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Biomedical subjects

D Cook

Publications and source records attributed to D Cook.

At least 145 records · Page 8Linked to original sources
PubMed1994

Antagonism of eicosanoid-induced contraction of rat aorta by sulphonylureas.

Glibenclamide and other sulphonylureas are extensively used as specific blockers for ATP-dependent potassium channels in vascular smooth muscle. However, glibenclamide has recently been shown to inhibit actions of some prostanoids in vascular smooth muscle. We extend our previous study by examining the relaxant actions of five different sulphonylureas in rat aorta. The inhibitory effects of sulphonylureas on the contractions induced by prostaglandins F2 alpha, E2 and D2, norepinephrine, 5-hydroxytryptamine (5-HT) or potassium chloride (KCl) were examined. Glibenclamide significantly inhibited the contractions produced by prostaglandins F2 alpha, E2 and D2 but was without effect on responses to norepinephrine, 5-HT or KCl. Glimepiride produced significant attenuation of the responses to all agents tested (5-HT, norepinephrine, KCl), although the inhibition of the responses to prostaglandin F2 alpha was most pronounced. Glipizide and tolbutamide had activities similar to that of glibenclamide, while chlorpropamide was devoid of any antagonist action in rat aorta. In rat aorta precontracted with norepinephrine, glibenclamide inhibited the relaxant responses to lemakalim and pinacidil. Thus, in addition to the effect on ATP-dependent potassium channels, glibenclamide inhibits responses to prostaglandins F2 alpha, E2 and D2 but not to other agents. This effect is shared by glimepiride, tolbutamide and glipizide.

Animals↗
PubMed1994

Maternal factors and development of cardiovascular risk: evidence from a study of blood pressure in children.

It has been suggested that risks of hypertension and cardiovascular disease begin in utero and that maternal nutrition plays an important role. We have examined the relation between maternal factors and BP in a study of 1,311 children in which physical measurements at 9-11 years of age have been linked to a parental questionnaire; birth record data were also available in a subsample of 662 children. Maternal height was inversely related to childhood BP after adjustment for the child's current height. However, several social factors related to maternal nutrition in pregnancy in earlier studies (including social class, housing tenure, maternal educational attainment and maternal smoking in pregnancy) showed weak and inconsistent relations with BP at 9-11 years. Minimum maternal haemoglobin in pregnancy and change in mean corpuscular volume in pregnancy (identified as potentially important markers of maternal nutrition in earlier studies) showed no consistent relationships either with placental weight to birthweight ratio or with childhood BP, although both factors showed strong inverse associations with birthweight. The association between maternal height and childhood BP may reflect the influence of early life factors on cardiovascular risk. However, the absence of consistent relationships between social factors and BP in offspring provides little support for the possibility that maternal diet is an important influence on cardiovascular risk factors in childhood. Minimum maternal haemoglobin and change in maternal mean corpuscular volume are unlikely to be specific markers of maternal nutrition in pregnancy. More specific hypotheses relating maternal nutrition to the development of cardiovascular risk in offspring are required.

Adult↗
PubMed1993

A measurement process for evaluating clinical teachers in internal medicine.

With input from faculty members and residents in the internal medicine residency training program at McMaster University, Hamilton, Ont., the authors developed a form to evaluate attending physicians in clinical teaching units according to 14 domains of performance. Although brief, the form included all main areas of teacher performance, allowed specification of attending physician behaviour and differentiated areas of strengths and weaknesses between and within attending physicians. The authors describe the new evaluation process and the results for 41 attending physicians.

Canada↗
PubMed1993

Maize Spm transposable element has an enhancer-insensitive promoter.

