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Biomedical subjects

R C Strunk

Publications and source records attributed to R C Strunk.

At least 55 records · Page 3Linked to original sources
PubMed1988

Synergism between gamma interferon and lipopolysaccharide for synthesis of factor B, but not C2, in human fibroblasts.

Four different human fibroblast cell lines synthesized C2 and factor B. Factor B synthesis was increased 12.1-fold by 50 ng/ml LPS and 7.1-fold by 100 U/ml IFN-gamma. C2 synthesis was increased only 2.1-fold by LPS, but 6.4-fold by IFN-gamma. Both LPS and IFN-gamma increased levels of factor B mRNA. LPS induced a 4.7-fold greater increase in factor B protein than in factor B mRNA, whereas IFN-gamma stimulated comparable increases in protein and mRNA. These data suggest that LPS acts to increase factor B synthesis at both pretranslational and translational sites, while IFN-gamma acts primarily at a pretranslational level. In contrast to factor B, increases in C2 protein and C2 mRNA were comparable for both stimuli. A synergistic effect between the two stimuli was observed for factor B only: protein synthesis was increased 54.5-fold or 2.8-fold greater than the additive effects of the stimuli separately. The rate of synthesis in the presence of LPS and IFN-gamma together could not be achieved by increasing concentrations of, or the times of incubation with, either stimulus separately. The synergism was not the result of an increased sensitivity of the cells to either stimulus and was not reproduced by preincubation with one stimulus before incubation with the other stimulus. Several lines of evidence suggest that the synergism, like the stimulation of factor B synthesis by LPS, was dependent on both translational and pretranslational regulation of factor B mRNA. C2 and factor B synthesized in human fibroblasts may play a role in host defense in inflammatory reactions before increases in vascular permeability and recruitment of other complement producing cells.

Cells, Cultured↗
PubMed1988

Determination of fitness in children with asthma. Use of standardized tests for functional endurance, body fat composition, flexibility, and abdominal strength.

Children with asthma frequently have exercise-induced disease that can limit their participation in both organized sports and vigorous free play. We measured fitness in a group of children with moderately severe to severe asthma with an instrument that is used widely and is available to clinicians for assessment of the physical capability of their patients. Abnormalities in physical fitness were present primarily in the area of endurance, with performance in the nine-minute run frequently found to be low. Increased skin-fold thickness was also present more frequently than in the normal population. Abdominal strength and flexibility were normal. Abnormalities in fitness were not well explained by measures indicating the presence of poorly controlled disease. All children with significant asthma probably should be tested to document the level of fitness so that appropriate intervention can be initiated.

Adolescent↗
PubMed1988

Synovial fibroblast-like cells synthesize seven proteins of the complement system.

Fibroblast-like cells from synovial tissue obtained during arthroscopy in 4 young adults with recent knee trauma were biosynthetically labeled with 35S-methionine, and protein production was quantitated by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Synovial fibroblast-like cells synthesized C1r, C1s, C1 inhibitor, C2, C3, factor B, and factor H, all with the same sizes and subunit structures as the proteins synthesized in skin fibroblasts. The capacity to synthesize these proteins was not lost with passages or freeze-thawing. Gamma-interferon stimulation increased synthesis of all 7 proteins. Lipopolysaccharide increased synthesis of only C3 and factor B. Unlike in whole rheumatoid tissue, C4 and C5 were not detected. Synovial lining cells may be an important source of local complement for participation in local defense or development of pathologic states.

Cell Adhesion↗
PubMed1988

Need for theophylline in severe steroid-requiring asthmatics.

Concern about side-effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi-medication regimen of severe asthmatics. We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti-asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability. Five in-patients, 12-15 years old, completed a double-blind, cross-over trial of theophylline vs placebo. All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes. Regular medications consisted of long-acting theophylline with levels between 12 mcg/ml and 16 mcg/ml, and prednisone 10-30 mg on alternate days. In addition, they were all taking inhaled metaproterenol, cromolyn sodium, atropine sulphate, and beclomethasone dipropionate four times daily (qid). Patients received either theophylline or placebo during two drug periods. All other medications were unchanged. Parameters measured were symptom score, number of extra respiratory treatments (prn RTs), increase in steroid dosage, and daily spirometry. During the placebo period, all five patients required increased steroids, daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection. A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all. These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who cannot be controlled with all other available bronchodilators, cromolyn, and inhaled and systemic steroids.

Adolescent↗
PubMed1988

Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.

