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Biomedical subjects

D R Taylor

Publications and source records attributed to D R Taylor.

At least 55 records · Page 3Linked to original sources
PubMed1999

Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma.

BACKGROUND: Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken. METHODS: Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment. RESULTS: Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness. CONCLUSIONS: In this group of mild to moderate asthmatic subjects the combination of beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid.

Administration, Inhalation↗
PubMed1999

Effects of inhaled beta agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma.

BACKGROUND: Inhaled corticosteroids and beta agonists are the most commonly used treatments in asthma and are often used together. Recent evidence suggests that many of the anti-inflammatory actions of corticosteroids are mediated by cross-talk between the activated glucocorticoid receptor (GR) and other transcription factors such as the pro-inflammatory nuclear factor kappa B (NFkappaB). Beta agonists can activate the transcription factor cAMP response element binding protein (CREB). A mutual inhibition between GR and CREB occurs in vitro which raises the possibility of a negative interaction between corticosteroid and beta agonist drugs. A study was undertaken to determine whether these interactions occur during treatment with beta2 agonists and corticosteroids in asthma. METHODS: Seven subjects who were participating in a randomised, placebo controlled, crossover study of six weeks treatment with inhaled budesonide (400 microg twice daily), terbutaline (1 mg four times daily), and combined treatment were recruited. Biopsy samples of the bronchial mucosa were obtained after each treatment and analysed for the DNA binding activity of GR, CREB, and NFkappaB. RESULTS: Budesonide increased GR activity (p<0.05) and decreased NFkappaB activity (p<0.05). No treatment combination altered CREB activity and terbutaline had no significant effects on any transcription factor. CONCLUSIONS: Inhaled corticosteroids have significant effects on GR and NFkappaB activity in bronchial mucosa. A negative interaction between inhaled corticosteroids and beta agonists was not found.

Administration, Inhalation↗
PubMed1998

T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching.

The respective production of specific immunoglobulin (Ig)G2a or IgG1 within 5 d of primary immunization with Swiss type mouse mammary tumor virus [MMTV(SW)] or haptenated protein provides a model for the development of T helper 1 (Th1) and Th2 responses. The antibody-producing cells arise from cognate T cell B cell interaction, revealed by the respective induction of Cgamma2a and Cgamma1 switch transcript production, on the third day after immunization. T cell proliferation and upregulation of mRNA for interferon gamma in response to MMTV(SW) and interleukin 4 in response to haptenated protein also starts during this day. It follows that there is minimal delay in these responses between T cell priming and the onset of cognate interaction between T and B cells leading to class switching and exponential growth. The Th1 or Th2 profile is at least partially established at the time of the first cognate T cell interaction with B cells in the T zone. The addition of killed Bordetella pertussis to the hapten-protein induces nonhapten-specific IgG2a and IgG1 plasma cells, whereas the anti-hapten response continues to be IgG1 dominated. This indicates that a Th2 response to hapten-protein can proceed in a node where there is substantial Th1 activity.

Animals↗
PubMed1998

Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2alpha kinases PKR and GCN2.

The human double-stranded RNA-dependent protein kinase (PKR) is an important component of the interferon response to virus infection. The activation of PKR is accompanied by autophosphorylation at multiple sites, including one in the N-terminal regulatory region (Thr-258) that is required for full kinase activity. Several protein kinases are activated by phosphorylation in the region between kinase subdomains VII and VIII, referred to as the activation loop. We show that Thr-446 and Thr-451 in the PKR activation loop are required in vivo and in vitro for high-level kinase activity. Mutation of either residue to Ala impaired translational control by PKR in yeast cells and COS1 cells and led to tumor formation in mice. These mutations also impaired autophosphorylation and eukaryotic initiation factor 2 subunit alpha (eIF2alpha) phosphorylation by PKR in vitro. Whereas the Ala-446 substitution substantially reduced PKR function, the mutant kinase containing Ala-451 was completely inactive. PKR specifically phosphorylated Thr-446 and Thr-451 in synthetic peptides in vitro, and mass spectrometry analysis of PKR phosphopeptides confirmed that Thr-446 is an autophosphorylation site in vivo. Substitution of Glu-490 in subdomain X of PKR partially restored kinase activity when combined with the Ala-451 mutation. This finding suggests that the interaction between subdomain X and the activation loop, described previously for MAP kinase, is a regulatory feature conserved in PKR. We found that the yeast eIF2alpha kinase GCN2 autophosphorylates at Thr-882 and Thr-887, located in the activation loop at exactly the same positions as Thr-446 and Thr-451 in PKR. Thr-887 was more critically required than was Thr-882 for GCN2 kinase activity, paralleling the relative importance of Thr-446 and Thr-451 in PKR. These results indicate striking similarities between GCN2 and PKR in the importance of autophosphorylation and the conserved Thr residues in the activation loop.

