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Biomedical subjects

P Ernst

Publications and source records attributed to P Ernst.

At least 127 records · Page 7Linked to original sources
PubMed1994

The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene.

The lymphocyte-specific DNA-binding protein LyF-1 interacts with a critical control element in the terminal deoxynucleotidyltransferase (TdT) promoter as well as with the promoters for other genes expressed during early stages of B- and T-cell development. We have purified LyF-1 and have obtained a partial amino acid sequence from proteolytic peptides. The amino acid sequence suggests that LyF-1 is a zinc finger protein encoded by the Ikaros gene, which previously was implicated in T-cell development. Recombinant Ikaros expressed in Escherichia coli bound to the TdT promoter, and antisera directed against the recombinant protein specifically blocked the DNA-binding activity of LyF-1 in crude extracts. Further analysis revealed that at least six distinct mRNAs are derived from the Ikaros/LyF-1 gene by alternative splicing. Only two of the isoforms possess the N-terminal zinc finger domain that is necessary and sufficient for TdT promoter binding. Although both of these isoforms bound to similar sequences in the TdT, lambda 5, VpreB, and lck promoters, one isoform contains an additional zinc finger that resulted in altered recognition of some binding sites. At least four of the Ikaros/LyF-1 isoforms were detectable in extracts from B- and T-cell lines, with the relative amounts of the isoforms varying considerably. These data reveal that the LyF-1 protein is encoded by specific mRNAs derived from the alternatively-spliced Ikaros gene, suggesting that this gene may be important for the early stages of both B- and T-lymphocyte development.

Alternative Splicing↗
PubMed1994

A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists.

The association between the use of inhaled beta-agonists and the risk of death and near-death from asthma has previously been reported. It was based on a nested case-control study of 129 cases and 655 control subjects selected from a cohort of 12,301 users of asthma drugs followed during the period 1980 through 1987. In this paper we examine the question of asthma and non-asthma mortality using data from the entire cohort of 12,301 asthmatics. There were 46 asthma and 134 non-asthma deaths in this cohort, for which there were 47,842 person-years of follow-up. The overall rate of asthma death was 9.6 per 10,000 asthmatics per year. This rate varied significantly according to the use of fenoterol, albuterol, or oral corticosteroids in the prior 12 months and the number of asthma hospitalizations in the prior 2 years. The rate decreased significantly, by 0.6 asthma deaths per 10,000 asthmatics per year over the study period, after controlling for the effect of the four other risk factors. It also increased significantly with the use of all beta-agonists, and more so for fenoterol than for albuterol, although this difference was partly explained by the dose inequivalence of the two drugs. Change-point dose-response curves showed that the risk of asthma death began to escalate drastically at about 1.4 canisters (of 20,000 micrograms each) per month of inhaled beta-agonist, the recommended limit. For non-asthma death, the overall rate of 28 deaths per 10,000 asthmatics per year was not related to the use of inhaled beta-agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Elimination of antipyrine and its metabolites in interferon treated hepatitis C.

1. To study the effect of interferon on hepatic drug metabolism in chronic hepatitis C, we examined nine patients before and at the end of 6 months of interferon treatment. 2. Routine liver function was determined together with the salivary clearance of antipyrine and the 48 h urinary excretion of the main metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine before and after 6 months of interferon treatment. 3. Liver pathology, routine liver function, and antipyrine metabolism remained unchanged after patients were treated for 6 months with interferon for a histologically advanced but clinically compensated chronic hepatitis C.

Administration, Oral↗
PubMed1994

Elimination studies of antipyrine and its metabolites in healthy Saudi Arabians.

1. We measured the antipyrine clearance in 18 healthy Saudi subjects and determined the urinary excretion of three of its metabolites: 4-hydroxyantipyrine (4-OH AP), norantipyrine (NOR AP) and 3 hydroxymethylantipyrine (3-OHM AP) in 21 subjects. 2. The mean +/- SD of the antipyrine clearance was 2.4 +/- 1.1 h-1 (range 1.0-5.5 l h-1) and the corresponding value per kg body weight was 0.6 +/- 0.2 ml min-1 kg-1. Urinary excretion of antipyrine (AP), 4-OH AP, NOR AP and 3-OHM AP expressed as a percentage of the oral dose of antipyrine given was 2.8 +/- 2.2, 14.5 +/- 6.9, 12.3 +/- 5.6 and 7.6 +/- 3.2 respectively. 3. Compared to Africans, Saudis preferentially metabolize AP to NOR AP and compared to Caucasians to 3-OHM AP, rather than to 4-OH AP. These discrepancies may reflect age differences between the study populations rather than genetic or ethnic variations.