The serum complement system is a major mediator of inflammation reactions. Two of the complement proteins, the third (C3) and fifth (C5) components, are precursors of potent phlogistic molecules, C3a and C5a. C5a has potent chemotactic activity and plays an active role in pulmonary inflammation. We present evidence suggesting that several complement proteins, including C5, are synthesized locally in the lung in alveolar type II epithelial cells. Lung tissue from normal mice synthesized and secreted C5 protein similar to the C5 protein in mouse serum, whereas lung tissue from C5-deficient mice did not. Lung tissues from both normal and C5-deficient mice synthesized C3. Rat lung tissue synthesized and secreted C5, as well as C2, C4, C3, and factor B. Cultures of type II cells (95% type II cells, 5% macrophages) regularly synthesized all these proteins. In contrast, cultures of macrophages alone synthesized large amounts of C2 and factor B, and in some experiments C3 and C4, but never C5. The C5 synthesized by the rat cells was slightly larger than serum C5 (200 kD compared with 180 kD) and was not processed to the two-chain molecule seen in serum. Rat lung tissue and purified type II cells contained C5 mRNA with the same molecular mass as the C5 mRNA in rat liver and in mouse lung and liver. Human type II cells also synthesized C5, as well as C2, C4, C3, and factor B. Human pulmonary macrophages synthesized only C2, factor B, and, in some experiments, C3. Synthesis of complement proteins in cells that line the alveolar wall may provide a local source of these proteins for inflammatory responses in the lung. Local synthesis of complement proteins could be regulated independently of the synthesis in the liver.

Animals↗
PubMed1988

Methacholine inhalation challenge in young children: results of testing and follow-up.

The diagnosis of asthma is often difficult in young children because their symptoms may not be typical and pulmonary function testing cannot be performed by the patient. We therefore performed methacholine inhalation challenges (MIC) in 24 patients 1 to 5.8 years of age in whom the diagnosis of asthma was uncertain. These patients had histories of recurrent respiratory symptoms for a mean duration of 2.4 years (range = 0.5 to 5.1) in the absence of other systemic diseases. Testing was done by either the 5-breath technique or 1-min inhalation via face mask until wheezing or coughing and retractions developed or a maximum methacholine concentration of 5 to 25 mg/mL was reached. Eighteen MIC were positive and six negative. The mean provocative dose was 3.0 mg/mL (range = 0.6 to 10). No patients suffered serious or delayed reactions and all symptoms reversed with inhaled bronchodilators (BD). During the MIC, the progression of symptoms often mimicked progression of those observed in the past and was useful in teaching the parents. Patients were followed for 0.5 to 3.8 years (mean = 2.3). All patients with a positive MIC have continued to have recurrent respiratory symptoms and require regular or intermittent BD. Only one patient with a negative MIC at 5 mg/mL has recurrent respiratory symptoms and requires daily BD 3 years after the initial evaluation. We conclude that MIC can safely be performed in young children in whom the diagnosis of asthma is uncertain. A positive MIC in this context demonstrates increased bronchial reactivity and is supportive of a clinical diagnosis of asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed1987

The fifth component of complement (C5) in the mouse. Analysis of the molecular basis for deficiency.

C5-deficient mice differed from C5-sufficient mice both quantitatively and qualitatively in C5 protein, C5 mRNA, and the C5 gene. C5-deficient protein was present as decreased amounts of an unprocessed, single-chain precursor. C5-deficient mRNA was decreased in amount and present in two forms, the smaller of which was the same as the single form in normal cells. Nuclei from both normal and deficient cells contained the larger form of C5 mRNA, and C5-deficient DNA demonstrated differences from the normal pattern on Southern analysis for two restriction enzymes. These data suggest that the primary transcript of the C5-deficient gene is abnormal, retarding the processing of the C5 mRNA, and that the C5-deficient mRNA codes for an abnormal protein.

Animals↗
PubMed1987

Myocardial contraction band lesions in patients with fatal asthma: possible neurocardiologic mechanisms.

Myocardial contraction band necrosis (MCBN) occurs in catecholamine infusion, central nervous system stimulation, stress, and transient myocardial ischemia with reperfusion. In 4 of 13 children who died with asthma, MCBN was present, suggesting that this cardiac lesion may contribute to the deaths of some asthmatic patients. Two of the 4 patients who had MCBN had not received sympathomimetics intravenously or by an intracardiac route. Therefore, mechanisms other than infusions of large doses of catecholamines are probably involved in production of this cardiac lesion in asthmatics.

Adolescent↗
PubMed1987

Psychomotor adaptation in children with severe chronic asthma.

Acute effects of steroid medications or hypoxic-induced brain damage have been hypothesized to cause neuropsychologic impairment in children with severe asthma. The present investigation included neuromotor, cognitive, psychosocial, and medical evaluations of 67 hospitalized asthmatic children from 9 to 14 years of age, at risk for motor dysfunction. Mean scores from the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) were similar to test norm means and were not indicative of neuromotor impairment. Scores of the BOTMP correlated significantly (P less than .01) with measures of child and family psychosocial adaptation but not with measures of cognitive ability, steroid dose at admission, or severity of asthma. Thirteen children had battery composite scores more than 1 SD below age means but did not demonstrate decreased IQ or increased steroid use, respiratory failure, seizures, or abnormal neurologic signs compared with the other 55 children. These results indicate that most severely asthmatic children, including many with histories of hypoxia and high-dose steroid use, do not demonstrate psychomotor impairments indicative of brain damage. It is concluded that neuromotor development in asthmatic children is associated with psychologic characteristics that influence adaptation to illness and activity level.