3T3 Cells↗
PubMed1998

Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol.

BACKGROUND: The adverse effects of long term treatment of asthma with the short acting beta agonist fenoterol have been established in both epidemiological and clinical studies. A study was undertaken to investigate the efficacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma. METHODS: In a two centre double dummy crossover study 165 patients were randomly assigned to receive salbutamol 400 micrograms q.i.d., salmeterol 50 micrograms b.i.d., or placebo via a Diskhaler. All patients used salbutamol as required for symptom relief. The study comprised a four week run in and three treatment periods of 24 weeks, each of which was followed by a four week washout. Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate (PEFR), a composite daily asthma score, and minor and major exacerbation rates. Washout assessments included methacholine challenge and bronchodilator dose response tests. Analysis was by intention to treat. RESULTS: Data from 157 patients were analysed. Relative to placebo, the mean morning PEFR increased by 30 l/min (95% CI 26 to 35) for salmeterol but did not change for salbutamol. Evening PEFR increased by 25 l/min (95% CI 21 to 30) and 21 l/min (95% CI 17 to 26), respectively (p < 0.001). Salmeterol improved the asthma score compared to placebo (p < 0.001), but there was no overall difference with salbutamol. Only daytime symptoms were improved with salbutamol. The minor exacerbation rates were 0.29, 0.88, and 0.97 exacerbations/patient/year for salmeterol, salbutamol and placebo, respectively (p < 0.0001 for salmeterol). The corresponding major exacerbation rates were 0.22, 0.51 and 0.40, respectively (p < 0.03 for salmeterol). For salbutamol the asthma score deteriorated over time (p < 0.01), and the time spent in major exacerbation was significantly longer compared with placebo (12.3 days (95% CI 4.2 to 20.4) versus 8.4 days (95% CI 5.2 to 11.6), p = 0.02). There was no evidence of rebound deterioration in asthma control, lung function, or bronchial hyper-responsiveness following cessation of either active treatment, and no evidence of tolerance to salbutamol or salmeterol. CONCLUSIONS: Regular treatment with salmeterol is effective in controlling asthma symptoms and reduces minor more than major exacerbation rates. Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time. Salbutamol should therefore be used only as required.

Administration, Inhalation↗
PubMed1998

Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma.

Polymorphisms affecting amino acids 16 and 27 of the beta2-adrenoceptor alter receptor regulation in vitro. Whether these polymorphisms alter the response to beta2-agonist therapy in asthma is unknown. In a previous study of 64 asthmatics, most experienced a deterioration in asthma control during regular inhaled beta2-agonist (fenoterol) treatment, while a minority improved. We have determined the beta2-adrenoceptor genotypes in these subjects, to establish whether changes in asthma control during the earlier study were influenced by beta2-adrenoceptor polymorphism. The genotypes coding for amino acids 16 and 27 were identified in 60 subjects using allele-specific polymerase chain reaction. The effects of regular beta2-agonist treatment on asthma control were compared between genotypes. There was no association between genotype and change in overall asthma control during regular beta2-agonist treatment. Only two of 10 markers of asthma control showed changes that were significantly associated with genotype: subjects homozygous for glycine at position 16 had no increase in bronchial responsiveness to methacholine during regular treatment; subjects homozygous for glutamic acid at position 27 had no increase in evening peak expiratory flow rates during regular treatment. These differences are the opposite of those that would have been predicted by the results of in vitro studies. In these subjects, the deleterious response to regular inhaled beta2-agonist treatment was not related to beta2-receptor polymorphism.

Administration, Inhalation↗
PubMed1997

The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction.

