Search PubMed⌕ Search

Biomedical subjects

R Dahl

Publications and source records attributed to R Dahl.

At least 109 records · Page 6Linked to original sources
PubMed1996

Subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis.

Hyaluronan (HA) is a high molecular weight glycosaminoglycan found in large amounts in the skin, joints, and other organs. Previous studies have shown that HA stimulates neutrophil functions both in vitro and in vivo. The object of this study was to test the hypothesis that HA administration subcutaneously might reduce the number of bacterial infections in humans with an increased susceptibility to such infections. For this purpose we have studied 29 patients with chronic bronchitis and recurrent acute exacerbations of their disease. The patients were randomly separated into two groups. One group had HA for 6 mo followed by 6 mo of placebo, and the other group started with placebo treatment followed by HA. The treatment periods occurred during two consecutive winter periods. HA-treated patients had significantly fewer acute exacerbations (p = 0.01) than did placebo-treated patients. Likewise the consumption of antibiotics and other signs of bacterial infections were reduced. In the crossover study the placebo-treated patients again had much higher numbers of acute exacerbations than did the HA-treated patients (p < 0.0001). It is concluded that HA reduces the number of infectious exacerbations in patients with chronic bronchitis, possibly by enhancing cellular host defense mechanisms. HA is a new endogenous substance that can be used to stimulate host defense reactions and reduce the need of antibiotics. Before being recommended for clinical use, however, our results should be confirmed by further studies.

Aged↗
PubMed1996

Eosinophil and neutrophil activity in asthma in a one-year trial with inhaled budesonide. The impact of smoking.

The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects. For this purpose 85 allergic and nonallergic asthmatic subjects were randomized into three groups, which were given high-dose (1,600 micrograms/d) inhaled budesonide, low-dose (400 micrograms/d) inhaled budesonide, and oral theophylline (600 mg/d), respectively, and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein (ECP), eosinophil protein x/eosinophil derived neurotoxin (EPX/EDN) as eosinophil markers, and myeloperoxidase (MPO) and lactoferrin (LF) as neutrophil markers. Lung functions (FEV1% predicted, and histamine PC20) and the eosinophil markers ECP and EPX/EDN were improved and reduced, respectively, by budesonide in a dose-dependent and temporally parallel fashion. Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment. The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects, since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide. MPO but not LF was reduced after several months of treatment in all three groups, but only in nonsmokers. We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients, and that smoking asthmatic subjects are resistant to inhaled corticosteroids.

Adult↗
PubMed1996

p172: An alveolar type II and Clara cell specific protein with late developmental expression and upregulation by hyperoxic lung injury.

The epithelium of the alveolus and distal airway meets unique requirements, functioning as a gas exchange membrane and barrier to alveolar flooding by vascular contents as well as to bloodstream contamination by airborne toxins and pathogens. Gene products specifically expressed by this epithelium, notably the surfactant apoproteins, have had important clinical application. No cell surface antigen specific for alveolar type II and Clara cells has been described. We report the biochemical characterization, tissue and developmental expression, and upregulation by injury of a 172 kD protein recognized by a monoclonal antibody, 3F9, synthesized in response to immunization with freshly isolated rat alveolar type II cells. p172 is expressed in a polarized fashion by the apical surface of rat alveolar type II and Clara cells. An immunohistochemical survey of various rat tissues and organs reveals lung specificity. p172 is first detectable in rare epithelial cells at 19 days of gestation, a time when the fully differentiated alveolar type II cell is identified by the first detection of lamellar bodies. There is a dramatic increase in p172 expression just prior to birth. Hyperoxic lung injury results in increased expression of p172. The upregulation of p172 by hyperoxia and its cell-specific expression suggests an important adaptive function.

Animals↗
PubMed1996

Using data to design systems of care adults with chronic illness.

