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Biomedical subjects

C E Wright

Publications and source records attributed to C E Wright.

At least 19 recordsLinked to original sources
PubMed2006

Averting iatrogenic hypoglycemia through glucose prediction in clinical practice: progress towards a new procedure in diabetes.

BACKGROUND: Hypoglycemia is a risk factor common to all insulin therapy. The hypothesis is that efforts to reduce or prevent this adverse side effect may fail because providers generally lack the resources to predict not only future blood glucose levels but also future risks of hypoglycemia. This lack has been remedied. A controlled study was undertaken to test the hypothesis. METHODS: Twenty-two insulin dependent subjects suffering more than one (1) episode/week of hypoglycemia with similar insulin regimens, similar diabetes education and similar self-management training participated in this study. For all subjects, a remote monitoring resource (registry and database) was used to capture daily SMBG and afford a return path for provider interventions and decision support. Identical telemedical methods were used which differed only for the provider either by the presence (prediction group) or by the absence (control group) of an on-screen, visual display of predicted glycemia and predicted risks of hypoglycemia. The study lasted 2 months. RESULTS: Over an average of 41 days from baseline to follow up and while using the glycemic prediction resource, providers intervened more effectively in the prediction group reducing rates of hypoglycemia nine-fold (P<0.0001) and insulin therapy by just -9 U/day (P<0.01). Mean pre-meal glycemia was not compromised. Over 61 days from baseline to final follow up but without glycemic predictions in the control group, providers' interventions were less effective and resulted in no net changes in rates of hypoglycemia, daily insulin therapy, or mean pre-meal glycemia. CONCLUSIONS: Given knowledge of future glycemia and future risks of hypoglycemia, providers in clinical practice can now avert iatrogenic hypoglycemia in less than 2 months. A shared diabetes data center furnishing remote data capture and decision support is fundamental to the implementation of this as a new clinical procedure in diabetes.

Adolescent↗
PubMed2005

Physiological correlates of cognitive functioning in an elderly population.

Cognitive decline in old age is not universal or inevitable. Associations have been observed with neuroendocrine function, but the relevance of other physiological processes is unclear. We predicted that impairment of memory in an ageing population would be related to the dysregulation of neuroendocrine and cardiovascular responses. One hundred and thirty-nine participants (65-80 years) were recruited from general practice in London. Two standardised verbal paired-associates recall tasks were administered in order to determine declarative memory performance, and a fluid intelligence task (matrix reasoning) was also performed. Salivary cortisol samples were collected every 10 min, while blood pressure and heart rate were measured before, during and after each task. Illness history and medication use were obtained from medical records. Multiple linear regression analysis, adjusted for age, gender, education, chronic illness, and medication use, revealed that cortisol responses were inversely related to memory performance. Additionally, superior memory was associated with more effective post-task recovery of heart rate (in both men and women) and diastolic blood pressure recovery in men. Cardiovascular recovery effects were independent of covariates, and of levels of heart rate and blood pressure measured during tasks themselves. These associations were also independent of subjective ratings of stress and perceived performance. Neither neuroendocrine nor cardiovascular responses were related to performance of the reasoning task. We conclude that memory in the elderly is associated both with hypothalamic-pituitary-adrenocortical function and cardiovascular regulation. Disturbances of neuroendocrine and hemodynamic function may be related to greater vulnerability to cognitive decline.

Aged↗
PubMed2004

Acute inflammation and negative mood: mediation by cytokine activation.

Inflammatory diseases are commonly associated with depressed mood. This association may be influenced by the production of proinflammatory cytokines. Accordingly, we assessed whether cytokine levels and mood (measured with the profile of mood states) could be altered by a mild, non-sickness inducing, acute inflammatory stimulus. Using a randomised placebo-controlled, double-blind design, 30 healthy male volunteers were injected with Salmonella typhi vaccine or placebo. Assessments of mood, symptoms of illness and temperature were made at baseline and at 1.5, 3, and 6 h post-injection. Plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and tumour necrosis factor-alpha (TNF-alpha) were assessed at baseline and 3 h post-injection. No significant symptoms of illness were reported in either group. Mood was more negative following injection in the vaccine than the placebo group, and the vaccine group experienced a 106% increase in IL-6 concentration. Negative changes in mood following injection were significantly correlated with increases in IL-6 production. No changes in TNF-alpha or IL-1Ra concentration were recorded in either group. It is concluded that S. typhi vaccination may be a useful model of mild inflammatory challenge, producing a significant transient cytokine-induced decrease in mood in the absence of any febrile response. Implications for depressed mood in physical illness are discussed.