AIMS: The aims of this investigation were to evaluate the efficacy of regular inhaled beclomethasone in the control of symptoms and lung function with non-asthmatic smoking related obstructive pulmonary disease and to evaluate the relationship between clinical responses to a short course of oral prednisone and longer term outcomes using inhaled steroid. METHODS: The study was a randomised, double blind, placebo controlled, crossover investigation in 18 patients. The active treatment was inhaled beclomethasone 1000 micrograms given twice daily for three months by metered dose inhaler. At the end of each treatment period, patients received oral prednisone 30 mg/day for ten days. The two treatment phases were separated by a one month washout interval. Peak flow rates, symptom scores and "rescue" bronchodilator use were recorded twice daily. Lung function (FEV1, FVC and lung volumes) and bronchial hyperresponsiveness (PC20 methacholine) were measured at monthly visits. The number of exacerbations requiring intervention therapy were also recorded. RESULTS: There were no consistent benefits attributable to beclomethasone. Lung function was not significantly better as a result of active treatment. Sputum production improved but other symptom scores were similar during active and placebo therapy. Three patients exhibited an increase in FEV1 of 15% or more during active treatment but did not do so when oral prednisone was administered immediately after the period of placebo treatment. A further three patients showed an improvement in FEV1 of 15% or more with oral prednisone but failed to improve during treatment with inhaled beclomethasone. The predictive value of the "trial of steroid" was 0% and 81.3% for positive and negative outcomes respectively. CONCLUSIONS: Our results indicate that in non-asthmatic chronic obstructive pulmonary disease inhaled corticosteroid fails to achieve significant improvements in either lung function or symptoms. The response to a "trial of steroid" using oral prednisone is not clinically helpful in selecting the small number of patients who may subsequently benefit from this form of therapy.

Administration, Inhalation↗
PubMed1997

Activation of human neutrophils by calcium carbonate polymorphs.

Gallstone formation is frequently accompanied by inflammation of the gallbladder mucosa. Some gallstone components such as cholesterol, calcium bilirubinate, and calcium hydroxyapatite have been previously shown to activate neutrophils. We investigated the effect on neutrophils of the calcium carbonate polymorphs aragonite, calcite, and vaterite (all found in gallstones). By chemiluminescence, superoxide, and degranulation assay, all three crystals were shown to cause rapid activation of neutrophils. The potency of the crystals was aragonite > vaterite > calcite. In vivo, crystals may be plasma-protein-coated before they encounter neutrophils; therefore some experiments were repeated using crystals that had been preincubated with plasma. For aragonite and vaterite, protein adsorption decreased the chemiluminescence response by approximately 50%. In contrast, protein-coated calcite crystals elicited a greater chemiluminescence response than did uncoated crystals. In summary, the calcium carbonate polymorphs are potent activators of neutrophils and thus have the potential to contribute to gallstone-associated cholecystitis.

Calcium Carbonate↗
PubMed1997

The effect of regular salbutamol on lung function and bronchial hyperresponsiveness in normal subjects and nonasthmatic atopic subjects with allergic rhinitis.

BACKGROUND: The effects of regular inhaled beta-agonist treatment on lung function remain a controversial issue. In an earlier study, the administration of regular inhaled salbutamol resulted in negative changes in FEV1 not only in asthmatics, but also in nonasthmatic atopic subjects. OBJECTIVE: The aim of this study was to confirm these findings and also to examine whether regular inhaled salbutamol would increase bronchial hyperresponsiveness in atopic or normal individuals. DESIGN: The study was a randomized, double-blind, placebo-controlled, crossover investigation. PARTICIPANTS: There were two groups: 10 normal healthy subjects (group A) and nine nonasthmatic atopic subjects (group B). INTERVENTIONS: Subjects received inhaled salbutamol or identical placebo for periods of 6 weeks, the dose being increased in stepwise fashion at 2-week intervals. MEASUREMENTS: Changes in lung function were assessed by measuring spirometric values, airways conductance, and changes in complete and partial expiratory flow volume curves. Changes in these parameters following a methacholine challenge were used to assess bronchial hyperresponsiveness. RESULTS: No statistically significant differences in lung function or bronchial hyperresponsiveness were noted to occur as the result of treatment in either group. CONCLUSION: Our results do not support the view that regular inhaled salbutamol in normal or atopic subjects without asthma causes adverse changes in the airways.

Administration, Inhalation↗
PubMed1997

A new index of prognostic severity for chronic asthma.

OBJECTIVE: To develop a prognostic clinical index for adults with chronic stable asthma. DESIGN: Analysis of data from a 48-week randomized, crossover trial of regular vs as-needed inhaled beta-agonist therapy. PATIENTS: Eligible patients included 70 men and women between the ages of 15 and 64 years with asthma for > 1 year. OUTCOME MEASURE: Asthma deterioration within 20 weeks, defined as either a marked decline in FEV1 (> or = 1.0 L or > or = 30% from baseline) or initiation of systemic corticosteroid therapy for asthma exacerbation. RESULTS: Three baseline factors independently predicted asthma deterioration: frequent symptoms on waking in the 4 weeks before baseline, past hospitalization for asthma, and age 35 years or older. Based on cross-stratification and consolidation of these prognostic factors, an index was developed that stratified subjects into four risk groups with distinctive deterioration rates of 9%, 21%, 39%, and 67% (p<0.001). CONCLUSION: For adults with chronic stable asthma, three simple clinical factors can be combined to stratify effectively for risk of subsequent asthma deterioration.