We have used a transient assay system to investigate the promoter region of the maize Suppressor-mutator (Spm) transposable element. All of the sequence required for constitutive promoter activity is confined to the 0.2-kb sequence upstream from the transcription start site of the element at nt 209 and designated the upstream control region. The element's promoter is weak, lacks a conventional TATA box, and depends on the presence of multiple, short repetitive sequence elements. The Spm promoter is quite insensitive to the enhancer sequence of the cauliflower mosaic virus 35S promoter. Enhancer sensitivity can be restored by providing a -30 TATA sequence and removing the G + C-rich sequence encoding the untranslated leader of the element, designated the downstream control region. Although the downstream control region is without effect on Spm promoter activity, it completely inhibits the 35S core promoter and markedly inhibits activity of the complete 35S promoter. The properties of the Spm element's promoter buffer it from both mutational and position-dependent changes in activity. We suggest that the inherent characteristics of the promoter are part of the genetic mechanism that controls the element's transposition frequency, ensuring it remains low and insertion-site independent.

Base Sequence↗
PubMed1993

Alternative mechanisms with and without steel factor support primitive human hematopoiesis.

As a first approach to defining the molecular requirements for supporting human hematopoietic stem cell maintenance and differentiation in vitro, we have analyzed and compared the ability of various factors to support the maintenance and initial differentiation of human long-term culture-initiating cells (LTC-ICs), a distinct, rare primitive hematopoietic cell type whose progeny after 5 weeks include cells detectable as colony-forming cells. Normal human marrow cells highly enriched in LTC-ICs (approximately 1% pure) were placed in cultures containing either preestablished, irradiated human marrow adherent feeder layers, or feeders consisting of Steel factor-deficient SI/SI, or normal +/+ murine fibroblasts, or no feeders. In some groups, either Steel factor alone, granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3), or all three factors combined were also added repeatedly. SI/SI murine fibroblasts were equivalent to +/+ controls and to normal human marrow feeders in supporting both LTC-IC maintenance and clonogenic cell output over a 5-week period. Soluble Steel factor alone could, however, effectively substitute for human marrow feeders to support LTC-IC maintenance, although clonogenic cell output was markedly reduced under these conditions. Conversely, soluble Steel factor with G-CSF and IL-3 or with feeders (or all together) did not further enhance (or depress) LTC-IC maintenance, although under these conditions clonogenic cell output was markedly increased. These findings confirm previous evidence that LTC-IC maintenance and clonogenic cell production are differentially regulated and show for the first time that LTC-IC maintenance can be supported by different nonsynergizing factors that may, but need not, include Steel factor.

Animals↗
PubMed1993

Transfer of humoral immunity against cytomegalovirus proteins following transplantation of T-cell-depleted allogeneic bone marrow from seropositive donors.

Previous work by Grob et al. [Lancet i: 774, 1987] has demonstrated that allogeneic, T-cell-depleted bone marrow transplant recipients have a better prognosis for reactivated cytomegalovirus (CMV) infection if their donor is also immune. It was proposed that adoptively transferred humoral immunity was responsible for the protective effect of active infection. Immunoblot analysis using purified virions was used here to examine pre- and posttransplant antibody responses of seropositive recipients who had undergone active viral infection after transplantation. Immunoblots were assessed for the numbers of polypeptides recognised and reactivity against individual polypeptides. Immunoblots were also scanned by quantitative densitometry, and the intensity of antibody responses against total viral protein and individual polypeptides was determined. Sera from recipients with immune donors exhibited a secondary-type immune response in terms of both intensity and polypeptide specific pattern of antibody reactivity, compared with those recipients with nonimmune donors. In particular, recipients with immune donors appeared to show a greater reactivity against a protein of M(r) 55,000; this may represent the envelope glycoprotein gB, which is a major target for neutralising antibodies, and might also be utilised for preparing an effective vaccine for CMV.

Antibodies, Viral↗
PubMed1993

Strain variation in Epstein-Barr virus immediate early genes.

