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Biomedical subjects

P Ernst

Publications and source records attributed to P Ernst.

At least 37 records · Page 2Linked to original sources

Persistent asthma: disease control, resource utilisation and direct costs.

Despite evidence that adverse outcomes are less frequent when asthma management is optimised, the link between the level of control, disease severity and medical resource utilisation (MRU) is poorly documented. This relationship was investigated in a group of patients suffering from persistent asthma (Global Initiative for Asthma (GINA) > or = 2) in France. In 1998 a computerised family practice database was used to identify asthma patients aged 17-50 yrs. Information from the database was complemented by a patient survey to retrospectively assess the level of asthma control and hospital contacts. Costs of MRU over a 12-month study period were related to demographics, medical history, asthma control, and doses of inhaled corticosteroids prescribed during the prestudy period. A review of the computerised medical database identified 1,038 adult patients with persistent asthma, who completed the survey questionnaire. Over a 12-month period, the mean cost of MRU was 549.8 euros for well-controlled patients, 746.3 euros per patient with moderate control, and 1,451.3 euros per patient with poor control. Costs also increased significantly with age, access to free asthma care, comorbid conditions, asthma symptoms in the past year and whether inhaled corticosteroids had been prescribed before the study period. In patients with persistent asthma, large differences were observed in the use of medical resources according to control and severity. Therefore, if patients appropriately use prescribed control therapy, their use of medical resources may be reduced.

Adolescent↗

[High dose therapy with autologous stem cell support--finally a progress in myelomatosis].

BACKGROUND: Since the introduction of the simple cyclic oral treatment with melphalan and prednisone in the late 1960s, there has been no substantial improvement in the therapy of multiple myeloma. In 1994, the Nordic Myeloma Study Group initiated a population-based, prospective study to evaluate the impact on survival of high dose chemotherapy in newly diagnosed, symptomatic patients under 60 years of age, compared to a conventionally treated control group. MATERIAL AND METHODS: 274 patients were treated according to a specified high dose protocol and compared to 274 patients from previous population-based trials fulfilling the same eligibility criteria. RESULTS: Median survival was 44 months in the control group and 62 months in the intensive treatment group (risk ratio 1.65; 95% CI = 1.28-2.14, P = 0.0001). A study of health-related quality of life (HRQoL) which was integrated in the trial showed a moderately reduced HRQoL associated with the intensive treatment phase, but no statistically significant difference beyond the first year of follow-up. In a cost-utility analysis of the trial, the cost per (quality-adjusted life years) was estimated at USD 26,000. INTERPRETATION: The incremental cost of the treatment is within what is usually thought to be acceptable limits. Further improvement of the results and reduction of stay in hospital would give an even more favourable cost-utility ratio.

Adult↗

Prevalence of bronchial hyperresponsiveness among HIV-infected men.

HIV infection is associated with immune dysregulation primarily affecting T-cell function, whereas asthma is related to excessive T-cell activity. We compared the prevalence of asthma and related conditions among adult seropositive men with the prevalence among men of similar age drawn from the general population. Seropositive men had a significantly more frequent occurrence of wheezing (54.4 versus 21.2%), bronchial hyperresponsiveness (BHR) to methacholine (26.2 versus 14.4%), and an elevated total serum IgE (37.8 versus 25.7%). Differences in BHR were significant only among smokers. Among the seropositive men, FEV(1)/FVC and an elevated IgE were the principal determinants of BHR. Our results suggest that the frequency of asthma may be underestimated in HIV disease. Furthermore, the frequent occurrence of BHR in HIV-infected men who smoke (30.1%) suggests this group may be especially susceptible to the adverse effects of cigarette smoke.

Adult↗

Down-regulation of TDT transcription in CD4(+)CD8(+) thymocytes by Ikaros proteins in direct competition with an Ets activator.

Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation. Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte-specific TdT promoter. Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4(+)CD8(+) thymocyte line. However, these mutations abolished down-regulation on differentiation, providing evidence that Ikaros plays a direct role in repression. Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down-regulation. The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning. Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain. Surprisingly, in the CD4(+)CD8(+) thymocyte line, overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA-binding properties of Ikaros. Rather, the small isoform assembled into multimeric complexes with DNA-bound Ikaros at the pericentromeric foci. The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene.

Binding Sites↗

Prevalence of asthma symptoms among adults aged 20-44 years in Canada.

BACKGROUND: Reported prevalence rates of asthma vary within and between countries around the world. These differences suggest environmental factors in addition to genetic factors in the cause of the disease and may provide clues for preventive strategies. We examined the variability of asthma-related symptoms and medication use among adults in 6 sites across Canada (Vancouver, Winnipeg, Hamilton, Montreal, Halifax and Prince Edward Island) and compared our findings with those from sites that had participated in a recent European survey. METHODS: We used the same sampling strategy and standardized questionnaire as those used in the European Community Respiratory Health Survey (ECRHS). The 6 Canadian sites were selected to represent different environments with respect to climate, air pollution and occupational exposure. Community-based samples of 3000 to 4000 people aged 20-44 years were randomly selected in each site. Subjects were asked to complete the questionnaire by mail between March 1993 and November 1994. Prevalence rates (and 95% confidence intervals [CIs]) of asthma symptoms, self-reported asthma attacks and use of asthma medication were compared across the Canadian sites and with sites that had participated in the ECRHS. RESULTS: The overall response rate of those selected to receive the questionnaire was 86.5% (range 74.5%-92.8%). The prevalence rates of most asthma symptoms varied significantly among the Canadian sites. For instance, 21.9% (Montreal) to 30.4% (Halifax) of the men and 24.0% (Vancouver) to 35.2% (Halifax) of the women reported wheezing in the year before the survey. Depending on the site, 4.4% to 6.3% of the men and 5.2% to 9.5% of the women reported an asthma attack in the last year, and 4.0% to 6.1% of the men and 4.9% to 9.7% of the women were currently using asthma medication. Prevalence rates of symptoms, asthma attacks and medication use did not change with age, but they were higher among women than among men. Compared with the results from the ECRHS sites, those from the Canadian sites were among the highest. INTERPRETATION: Significant variation in the prevalence of asthma symptoms, asthma attacks and use of asthma medication between Canadian sites and international sites suggests environmental influences. Different combinations of factors in different sites may be responsible for the high prevalence rates and should be the subject of further research to guide clinical management and public health intervention.

Adult↗

Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses.

Helicobacter pylori infection is linked to chronic gastritis, peptic ulcer and gastric carcinoma. During H. pylori infection, class II MHC expression by the gastric epithelium increases, as does the number of local CD4(+) T cells, which appear to be important in the associated pathogenesis. These observations suggested that the epithelium might present antigens to T cells. Thus, we sought to determine whether gastric epithelial cells process antigens to establish their function as local antigen presenting cells (APC). We examined a panel of gastric epithelial cell lines for expression of the antigen processing cathepsins B (CB), L (CL), S (CS), and D (CD). The mRNA for these enzymes were detected by RT-PCR and the enzymes in the gastric epithelial cells were identified by various independent methods. We corroborated the expression of CB and CD on gastric epithelial cells from human biopsy samples. The functions of these proteases were confirmed by assessing their ability to digest ovalbumin, a conventional dietary antigen, and proteins from H. pylori. In summary, multiple lines of evidence suggest gastric epithelial cells process antigens for presentation to CD4(+) T cells. To our knowledge, these are the first studies to document the antigen processing capacity of human gastric epithelial cells.

Antigen Presentation↗

Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992.

