vasoconstrictor effects of endothelin-1. 4 Pretreatment with the non-peptide angiotensin II receptor antagonist, DuP 753 (10 mg kg-1), caused slight hypotension associated with renal, mesenteric and hindquarters vasodilatations, but DuP 753 did not affect responses to endothelin-1 infusion. However, under these conditions co-infusion of human alpha-CGRP (15 nmol kg-1 h-1) caused a sustained reversal of the renal vasoconstrictor effects of endothelin-1. 5 These results indicate that the failure of human alpha-CGRP to cause sustained reversal of the renal vasoconstrictor effects of endothelin-1 in the absence of DuP 753 was due to activation of the reninangiotensin system (possibly as a consequence of the hypotension). 6. In the second experiment, L-NAME (l0mgkg-1) caused renal, mesenteric and hindquarters vasoconstrictions similar to those seen in the presence of endothelin-1. However, the renal vasoconstrictor effects of L-NAME were reversed completely by human alpha-CGRP (l5nmolkg- h-1), even though the latter caused hypotension comparable to that seen in the presence of endothelin-1. These results are consistent with a lack of functional activation of the renin-angiotensin system by human alpha-CGRP in the presence of L-NAME. 7. The vasoconstrictor effects of L-NAME on the hindquarters were completely reversed by infusion of human alpha-CGRP, but hindquarters flow and vascular conductance did not rise above baseline levels. Hence these results indicate the hindquarters hyperaemic vasodilator effects of human alpha-CGRP seen in the presence of endothelin-1 were contributed to by nitric oxide-mediated mechanisms.

Angiotensin II↗
PubMed1991

Chemotactic factors regulate lectin adhesion molecule 1 (LECAM-1)-dependent neutrophil adhesion to cytokine-stimulated endothelial cells in vitro.

Monoclonal antibodies recognizing CD18, CD11a, CD11b, and neutrophil lectin adhesion molecule 1 (LECAM-1), i.e., the human homologue of the murine MEL-14 antigen, were used to assess the relative contribution of these glycoproteins to neutrophil-endothelial adhesion. Under static conditions, the adhesion of neutrophils to IL-1-stimulated human umbilical vein endothelial cell (HUVEC) monolayers was inhibited by antibodies to CD18, CD11a, and the neutrophil LECAM-1, and the effect of combining anti-LECAM-1 and anti-CD11a was almost additive. Under flow at a wall shear stress 1.85 dyn/cm2, a condition where CD18-dependent adhesion is minimal, anti-LECAM-1 inhibited adhesion by greater than 50%. Chemotactic stimulation of neutrophils induced a rapid loss of LECAM-1 from the neutrophil surface, and the level of neutrophil surface LECAM-1 was closely correlated with adhesion under flow. Neutrophils contacting the activated endothelial cells for 30 min lost much of their surface LECAM-1, a phenomenon induced by a soluble factor or factors released into the medium by the stimulated monolayers, and a high percentage migrated through the HUVEC monolayer. This migration was almost completely inhibited by anti-CD18, but was unaffected by antibodies to neutrophil LECAM-1. These results support the concept that LECAM-1 is a neutrophil adhesion molecule that participates in the adherence of unstimulated neutrophils to cytokine-stimulated endothelial cells under conditions of flow, and is then lost from the neutrophil surface coincident with the engagement of CD18-dependent mechanisms leading to transendothelial migration.

Adult↗
PubMed1991

Antagonistic effect of human alpha-calcitonin gene-related peptide (8-37) on regional hemodynamic actions of rat islet amyloid polypeptide in conscious Long-Evans rats.