RNase protection analysis of mRNAs for Epstein-Barr virus (EBV) genes activated early in the induction of the productive cycle in Akata cells has confirmed that BZLF1 and BRLF1 behave as immediate early genes. These are likely to be the only virus immediate early genes since analysis of three other transcripts previously suggested to behave as immediate early genes in this system shows that they are, in fact, early genes. Western blotting of BRLF1 and BZLF1 demonstrates expression of these proteins early in induction of the productive cycle and reveals that the BZLF1 protein of Akata virus migrates more slowly on SDS gels than the BZLF1 protein of the prototypic virus strain B95-8. The nucleotide sequence of the BZLF1 gene and the immediate early promoters of Akata EBV have been determined and compared to other EBV strains. RFLP analysis of sequence variation in the BZLF1 gene of EBV strains from many different parts of the world shows a distribution of BZLF1 types which are not simply related to the established A and B EBV types.

Amino Acid Sequence↗
PubMed1993

The effect of increasing doses of beta-agonists on airflow in patients with chronic airflow limitation.

OBJECTIVE: To determine the increase in FEV1 associated with increasing doses of inhaled terbutaline and salbutamol, the reproducibility of the increase in FEV1, and the reproducibility of the associated optimal bronchodilator dose, in patients with chronic airflow limitation (CAL). DESIGN: Double-blind, randomized, controlled trial examining spirometric response to cumulative doses of bronchodilators. PATIENTS AND SETTING: Patients with clinical diagnosis of CAL, FEV1 below 70% predicted, and FEV1 to FVC ratio less than 0.7 after administration of bronchodilator recruited from secondary care respirology practices. MEASURES OF OUTCOME: The estimates of maximum and optimal bronchodilation, as well as the associated drug dosages, were established in each patient on three occasions (twice on terbutaline and once on salbutamol). The 'optimal' drug dose was defined as the lowest dose associated with an FEV1 not exceeded by 50 ml on any other dose. MAIN RESULTS: Thirty-five patients completed the trial. FEV1 improved from 0.93 to a maximum of 1.191 with terbutaline (average of the two administrations) and from 0.951 to 1.141 with inhaled salbutamol (difference in increase in FEV1 between terbutaline and salbutamol P = 0.006). In less than 50% of cases administration of more than four puffs of bronchodilator resulted in FEV1 increase by more than 50 ml. The average dose of salbutamol and terbutaline associated with optimal bronchodilation were 430 micrograms and 1160 micrograms respectively. Patients varied widely in the optimal dose. Estimates of optimal dose were not reproducible (intraclass correlation coefficient < 0.5). CONCLUSION: Substantial incremental increase in FEV1 in response to increasing doses of beta-agonists beyond those commonly used in clinical practice is restricted to a minority of patients. Lack of reproducibility limits the clinical usefulness of establishing the optimal dose of beta-agonist for a given patient.

Administration, Inhalation↗
PubMed1993

Diversity of V3 region sequences of human immunodeficiency viruses type 1 from the central African Republic.

Nucleotide sequences of the central portion of gp120, including the third hypervariable (V3) loop, were obtained from lymphocytes cocultivated with SupT1 cells from 29 AIDS patients in Bangui, Central African Republic. These sequences displayed significantly greater diversity (average distance, 23%) than has been previously observed in isolates from comparably restricted geographical areas. Isolates belonging to four major subtypes of HIV-1 were found; the only subtype not represented was the North American/European subtype B. Unlike the situation in Zaire and Uganda, where subtypes A and D account equally for virtually all isolates of HIV-1, the predominant subtypes in the Central African Republic, accounting for two-thirds of the isolates, were subtypes A (10 isolates) and E (9 isolates). Subtype E represents a group of variants that have previously been found only in Thailand. Only one isolate belonging to subtype D was found. Also recovered were two isolates of subtype C, a subtype associated with southern African and Indian isolates but not previously detected in central Africa. These isolates, although clearly clustering with subtype C, formed a distinct subset, differing from one another by 8.8% and from the Indian and South African subtype C isolates by an average of 22.5%. High interpatient, intrasubtype variation was also seen among the CAR subtype A (average pairwise difference, 19.3%) and subtype E (10.9%) isolates. The diversity of V3 sequences in this set has implications for immunization protocols that rely on the recognition of V3. This study underscores the necessity of basing intervention strategies on knowledge of the particular sequences present in the target population or geographical area.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Vasodilatation of canine cerebral arteries by nicorandil, pinacidil and lemakalim.