Increased Medicare risk contracts led to rising concern with readmission rates among the senior population with chronic illness at Carondelet Health Network. Using readily available data, Carondelet providers and administrators created intervention and evaluation strategies to redesign chronic care services to reduce increased readmissions. The strategies showed health plans can develop such strategies without waiting for sophisticated information systems to be put in place.

Adult↗
PubMed1996

Pig farmers have signs of bronchial inflammation and increased numbers of lymphocytes and neutrophils in BAL fluid.

The purpose of this study was to investigate whether pig farmers had inflammation of the bronchial mucosa and activation of bronchoalveolar lavage (BAL) cells. Pig farmers are exposed to high dust levels and have a prevalence of work-related respiratory symptoms. Bronchoscopy and BAL were performed in 27 young large-scale pig farmers, who had never smoked. Fifty three lifetime nonsmoking healthy students participated as controls. All farmers and controls had normal lung function (forced expiratory volume in one second (FEV1) 109 and 105% predicted respectively. Estimation of macroscopic signs of inflammation in the bronchi (erythema, oedema, secretion and friability) showed that pig farmers had significantly increased signs of inflammation. The median score was 3 (range 0-6) compared to a median score of 0 (range 0-3) in controls. More pig farmers than controls (41 versus 25%) had a positive histamine challenge (provocative dose producing a 20% fall in FEV1 (PC20) < or = 32 mg.mL-1) but the difference was not significant. The cell concentration in BAL fluid was identical in the two groups. Pig farmers had a significantly increased percentage of lymphocytes (median 7, range 1-27 versus median 2, range 0-7) and neutrophils (median 2, range 0-30 versus median 1, range 0-4) compared to controls. Spontaneous migration (19.8 versus 5.5 microns) and chemotaxis (62.6 versus 11.2 microns) was significantly increased in pig farmers compared to controls. After stimulation with zymosan and phorbol myristrate acetate (PMA), the reactive oxygen radical generation of purified alveolar macrophages was also significantly increased in pig farmers. Lifetime nonsmoking pig farmers with normal lung function have macroscopic signs of bronchial inflammation and an increased number of neutrophils in bronchoalveolar lavage. Their alveolar macrophages showed biological signs of activation. The inflammation of pig farmers bronchi may be early signs of bronchitis.

Adult↗
PubMed1996

Assessment of the allergic reaction in seasonal rhinitis: acoustic rhinometry is a sensitive and objective method.

BACKGROUND: Seasonal allergic rhinitis constitutes an excellent in vivo model of an allergic mucosal inflammatory reaction. This offers the opportunity of studying the fundamentals of allergic inflammation in addition to improvement of knowledge on the basal pathophysiological mechanisms of the disease. So far, monitoring methods of disease activity and treatment efficacy have mainly been based upon subjective assessments, illustrating the impact of introducing reliable objective methods. OBJECTIVE: To investigate the allergic inflammatory reaction of seasonal rhinitis through different objective methods and evaluate these as indicators of disease activity and treatment efficacy. METHODS: Functional parameters, i.e. acoustic rhinometry and nasal metacholine challenge, and biological markers, i.e. blood eosinophil count, eosinophil cationic protein in serum (s-ECP) and nasal lavage fluid (n-ECP), were assessed before and at peak pollen season in 27 patients with grass pollen induced rhinitis. Patients were randomized to either nasal corticosteroid or placebo treatment and recorded nasal symptom scores. RESULTS: Acoustic rhinometry revealed a significant difference in favour of steroid treatment (P < 0.05) comparing nasal volumes before and during season. This difference primarily relied upon a decrease in the placebo group (P = 0.05). A reduction from baseline of s-ECP in the steroid group (P < 0.01) was obtained. N-ECP demonstrated a difference between treatment groups, although not significant. Symptom scores increased in all patients during the pollen season, although this was only significant in the placebo treated patients (P < 0.01). The remaining methods applied did not demonstrate further differences, either within or between treatment groups. CONCLUSION: Our results demonstrate acoustic rhinometry to be a sensitive and objective method of assessment of nasal obstruction. Furthermore, acoustic rhinometry and s-ECP reflect the impact of nasal steroid therapy on seasonal allergic rhinitis.