Acute Disease↗
PubMed2004

Dietary intake, physical activity, and obesity in women with polycystic ovary syndrome.

OBJECTIVE: To determine whether dietary intake and physical activity contribute to obesity in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SUBJECTS: A total of 84 cases and 79 neighborhood controls of similar age. MEASUREMENTS: Fasting insulin, body mass index (BMI, kg/m2), waist/hip ratio, Block Food Frequency Questionnaire, Paffenbarger Physical Activity Questionnaire. RESULTS: Although women with PCOS had a higher BMI than control women, an overall comparison of women with and without PCOS showed no significant difference in dietary intake. However, stratification by BMI revealed that lean women with PCOS reported significantly lower energy intake than lean women without PCOS. CONCLUSION: Differences in dietary intake and physical activity alone are not sufficient to explain differences in weight between women with and without PCOS. Further research is necessary to determine the relative contributions of lifestyle factors and metabolism to obesity in PCOS.

Adult↗
PubMed2003

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition.

AIMS: To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX. METHODS: Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms. RESULTS: The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)). CONCLUSIONS: Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.

Administration, Oral↗
PubMed2001

The placebo response to citric acid-induced cough: pharmacodynamics and gender differences.

Characteristics of the response to placebo in a citric acid-induced cough challenge were investigated as part of a randomized, double-blind crossover trial to assess the antitussive effect of dextromethorphan. Baseline cough responses were established on two occasions in 22 healthy subjects. They received 60 ml placebo antitussive syrup and cough frequency following five inhalations of 10% citric acid over 5 min was measured at regular intervals up to 12 h. Response-time models of varying complexity were used to describe the placebo cough suppression data. The cough response to placebo was also compared to that of the untreated state. The placebo cough response was best characterized by a non-linear increase in cough suppression up to a maximum reduction of 1.6 coughs from baseline at 4-4.5 h, followed by a non-linear return to baseline. The cough response in the untreated state was not different from that of placebo (P=0.99). Females coughed more frequently than males (median number of coughs=10.5 vs. 9.0, respectively P<0.001; Mann-Whitney U test), and adaptation to the cough stimulus was significantly more rapid in females (P<0.025). Accordingly, in trials that use citric acid-induced cough, gender should be considered in study design, particularly in relation to the timing of measurements.

Administration, Inhalation↗
PubMed2001

A comparative study of buttressed versus nonbuttressed staple line in pulmonary resections.

BACKGROUND: Prolonged air leak is the major limiting factor in early hospital discharge following pulmonary resection. The purpose of this study was to determine whether the use of bovine pericardial strips as a buttress along the lung staple line would decrease air leaks and hospital stay after lobectomy and segmentectomy. METHODS: This was a multicenter trial consisting of 80 patients undergoing pulmonary resection, randomly assigned to the control group (40 patients) or treatment group (40 patients). The treatment group had reinforcement with bovine pericardium. RESULTS: No statistical differences were noted in the mean intensive care unit length of stay (p = 0.9), number of days with a chest tube (p = 0.6), or total length of stay (p = 0.24). Increased air leak duration was associated with assignment to the control group (r = 0.27, p = 0.02). The mean duration of air leak was 2 days and the mean time to chest tube removal was 5.9 days in patients with a buttressed staple line compared to 3 days and 6.3 days, respectively, for patients with nonbuttressed staple lines. CONCLUSIONS: Within the data of this study, no statistical differences were noted between buttressed and nonbuttressed patients. However, the trend toward shortened air leak time and tube removal time was apparent in the buttressed group. With greater number of patients studied, it is likely that the cost of bovine pericardium would be justified by shorter air leak duration and hospitalization.

Adult↗
PubMed2001

Interplay of biomechanical constraints and kinematic strategies in selecting arm postures.

In this study, the authors examined the interplay between biomechanics and control strategies in the resolution of excess degrees of freedom at the joint level. Seven participants made aimed arm movements from 30 starting points and several starting postures to targets. Final arm postures for movements to a target exhibited substantial joint angle variation. Through regression modeling and by comparing observed final arm postures with biomechanically plausible postures, the authors identified 3 kinematic strategies: (a) Maintain deviations from the average angle at the starting point to the joint's final posture; (b) make torso rotations that are a fixed proportion of shoulder rotations; and (c) adopt a characteristic combination of 4 wrist-positioning approaches. The results demonstrated that kinematic strategies can account for substantial variance in final arm postures, if one takes into account 2 types of individual differences-those that arise inevitably from biomechanical constraints and those that reflect choices in movement strategy.