1. Nicorandil, pinacidil and lemakalim relaxed precontracted rings of canine cerebral artery. 2. The order of potency was lemakalim greater than nicorandil approximately equal to pinacidil, but all these agents were less effective than nimodipine. 3. The effects of nicorandil were inhibited by methylene blue but not by glibenclamide, while the effects of pinacidil and lemakalim were inhibited by glibenclamide but not by methylene blue. 4. Thus nicorandil probably causes relaxation mostly by effects on guanylate cyclase while lemakalim and pinacidil produce the same effect by action at ATP-dependent potassium channels.

Animals↗
PubMed1992

Risk factors for melanoma: site variation in minimal erythema dose.

Skin types 1 and 2, increased numbers of moles, and excessive intermittent sun exposure are known risk factors for cutaneous melanoma, but the inter-relationship between UV radiation exposure, moles and melanoma remains unclear. There is a noteworthy site variation in melanoma, it being more common on the lower leg in women and on the back in men. In order to determine whether this site variation could provide further clues to the pathogenesis of melanoma, we examined site variation in photosensitivity and its relationship to other known melanoma risk factors (number of moles, skin type and skin colour) in 25 healthy volunteers. A marked site variation in photosensitivity was found. The pale skin of the volar aspect of the forearm was markedly less photosensitive than the darker skin of the back. Females were more photoresistant than males on the lower legs even though this is the more common site for melanoma in women. There was some correlation between the number of moles and photosensitivity at the two sites.

Adult↗
PubMed1992

Relaxant effects on iloprost in canine cerebral artery.

Iloprost caused relaxation of rings of canine cerebral arteries precontracted with prostaglandin F2 alpha or the thromboxane A2 analogue U46619, but it was without effect on arteries precontracted with potassium chloride. Pretreatment with iloprost did not significantly affect the concentration-response curve to any agent. Contractile responses to oxyhemoglobin were completed relaxed by iloprost. In arteries from animals with moderate cerebrovascular spasm, the response to prostaglandin F2 alpha was also reduced by iloprost. The observation that iloprost relaxes the response to oxyhemoglobin to prostaglandin F2 alpha in spastic arteries may be of interest in the management of cerebral vasospasm.

Animals↗
PubMed1992

Respiratory muscle training in chronic airflow limitation: a meta-analysis.

The purpose of this study was to determine the effect of respiratory muscle training on muscle strength and endurance, exercise capacity, and functional status in patients with chronic airflow limitation. Computerized bibliographic data bases (MEDLINE AND SCISEARCH) were searched for published clinical trails, and an independent review of 73 articles by two of the investigators identified 17 relevant randomized trials for inclusion. Study quality was assessed and descriptive information concerning the study populations, interventions, and outcome measurements was extracted. We combined effect sizes across studies (the difference between treatment and control groups divided by the pooled standard deviation of the outcome measure). Across all studies, the effect sizes and associated p-values were as follows: maximal inspiratory pressure 0.12, p = 0.38; maximal voluntary ventilation 0.43, p = 0.02; respiratory muscle endurance 0.21, p = 0.14; laboratory exercise capacity -0.01, p = 0.43; functional exercise capacity 0.20, p = 0.15; functional status 0.06, p = 0.72. Secondary analyses suggested that endurance and function may be improved if resistance training with control of breathing pattern is undertaken. Overall, there is little evidence of clinically important benefit of respiratory muscle training in patients with with chronic airflow limitation. The possibility that benefit may result if resistance training is conducted in a fashion that ensures generation of adequate mouth pressures may be worthy of further study.