Administration, Oral↗
PubMed1994

Patterns of increasing beta-agonist use and the risk of fatal or near-fatal asthma.

The association between the use of inhaled beta-agonists by metered-dose inhaler and the risk of fatal or near-fatal asthma has been demonstrated. It shows that asthmatics who use one canister of beta-agonist per month more than the number used by other similar asthmatics have twice the risk of fatal or near-fatal asthma. The present investigation assesses the magnitude of this excess risk when an asthmatic increases his/her own monthly use of inhaled beta-agonists over time. From a previous nested case-control study of 129 deaths and near-deaths from asthma (cases) and 655 controls from a cohort of 12,301 asthmatics, the subset using at least 12 inhalers during the 12 month study period was identified (97 cases and 258 controls). A profile score, ranging 0-11, was formed to quantify the patterns of beta-agonist use over time for each subject, covering the entire spectrum extending from decreasing to increasing use. The relative risk was 15.2 (95% confidence interval (CI) 2.4-96.2) per unit increase of the profile score in subjects with a pattern of increasing beta-agonist use (profile score of 6.5 or more), but this relative risk was only 1.5 (95% CI 0.8-2.6) per unit when the profile score was less than 6.5 (non-increasing use). This relative risk was independent of the risk associated with the total quantity of beta-agonist use in the 12 month period, which remained around 1.6 (95% CI 1.3-2.0) per inhaler per month.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Inhibition of neutrophil functions by human immunoglobulin E.

Incubation of human neutrophils with human immunoglobulin (Ig) E caused dose-dependent inhibition of adhesion, phagocytosis, secretion of myeloperoxidase, and oxygen radical production. The concentrations of IgE that caused 50% inhibition of adhesion, phagocytosis, and secretion were 2 +/- 0.3, 2.16 +/- 0.21, and 1.95 +/- 0.28 ng/ml, respectively. Oxidase activation as measured by luminol-dependent chemiluminescence by the receptor-mediated N-formyl-methionyl-leucyl-phenylalanine, phorbol 12-myristate 13-acetate, or the particulate stimulus Staphylococcus aureus was inhibited by IgE with concentrations causing 50% effect of 1.2 +/- 0.13, 1.09 +/- 0.16, and 0.6 +/- 0.09 ng/ml, respectively. IgE also inhibited oxygen consumption rate and cytochrome c reduction with similar K0.5 values. The effect of IgE was unlikely to be due to nonspecific cytotoxicity because trypan blue exclusion test and the cytoplasmic marker lactate dehydrogenase revealed that the cells retained their viability after IgE treatment. Similar or higher concentrations of IgG invoked either no inhibition or a slight enhancement of neutrophil functions. Pretreatment of neutrophils with IgG failed to affect the IgE-induced inhibition. Because the effect of IgE occurs at concentrations less than those reported in hyperimmunoglobulinemia E, we propose that direct inhibition of neutrophil functions may underlie the pathogenesis of recurrent infection associated with hyperimmunoglobulinemia E.

Adjuvants, Immunologic↗
PubMed1993

Helicobacter pylori infection in adolescents with eating disorders and dyspeptic symptoms.

The potential role of Helicobacter pylori infection of the antrum as a cause of symptoms of dyspepsia in patients with eating disorders was evaluated with an assay to detect H. pylori-specific IgG in serum. H. pylori-specific optical-density readings were comparable for adolescents with eating disorders (0.133 +/- 0.063, mean +/- SD) and for two comparison groups, and were lower than readings for children with documented H. pylori infection. Symptoms referable to the gastrointestinal tract did not correlate with H. pylori status in the teenagers with eating disorders.

Adolescent↗
PubMed1993

Both LyF-1 and an Ets protein interact with a critical promoter element in the murine terminal transferase gene.

Terminal deoxynucleotidyltransferase (TdT) is a template-independent DNA polymerase that is expressed transiently during the earliest stages of B- and T-cell ontogeny. Previously, we characterized the promoter for the murine TdT gene and identified a novel DNA-binding protein, called LyF-1, that interacts with a DNA sequence element found to be critical for transcriptional activity in lymphoid cell lines. Here, we present a more detailed analysis of this 30-bp control element, called the TdT D' element, which is centered approximately 60 bp upstream of the transcription start site. We found that both the murine and human D' elements are recognized by multiple proteins, including LyF-1 and at least two Ets family proteins, Ets-1 and Fli-1. Additional protein-DNA interactions were identified through studies using unfractionated nuclear extracts, in which the D' element was apparently incorporated into a multiprotein complex, possibly containing an Ets protein as a core component. By analyzing a series of substitution mutations, two adjacent binding sites for LyF-1 were identified in the murine D' element, with the Ets protein binding site closely coinciding with the proximal, lower-affinity LyF-1 site. Transient transfection analysis with these mutations revealed that only a 10-bp region, containing precisely the Ets and proximal LyF-1 binding sites, was needed for D' activity. These results suggest an important role for an Ets family protein in the expression of the TdT gene. The role of LyF-1 is less clear; it might act in conjunction with the Ets protein bound at the D' element or it might be unnecessary for D' activity.