Adult↗
PubMed2001

In vivo regulation of the beta-myosin heavy chain gene in hypertensive rodent heart.

The main goal of this study was to examine the transcriptional activity of different-length beta-myosin heavy chain (beta-MHC) promoters in the hypertensive rodent heart using the direct gene transfer approach. A hypertensive state was induced by abdominal aortic constriction (AbCon) sufficient to elevate mean arterial pressure by approximately 45% relative to control. Results show that beta-MHC promoter activity of all tested wild-type constructs, i.e., -3500, -408, -299, -215, -171, and -71 bp, was significantly increased in AbCon hearts. In the normal control hearts, expression of the -71-bp construct was comparable to that of the promoterless vector, but its induction by AbCon was comparable to that of the other constructs. Additional results, based on mutation analysis and DNA gel mobility shift assays targeting betae1, betae2, GATA, and betae3 elements, show that these previously defined cis-elements in the proximal promoter are indeed involved in maintaining basal promoter activity; however, none of these elements, either individually or collectively, appear to be major players in mediating the hypertension response of the beta-MHC gene. Collectively, these results indicate that three separate regions on the beta-MHC promoter are involved in the induction of the gene in response to hypertension: 1) a distal region between -408 and -3500 bp, 2) a proximal region between -299 and -215 bp, and 3) a basal region within -71 bp of the transcription start site. Future research needs to further characterize these responsive regions to more fully delineate beta-MHC transcriptional regulation in response to pressure overload.

Animals↗
PubMed2000

Pharmacological characterisation of cannabinoid CB(1) receptors in the rat and mouse.

The role of cannabinoid CB(1) receptors in sympathetic neurotransmission was characterised in nerve-mediated responses of isolated right atria, vasa deferentia and small mesenteric resistance arteries using the cannabinoid CB(1) receptor agonists Delta(9)-tetrahydrocannabinol, CP 55,940 and anandamide and the cannabinoid CB(1)-selective antagonist SR 141716A. In the mouse vas deferens, the twitch response was completely inhibited by each of the putative cannabinoid receptor agonists with pIC(50) values of CP 55,940, 9.2+/-0.1; Delta(9)-tetrahydrocannabinol, 8.4+/-0.1; anandamide, 7.1+/-0.1. SR 141716A 10-100 nM was a competitive antagonist of all three agonists with a pK(B) value of 8.4-8.6, consistent with an interaction at the cannabinoid CB(1) receptor. In the rat vas deferens CP 55,940 (0.01-10 microM) inhibited the contractions to a significant extent (88.5+/-0.5% at 10 microM; pIC(50) of 7.1+/-0.1) while Delta(9)-tetrahydrocannabinol and anandamide (both up to 10 microM) were inactive. CP 55,940 exhibited low potency in rat compared with mouse vas deferens and the rat concentration-response curve was not competitively antagonised by SR 141716A (100 nM) or SR 144528 (10 nM-10 microM), suggesting an interaction at a receptor(s) distinct from cannabinoid CB(1) or CB(2). Sympathetic nerve-induced tachycardia in rat and mouse atria, and rat mesenteric artery smooth muscle contractile responses to perivascular nerve stimulation, were not inhibited by Delta(9)-tetrahydrocannabinol, CP 55,940 or anandamide up to 1 microM. These data indicate that cannabinoid CB(1) receptor activation inhibits sympathetic neurotransmission only in the mouse vas deferens and thus point to species and regional differences in cannabinoid CB(1) receptor involvement in pre-synaptic inhibition of sympathetic neurotransmission and CP 55,940 may have inhibitory actions in rat vas deferens unrelated to cannabinoid receptor activity.

Animals↗
PubMed2000

Comparison of pramipexole, fluoxetine, and placebo in patients with major depression.

Pramipexole, a dopamine D2 receptor agonist, was tested in 174 patients with major depression, with or without melancholia and without psychotic features. Three daily dose levels (0.375 mg, 1.0 mg, and 5.0 mg) were compared to fluoxetine (Prozac) at 20 mg and placebo in a randomized, double-blind, parallel-group study. After a 1 week placebo run-in period, patients were treated for 8 weeks, had a post-study follow-up (week 9), and were evaluated primarily with the Hamilton Psychiatric Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinician's Global Impressions-Severity of Illness scale (CGI-SI). All patients who received one dose of study medication were included in the observed-case analysis (no missing data were replaced). Results indicated that by endpoint (week 8), patients receiving pramipexole at the 1.0 mg per day dose had significant improvement over baseline compared to the placebo group by measure of the HAM-D, MADRS, and CGI-SI. Significant improvement in this dose group was seen at other timepoints as well. The most obvious improvement was seen in the pramipexole 5.0 mg group, although a substantial dropout rate for this group precluded statistical tests vs. placebo late in the study. Patients taking fluoxetine also showed significant improvements at endpoint on the MADRS and earlier in the study on the HAM-D. No new or unusual safety concerns were generated during this study. Pramipexole helped safely alleviate the symptoms of depression at 1.0 mg per day and especially in those patients who could tolerate the escalation to 5 mg per day.