Breathing Exercises↗
PubMed1992

Time course of changes in concentration of intracellular free calcium in cultured cerebrovascular smooth muscle cells exposed to oxyhemoglobin.

A culture of smooth muscle cells obtained from monkey middle cerebral arteries was developed to allow quantitative assessment of intracellular calcium and immunofluorescence analysis after various periods of exposure to oxyhemoglobin. Intracellular calcium concentration was examined for up to 7 days after a single exposure to oxyhemoglobin. Intracellular calcium concentrations were measured with the fluorescent dye fura-2 and were significantly elevated for 7 days after exposure to oxyhemoglobin (P less than 0.01). Less than 2 minutes after application of oxyhemoglobin, there was marked elevation of intracellular calcium from the control value of 75 +/- 2 nmol/L to 240 +/- 28 nmol/L (P less than 0.01 by analysis of variance). Intracellular calcium concentration of cells exposed for 24 hours to oxyhemoglobin and then grown in normal oxyhemoglobin-free medium fell close to normal levels on Days 3 and 7. On Day 3, the increase in intracellular calcium that followed repeated daily exposure to oxyhemoglobin was greater than that resulting from a single application of oxyhemoglobin (P less than 0.01 by Student's t test), but by Day 7 the elevation produced by these different approaches was similar. Smooth muscle cells exposed to oxyhemoglobin showed a reduction in immunoreactivity to alpha-actin. These data support the hypothesis that disruption of intracellular calcium regulation and calcium overloading may be important in the process of cell injury, which results in vasoconstriction and sometimes cell death, after exposure to oxyhemoglobin.

Actins↗
PubMed1992

Quality of life instruments in the evaluation of new drugs.

The importance of measuring changes in a patient's quality of life when evaluating the efficacy of new drugs is increasingly recognised. In this paper, we review the steps associated with this process--recognising the opportunity and the need to include quality of life instruments during the investigation, choosing the most suitable instrument(s) and interpreting the results. To be useful in clinical trials, quality of life measures must be both responsive (able to detect all important differences) and valid. Generic instruments are applicable to a wide variety of populations but may lack responsiveness. Disease-specific instruments are more likely to be responsive and are directly relevant to patients and clinicians. The approach to measurement in a specific clinical trial should be dictated by the goals of the investigators.

Data Interpretation, Statistical↗
PubMed1992

Effects of phenothiazine on contractions induced by prostaglandin F2 alpha and 5-hydroxytryptamine in normal and spastic canine cerebral artery.

We have investigated the effect of phenothiazine, a compound known to inhibit calmodulin, on the responses of normal and spastic cerebral arteries, using the canine "two hemorrhage" model of cerebrovascular spasm. Ring preparations from control vessels or vessels removed three or seven days after injection of blood, were contracted with either 5-hydroxytryptamine (5-HT) or prostaglandin F2 alpha (PGF2 alpha) and then exposed to increasing concentrations of phenothiazine. In normal arteries, low concentrations of phenothiazine enhanced the response to PGF2 alpha, while higher concentrations caused relaxation. Responses to 5-HT were inhibited by all concentrations of phenothiazine tested. When normal arteries were compared with arteries from animals injected with blood, in the case of 5-HT, phenothiazine was a less effective antagonist at low doses, but equieffective at higher doses. Similar experiments conducted with PGF2 alpha showed that phenothiazine was a more effective antagonist in spastic vessels. We conclude that 5-HT and PGF2 alpha have significant differences in the mechanism by which they produce contraction of cerebral vessels, that phenothiazine has secondary effects on contraction independent of inhibition of calmodulin, and, finally that the effects of phenothiazine in clinical vasospasm may be insufficient to reverse the condition, despite the observation that vessels in spasm may be more sensitive to this agent.

Animals↗