Acoustics↗
PubMed1995

In vitro growth of factor-dependent multipotential hematopoietic cells is induced by the nuclear oncoprotein v-Ski.

Understanding how self renewal, commitment and differentiation are regulated in normal, multipotent hematopoietic progenitors is important for our understanding of underlying mechanisms involved in leukemogenesis. In addition, knowledge of progenitor cell biology is critical if these cells are to be used for gene therapy. In this communication, we demonstrate that the oncogenic transcription factor v-Ski, together with the ligand activated receptor tyrosine kinase c-Kit, induces the continuous in vitro self renewal of primary avian multipotent progenitors. These cells have an in vitro life span of > 100 generations. In addition they spontaneously differentiate into cells of the erythroid, monocytic and granulocytic lineages. If clonal strains of these multipotent progenitors are exposed to specific mixtures of growth factors and hormones, they develop into committed cells of either the erythroid or myeloid lineages. These committed cells underwent efficient terminal differentiation when they were treated with the relevant lineage-specific growth/differentiation factors, but underwent apoptosis when exposed to the incorrect factors for the respective lineage. While the committed cells coexpress marker proteins from different lineages, expression of the 'wrong' lineage marker is repressed during terminal differentiation. Our results indicate that a combination of v-Ski and activated c-Kit induces long-term self renewal in primary multipotent progenitors, which can be induced to commit and differentiate along specific lineages under different, defined conditions. Our data also suggest that growth factors and steroid hormones control terminal differentiation by a combined induction of commitment, growth and apoptosis, a process likely to be affected in stem cell leukemias.

Cell Division↗
PubMed1995

The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma.

OBJECTIVE: To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma. METHODS: Cisatracurium was incubated in aqueous buffer at various pH values or in human and rat plasma maintained at pH 7.4 with HEPES buffer. Cisatracurium and the degradation products, laudanosine and the monoquaternary alcohol, were quantitated by HPLC with use of fluorescence detection. RESULTS: In Sørenson's phosphate buffer, cisatracurium degraded spontaneously by a chemical process commonly referred to as "Hofmann elimination." The rate of degradation increased with increasing pH. From pH 6.4 to 7.8 there was a 6.5-fold increase in the rate of degradation of cisatracurium and, on a molar basis, the final decomposition product laudanosine accounted for all of the drug. At a pH of 7.4, cisatracurium degraded with a half-life of about 34.1 +/- 2.1 minutes. Cisatracurium incubated in human plasma degraded with a mean (+/- SD) half-life of 29.2 +/- 3.8 minutes, which is consistent with Hofmann elimination. Besides laudanosine, and unlike that observed in Sørenson's phosphate buffer, significant amounts of the monoquaternary alcohol were formed that slowly degraded to laudanosine. The micromoles of laudanosine formed eventually accounted for the total amount of cisatracurium incubated with human plasma. The monoquaternary alcohol appears to be a product of ester hydrolysis of a monoquaternary acrylate formed during the first step in Hofmann elimination. Evidence for esterase involvement at this step in the degradation of cisatracurium was based on inhibition studies with O-cresyl benzodioxaphosphorin oxide (CBDP), a specific carboxylesterase inhibitor. The addition of CBDP to human plasma completely blocked the formation of monoquaternary alcohol and converted the degradation of cisatracurium to total Hofmann elimination. In rat plasma cisatracurium was hydrolyzed, with a half-life of only 3 1/2 minutes, by carboxylesterases. The addition of CBDP increased the half-life to 25 minutes, which is consistent with Hofmann elimination. CONCLUSION: In human plasma the rate-limiting step in the degradation of cisatracurium is Hofmann elimination, with the initial formation of a monoquaternary acrylate. The observation that the monoquaternary alcohol results from ester hydrolysis of the monoquaternary acrylate by plasma esterase(s) explains the presence of the monoquaternary alcohol metabolite in human plasma during clinical studies with cisatracurium. The rapid hydrolysis of cisatracurium by rat plasma relative to human indicates a major species difference in plasma esterase(s).