Administration, Inhalation↗
PubMed1997

Low seroprevalence of Helicobacter pylori antibodies in historical sera of patients with Crohn's disease.

BACKGROUND: Our aim was to determine the seroprevalence of Helicobacter pylori antibodies in historical sera from a large group of patients with Crohn's disease and to compare the findings with those of a control group of healthy blood transfusion donors. METHODS: The historical sera from 386 patients with Crohn's disease were studied (serum age, 9.9 years; range, 0.4-21.6 years). Serum IgG and IgA H. pylori antibodies were measured with enzyme-linked immunosorbent assay. Western blots (detecting IgG only) were also used to study a subpopulation of the patients' sera and to assess the presence of cagA bands, indicating a cytotoxic variety of H. pylori. The serology of the Crohn's disease patients was compared with that of 277 age-matched controls. A longitudinal follow-up study of 14 IgG and IgA anti-H. pylori-positive and 14 IgG- and IgA-negative Crohn's disease patients was also performed (mean follow-up, 7.6 years; range, 1.7-20.5 years). RESULTS: Of the total Crohn's disease patients, 47 (12.2%) had IgG antibodies against H. pylori, 67 (17.4%) had IgA antibodies, and 31 (8.0%) had both IgG and IgA antibodies. The corresponding antibody positivities for the controls were 98 (35.4%) for IgG, 77 (27.8%) for IgA, and 64 (23.1%) for both IgG and IgA. When compared, with the control group, the seroprevalence of H. pylori in the Crohn's disease patients was significantly lower (P < or = 0.002). In addition the relative IgG response of the patients was lower than the IgA response. The opposite was true for the controls. There was no difference in the absolute levels of H. pylori antibodies between patients and controls. In the follow-up study two patients initially IgG-positive for H. pylori became negative over time; these patients had been treated for their infection. the rest, who continued to be positive, were not treated. One patient who was initially IgA-positive also became IgA-negative over time. The follow-up group, who were initially IgG- and IgA-negative, remained IgG-negative with time, and two patients became IgA-positive. Findings of anti-H. pylori IgG were confirmed with Western blots. Furthermore, these showed that of the H. pylori-positive patients (indicated by their IgG positivity), 66% were infected with a cytotoxic (cagA-positive) variety, compared to 69.4% of the controls. CONCLUSIONS: Patients with Crohn's disease have a lower prevalence of H. pylori antibodies than an age-matched control group. There is a reversal of the relative IgG and IgA responses in Crohn's disease patients compared with the controls. Of the Crohn's disease patients with H. pylori most are infected with cytotoxic varieties, similar to controls.

Adult↗
PubMed1996

Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation.

Immunoglobulin (Ig) class switch recombination is associated with the production and splicing of germline IgCH messenger RNA transcripts. Levels of gamma 1 transcripts in mouse spleen sections were assessed by semiquantitative analysis of reverse transcriptase polymerase chain reaction (PCR) products during primary and secondary antibody responses to chicken gamma globulin (CGG). This was correlated with the appearance of CGG-specific B cells and their growth and differentiation to plasma cells. After primary immunization with CGG, gamma 1 switch transcripts appeared after 4 d, peaked at a median of six times starting levels between 10 and 18 d after immunization, and returned to background levels before secondary immunization at 5 wk. By contrast, after secondary challenge with CGG, a sevenfold increase in transcripts occurs during the first d. The level again doubles by day 3, when it is six times that which is seen at the peak of the primary response. After day 4, there was a gradual decline over the next 2-3 wk. Within 12 h of secondary immunization, antigen-specific memory B cells appeared in the outer I zone and by 24 h entered S phase, presumably as a result of cognate interaction with primed T cells. Over the next few hours, they migrated to the edge of the red pulp, where they grew exponentially until the fourth day, when they synchronously differentiated to become plasma cells. The same pattern was seen for the migration, growth, and differentiation of virgin hapten-specific B cells when CGG-primed mice were challenged with hapten protein. The continued production of transcripts after day 3 indicates that switching also occurs in germinal centers, but in a relatively small proportion of their B cells. The impressive early production of switch transcripts during T cell-dependent antibody responses occurs in cells that are about to undergo massive clonal expansion. It is argued that Ig class switching at this time, which is associated with cognate T cell-B cell interaction in the T zone, has a major impact on the class and subclasses of Ig produced during the response.