Adaptation, Psychological↗
PubMed1986

Regulation of the synthesis of the third component of complement and factor B in cord blood monocytes by lipopolysaccharide.

We compared the regulation of C3 and factor B synthesis in cord blood and adult monocytes by using techniques for identification and quantification of newly synthesized proteins, lipopolysaccharide (LPS) from several Gram-negative organisms, and precursors of LPS. Synthesis of C3 and factor B in cord blood monocytes was unaffected by lipid A (the active moiety of LPS extracted by the Westphal procedure). In contrast, adult monocytes increased C3 synthesis by 11.5-fold and factor B synthesis by 3.1-fold in response to LPS. This difference in cord blood monocyte response to LPS was specific in that other LPS-induced monocyte functions (superoxide production and phagocytosis) were stimulated comparably in both cord blood and adult monocytes by LPS. To characterize further this regulatory difference, the roles of LPS precursors, arachidonic acid metabolites, and of factor(s) released by adult monocytes were examined. Precursors of the lipid portion of LPS (lipid X and lipid Y), LPS isolated by trichloroacetic acid extraction, and endotoxin-associated protein (EAP) increased C3 and factor B synthesis in cord blood monocytes. Inhibitors of the lipoxygenase pathway (dexamethasone, ETYA) but not of the cyclooxygenase pathway (indomethacin) abrogated the response of adult monocytes to lipid A and EAP and of cord blood monocytes to EAP. Finally, co-incubation of adult monocytes and cord blood monocytes in LPS-containing medium resulted in enhancement of C3 and factor B synthesis in cord blood monocytes. These data suggest that the difference in LPS response between cord blood and adult monocytes may result from differences in lipid processing or protein recognition of LPS, differences in the production of lipoxygenase pathway products, and/or one or more regulatory factors. The availability of human mononuclear phagocytes which exhibit distinct differences in biosynthetic responsiveness to LPS should permit investigation of the molecular mechanism(s) by which LPS affects C3 and factor B gene expression.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1986

Regulation of complement protein biosynthesis in mononuclear phagocytes.

Proteins of the complement system (with the exception of the terminal components C6-9) are synthesized in mononuclear phagocytes. The extrahepatic macrophage is therefore an important local source of the complement proteins which may serve as a first-line host defence mechanism. Net synthesis and secretion of complement by these cells is a function of maturation of the mononuclear phagocytic series, the tissue from which the cells are isolated, and the state of macrophage activation. To define some of the mechanisms for regulation of complement gene expression in mononuclear phagocytes, the major histocompatibility complex class III genes and C3 have been investigated. These genes are expressed constitutively in hepatocytes and monocytes/macrophages. In the mononuclear phagocyte, interferon-gamma, at physiological concentrations, effects a dose- and time-dependent increase in factor B and C2 mRNA and a corresponding increase in factor B and C2 biosynthesis. This effect is specific inasmuch as the expression of other genes (e.g. C3) is decreased by interferon-gamma, and interferon-alpha and beta at concentrations one to two logs greater have only a minimal effect on C2 and factor B gene expression. Endotoxin acting directly on monocytes has qualitatively different effects on expression of the complement genes. These complex regulatory mechanisms are being investigated with the use of murine fibroblasts transfected with human DNA bearing the relevent complement genes.

Animals↗
PubMed1986

Normalization of cardiopulmonary endurance in severely asthmatic children after bicycle ergometry therapy.

Sixty-five children with severe asthma were tested on a bicycle ergometer to determine their cardiopulmonary endurance and to determine whether they could achieve normal levels of endurance after a physical rehabilitation program. Workloads on entry into the study ranged from 12% to 222% (median 70%) of predicted. Abnormalities in cardiopulmonary endurance did not correlate with historical features commonly used to define severe asthma or degree of airways obstruction. Forty (58%) patients required further bicycle ergometry training two to five times per week: 32 had scores less than 2 SD below the mean, and eight had scores between 1 and 2 SD below the mean. No adverse side effects were encountered during either testing or training. Of the children with scores less than 2 SD below the mean, 84% achieved normal workloads within 2 to 17 weeks of hospitalization. Rates of improvement were similar in the 27 children who subsequently passed and the five children who did not pass, suggesting that duration of program participation was the most important variable in determining success. Thus severely asthmatic children with abnormal fitness levels can achieve normal cardiopulmonary fitness after training on the bicycle ergometer.