Animals↗
PubMed1993

Respiratory symptoms in young adults should not be overlooked.

The purpose of this study was to examine the relation between development of respiratory symptoms and the rate of change in ventilatory lung function in young adults during a study period of 8 yr. The study population consisted of 391 subjects who were 15 to 40 yr of age at initial examination, when they underwent spirometry and an interviewer-administered ATS-DLD-78-A questionnaire on respiratory health, and who were reexamined 8 yr later. The association between the development of symptoms and the rate of change in FEV1 over time (delta FEV1, ml/yr) was studied in a linear regression model that included the potential confounders and other determinants of the outcome. The presence of modification by such factors as smoking, childhood exposure to environmental tobacco smoke, gender, or atopy was assessed by the significance of interaction terms between potential modifiers and incident symptoms. Subjects who developed wheezing and dyspnea and in whom a doctor diagnosed asthma had a significantly greater average annual change in FEV1 compared with those without respiratory symptoms or asthma (-12.3 ml/yr, SE 5.0; -16.2 ml/yr, SE 5.5; and -42.6 ml/yr, SE 11.5, respectively). When focusing on subjects without a diagnosis of asthma, the associations with appearance of wheezing and dyspnea remained significant. The associations were in general stronger in never smokers compared with smokers and were strongest in ex-smokers. The presence of atopy was a significant modifier, so that in subjects with atopy there was a stronger negative association between the onset of cough and asthma and delta FEV1 than in those without.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity?

We have previously reported an increasing dose-response relationship between the regular use of beta-agonist inhalers and the risk of asthma death and near death among a cohort of 12,301 subjects who had been dispensed 10 or more prescriptions of asthma drugs from January 1980 to April 1987. That analysis was based solely on information obtained from linkable computerized data bases. Such an association might be explained in part by the tendency of patients with more severe asthma, that is, those at greatest risk for an adverse outcome, to use more beta-agonist medication. To further examine this potential confounding by severity, we gathered clinical information independently from the field on the 129 case patients and their 655 control patients from the matched case-control analysis of 12,301 subjects. In 68% of the control patients with a life-threatening episode and 75% of the matched control subjects, we obtained a valid questionnaire from at least one physician who had seen the patient during the previous 2 yr. Acceptable information on hospitalizations because of asthma was obtained in 87% of those hospitalized. Clinical features associated with an increased risk of fatal and near-fatal asthma were: a history of loss of consciousness or seizures during a previous asthma attack (odds ratio, 10.2; 95% CI, 3.9 to 26.7), a history of attacks of asthma precipitated by eating certain foods (odds ratio, 5.1; 95% CI, 2.4 to 11.1), a clinical score designed to reflect the severity of prior attacks of asthma leading to hospitalization, and prior respiratory acidosis among those in whom a blood gas determination was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Splenic irradiation before bone marrow transplantation for chronic myeloid leukemia: update of a prospective randomized study.

Two hundred and twenty-nine patients with chronic myeloid leukaemia in chronic phase awaiting bone marrow transplantation from an HLA-identical sibling donor were randomized as part of their conditioning, to receive splenic irradiation (SI+, 115 patients), or not (SI-, 114 patients). Both groups were identical in regard to age, sex, donor/recipient sex combination and disease activity. Survival, leukaemia-free survival, incidence of transplant-related mortality, acute and chronic graft versus host disease, incidence of rejection and probability of relapse were not different in either groups at a median follow-up time of 4.5 years (minimum follow-up 2 years). Recovery of peripheral white blood cell counts to 1 x 10(9)/l but not of platelet counts to 50 x 10(9)/l was significantly faster in patients with SI+ (21 vs 24 days). This small benefit does not justify routine splenic irradiation prior to BMT, in CML.

Adolescent↗
PubMed1993

Questionnaire assessments of recent exposure to environmental tobacco smoke in relation to salivary cotinine.