Animals↗
PubMed1996

The beta-agonist controversy.

After many years of increasing morbidity and mortality, several avenues of scientific investigation now appear to be converging to offer an explanation for the asthma paradox and indicate that regular or long-term use of short-acting inhaled beta-agonist drugs is inappropriate. Pharmacoepidemiologic studies indicate a strong association between increased beta-agonist use and asthma deaths, which does not appear entirely related to confounding by severity. Clinical data, although still limited, show little evidence for symptomatic or functional improvement during long-term beta-agonist therapy and, in many instances, reveal significant adverse effects. Related investigations offer evidence of potential plausible mechanisms, notably increased bronchial responsiveness to inhaled allergen, to explain these findings. A radical revision of the therapeutic use of these drugs in asthma has been prompted by these findings. Beta-agonist drugs remain essential for the management of acute severe attacks. They are also useful on demand for the relief of breakthrough symptoms and for prophylaxis of exercise-induced symptoms. In chronic asthma, however, adequate anti-inflammatory therapy is the treatment of choice. Long-term treatment with short-acting beta-agonist, even in the presence of seemingly adequate anti-inflammatory therapy, may be associated with deterioration of asthma over the long-term. The effects of long-acting beta-agonists remain under review. To date, there are no data that clearly indicate a deleterious effect, and many clinical trials show benefits in symptom control and improved lung function associated with their regular use. The significance of tachyphylaxis remains to be defined. Their current role is still somewhat unclear, but they have been successfully used in subjects in whom, despite the use of moderate doses of inhaled corticosteroid, short-acting bronchodilator is still frequently required. The use of twice-daily long-acting beta-agonist appears preferable to frequent use of short-acting beta-agonists.

Adrenergic beta-Agonists↗
PubMed1996

Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR.

The interferon-induced RNA-dependent protein kinase PKR is found in cells in a latent state. In response to the binding of double-stranded RNA, the enzyme becomes activated and autophosphorylated on several serine and threonine residues. Consequently, it has been postulated that autophosphorylation is a prerequisite for activation of the kinase. We report the identification of PKR sites that are autophosphorylated in vitro concomitantly with activation and examine their roles in the activation of PKR. Mutation of one site, threonine 258, results in a kinase that is less efficient in autophosphorylation and in phosphorylating its substrate, the initiation factor eIF2, in vitro. The mutant kinase is also impaired in vivo, displaying reduced ability to inhibit protein synthesis in yeast and mammalian cells and to induce a slow-growth phenotype in Saccharomyces cerevisiae. Mutations at two neighboring sites, serine 242 and threonine 255, exacerbated the effect. Taken together with earlier results (S. B. Lee, S. R. Green, M. B. Mathews, and M. Esteban, Proc. Natl. Acad. Sci. USA 91:10551-10555, 1994), these data suggest that the central part of the PKR molecule, lying between its RNA-binding and catalytic domains, regulates kinase activity via autophosphorylation.

Amino Acid Sequence↗
PubMed1996

Comprehensive management of non-insulin-dependent diabetes mellitus. A diabetes clinic revisited.

OBJECTIVE: To 'revisit' the Johannesburg Hospital diabetes clinic to ascertain whether the established risk factors for CAD were being identified and appropriately managed. DESIGN: Body mass indices (BMI), fasting lipograms and glycated haemoglobin (HBA) estimations were done on a random sample of white NIDDM patients aged over 35 years. RESULTS: Eighty-two patients (39 males, 43 females) were tested. The mean age was 60 years (range 36-80 years) and the mean duration of NIDDM 6.2 years (range 1-25 years). The mean HBA value was 10% (normal 4-8%). Obesity was present in 82%; it was moderate (BMI 25-30 kg/m2) in 46% and severe (BMI > 30 kg/m2) in 36%. Hypercholesterolaemia was present in 46%, hypertriglyceridaemia in 68%, and both in 34%. Uncontrolled hypertension was present in 20% of patients, and 27% smoked. CONCLUSIONS: Management of patients at our clinic remains confined to the control of hyperglycaemia. Despite increased awareness of the risk factors for CAD, these factors have largely been ignored.

Adult↗