Alcohols↗
PubMed1995

Assessing equivalence of inhaled drugs.

The move to disease management has led to an increase in the practice of drug or formulation substitution on the basis of equivalence. Well established guidelines are available for judging equivalence between oral, but not inhaled, formulations. This article describes the criteria by which equivalence can be assessed and concludes that although traditional issues such as adequate sample size are important, studies also need to be designed in such a way as to avoid the possibility of falsely concluding clinical equivalence.

Administration, Inhalation↗
PubMed1995

Do inhaled steroids have similar efficacy? A case of bronchial asthma suggesting different efficacy of inhaled glucocorticosteroids.

We report a 35-year-old woman who had had bronchial asthma for 17 years. Her asthma worsened and became unstable on treatment with beclomethasone dipropionate (BDP), budesonide (BUD), and oral glucocorticosteroids (GC). At the age of 31, she had participated in a clinical trial with fluticasone propionate (FP), and after 2 weeks' treatment her asthma was well controlled. Because of pregnancy, her participation was terminated and treatment continued with available inhaled GC; however, the disease deteriorated and treatment with FP was resumed 2 years ago. Lung function normalized after 3 weeks and she has remained clinically stable since.

Administration, Inhalation↗
PubMed1995

Once daily fluticasone propionate aqueous nasal spray controls symptoms of most patients with seasonal allergic rhinitis.

This multicentre, randomized, double-blind, parallel-group study was designed to compare the efficacy and tolerability of fluticasone propionate aqueous nasal spray 200 micrograms once daily (FPANS 200 micrograms od) with FPANS 200 micrograms twice daily (bd) in patients whose seasonal rhinitis symptoms were not completely controlled with FPANS 200 micrograms od. A total of 549 patients initially received FPANS 200 micrograms od during the open-treatment phase of the study. After 2 weeks, 65% of patients had their symptoms well controlled by FPANS 200 micrograms od and continued with this treatment for a further 2 weeks. The remainder received either FPANS 200 micrograms od or FPANS 200 micrograms bd for a further 2 weeks. Efficacy was evaluated by the analysis of symptom-free days. In the uncontrolled group, there was a significant increase in the percentage of symptom-free days in the FPANS 200 micrograms bd group over the FPANS 200 micrograms od group for nasal blockage on waking (P < 0.05) and nasal blockage during the day (P < 0.05). Similar trends were observed for sneezing, rhinorrhoea, nasal itching, and eye symptoms. There was a significant increase in the percentage of days with a symptom score of less than 2 in FPANS 200 micrograms bd group for nasal blockage during the day (P < 0.05). Adverse events were similar in nature and frequency in each treatment group. It is concluded that in the majority of patients symptoms of seasonal rhinitis are well controlled by FPANS 200 micrograms od. In the minority of patients whose symptoms are not adequately controlled by a once daily dose, FPANS 200 micrograms bd provides additional relief, particularly from nasal blockage.

Administration, Intranasal↗
PubMed1995

Mechanisms of acetaldehyde-mediated growth inhibition: delayed cell cycle progression and induction of apoptosis.