Adult↗
PubMed2000

Stroke after coronary artery operation: incidence, correlates, outcome, and cost.

BACKGROUND: Stroke is a major complication of coronary operation, with reported rates of postoperative cerebral dysfunction ranging from 0.4% to 13.8%. In this report, the incidence, correlates, outcomes, and costs of stroke in coronary operation were evaluated at Emory University between 1988 and 1996. METHODS: Data were entered prospectively into a dedicated computerized database at Emory University and analyzed retrospectively. Univariate and multivariate analyses were utilized where appropriate. RESULTS: Data from 10,860 patients undergoing primary coronary operation between 1988 and 1996 were analyzed. There were 250 patients not entered into the database. Stroke occurred in 244 (2.2%). Univariate predictors of stroke (p<0.05) included age, female gender, hypertension, diabetes, prior stroke, prior transient ischemic attack (TIA), and carotid bruits. Multivariate correlates included age (odds ratio 1.07) previous TIA (odds ratio 2.2), and carotid bruits (odds ratio 1.9), although the area under the Receiver Operating Characteristics (ROC) curve was only 0.69, suggesting limited ability to predict stroke. One and 5 year survival rates were 64% and 44% with stroke, and 94% and 81% without stroke, respectively. Among the stroke group, 23% of the patient population died before hospital discharge. The stroke group had a significantly longer length of hospital stay, as well as higher costs. CONCLUSIONS: Stroke is a devastating complication of coronary operation, significantly increasing morbidity, mortality, and cost. Three independent variables were identified for predicting stroke, including age, previous TIA, and carotid bruits. Patients should be carefully screened for cerebrovascular disease to help prevent stroke and its associated morbidity.

Cardiopulmonary Bypass↗
PubMed2000

Cardiovascular and autonomic effects of omega-conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays.

1. The effects of a novel N-type voltage-operated calcium channel antagonist, omega-conotoxin CVID, were compared with omega-conotoxin MVIIA on sympathetic-evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their effects were also compared on blood pressure and cardiovascular reflexes in conscious rabbits. 2. The pIC(50) values for MVIIA and CVID, respectively, for inhibiting sympathetic-evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA - plog MA), for MVIIA and CVID were 2 and 10. The offset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization. 3. In the conscious rabbit, CVID and MVIIA (100 microg kg(-1) i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal- and sympathetic-mediated components of the baroreflex, but had no effect on the vagal nasopharyngeal reflex. The orthostatic reflex to 90 degrees tilt was blocked by MVIIA with sustained postural hypotension for > or = 90 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly. 4. Neither CVID nor MVIIA (3 microg kg(-1) i.t.) significantly altered cardiovascular variables or autonomic reflexes. 5. In conclusion, CVID appears to be relatively weak at inhibiting the reflex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N-type calcium channel selectivity.

Animals↗
PubMed2000

A comparative pharmacokinetic and dynamic evaluation of alprazolam sustained-release, bromazepam, and lorazepam.

Sustained-release (SR) alprazolam may facilitate compliance with oral benzodiazepine treatment of panic disorders that currently requires doses administered three or four times daily. To compare the pharmacokinetic, psychomotor performance, and subjective effects of alprazolam SR (1.5 mg), bromazepam (3 mg taken three times daily), and lorazepam (1 mg taken three times daily), 13 male volunteers (aged 20-45 years) randomly received on four separate occasions one of these medications or placebo. Once before and 11 times after drug administration, the subjects were tested using psychomotor performance tests (manual tracking and digit-symbol substitution test [DSST]) and computerized questionnaires (such as the Tufts University Benzodiazepine Scale [TUBS], the Addiction Research Center Inventory, and the visual analog scales) to determine the subjective effects of the drugs. Blood samples for the determination of the plasma levels of the drugs were collected before and 17 times after the drug was administered. A peak plateau of plasma alprazolam began approximately 6 hours after the dose, which was later than the initial peaks for lorazepam and bromazepam (1-2 hours after the dose). Once this plateau had begun, alprazolam SR sustained that concentration better than did the other two formulations. Of the 10 measures on which the response averaged for the first 14 hours differed among drugs (p < 0.05), bromazepam differed from placebo on two measures, lorazepam on four (including DSST Performance and TUBS Sedation), and alprazolam SR on nine (including all four affected by lorazepam). Lorazepam and alprazolam, but not bromazepam, produced significantly more sedation than placebo. The doses of the three drugs were not equipotent in sedation and mood effects. None of the drugs tested differed from placebo on measures relevant to abuse liability.