A highly increased risk of myelodysplasia (MDS) and acute myeloid leukaemia (AML) is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors. More recently, single cases of acute lymphoblastic leukaemia (ALL), often presenting balanced translocations involving chromosome band 11q23, have been observed. We present two such cases with t(4;11)(q21;q23), one of whom had previously received only single-agent chemotherapy with 4-epi-doxorubicin. A review of the literature since 1992 including these two patients reveals a total of 23 cases of ALL or lymphoblastic lymphoma after chemotherapy presenting balanced translocations to 11q23. All 23 patients had previously received at least one topoisomerase II inhibitor, and in two patients 4-epi-doxorubicin had been administered as single-agent chemotherapy for breast cancer. The latency period to development of t-ALL was 24 months or less in 20 out of 22 cases. The MLL gene was found to be rearranged in 14 out of 14 cases, and in three out of six cases the breakpoint was at the telomeric part of the gene, as observed in most cases of AML following therapy with topoisomerase II inhibitors. These results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors in the future should be included with cases of MDS or AML in calculations of risk of leukaemia.

Adult↗

Inhaled corticosteroids: impact on asthma morbidity and mortality.

Inhaled corticosteroids are now recommended as first-line therapy for asthma. Although these drugs clearly improve the symptoms of the disease and the associated physiologic abnormalities, epidemiologic studies provide important information on their effectiveness in preventing asthma morbidity and mortality. We review the evidence regarding the role of inhaled corticosteroids in the prevention of asthma fatality and hospitalization. In the process, we discuss the methodologic complexities of the nonexperimental studies and the implications of the methodologic issues on the evaluation of the impact of these drugs. Eight of the cohort and ecologic studies conducted to date strongly suggest that inhaled corticosteroids, when taken regularly, decrease the number of hospitalizations for asthma by up to 80%. For asthma death, the results of 11 investigations appear less consistent, especially those of several cohort and case-control studies whose principal objective was to examine not the benefit of inhaled corticosteroids but the adverse effects of other drug classes. Much of the inconsistency in the results, however, can be explained by weaknesses in study design and analysis-in particular, the failure to consider exposure in terms of regular use of inhaled corticosteroids. When the most recent study involving the use of the Saskatchewan databases is considered, it is evident that regular treatment with conventional or low-dose inhaled cortico-steroids results in a significant reduction in fatalities due to asthma. In all, the evidence to date strongly indicates that regular use of inhaled corticosteroids, even at low doses, would prevent the major portion of asthma hospitalizations and deaths.

Administration, Inhalation↗

Level of control and hospital contacts in persistent asthma.

The purpose of this study was to estimate relationships between asthma control and hospital contacts (visits to emergency rooms and hospitalizations) in a group of patients suffering from persistent asthma, after adjustment for prior use of inhaled corticosteroids. A computerized family practice database was used to identify patients (aged 6-50 years) with persistent asthma who received asthma therapy from January 1995. The database provided information on patient demographics and drug therapy. Asthma control was estimated by a survey of patients at the end of a 12-month study period. Frequency of hospital contacts during the study period was related to demographics, asthma control, and prescribed doses of inhaled corticosteroids during a prestudy period. Review of computerized medical files of 497 family practice physicians identified 1,966 patients with persistent asthma who met the study criteria. Of these patients, 1,251 completed the survey (63.6%). Asthma control was assessed in 1,130 patients; it was moderate or poor in 42% of the cases. During the 12-month study period, 14.8% of patients reported at least one hospital contact. The level of asthma control was significantly (p < 0.001) associated with hospital contacts. The odds ratio (OR) for hospital contact for good and poor asthma control was 0.5 (95% confidence interval [CI] 0.2-0.7) and 2.2 (95% CI 1.2-4.4), respectively. Asthma control was related to hospital contacts independently of use of inhaled corticosteroids before the study period. Overall, control of asthma was not optimal in this population. The occurrence of hospital contacts was closely related with the level of control. This association was independent of the dose of inhaled corticosteroids prescribed before the study, suggesting that in asthma, hospital contacts are primarily related to the level of control experienced by the patients.

Adolescent↗

MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein.