The increasing evidence of the ill-health effects of environmental tobacco smoke (ETS) has prompted the search for accurate measures of exposure to ETS. The present study examined whether it was possible to enhance the ability of questionnaire-derived assessments of ETS exposure, to predict salivary cotinine. Salivary samples were obtained from 258 nonsmoking bank employees, who simultaneously answered questions detailing their exposure to second-hand smoke within the last three days. Exposure models were created, to take into account the number of smokers nearby, length of time in their presence, half-life of cotinine in bodily fluids, level of aversion to cigarette smoke and time of year. All models, including the consideration of intensity and duration of exposure combined, explained an equal amount of variance of log cotinine levels (approximately 16%). The weak relationship between questionnaire estimates of ETS exposure and cotinine, found in the present study, suggests that further investigation is needed to improve the assessment of recent ETS exposure.

Adult↗
PubMed1993

Tracheal size is a determinant of the bronchoconstrictive response to inhaled methacholine.

We hypothesized that the size of the large airways is a determinant of bronchial responsiveness to inhaled methacholine. This was investigated by measuring the relationship of tracheal size and branching angle to the bronchoconstrictive response to methacholine, in 169 male construction insulators, aged 20-50 yrs, as part of a workforce-based, cross-sectional survey of respiratory health. Bronchial responsiveness was expressed as the concentration of methacholine, inhaled for 2 min of tidal breathing, which provoked a 15% fall in forced expiratory volume in one second (FEV1). Tracheal size was assessed from tracings of standard posteroanterior chest radiographs, at full inspiration. After accounting for the effect of airway calibre (FEV1/forced vital capacity (FVC)), age, height, and pack-years of cigarette smoking, on airways responsiveness, there was a significant association (p < 0.05) between tracheal length, diameter, or surface area and the degree of bronchoconstriction obtained by inhaling methacholine. The increase in airway responsiveness with decreasing tracheal size may reflect increased deposition of methacholine, secondary to smaller cross-sectional area and greater linear velocity of air in the trachea and main bronchi.

Adult↗
PubMed1992

Effect of negative pressure ventilation in severe chronic obstructive pulmonary disease.

The hypothesis that patients with chronic obstructive pulmonary disease (COPD) have chronic inspiratory muscle fatigue was tested in an effectiveness trial in which negative pressure ventilation (NPV) was used to produce inspiratory muscle rest. In a double-blind study 184 patients with severe COPD were randomly allocated active or sham NPV treatment for a 12-week period of home use. The distance walked in a 6 min walk test was the primary outcome variable. Secondary outcome measures were cycle exercise endurance time, severity of dyspnoea, quality of life, arterial blood gas tensions, and respiratory muscle strength. The percentage reduction in amplitude of the diaphragmatic electromyographic signal multiplied by hours of NPV was used to reflect the dose of NPV so we could examine dose-response relations. Analysis was based on intention to treat. We found no evidence of a clinically or statistically significant difference in any outcome measure between active and sham groups. No dose-response relation was observed. Moreover, the intervention was poorly accepted despite substantial clinical support. We conclude that NPV as used in this study is difficult to apply and ineffective when used with the aim of resting the respiratory muscles in patients with stable COPD.

Aged↗
PubMed1992

The use of beta-agonists and the risk of death and near death from asthma.

BACKGROUND: Morbidity and mortality from asthma appear to be increasing, and it has been suggested that medications used to treat asthma are contributing to this trend. We investigated a possible association between death or near death from asthma and the regular use of beta 2-agonist bronchodilators. METHODS: Using linked health insurance data bases from Saskatchewan, Canada, we conducted a matched case-control study of subjects drawn from a cohort of 12,301 patients for whom asthma medications had been prescribed between 1978 and 1987. We matched 129 case patients who had fatal or near-fatal asthma with 655 controls (who had received medications for asthma but had not had fatal or near-fatal events) with respect to region of residence, age, receipt of social assistance, and previous hospitalization for asthma. RESULTS: The use of beta-agonists administered by a metered-dose inhaler was associated with an increased risk of death from asthma (odds ratio, 2.6 per canister per month; 95 percent confidence interval, 1.7 to 3.9) and of death or near death from asthma, considered together (odds ratio, 1.9; 95 percent confidence interval, 1.6 to 2.4). For death from asthma, use of the beta-agonist fenoterol was associated with an odds ratio of 5.4 per canister, as compared with 2.4 for the beta-agonist albuterol. On a microgram-equivalent basis, the odds ratio for this outcome with fenoterol was 2.3, as compared with 2.4 with albuterol. CONCLUSIONS: An increased risk of death or near death from asthma was associated with the regular use of inhaled beta 2-agonist bronchodilators, especially fenoterol. Regardless of whether beta-agonists are directly responsible for these adverse effects or are simply a marker for more severe asthma, heavy use of these agents should alert clinicians that it is necessary to reevaluate the patient's condition.

Administration, Inhalation↗