Adolescent↗
PubMed1986

Pathogenesis of exercise-induced asthma: implications for treatment.

Although the clinical features of exercise-induced asthma (EIA) have been clearly described, the pathophysiology is incompletely understood. This review addresses some of the current concepts about the pathogenetic mechanisms of EIA and their implications for treatment of this problem.

Asthma↗
PubMed1985

gamma-Interferon increases expression of class III complement genes C2 and factor B in human monocytes and in murine fibroblasts transfected with human C2 and factor B genes.

gamma-Interferon (IFN-gamma) is a well characterized lymphokine known to regulate many mononuclear phagocyte functions, including expression of class I and class II major histocompatibility complex genes. The second component of complement (C2) and factor B are major histocompatibility complex class III gene products synthesized in mononuclear phagocytes. Recombinant IFN-gamma increased the synthesis of C2 and factor B in primary cultures of human mononuclear phagocytes and in murine fibroblasts transfected with cosmid DNA bearing the human C2 and factor B genes. In both cell types the increases in C2 and factor B protein synthesis were detected at concentrations of IFN-gamma less than 1 unit/ml and the regulation of each was pretranslational. The IFN-gamma-induced increases in C2 and factor B mRNA did not require new protein synthesis. In primary cultures of human monocytes, the kinetics of induction of C2 and factor B synthesis differed, but in the transfected L-cells the kinetics were similar, suggesting differences in transduction of the IFN-gamma signal, transcriptional, and/or post-transcriptional events in the two cell types. The small size of the factor B 5' flanking region, which is bounded by the 3' terminus of the IFN-gamma-regulated C2 gene, provides a well defined region to probe the structural basis for IFN-gamma regulation of gene expression.

Animals↗
PubMed1985

Physiologic and psychological characteristics associated with deaths due to asthma in childhood. A case-controlled study.

Several reports have documented characteristics of children who die of asthma; however, to the best of our knowledge, no studies have used case controls to clarify the clinical characteristics associated with death. We conducted a case-controlled study of 21 patients with severe asthma hospitalized between 1973 and 1982 who died of asthma sometime following discharge. Average age at death was 13 years (range, 8 to 18 years). Twenty-one asthmatic control cases were matched for age at the time of hospitalization, sex, and severity of illness. Hospital records were evaluated for 57 physiologic and psychological variables. A stepwise discriminant analysis determined that the following eight variables could discriminate the two groups effectively: history of seizures associated with an asthma attack; conflicts between the patient's parents and hospital staff regarding medical management of the patient; self-care of asthma while in the hospital that was not appropriate for age; prednisone dosage having been decreased by more than 50% during the course of hospitalization; inhaled beclomethasone dipropionate required for treatment; increased asthmatic symptoms during the week preceding discharge; depressive symptoms; and disregard of asthmatic symptoms. Most of the clinical characteristics previously thought to place patients at greater risk for a fatal asthmatic attack were found as often in the control cases as in the children who died. This study indicates that psychologic risk factors were prominent in severely asthmatic children who subsequently died of asthma. The variables defined in this study may be important in identifying patients who are at high risk for dying of asthma and in developing treatment plans to prevent deaths.

Adolescent↗
PubMed1985

Inhibition of cleavage of the third component of human complement (C3) by its small cleavage fragment, C3a: inhibition occurs with the classical-pathway, but not the alternative-pathway, C3 convertase.

Activation of the third component of complement (C), C3, is central to the functioning of the C system in inflammation. Cleavage of C3 by the C3 convertases of both the classical and alternative pathways results in the formation of two split products, C3b and C3a. C3a inhibited cleavage of C3 by the classical-pathway C3 convertase. The inhibition varied in a concn-dependent relationship, with a concn of approximately 40 micrograms/ml yielding 50% inhibition. Removal of the carboxy terminal arginine from the C3a did not alter the inhibition. C3a did not inhibit cleavage of C3 by the alternative C pathway C3 convertase, or cleavage of C5 by C5 convertase. The C3-cleaving capacity of EAC142oxy that had been previously incubated with C3a could be recovered completely by washing the cells, indicating that the C3a binding to the EAC42oxy cell must have been reversed without having had an effect on the amount of C2 bound. Ribonuclease, a molecule of similar size and charge to C3a, did not affect C3 cleavage and C3a inhibition was not reduced by providing a surface for non-specific adsorption of the C3a, suggesting that the effect of C3a on C3 cleavage was not mediated by non-specific interaction with cell surfaces. C3a inhibited the C3-cleaving capacity of the fluid-phase enzyme, C42oxy, to the same degree as it inhibited the cell-bound enzyme, EAC42oxy, indicating that the C3a must interact with the C42 complex directly. Inhibition of C3 cleavage by C3a is the first demonstration of product inhibition of a complement enzyme. It may provide another control of C3 activation.

Arginine↗