A fragment of the mixed-lineage leukemia (MLL) gene (Mll, HRX, ALL-1) was identified in a yeast genetic screen designed to isolate proteins that interact with the CREB-CREB-binding protein (CBP) complex. When tested for binding to CREB or CBP individually, this MLL fragment interacted directly with CBP, but not with CREB. In vitro binding experiments refined the minimal region of interaction to amino acids 2829 to 2883 of MLL, a potent transcriptional activation domain, and amino acids 581 to 687 of CBP (the CREB-binding or KIX domain). The transactivation activity of MLL was dependent on CBP, as either adenovirus E1A expression, which inhibits CBP activity, or alteration of MLL residues important for CBP interaction proved effective at inhibiting MLL-mediated transactivation. Single amino acid substitutions within the MLL activation domain revealed that five hydrophobic residues, potentially forming a hydrophobic face of an amphipathic helix, were critical for the interaction of MLL with CBP. Using purified components, we found that the MLL activation domain facilitated the binding of CBP to phosphorylated CREB. In contrast with paradigms in which factors compete for limiting quantities of CBP, these results reveal that two distinct transcription factor activation domains can cooperatively target the same motif on CBP.

Binding Sites↗

Identification of persons with cardiorespiratory conditions who are at risk of dying from the acute effects of ambient air particles.

This study was undertaken to identify subgroups of the population susceptible to the effects of ambient air particles. Fixed-site air pollution monitors in Montreal, Quebec, Canada, provided daily mean levels of various measures of particulates and gaseous pollutants. Total sulfates were also measured daily (1986-1993) at a monitoring station 150 km southeast of the city (Sutton, Quebec, Canada). We used coefficient of haze (COH), extinction coefficient, and Sutton sulfates to predict fine particles and sulfates from a fine particles model for days that were missing. We used the universal Quebec medicare system to obtain billings and prescriptions for each Montreal resident who died in the city from 1984 to 1993. These data were then used to define cardiovascular and respiratory conditions that subjects had before death. Using standard Poisson regression time-series analyses, we estimated the association between daily nonaccidental mortality and daily concentrations of particles in the ambient air among persons with cardiovascular and respiratory conditions diagnosed before death. We found no persuasive evidence that daily mortality increased when ambient air particles were elevated for subgroups of persons with chronic upper respiratory diseases, airways disease, cerebrovascular diseases, acute coronary artery disease, and hypertension. However, we found that daily mortality increased linearly as concentrations of particles increased for persons who had acute lower respiratory diseases, chronic coronary artery diseases (especially in the elderly), and congestive heart failure. For this latter set of conditions, the mean percent increase in daily mortality (MPC) for an increase in the COH across its interquartile range (18.5 COH units per 327.8 linear meters), averaged over the day of death and the 2 preceding days, was MPC = 5.09% [95% confidence interval (CI) 2.47-7.79%], MPC = 2.62 (95% CI 0.53-4.75%), and MPC = 4.99 (95% CI 2.44-7.60%), respectively. Adjustments for gaseous pollutants generally attenuated these associations, although the general pattern of increased daily mortality remained. In addition, there appeared to be a stronger association in the summer season. The positive associations found for persons who had acute lower respiratory diseases and congestive heart failure are consistent with some prevailing hypotheses and may also be consistent with recent toxicologic data implicating endothelins. Further epidemiologic studies are required to confirm these findings.

Aged↗

The impact of combined inhaled bronchodilator therapy in the treatment of COPD.