Adult↗
PubMed2000

Postural hypotension following N-type Ca2+ channel blockade is amplified in experimental hypertension.

OBJECTIVE: To determine the relative importance of the cardiac and vascular sympathetic components of the orthostatic response to 90 degrees head-up tilt after N-type calcium-channel blockade in normotensive (sham renal cellophane wrap) and hypertensive (renal wrap) conscious rabbits. METHODS: The effects of N-type calcium-channel blockade with omega-conotoxin GVIA (omega-CTX, 10 microg/kg i.v. bolus) were assessed in the absence or presence of cardiac block by propranolol and methscopolamine. These were contrasted with the effects of alpha1-adrenoceptor antagonism (prazosin 0.5 mg/kg i.v. bolus, in the presence of cardiac block) or ganglion blockade (mecamylamine 4 mg/kg i.v. bolus). RESULTS: In vehicle (0.9% saline) treatment groups, the response to tilt consisted of a small pressor effect (4 +/- 2 and 7 +/- 1 mmHg) and tachycardia (29 +/- 6 and 17 +/- 6 beats/min) in sham (n = 6) and wrap (n = 5) rabbits, respectively. After prazosin administration (with cardiac block), there were significant falls in MAP of 3 +/- 1 and 7 +/- 2 mmHg in sham (n = 7) and wrap (n = 6) rabbits, respectively, in response to tilt omega-CTX caused postural hypotensive responses of 8 +/- 2 and 13 +/- 2 mmHg in sham (n = 6) and wrap (n = 7) rabbits, respectively, and 7 +/- 1 and 14 +/- 2 mmHg in sham (n = 7) and wrap (n = 7) rabbits with prior cardiac block. Similarly, mecamylamine caused falls in MAP of 8 +/- 1 and 10 +/- 2 mmHg in response to tilt in sham (n = 6) and wrap (n = 9) animals, respectively. CONCLUSION: Sympathetic vasoconstrictor effectors are primarily responsible for maintaining blood pressure during tilt in conscious rabbits. The postural hypotension caused by sympatholytic agents is about double in hypertensive rabbits, and N-type calcium-channel blockade is as effective as ganglion blockade at inducing this syndrome.

Adrenergic alpha-Agonists↗
PubMed2000

Role of NPY Y1 receptors in cardiovascular control in the conscious rabbit.

Prejunctional neuropeptide Y (NPY) Y1 receptors on cardiac sympathetic neurons mediate transient inhibition of chronotropic responses in rabbit isolated right atria. The function of these receptors remains speculative. We investigated a possible functional role for these receptors in modulation of the baroreceptor-heart rate (HR) reflex in the conscious rabbit. Mean arterial pressure (MAP) responses to a range of doses of the Y1 receptor agonist [Leu31,Pro34]NPY (1-8 microg/kg, i.v.) were constructed in ganglion-blocked rabbits. After administration of the selective Y1 receptor antagonist GR231118(150 microg/kg, i.v.), two-point [Leu31,Pro34]NPY dose-pressor responses were assessed. Linear regression analysis of the relation between the shift in the [Leu31,Pro34]NPY dose-pressor response lines against time was used as an estimate of the functional half-life of GR231118. GR231118 shifted the two-point [Leu31,Pro34]NPY dose-pressor response relation by 10- to 30-fold. A single estimate of the functional half-life of a bolus dose of GR231118 was 25 +/- 2 min. This determination allowed a steady-state Y1-receptor blockade to be established by a bolus and infusion. In a separate group of rabbits, the baroreceptor-HR reflex was assessed before and 30 min after administration of GR231118 (150 microg/kg bolus, then 150 microg/ kg/h, i.v.). GR231118 caused an initial transient pressor response and bradycardia, followed by a depressor response and a more sustained tachycardia. Infusion of GR231118 had no effect on the baroreceptor-HR reflex. Prejunctional Y1 receptors appear not to mediate a tonic inhibition of cardiac sympathetic neurotransmission in the conscious rabbit during physiological manipulations in MAP. However, activation of postjunctional Y1 receptors by neuronal or circulating NPY may be important in maintenance of vascular tone in the conscious rabbit.

Animals↗