Rat synthetic amidated islet amyloid polypeptide (IAPP) was infused into conscious Long-Evans rats chronically instrumented for the measurement of regional hemodynamics. Rat IAPP (0.25-2.5 nmol.kg-1.min-1) had dose-dependent tachycardiac and hypotensive effects. Renal blood flow increased at all dose levels in association with incremental rises in renal vascular conductances. Hindquarters blood flow and vascular conductance increased at the higher dose levels, but mesenteric blood flow fell with mean arterial blood pressure (i.e., there was no change in mesenteric vascular conductance). Concurrent infusion of 25 nmol.kg-1.min-1 human alpha-calcitonin gene-related peptide (CGRP) (8-37) abolished the hypotensive, tachycardiac, and renal and hindquarters vasodilator effects of rat IAPP, and during administration of both peptides, there was a transient renal and sustained mesenteric vasoconstriction. When the infusion of human alpha-CGRP (8-37) was stopped, the effects of the continued infusion of rat IAPP were reestablished. The results indicate that the reported ability of IAPP to induce insulin resistance cannot be due to decreased skeletal muscle blood flow. In addition, human alpha-CGRP (8-37) is an effective antagonist of the hemodynamic actions of rat IAPP. Because it has been shown previously that human alpha-CGRP (8-37) antagonizes the hemodynamic effects of human alpha-CGRP, these results, collectively, indicate that human alpha-CGRP and rat IAPP might act on the same receptor at which human alpha-CGRP (8-37) is an effective antagonist or that the latter is a nonselective antagonist of separate receptors on which human alpha-CGRP and rat IAPP act.

Amyloid↗
PubMed1990

Antagonistic effect of human alpha-CGRP [8-37] on the in vivo regional haemodynamic actions of human alpha-CGRP.

In conscious rats, infusion of human alpha-CGRP [8-37] (30 nmol/kg/min) caused small, reversible reductions in hindquarters flow and vascular conductance only, whereas at a dose of 300 nmol/kg/min there was a tachycardia and an increase in mean arterial blood pressure, together with renal, mesenteric and hindquarters vasoconstrictions. Human alpha-CGRP (0.03 nmol/kg/min) caused tachycardia, hypotension, and transient renal, but sustained hindquarters, vasodilatation; these changes were accompanied by mesenteric vasoconstriction. Infusion of human alpha-CGRP [8-37] (30 nmol/kg/min) during administration of human alpha-CGRP (0.03 nmol/kg/min) abolished the effects of the latter but these re-appeared when the human alpha-CGRP [8-37] infusion was stopped. This dose of human alpha-CGRP [8-37] did not affect cardiovascular responses to isoprenaline. These results indicate that human alpha-CGRP [8-37] is an effective antagonist of the cardiovascular actions of human alpha-CGRP in vivo.

Animals↗
PubMed1990

GABA and benzodiazepine receptors in the cat motor thalamus after lesioning of nigro- and pallidothalamic pathways.

Binding parameters of [3H]muscimol ([3H]MUS) and [3H]flunitrazepam ([ 3H]FLU) were determined in the thalamic area of overlap of nigro- and pallidothalamic pathways at short- (1-10 weeks) and long-term (6-11 months) survival times after kainic acid lesioning of substantia nigra pairs reticularis (SNr) and/or entopeduncular nucleus (EPN). No statistically significant lesion-induced changes in Kd could be established in any of the lesioned groups. Bmax values for both binding sites, when corrected for nerve cell densities, revealed some changes in all but one instance (no statistically significant changes in the number of [3H]MUS binding sites were detected after SNr lesions). Significant bilateral increase in the number of [3H]MUS binding sites was found after unilateral EPN and combined EPN + SNr lesions. In the first group the changes were transient; in the second, the number of binding sites appeared to be still on the rise at 8 months postlesion. The latter increase was interpreted as resulting from plasticity type changes in GABAergic local circuit neurons in response to massive deafferentation from extrinsic inhibitory inputs. Changes in [3H]FLU binding sites were of different character and of extremely low magnitude compared to changes in [3H]MUS binding sites. Subtle, but statistically significant, ipsilateral increase in the number of [3H]FLU binding sites as a function of time postlesion was found in the SNr lesioned group. In two other lesioned groups small magnitude increase occurred bilaterally, although in the EPN lesioned group it was more pronounced on the operated side. The results are consistent with earlier suggestion that [3H]MUS and [3H]FLU binding sites in the motor thalamus appear to be associated with different types of GABAergic synapses with none of them being directly associated with the basal ganglia thalamic pathways.

Animals↗
PubMed1990

The use of charge-coupled devices in the quantitative evaluation of images, on photographic film or membranes, obtained following electrophoretic separation of DNA fragments.

Charge-coupled devices can provide an excellent means for the quantification of DNA band images on membranes and photographic film. However, proper consideration must be given to important parameters such as signal-to-noise ratio and resolution, especially in applications which demand the use of large format media. When employed in the direct imaging of chemiluminescent blots, the charge-coupled device can provide equal or better sensitivity than that obtained by indirect methods using film, with the additional advantages of wide dynamic range and freedom from the vagaries of film processing.

DNA↗