BACKGROUND: Treatment guidelines recommend concomitant use of ipratropium bromide and inhaled beta2-agonists as severity of COPD progresses. While the use of these two agents in a single inhaler may enhance patient compliance and result in cost savings, it may, by itself, increase medication use. We assessed whether the introduction of a combined inhaled bronchodilator in the treatment of COPD modifies the use and costs related to prescribed medications. METHOD: A cohort of subjects > or =45 years old initiating treatment with either a combined inhaled bronchodilator (641 subjects) or ipratropium bromide and inhaled beta2 -agonist (411 subjects) between July 1, 1996, and June 30, 1997, was identified using the Saskatchewan Health databases. The primary outcomes were prescribed medication usage and the subsequent related costs during a 1-year follow-up period. Poisson regression analysis was used to estimate rate ratios (RRs) adjusted for drug use and hospitalization during the year prior to cohort entry. RESULTS: The adjusted RR of inhaled bronchodilator use was elevated for combined inhaled bronchodilator therapy (adjusted RR, 1.16; 95% confidence interval [CI], 1.07 to 1.26). However, the overall costs associated with these inhaled bronchodilators were reduced with combined inhaled bronchodilator therapy (adjusted mean ratio, 0.83; 95% CI, 0.76 to 0.92). The rate of use of other respiratory drugs and antibiotics was similar (adjusted RR, 1.03; 95% CI, 0.93 to 1.16). Applying the rate ratio for cost savings to all new, combined inhaled bronchodilator users led to estimated annual savings in Canadian dollars of 103,468 dollars (95% CI, 48,694 dollars to 146,082 dollars) in this province. CONCLUSION: The introduction of a simpler bronchodilator dosing regimen did not significantly alter the treatment of COPD and resulted in appreciable cost savings.

Administration, Inhalation↗

Low-dose inhaled corticosteroids and the prevention of death from asthma.

BACKGROUND: Although inhaled corticosteroids are effective for the treatment of asthma, it is uncertain whether their use can prevent death from asthma. METHODS: We used the Saskatchewan Health data bases to form a population-based cohort of all subjects from 5 through 44 years of age who were using antiasthma drugs during the period from 1975 through 1991. We followed subjects until the end of 1997, their 55th birthday, death, emigration, or termination of health insurance coverage; whichever came first. We conducted a nested case-control study in which subjects who died of asthma were matched with controls within the cohort according to the length of follow-up at the time of death of the case patient (the index date), the date of study entry, and the severity of asthma. We calculated rate ratios after adjustment for the subject's age and sex; the number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled beta-adrenergic agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date. RESULTS: The cohort consisted of 30,569 subjects. Of the 562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who died of asthma for whom there were complete data with 2681 controls. Fifty-three percent of the case patients and 46 percent of the control patients had used inhaled corticosteroids in the previous year, most commonly low-dose beclomethasone. The mean number of canisters was 1.18 for the patients who died and 1.57 for the controls. On the basis of a continuous dose-response analysis, we calculated that the rate of death from asthma decreased by 21 percent with each additional canister of inhaled corticosteroids used in the previous year (adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The rate of death from asthma during the first three months after discontinuation of inhaled corticosteroids was higher than the rate among patients who continued to use the drugs. CONCLUSIONS: The regular use of low-dose inhaled corticosteroids is associated with a decreased risk of death from asthma.

Administration, Inhalation↗

Autologous stem cell transplantation as post-remission therapy in adult acute myelogenous leukemia: does platelet contamination of peripheral blood mobilized stem cell grafts influence the risk of leukemia relapse?

Conventional chemotherapy of acute myelogenous leukemia (AML) results in an overall long-term disease-free survival of less than 50%, but for selected subsets of younger patients the prognosis can be improved by allogeneic stem cell transplantation. The use of autologous stem cell transplantation is now investigated as an alternative to allotransplantation due to its lower risk of serious complications. However, autotransplantation is associated with a relatively high risk of post-transplant AML relapse that can be derived from contaminating leukemia cells in the autograft. Peripheral blood mobilized stem cell (PBSC) grafts usually contain a higher number of platelets. The degree of platelet contamination is determined by the peripheral blood platelet count at the time of harvesting, and the platelets become activated and release soluble mediators during the ex vivo handling of PBSC grafts. Many of these platelet-derived mediators can bind to specific receptors expressed by AML blasts, and the platelet contamination may then alter AML blast survival and thereby influence the risk of post-transplant leukemia relapse. Therefore, we conclude that the platelet contamination of autologous stem cell grafts is possibly of clinical importance, but the effect of this nonstandardized parameter is difficult to predict in individual patients because the number of graft-contaminating platelets, the degree of platelet activation, and the effects of platelet-derived mediators on AML blasts differ between patients.