Chronic ethanol exposure has been associated with pleiotropic effects on cellular function in vivo and in vitro, including inhibition of growth. To date, it has been difficult to dissociate the primary effects of ethanol from the effects of ethanol metabolism, generation of acetaldehyde, and reducing equivalents. We have previously described the development of a Chinese hamster ovary cell line, A-10, which expresses a transfected murine-liver alcohol dehydrogenase. Cultures of these cells accumulate acetaldehyde due to the low level of aldehyde dehydrogenase. One noticeable effect of chronic acetaldehyde exposure, but not ethanol exposure, is the inhibition of cell growth. This study focuses on the mechanisms that underlie this growth inhibition. Our studies with the A-10 cell on the rates of [3H]thymidine incorporation and flow cytometry of asynchronous cultures indicated that acetaldehyde did not lead to arrest of the cell cycle in the G1 phase as has been found in other models of ethanol exposure. Rather, we observed a generalized delay in cell cycle progression. However, the slower cell cycle did not account exclusively for the slower rates of cell accumulation. Chronic exposure to acetaldehyde also increased the rate of cell death. The increased rate of cell death was both cumulative and dose-dependent. The dead cells accumulated in the medium and were apoptotic. Apoptosis was confirmed using morphological criteria and quantitation of DNA fragmentation. These data lend additional support to the idea that chronic acetaldehyde exposure can affect the mechanisms that regulate cell division and the apoptotic program.

Acetaldehyde↗
PubMed1995

Hepatic Na(+)-K(+)-ATPase enzyme activity correlates with polarized beta-subunit expression.

We have examined underlying causes for observations made in hepatocytes in which catalytic subunits of Na(+)-K(+)-ATPase are found both in bile canalicular (apical) and sinusoidal (basolateral) membrane domains, whereas functional activity is associated preferentially with sinusoidal membrane sites. In a series of parallel studies, we determined by both light and electron microscopy that Na(+)-K(+)-ATPase alpha-subunits were localized to both membrane domains of hepatocytes. With the use of purified liver plasma membrane subfractions, ouabain inhibition curves demonstrated similar inhibition constants (inhibition constant 10(-5) M), and immunoblots using alpha 1-, alpha 2-, and alpha 3-polyclonal and monoclonal antibodies demonstrated antigenic sites predominantly for alpha 1 in both membrane fractions. Also, Northern blot hybridization analysis revealed only the alpha 1-isoform in hepatocytes. In contrast to the bipolar distribution of the alpha 1-subunit, the beta-subunit was identified only at the sinusoidal surface using fluorescence labeling with a monoclonal antibody. The beta 1-isoform was demonstrated by Northern blot analysis and was present predominantly at the sinusoidal domain by immunoblotting with polyclonal antibodies. In addition to the bipolar distribution of alpha 1, immunoblotting of liver plasma membrane subfractions demonstrated a symmetrical distribution of fodrin, ankyrin, actin, and E-cadherin at both domains. These results suggest that functionally competent alpha/beta-complexes form at the sinusoidal domain, whereas only alpha 1-subunits are present at the apical pole.

Animals↗
PubMed1995

Convergence of apical and basolateral endocytic pathways for beta 2-microglobulin in LLC-PK1 cells.

Polarized epithelial cells internalize molecules from both apical and basolateral (BL) plasma membrane (PM) domains via receptor-mediated endocytosis. In the kidney, low-molecular-weight proteins (LMWP) are internalized across the apical membrane of proximal tubule cells and degraded in lysosomes. Although indirect evidence suggests some uptake may occur at the BL surface, in vivo studies performed in rats suggest little if any LMWP uptake occurs at the BL surface. The studies presented here showed that native human beta 2-microglobulin (beta 2M) was internalized across the apical surface and followed the same intracellular pathway in the proximal tubule-derived cell line LLC-PK1 as that described in vivo. Either 125I- or gold-labeled beta 2M (125I-beta 2M and gold-beta 2M) bound specifically and reversibly to the apical surface of confluent LLC-PK1 cells. These results were qualitatively similar to previously documented in vivo results. Subsequently, using gold-beta 2M and LLC-PK1 cells grown on porous supports, we showed that a functional uptake system for the LMWP beta 2M was present at the BL surface. Finally, using different-size gold particles conjugated to beta 2M applied simultaneously to the apical and BL surfaces, we observed that apical and BL endocytic routes converged in multivesicular acid phosphatase-negative endosomal structures. Taken together, these data imply that beta 2M can be internalized across both apical and BL domains and that the two pathways converge at a multivesicular level within the endosomal pathway.

Animals↗