Adult↗

Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease.

Products of the prostaglandin H synthase (PGHS) metabolic pathway are thought to play a role in the pathogenesis of asthma. We determined the level of expression of the constitutive (PGHS-1) and inducible (PGHS-2) isoforms of the enzyme in induced sputum and bronchial biopsies of patients with asthma, patients with chronic obstructive pulmonary disease (COPD), and unaffected control subjects by immunocyto- and immunohistochemistry. Immunoreactivity for PGHS-2 was significantly greater in the induced sputum of patients with asthma and patients with COPD compared with unaffected control subjects. The level of PGHS-2 was greater in asthma than in COPD. Immunoreactivity for PGHS-1 increased in cells in the induced sputum of patients with asthma and patients with COPD compared with that of unaffected control subjects. Immunostained cells included macrophages, eosinophils, and neutrophils. Greater PGHS-2 immunoreactivity was seen in the submucosal inflammatory infiltrate and in the airway epithelium of patients with asthma compared with unaffected control subjects. In summary, we demonstrate an induction of PGHS-2 in asthma, suggesting increased formation of prostanoids, which may contribute to the inflammatory process.

Adult↗

Relative scarcity of asthma and atopy among rural adolescents raised on a farm.

We determined the prevalence of markers of atopy and asthma among 1, 199 rural secondary school students ages 12 to 19 yr. Subjects identified as having been raised on a farm and half as many subjects without regular exposure to a farming environment from the same school class completed a respiratory symptom questionnaire and underwent allergy skin tests and a methacholine bronchoprovocation test. Current wheeze, airways hyperresponsiveness (AHR), and skin test positivity to inhaled allergens were all significantly less common among adolescents raised on the farm and these differences were especially pronounced in girls. After adjusting for gender and current smoking, the odds ratios for being raised on a farm were: 0. 70 (95% CI 0.52 to 0.95) for current wheeze; 0.59 (95% CI 0.37 to 0. 95) for asthma, defined as the concomitant occurrence of wheeze and AHR; and 0.58 (95% CI 0.46 to 0.75) for atopy defined as a positive reaction to any one of 24 common inhaled allergens. These associations were also not significantly altered by adjusting for the difference in the number of siblings.

Adolescent↗

Occupational asthma in adults in six Canadian communities.

We examined the prevalence, population attributable risk (PAR), and clinical characteristics of occupational asthma (OA) in a randomly selected population in six communities in Canada. Our study followed the European Community Respiratory Health Survey protocol. A randomly selected population of 18,701 (87% response rate) persons from the study communities, ranging in age from 20 to 44 yr, completed an initial questionnaire, of whom 2,974 (39% response rate) attended the laboratory and completed supplementary questionnaires. Of these latter individuals, 383 had asthma. Asthma was defined as physician-diagnosed asthma, and adult-onset asthma was defined as a first attack at age 15 yr or older. We used several methods for estimating OA as follows: (1) reporting of a high-risk job (occupation and industry) for OA at the time of asthma onset (Probable OA); (2) reporting of exposure to a substance that may cause OA (Possible OA) while not in a high-risk job at the time of asthma onset; and (3) combination of the PAR for high-risk jobs and exposures. The prevalence (95% confidence interval [CI]) of Probable OA and Possible OA combined was 36.1% (31.3 to 41.0%) among subjects with adult-onset asthma. The occupations most commonly reported in association with OA were nursing in the Probable OA group and clerical and food preparation in the Possible OA group. The clinical characteristics and exposures reported by both groups were similar. The PAR for adult-onset asthma in high-risk jobs and exposures was 18.2%. The assessment of occupation and industry alone, rather than of exposures, may underestimate the contribution of occupational exposures to asthma prevalence.

Adult↗